NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®)

Hematopoietic Cell
Transplantation
Version 1.2025 — February 28, 2025
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Hematopoietic Cell Transplantation Discussion

*Alison W. Loren, MD, MSCE/Chair ‡ ξ Adetola Kassim, MD, MS ‡ ξ Caspian Oliai, MD †

Abramson Cancer Center Vanderbilt-Ingram Cancer Center UCLA Jonsson Comprehensive Cancer Center
at the University of Pennsylvania Mohamed Kharfan Dabaja, MD ‡ ξ Genovefa Papanicolaou, MD F
*Marco Mielcarek, MD, PhD/Vice-Chair ‡ ξ Mayo Clinic Comprehensive Cancer Center Memorial Sloan Kettering Cancer Center
Fred Hutchinson Cancer Center Aaron Logan, MD, PhD, MPhil ‡ Joseph Pidala, MD, PhD †
Javier Bolaños-Meade, MD ‡ ξ UCSF Helen Diller Family Comprehensive Moffitt Cancer Center
Johns Hopkins Kimmel Cancer Center Cancer Center Brion Randolph, MD ξ
Jonathan Brammer, MD ‡ John M. Magenau, MD ‡ St. Jude Children's Research Hospital/
The Ohio State University Comprehensive University of Michigan Rogel Cancer Center The University of Tennessee Health
Cancer Center - James Cancer Hospital Thomas G. Martin, MD ‡ Science Center
and Solove Research Institute UCSF Helen Diller Family Mark A. Schroeder, MD ‡ ξ
Meredith Cowden, MA ¥ Comprehensive Cancer Center Siteman Cancer Center at Barnes-
Meredith A. Cowden Foundation Varun Mittal, MD ξ Jewish Hospital and Washington
Antonio Di Stasi, MD Þ ‡ Indiana University Melvin and Bren Simon University School of Medicine
O'Neal Comprehensive Comprehensive Cancer Center Jeffrey Tessier, MD ξ F
Cancer Center at UAB Jonathan Moreira, MD ‡ † UT Southwestern Simmons
Areej El-Jawahri, MD † ξ Robert H. Lurie Comprehensive Cancer Comprehensive Cancer Center
Mass General Cancer Center Center of Northwestern University Jeffrey Topal, MD F Þ
Hany Elmariah, MD, MS ‡ ξ Lori Muffly, MD ‡ Yale Cancer Center/Smilow Cancer Hospital
Moffitt Cancer Center Stanford Cancer Institute Dimitrios Tzachanis MD, PhD ‡ †
Krishna Gundabolu, MBBS, MS ‡ Ryotaro Nakamura, MD ‡ UC San Diego Moores Cancer Center
Fred & Pamela Buffett Cancer Center City of Hope National Medical Center Asya Nina Varshavsky-Yanovsky, MD, PhD ‡
Jonathan Gutman, MD † Mariam Nawas, MD ‡ ξ Fox Chase Cancer Center
University of Colorado Cancer Center The UChicago Medicine
Vincent Ho, MD ‡ † Comprehensive Cancer Center
NCCN
Dana-Farber/Brigham and Yago Nieto, MD, PhD ‡ Frankie Jones
Women's Cancer Center The University of Texas
Katie Stehman, MMS, PA-C
Rasmus T. Hoeg, MD ‡ ξ MD Anderson Cancer Center
UC Davis Comprehensive Cancer Center *Cameron Ninos, PharmD ‡ ξ ∑
University of Wisconsin Ξ Critical care medicine/Pulmonary medicine
Mitchell Horwitz, MD † ‡ Hematology/Hematology oncology
Duke Cancer Institute Carbone Cancer Center
x Hematopoietic cell transplantation
F Infectious disease
Continue Þ Internal medicine
† Medical oncology
¥ Patient advocacy
NCCN Guidelines Panel Disclosures ∑ Pharmacology
* Discussion Section Writing Committee
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Hematopoietic Cell Transplantation Discussion

NCCN Panel Members

Find an NCCN Member Institution:
Summary of the Guidelines Updates
https://www.nccn.org/home/member-
institutions.
Introduction (INTRO)
NCCN Categories of Evidence and
Indications for Transplantation (HCT-1)
Consensus: All recommendations are
Pre-Transplant Recipient Evaluation (HCT-2) category 2A unless otherwise indicated.
Hematopoietic Cell Mobilization (HCT-4)
See NCCN Categories of Evidence
Hematopoietic Cell Mobilization Regimens (HCT-4A)
and Consensus.
Conditioning for Hematopoietic Cell Transplant (HCT-5)
Principles of Conditioning for Hematopoietic Cell Transplant (HCT-A) NCCN Categories of Preference:
All recommendations are considered
Diagnosis/Workup of Graft-Versus-Host Disease (GVHD-1) appropriate.
Management of Acute GVHD (GVHD-2) See NCCN Categories of Preference.
Management of Chronic GVHD (GVHD-4)

Acute GVHD: Staging and Grading (GVHD-A)

Chronic GVHD: Diagnosis (GVHD-B)
Chronic GVHD: Grading (GVHD-C)
GVHD Steroid Response Definitions/Criteria (GVHD-D)
Suggested Systemic Agents for Steroid-Refractory GVHD (GVHD-E)
GVHD Supportive Care (GVHD-F)

Abbreviations (ABBR-1)

The NCCN Guidelines® are a statement of evidence and consensus of the authors regarding their views of currently accepted approaches to
treatment. Any clinician seeking to apply or consult the NCCN Guidelines is expected to use independent medical judgment in the context of individual
clinical circumstances to determine any patient’s care or treatment. The National Comprehensive Cancer Network® (NCCN®) makes no representations
or warranties of any kind regarding their content, use or application and disclaims any responsibility for their application or use in any way. The NCCN
Guidelines are copyrighted by National Comprehensive Cancer Network®. All rights reserved. The NCCN Guidelines and the illustrations herein may
not be reproduced in any form without the express written permission of NCCN. ©2025.
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Updates in Version 1.2025 of the NCCN Guidelines for Hematopoietic Cell Transplantation from Version 2.2024 include:
HCT-4A
• Hematopoietic Cell Mobilization Regimens
Autologous Donors
◊ Cyclophosphamide dosing language modified for the following regimens: Filgrastim + cyclophosphamide ± plerixafor and sargramostim +
cyclophosphamide ± plerixafor
– Cyclophosphamide 1500–3000 mg/m2 IV for one dose
Footnote r added: An FDA-approved biosimilar is an appropriate substitute for any recommended systemic biologic therapy in the NCCN Guidelines.
Footnote removed: An FDA-approved biosimilar is an appropriate substitute for pegfilgrastim.
HCT-5
• Post-Transplant Follow-Up
List of post-transplant complications has been revised.
◊ Bullets modified:
– Graft-versus-host disease (GVHD) (for allogeneic transplant), infections and
– Monitoring for disease relapse is recommended for all patients who have undergone HCT.
◊ Bullets added:
– Infections (See NCCN Guidelines for Prevention and Treatment of Cancer-Related Infections)
– Multi-organ dysfunction
▪ Footnote w added: Potential post-transplant organ toxicities are too numerous to list but can include cardiac, pulmonary, renal, and/or liver
complications. Hepatic VOD/SOS is one potentially life-threatening complication. Defibrotide is FDA approved for the treatment of hepatic VOD/
SOS in patients with renal or pulmonary dysfunction following HCT based on non-randomized trials. See defibrotide prescribing information for
further details.
◊ Footnote removed and added to algorithm bullet: NCCN Guidelines for Prevention and Treatment of Cancer-Related Infections.
HCT-A 1 of 10
• Principles of Conditioning for Hematopoietic Cell Transplant
Non-myeloablative (NMA) conditioning regimen, examples removed to simplify list of examples provided:
◊ Fludarabine + cyclophosphamide ± antithymocyte globulin (ATG)
◊ Fludarabine + cytarabine + idarubicin
◊ Cladribine + cytarabine
HCT-A 3 of 10
• MA Regimens: Allogeneic Transplant
Fludarabine + treosulfan added as a category 2A recommendation with the following regimen/dosing:
◊ Treosulfan-based
– Fludarabine 30 mg/m2/day for 5 days
– Treosulfan 10 g/m2/day for 3 days
HCT-A 7 of 10
• Suggested Doses/Modifications by Weight
Treosulfan added to table:
◊ Treosulfan: Dose adults and children on BSA based on total body weight
Continued
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® ® ®
UPDATES
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Updates in Version 1.2025 of the NCCN Guidelines for Hematopoietic Cell Transplantation from Version 2.2024 include:
HCT-A 8 of 10
• References have been updated.
GVHD-4
• Management of Chronic GVHD
First-Line Therapy
◊ Treatment option added: Sirolimus + prednisone
– Footnote s added with reference: Carpenter PA, et al. Haematologica 2018;103:1915-1924.
◊ ± changed to + for the following treatment options: Inhaled steroid + azithromycin + montelukast for lung involvement (eg, FAM [fluticasone,
azithromycin, and montelukast])
GVHD-E 1 of 3
• Suggested Systemic Agents for Steroid-Refractory GVHD
Acute and chronic GVHD headers modified:
◊ FDA-approved category 1 agents
◊ Other FDA-approved agents (listed in order by FDA approval date)
Acute GVHD: Alternative agents (listed in alphabetical order)
◊ Agent added: Urinary-derived human chorionic gonadotropin/epidermal growth factor (uhCG/EGF)
Footnote b added An FDA-approved biosimilar is an appropriate substitute for any recommended systemic biologic therapy in the NCCN Guidelines.
Footnote removed: An FDA-approved biosimilar is an appropriate substitute.
GVHD-E 2 of 3
• References have been updated.
GVHD-F 1 of 2
• GVHD Supportive Care
Chronic GVHD
◊ Bullet 1, sub-bullet 3 modified: Consider dexamethasone or CNI mouth rinses (swish and spit).

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INTRODUCTION

The NCCN Guidelines for Hematopoietic Cell

Transplantation (HCT) pertain to the care of adult patients
undergoing HCT for malignant diseases.

Note: All recommendations are category 2A unless otherwise indicated.

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INTRO
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INDICATIONS FOR TRANSPLANTATION

Indications for HCT vary by disease.
Indications for HCT can be found in the following NCCN Guidelines:
• NCCN Guidelines for Acute Lymphoblastic Leukemia
• NCCN Guidelines for Acute Myeloid Leukemia
• NCCN Guidelines for B-Cell Lymphomas
• NCCN Guidelines for Central Nervous System Cancers
• NCCN Guidelines for Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma
• NCCN Guidelines for Chronic Myeloid Leukemia
• NCCN Guidelines for Gestational Trophoblastic Neoplasia Pre-Transplant Recipient Evaluation (HCT-2)
• NCCN Guidelines for Hodgkin Lymphoma and
• NCCN Guidelines for Multiple Myeloma Hematopoietic Cell Mobilization (HCT-4)

• NCCN Guidelines for Myelodysplastic Syndromes

• NCCN Guidelines for Myeloproliferative Neoplasms (MPN)
• NCCN Guidelines for Primary Cutaneous Lymphomas
• NCCN Guidelines for Systemic Light Chain Amyloidosis
• NCCN Guidelines for Systemic Mastocytosis (SM)
• NCCN Guidelines for T-Cell Lymphomas
• NCCN Guidelines for Testicular Cancer
• NCCN Guidelines for Waldenström Macroglobulinemia/Lymphoplasmacytic Lymphoma

Note: All recommendations are category 2A unless otherwise indicated.

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HCT-1
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PRE-TRANSPLANT RECIPIENT EVALUATIONa,b

• Clinical Assessment: • Imaging:
Confirm histologic diagnosis Disease-specific restaging studies (NCCN Guidelines for
History & physical exam, including evaluation of performance Treatment by Cancer Type)
status (Eastern Cooperative Oncology Group [ECOG] or Chest x-ray (if no other chest imaging done)
Karnofsky Performance Scale [KPS]) and body mass index • Laboratory Tests:
Assess disease statusc (including cytogenetic/molecular Complete blood count with differential
testing for risk stratification and assessment of minimal ABO/Rh typing
residual disease, if applicable) Chemistry profile (including blood glucose, creatinine/
Bone marrow aspiration & biopsyd to confirm remission status estimated glomerular filtration rate,j electrolytes, and liver
(as indicated by underlying disease: pathology, flow cytometry, function tests [LFTs] [transaminases and bilirubin])k,l Additional
cytogenetics, molecular studies) and rule out other diseases Prothrombin time/partial thromboplastin time Evaluation
Pulmonary function tests (PFTs) including spirometry, lung Urinalysis as Clinically
volumes, and diffusing capacity of the lungs for carbon Infectious disease testing for cytomegalovirus (CMV), Indicated
monoxide (DLCO)e,f herpes simplex virus (HSV), varicella zoster virus (VZV), (HCT-3)
Electrocardiogram (with QTc interval assessment) hepatitis B virus (HBV), hepatitis C virus (HCV), human
Measure left ventricular ejection fraction (LVEF)g with immunodeficiency virus (HIV), and syphilis
echocardiogram (if valvular assessment required) or multigated Human leukocyte antigen (HLA) typing per FACT-JACIE
acquisition scan International Standardsb
Psychosocial evaluation h Toxoplasma serology (for allogeneic HCT)
HCT Comorbidity Index (HCT-CI)i score (for allogeneic HCT) Donor and recipient short tandem repeat (STR)
genotyping to inform post-transplant chimerism analysis
(for allogeneic HCT)
a The pre-transplant recipient evaluation generates data to estimate risks of post-transplant
complications including non-relapse mortality (NRM). It also generates information that g Consider cardiac consultation in patients with compromised LVEF.
may inform other transplant-related decisions. h Assess medication adherence, high-risk behavior, mood disorders, and caregiver
b For pre-transplant donor evaluation and HLA typing, refer to: Foundation for the availability to ensure patient adherence to treatment. If needs are identified, ensure
Accreditation of Cellular Therapy and Joint Accreditation Committee- ISCT and EBMT. referral to psycho-oncology, social work, mental health provider, or addiction psychiatry as
FACT-JACIE International Standards for Hematopoietic Cellular Therapy Product appropriate.
Collection, Processing, and Administration (8th edition); 2021. i The HCT-CI predicts the risk of NRM after transplant more accurately than age and
c Disease risk index may be used to predict overall survival based on only disease-related performance status; however, it does not predict the risk of relapse. Detailed explanation
risk factors: http://www.cibmtr.org/ReferenceCenter/Statistical/Tools/Pages/DRI.aspx. of the HCT-CI has been published (Sorror ML. Blood 2013;121:2854-2863). See HCT-CI
d For acute leukemia, bone marrow biopsy is ideally performed within 4 weeks of starting a score calculator: http://hctci.org.
conditioning regimen. j Calcineurin inhibitors (CNIs) are associated with increased risk of renal failure after HCT.
e DLCO should be corrected for hemoglobin concentration using the Dinakara method. k Cirrhosis (in particular with portal hypertension) is generally considered a contraindication
In patients with significantly reduced DLCO, caution should be exercised when using for allogeneic HCT.
busulfan or carmustine-based regimens. Coffey DG, et al. Bone Marrow Transplant l Veno-occlusive disease/sinusoidal obstruction syndrome (VOD/SOS) risk calculator may
2013;48:1253-1256. be used to predict risk of VOD/SOS: http://www.cibmtr.org/ReferenceCenter/Statistical/
f Consider pulmonary consultation and/or arterial blood gas analysis if DLCO <60%. Tools/Pages/VOD.aspx.

Note: All recommendations are category 2A unless otherwise indicated.

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PRE-TRANSPLANT RECIPIENT EVALUATIONa,b

ADDITIONAL EVALUATION AS CLINICALLY INDICATED

As clinically indicated:
• Additional Clinical Assessment
Lumbar puncture for cerebrospinal fluid analysis
Discuss fertility preservation
Pregnancy test for individuals of childbearing potential
Physical therapy evaluation (strength, flexibility, function)
Nutritional evaluation
Consider geriatric assessment for select patients (category 2B)
(See NCCN Guidelines for Older Adult Oncology)
Dental evaluation (for allogeneic HCT)
• Additional Imaging
CT (chest and/or sinuses)
• Additional Laboratory Tests
Epstein-Barr virus testing or other infectious disease testing
(if high risk) (eg, tuberculosis, strongyloides, human T-cell
lymphotropic virus types I and II [for allogeneic HCT])
HLA antibody assessment if using HLA-mismatched donor
24-hour urine creatinine clearance (for borderline renal
dysfunction or low muscle mass)
Urine toxicology screen if history of substance use disorder
Thyroid-stimulating hormone level
Iron profile (including ferritin level)
Blood lipid panel
Vitamin D level

a The pre-transplant recipient evaluation generates data to estimate risks of post-transplant complications including NRM. It also generates information that may inform
other transplant-related decisions.
b For pre-transplant donor evaluation and HLA typing, refer to: Foundation for the Accreditation of Cellular Therapy and Joint Accreditation Committee- ISCT and EBMT.
FACT-JACIE International Standards for Hematopoietic Cellular Therapy Product Collection, Processing, and Administration (8th edition); 2021.

Note: All recommendations are category 2A unless otherwise indicated.

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HCT-3
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HEMATOPOIETIC CELL MOBILIZATIONm

TREATMENTn,o ADDITIONAL THERAPY

Granulocyte colony-stimulating
factor (G-CSF) + plerixafor
or Stem cell collection
G-CSF + cyclophosphamide with minimum target
CD34
Stem cell ± plerixafor yield of
count
mobilization or 2–5 x 106 CD34 cells/kg
(preferred)
for Granulocyte-macrophage (preferred)p
autologous colony-stimulating factor +
donors cyclophosphamide ± plerixafor If insufficient collection, consider:
or Increasing G-CSF dose or
Pegfilgrastim + plerixafor changing dose schedule
or or
G-CSF + motixafortide Addition of plerixafor to G-CSF Conditioning
or Stem cell collection or for HCT
with minimum Chemo-mobilization ± plerixafor (HCT-5)
G-CSF CD34 target yield of
or count or
2–5 x 106 CD34 Bone marrow harvestq
G-CSF + disease-specific (preferred) cells/kg (preferred)p
chemotherapy ± plerixafor or
Rest for 2–4 weeks (if feasible)
before remobilization attempt

Stem cell Stem cell collection

If insufficient collection, consider:
mobilization CD34 with minimum
Addition of plerixafor to G-CSF
for G-CSF count target yield of
or
allogeneic (preferred) 4–5 x 106 CD34
Bone marrow harvestq
donors cells/kg (preferred)p

m For donor evaluation and follow-up recommendations, refer to: Foundation for the Accreditation of Cellular Therapy and Joint Accreditation Committee - ISCT and
EBMT. FACT-JACIE International Standards for Hematopoietic Cellular Therapy Product Collection, Processing, and Administration (8th edition); 2021.
n Hematopoietic Cell Mobilization Regimens (HCT-4A).
o Alternative chemo-mobilization regimens with disease-specific activity are also appropriate.
p Adequate stem cell collection depends on individual patient- and disease-related factors. Lower yields may be adequate, but >2 x 106 CD34 cells/kg is strongly
preferred, with a target of 4–5 x 106 CD34 cells/kg. Stem cell yields <2 x 106 CD34 cells/kg may result in delayed engraftment, while larger cell doses have been
associated with a more rapid time to platelet and neutrophil recovery.
q For bone marrow harvest recommendations, refer to the National Marrow Donor Program/Be the Match (https://bethematch.org).

Note: All recommendations are category 2A unless otherwise indicated.

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HEMATOPOIETIC CELL MOBILIZATION REGIMENSr

Autologous Donors Allogeneic Donors

Filgrastims ± Plerixafor Filgrastims
• Filgrastim: 10 mcg/kg weight SC for 4–5 days • 10 mcg/kg donor weight SC (or split twice daily)
Continued daily until collection goal is met • Daily for 4–5 days
• Plerixafor: 0.24 mg/kg actual body weight SC (max 40 mg/day) on the day before apheresist • Collect on day 4 or 5
Filgrastims + Cyclophosphamide ± Plerixafor
• Cyclophosphamide: 1500–3000 mg/m2 IV
• Filgrastim: 10 mcg/kg SC
Daily starting 24 hours after cyclophosphamide and continuing until collection goal is met.
Begin apheresis at least 4–5 days after cyclophosphamide administration.u
• Plerixafor: 0.24 mg/kg actual body weight SC (max 40 mg/day) on the day before apheresist
Sargramostim + Cyclophosphamide ± Plerixafor
• Cyclophosphamide: 1500–3000 mg/m2 IV
• Sargramostim: 250 mcg/m2/day SC
IV over 24 hours or SC once daily
Daily starting 24 hours after cyclophosphamide and continuing until collection goal is met.
Begin apheresis at least 4–5 days after cyclophosphamide administration.u
• Plerixafor: 0.24 mg/kg actual body weight SC (max 40 mg/day) on the day before apheresist
Pegfilgrastim + Plerixafor
• Pegfilgrastim: 6 mg SC on day 1
• Upfront plerixafor 0.24 mg/kg actual body weight SC (max 40 mg/day) on day 3 followed by
apheresis on day 4

Filgrastims + Motixafortide
• Filgrastim: 10 mcg/kg SC daily x 4 days prior to first dose of motixafortide
• Motixafortide: 1.25 mg/kg actual body weight SC 10–14 hours prior to initiation of apheresis

r An FDA-approved biosimilar is an appropriate substitute for any recommended systemic biologic therapy in the NCCN Guidelines.
s Tbo-filgrastim or an FDA-approved biosimilar is an appropriate substitute for filgrastim.
t Plerixafor is generally administered 11 hours prior to stem cell collection.
u Consider checking circulating CD34+ cells and initiating apheresis based on institutional guidelines.

Note: All recommendations are category 2A unless otherwise indicated.

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CONDITIONING FOR HCT POST-TRANSPLANT FOLLOW-UP

• Monitoring for post-transplant complications such as:

Graft-versus-host disease (GVHD) (for allogeneic transplant)
Conditioning for allogeneic Infections (See NCCN Guidelines for Prevention and
transplant based on diseasev Treatment of Cancer-Related Infections)
Multi-organ dysfunctionw
Monitoring for disease relapse is recommended for all
Infusion of patients who have undergone HCT.
hematopoietic cells
• Intensive supportive care is required for all post-transplant
recipients until engraftment occurs.
Conditioning for autologous
transplant based on diseasev • Allogeneic transplant: If GVHD is suspected, see Diagnosis/
Workup of GVHD (GVHD-1)

v Principles of Conditioning for Hematopoietic Cell Transplant (HCT-A).

w Potential post-transplant organ toxicities are too numerous to list but can include cardiac, pulmonary, renal, and/or liver complications. Hepatic VOD/SOS is one
potentially life-threatening complication. Defibrotide is FDA approved for the treatment of hepatic VOD/SOS in patients with renal or pulmonary dysfunction following
HCT based on non-randomized trials. See defibrotide prescribing information for further details.

Note: All recommendations are category 2A unless otherwise indicated.

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PRINCIPLES OF CONDITIONING FOR HEMATOPOIETIC CELL TRANSPLANT

• Indications for HCT vary by disease. Refer to applicable NCCN Guidelines for Treatment by Cancer Type.

Definitions of Conditioning Regimen Intensity1

• Myeloablative (MA) conditioning regimen: One that will cause irreversible (or close to irreversible) pancytopenia. Hematopoietic cell support
is required to rescue marrow function and prevent aplasia-related death. Examples include:
Total body irradiation (TBI) ≥5 Gy single dose or ≥8 Gy fractionated
Busulfan >8 mg/kg orally (>6.4 mg/kg IV) or busulfan plasma exposure unit equivalenta
• Non-myeloablative (NMA) conditioning regimen: One that will produce minimal cytopenia, and there is no absolute need for hematopoietic
cell support. Examples include:
TBI ≤2 Gy ± purine analog
Total lymphoid irradiation + antithymocyte globulin (ATG)
• Reduced-intensity conditioning (RIC) regimen: One that does not fulfill criteria for MA or NMA.

a Busulfanplasma exposure unit should be reported as area under the curve (AUC) in mg x h/L. For example, AUC 5000 µM x min is equivalent to 20.5 mg x h/L
(McCune JS, et al. Biol Blood Marrow Transplant 2019;25:1890-1897).
References on HCT-A (8 of 10)
Note: All recommendations are category 2A unless otherwise indicated.
Continued
HCT-A
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1 OF 10
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PRINCIPLES OF CONDITIONING FOR HEMATOPOIETIC CELL TRANSPLANT

Allogeneic Conditioning Regimen Selection Special Situations
• The choice among an MA, NMA, or RIC regimen is a nuanced • For patients with significant pulmonary dysfunction, caution is
decision that should be made by the transplant team at the recommended if using high-dose (HD) busulfan, carmustine, and
time of patient evaluation or upon review of pre-transplant HD TBI.
organ testing, frailty/geriatric assessment, or other evaluation. • Increased risk of SOS has been associated with the use of:
• Conditioning regimen intensity depends on: HD busulfan and HD TBI in patients with significant liver
Patient age (chronologic and physiologic) dysfunction.
Performance status Dual alkylator-based regimens with pre-transplant inotuzumab or
HCT-CI and other pertinent comorbiditiesb gemtuzumab.
Disease type • The combination of sirolimus3,4 and tacrolimus may be associated
Remission status (including measurable residual disease) with higher risk of SOS and thrombotic microangiopathy, especially
History of prior HCT if used with MA regimens.5-10
• MA regimens may be preferred for the following disease types, • Increased risk of GVHD has been associated with patients
if the patient is young and fitb,2: treated with immune checkpoint inhibitors (pre- or post-HCT) and
Acute lymphoblastic leukemia (TBI-based regimens mogamulizumab.
preferred) Consider a minimum 8- to 12-week window between these
Acute myeloid leukemia treatments and the start of transplant conditioning if clinically
Chronic myeloid leukemia feasible.7-10
Myelodysplastic syndromes
• Thiotepa can be excreted through the skin and requires special skin
• RIC/NMA regimens may be preferred for: care. Refer to the package insert.
Lymphoma (non-Hodgkin lymphoma [NHL] or Hodgkin
lymphoma [HL])
Chronic lymphocytic leukemia
Plasma cell disorders (eg, multiple myeloma, plasma cell
leukemia)
Patients who have received a prior autologous HCT
Patients who are older or unfitb

b The HCT-CI predicts the risk of NRM after transplant more accurately than age and performance status; however, it does not predict the risk of relapse. Detailed
explanation of the HCT-CI has been published (Sorror ML. Blood 2013;121:2854-2863). See HCT-CI score calculator: http://hctci.org.
References on HCT-A (8 of 10)
Continued
Note: All recommendations are category 2A unless otherwise indicated.
HCT-A
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Hematopoietic Cell Transplantation Discussion

PRINCIPLES OF CONDITIONING FOR HEMATOPOIETIC CELL TRANSPLANT

Examples of Commonly Used Conditioning Regimens
• This list is not comprehensive. Other options can be considered.
• See Suggested Doses/Modifications by Weight (HCT-A 7 of 10)
MA Regimens
TBI-Based Busulfan-Basedf
Cyclophosphamide + TBI11 Busulfan + Cyclophosphamideg,15
• Cyclophosphamide 60 mg/kg/day for 2 daysc • Busulfan 3.2 mg/kg/day for 4 days
• TBI 12–13.2 Gy fractionated • Cyclophosphamide 60 mg/kg/day for 2 daysc
Fludarabine + TBI12 Fludarabine + Busulfan16
• Fludarabine 30 mg/m2/day for 4 days • Busulfan 3.2 mg/kg/day (12.8 mg/kg total) for 4 days
• TBI 12–13.2 Gy fractionated • Fludarabine 30–32 mg/m2/day for 4–5 days
Allogeneic Transplant Etoposide + TBI13 Fludarabine + Busulfan + Thiotepa17,18
• Etoposide 60 mg/kg in 1 dose • Fludarabine 30–40 mg/m2/day for 4 days OR 50 mg/m2/day for 3 days
• TBI 12–13.2 Gy fractionated • Busulfan 3.2 mg/kg/day total for 3–4 days;
• Thiotepa 5 mg/kg/day for 1–2 days
Treosulfan-based Clofarabine + Busulfan19,20
Fludarabine + Treosulfan14 • Clofarabine 20–40 mg/m2/day for 4–5 days
• Fludarabine 30 mg/m2/day for 5 days • Busulfan AUC 4000–5500 (or 3.2 mg/kg/day) for 4 days
• Treosulfan 10 g/m2/day for 3 days

TBI-Based Busulfan-Basedf
Fludarabine + Cyclophosphamide + TBI12 Fludarabine + Busulfan + Thiotepa23
• Fludarabine 30–45 mg/m2/day for 4 days; • Thiotepa 5 mg/kg/day for 2 days
• Cyclophosphamide 60 mg/kg/day for 2 days • Busulfan 3.2 mg/kg/day for 3 days
Umbilical Cord Blood (UCB)d,e • TBI 13.2 Gy fractionated • Fludarabine 50 mg/m2/day for 3 days
Fludarabine + Thiotepa + TBI21,22
• Fludarabine 40 mg/m2/day for 4 days;
• Thiotepa 5 mg/kg/day for 2 days;
• TBI 13.2 Gy fractionated

NMA Regimens
TBI-Based Other
24 25
Fludarabine + TBI Fludarabine + Cyclophosphamide ± Rituximab
• Fludarabine 30 mg/m2/day for 3 days Fludarabine 30 mg/m /day for 3 days
2
Allogeneic Transplant • TBI 2 Gy • Cyclophosphamide 750 mg/m2/day for 3 days
• Rituximab
375 mg/m2 IV for 1 day before transplant; and
1000 mg/m2 IV on days 1, 8, and 15 after transplant
c If using post-transplant cyclophosphamide (PTCy) for GVHD prophylaxis, carefully evaluate
cyclophosphamide doses used for conditioning. f These recommendations are for IV busulfan, which is the preferred route of administration due
d Referral to a center with experience in UCB transplants is strongly recommended. to more favorable pharmacokinetic and toxicity profiles. Oral busulfan may be considered in
e If an MA conditioning regimen is planned for a recipient of UCB, omidubicel-onlv has been select cases but tends to exhibit more pharmacokinetic variability and requires different dosing.
shown to shorten the time to engraftment and reduce the risk of some infections. Horwitz ME, g Cyclophosphamide/busulfan is different than busulfan/cyclophosphamide (Rezvani AR, et al.
et al. Blood 2021;138:1429-1440. Biol Blood Marrow Transplant 2013;19:1033-1039). References on HCT-A (8 of 10)
Continued
Note: All recommendations are category 2A unless otherwise indicated.
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PRINCIPLES OF CONDITIONING FOR HEMATOPOIETIC CELL TRANSPLANT

Examples of Commonly Used Conditioning Regimens
• This list is not comprehensive. Other options can be considered.
• See Suggested Doses/Modifications by Weight (HCT-A 7 of 10)
RIC Regimensh
Fludarabine + Melphalan26
Fludarabine + Cyclophosphamide + TBI29
• Fludarabine 20–36 mg/m2/day for 4–5 days
• Fludarabine 30 mg/m2/day for 5 days OR 25 mg/m2/day for 6 days
• Melphalan 100–140 mg/m2 over 1–2 daysi
• Cyclophosphamide 14.5 mg/kg/day for 2 days
• TBI 2–4 Gy
Fludarabine + Busulfan27
Fludarabine + Melphalan + TBIi,30
• Fludarabine 30 mg/m2/day for 4–5 days
• Busulfan 3.2 mg/kg/day IV for 2–3 days OR
• Fludarabine 30 mg/m2/day for 5 days OR 25 mg/m2/day for 6 days
1.6 mg/kg/day IV for 4 days28
• Melphalan 100–140 mg/m2 over 1–2 days
• TBI 2–4 Gy
Allogeneic Transplant
Fludarabine + Melphalan + Thiotepa31,32
• Fludarabine 40 mg/m2/day for 4 days
• Melphalan 140 mg/m2 for 1 day
• Thiotepa 10 mg/m2 for 1 day
Fludarabine + Busulfan + Thiotepa17
• Thiotepa 5 mg/kg/day for 1 day
• Busulfan 130 mg/m2/day IV for 2 daysj
• Fludarabine 30–40 mg/m2/day for 4 days
Fludarabine + Cyclophosphamide + Thiotepa + TBI33
• Fludarabine 150 mg/m2
• Cyclophosphamide 50 mg/kg
• Thiotepa 10 mg/kg/day
UCBd • TBI 4 Gy
Fludarabine + Cyclophosphamide + TBI34
• Fludarabine 200 mg/m2
• Cyclophosphamide 50 mg/kg
• TBI 2 Gy

d Referral to a center with experience in UCB transplants is strongly recommended.

h See RIC regimens without fludarabine (HCT-A 5 of 10).
i If using PTCy for GVHD prophylaxis, carefully evaluate melphalan and TBI doses. Gaballa S, et al. Cancer 2016;122:3316-3326.
j Typically, this is equivalent to 3.2 mg/kg/day. References on HCT-A (8 of 10)
Continued
Note: All recommendations are category 2A unless otherwise indicated.
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PRINCIPLES OF CONDITIONING FOR HEMATOPOIETIC CELL TRANSPLANT

Conditioning Regimens Without Fludarabine

• The following is a non-inclusive list of non-fludarabine RIC regimens given the intermittent drug shortage in the
United States. However, because of lack of comparative data with fludarabine-based regimens, choice of regimen
should be based on institutional preference and experience. See Update on FDA Drug Shortages
• See Suggested Doses/Modifications by Weight (HCT-A 7 of 10)
• Please refer to corresponding published data for GVHD prophylaxis.

RIC Regimens Without Fludarabine

• Pentostatin + busulfan35
Pentostatin-based • Pentostatin + busulfan + cyclophosphamide36
• Pentostatin + TBI 4 Gy37
• Clofarabine + busulfan38,39
• Clofarabine + melphalan40 ± thiotepa41
Clofarabine-basedk
• Clofarabine + TBI 2 Gy42
• Clofarabine + cyclophosphamide + TBI 2 Gy43 (with PTCy)
• Cladribine + busulfan + ATG44,45
Cladribine-basedl
• Cladribine + busulfan + TBI 2 Gy46
Cyclophosphamide-based • Cyclophosphamide + TBI 5.5 Gy47

k A systemic inflammatory syndrome has been reported with clofarabine use. Concomitant steroid use may mitigate this risk. References on HCT-A (8 of 10)
l The use of busulfan ± TBI 2 Gy may be associated with risk of engraftment failure.
Continued
Note: All recommendations are category 2A unless otherwise indicated.
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PRINCIPLES OF CONDITIONING FOR HEMATOPOIETIC CELL TRANSPLANT

Examples of Commonly Used Conditioning Regimens
• This list is not comprehensive. Other options can be considered.
• See Suggested Doses/Modifications by Weight (HCT-A 7 of 10)

Autologous Regimens by Disease Type

• BEAM (carmustine + etoposide + cytarabine + melphalan)48
NHL (without central nervous • BEAC (carmustine + etoposide + cytarabine + cyclophosphamide)49-51
system disease) • Carmustine + thiotepa52
or • Busulfan + cyclophosphamide + etoposide53
HL • TEAM (thiotepa + etoposide + cytarabine + melphalan)54
• Bendamustine + etoposide + cytarabine + melphalan55
Primary Central Nervous System • Thiotepa + busulfan + cyclophosphamide52
Lymphoma • Carmustine + thiotepa52
or
NHL (with central nervous
system disease)
• Melphalan (200 mg/m2)56
Multiple Myeloma/Plasma Cell • Melphalan (70–140 mg/m2 for select patients)m,57-59
Leukemia • Melphalan + busulfan (high risk)60
Germ Cell Tumors • Carboplatin + etoposide61,62
• Busulfan + melphalan63-65
Acute Promyelocytic Leukemia • Cyclophosphamide + TBI65
• Busulfan + cyclophosphamide65

References on HCT-A (8 of 10)

m Lower dose melphalan can be considered for amyloidosis, older age, high HCT-CI, low KPS, and chronic kidney disease. Continued
Note: All recommendations are category 2A unless otherwise indicated.
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Suggested Doses/Modifications by Weight66

Busulfan • Adults: mg/kg dosing: dose based on 25% adjusted body weight
Body surface area (BSA) dosing: dose based on total body weight
• Pediatrics: dose based on total body weight
• Risk of SOS/VOD is correlated with higher busulfan exposure (higher AUC)
Carmustine • Dose adults on BSA
• Total body weight ≤120% ideal body weight: dose based on total body weight
• Total body weight >120% ideal body weight: dose based on 25% adjusted body weight
• Pulmonary toxicity >50% at 600 mg/m2 with multiple agent regimens. Maximum tolerated dose of 1200 mg/m2 as single
agent with 9.5% pulmonary toxicity
Cyclophosphamide • Cy200 regimen: dose based on the lesser of total body weight or ideal body weight
• Cy120 regimen: dosing can be either ideal body weight or total body weight until >120% ideal body weight, then dose
based on 25% adjusted body weightn
Cytarabine Dose adults and children on BSA based on total body weight
Etoposide • Mg/kg dosing: dose based on 25% adjusted body weightn
• BSA dosing: dose based on total body weight
Fludarabine Dose adults on BSA based on total body weight
Melphalan • Dose adults on BSA based on total body weight
• Adjustments for age and renal function are not standardized
Thiotepa • Dose adults on BSA if total body weight ≤120%
• Total body weight ≤120% ideal body weight dose on BSA based on total body weight
• Total body weight >120% ideal body weight dose on BSA based on 40% adjusted body weightn
Treosulfan Dose adults and children on BSA based on total body weight

n 25% adjusted body weight indicates ideal body weight + 0.25 (total body weight - ideal body weight); 40% adjusted body weight indicates ideal body weight + 0.4 (total
body weight - ideal body weight).
References on HCT-A (8 of 10)

Note: All recommendations are category 2A unless otherwise indicated.

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REFERENCES
1 Bacigalupo
 A, Ballen K, Rizzo D, et al. Defining the intensity of conditioning 14 Beelen DW, Trenschel R, Stelljes M, et al. Treosulfan or busulfan plus
regimens: working definitions. Biol Blood Marrow Transplant 2009;15:1628- fludarabine as conditioning treatment before allogeneic haemopoietic stem cell
1633. transplantation for older patients with acute myeloid leukaemia or myelodysplastic
2 Scott
 BL, Pasquini MC, Logan BR, et al. Myeloablative versus reduced- syndrome (MC-FludT.14/L): a randomised, non-inferiority, phase 3 trial. Lancet
intensity hematopoietic cell transplantation for acute myeloid leukemia and Haematol 2020;7:e28-e39.
myelodysplastic syndromes. J Clin Oncol 2017;35:1154-1161. 15 Lee JH, Joo YD, Kim H, et al. Randomized trial of myeloablative conditioning
3 Cutler
 C, Stevenson K, Kim HT, et al. Sirolimus is associated with veno- regimens: busulfan plus cyclophosphamide versus busulfan plus fludarabine. J
occlusive disease of the liver after myeloablative allogeneic stem cell Clin Oncol 2013;31:701-709.
transplantation. Blood 2008;112:4425-4431. 16 de Lima M, Couriel D, Thall PF, et al. Once-daily intravenous busulfan and
4 Cutler
 C, Logan B, Nakamura R, et al. Tacrolimus/sirolimus vs tacrolimus/ fludarabine: clinical and pharmacokinetic results of a myeloablative, reduced-
methotrexate as GVHD prophylaxis after matched, related donor allogeneic toxicity conditioning regimen for allogeneic stem cell transplantation in AML and
HCT. Blood 2014;124:1372-1377. MDS. Blood 2004;104:857-864.
5 Pidala
 J, Kim J, Jim H, et al. A randomized phase II study to evaluate 17 Pagliardini T, Castagna L, Harbi S, et al. Thiotepa, fludarabine, and busulfan
tacrolimus in combination with sirolimus or methotrexate after allogeneic conditioning regimen before T cell-replete haploidentical transplantation with post-
hematopoietic cell transplantation. Haematologica 2012;97:1882-1889. transplant cyclophosphamide for acute myeloid leukemia: A bicentric experience
6 Khimani
 F, Kim J, Chen L, et al. Predictors of overall survival among patients of 100 patients. Biol Blood Marrow Transplant 2019;25:1803-1809.
treated with sirolimus/tacrolimus vs methotrexate/tacrolimus for GvHD 18 Sora F, Grazia CD, Chiusolo P, et al. Allogeneic hemopoietic stem cell transplants
prevention. Bone Marrow Transplant 2017;52:1003-1009. in patients with acute myeloid leukemia (AML) prepared with busulfan and
7 Ijaz
 A, Khan AY, Malik SU, et al. Significant risk of graft-versus-host fludarabine (BUFLU) or thiotepa, busulfan, and fludarabine (TBF): A retrospective
disease with exposure to checkpoint inhibitors before and after allogeneic study. Biol Blood Marrow Transplant 2020;26:698-703.
transplantation. Biol Blood Marrow Transplant 2019;25:94-99. 19 Magenau J, Tobai H, Pawarode A et al. Clofarabine and busulfan conditioning
8 Merryman
 RW, Kim HT, Zinzani PL, et al. Safety and efficacy of allogeneic facilitates engraftment and provides significant antitumor activity in nonremission
hematopoietic stem cell transplant after PD-1 blockade in relapsed/refractory hematologic malignancies. Blood 2011;118:4258-4264.
lymphoma. Blood 2017;129:1380-1388. 20 Kebriaei P, Bassett R, Lyons G, et al. Clofarabine plus busulfan is an effective
9 Kamada
 Y, Arima N, Hayashida M, et al. Prediction of the risk for graft versus conditioning regimen for allogeneic hematopoietic stem cell transplantation in
host disease after allogeneic hematopoietic stem cell transplantation in patients patients with acute lymphoblastic leukemia: Long-term study results. Biol Blood
treated with mogamulizumab. Leuk Lymphoma 2022;27:1-7. Marrow Transplant 2017;23:285-292.
10 Merryman RW, Castagna L, Giordano L, et al. Allogeneic transplantation after 21 Horwitz ME, Stiff PJ, Cutler C, et al. Omidubicel vs standard myeloablative
PD-1 blockade for classic Hodgkin lymphoma. Leukemia 2021;35:2672-2683. umbilical cord blood transplantation: results of a phase 3 randomized study. Blood
11 Dusenbery
 KE, Daniels KA, McClure JS, et al. Randomized comparison of 2021;138:1429-1440.
cyclophosphamide-total body irradiation versus busulfan-cyclophosphamide 22 Anand S, Thomas S, Corbet K, et al. Adult umbilical cord blood transplantation
conditioning in autologous bone marrow transplantation for acute myeloid using myeloablative thiotepa, total body irradiation, and fludarabine conditioning.
leukemia. Int J Radiat Oncol Biol Phys 1995;31:119-128. Biol Blood Marrow Transplant 2017;23:1949-1954.
12 Al Malki MM, Tsai NC, Palmer J, et al. Posttransplant cyclophosphamide as 23 Sanz J, Boluda JC, Martín C, et al. Single-unit umbilical cord blood
GVHD prophylaxis for peripheral blood stem cell HLA-mismatched unrelated transplantation from unrelated donors in patients with hematological malignancy
donor transplant. Blood Adv 2021;5:2650-2659. using busulfan, thiotepa, fludarabine and ATG as myeloablative conditioning
13 Blume KG, Forman SJ, O'Donnell MR, et al. Total body irradiation and high-
regimen. Bone Marrow Transplant 2012;47:1287-1293.
dose etoposide: a new preparatory regimen for bone marrow transplantation in
patients with advanced hematologic malignancies. Blood 1987;69:1015-1020.
Continued
Note: All recommendations are category 2A unless otherwise indicated.
HCT-A
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REFERENCES
24 Kornblit B, Maloney DG, Storb R, et al. Fludarabine and 2-Gy TBI is superior 34 Brunstein CG, Barker JN, Weisdorf DJ, et al. Umbilical cord blood
to 2 Gy TBI as conditioning for HLA-matched related hematopoietic cell transplantation after nonmyeloablative conditioning: impact on transplantation
transplantation: a phase III randomized trial. Biol Blood Marrow Transplant outcomes in 110 adults with hematologic disease. Blood 2007;110:3064-3070.
2013;19:1340-1347. 35 Kharfan-Dabaja M, Anasetti C, Fernandez H, et al. Phase II study of CD4+-
25 Khouri IF, Saliba RM, Giralt SA, et al. Nonablative allogeneic hematopoietic guided pentostatin lymphodepletion and pharmacokinetically targeted busulfan
transplantation as adoptive immunotherapy for indolent lymphoma: low as conditioning for hematopoietic cell allografting. Biol Blood Marrow Transplant
incidence of toxicity, acute graft-versus-host disease, and treatment-related 2013;19:1087-93.
mortality. Blood 2001;98:3595-3599. 36 Dimitrova D, Gea-Banacloche J, Steinberg S, et al. Prospective study of a
26 Ciurea SO, Kongtim P, Varma A, et al. Is there an optimal conditioning novel, radiation-free, reduced-intensity bone marrow transplantation platform for
for older patients with AML receiving allogeneic hematopoietic cell primary immunodeficiency diseases. Biol Blood Marrow Transplant 2020;26:94-
transplantation? Blood 2020;135:449-452. 106.
27 Lee SS, Jung SH, Do YR, et al. Reduced-intensity conditioning with busulfan 37 Gvajaia A, Langston A, Esiashvil N , et al. Pentostatin/TBI conditioning is well-
and fludarabine for allogeneic hematopoietic stem cell transplantation in acute tolerated and permits engraftment of a second allogeneic stem cell transplant
lymphoblastic leukemia. Yonsei Med J 2020;61:452-459. following primary or secondary rejection of an allogeneic hematopoietic stem
28 Chen YB, Coughlin E, Kennedy KF, et al. Busulfan dose intensity and graft [abstract]. Blood 2019;134(Suppl):Abstract 5657.
outcomes in reduced-intensity allogeneic peripheral blood stem cell 38 Chevallier P, Labopin M, de La Tour RP, et al. Clofarabine versus fludarabine-
transplantation for myelodysplastic syndrome or acute myeloid leukemia. Biol based reduced-intensity conditioning regimen prior to allogeneic transplantation
Blood Marrow Transplant 2013;19:981-987. in adults with AML/MDS. Cancer Med 2016;5:3068-3076.
29 Luznik L, O'Donnell PV, Symons HJ, et al. HLA-haploidentical bone marrow 39 El-Jawahri A, Li S, Ballen KK, et al. Phase II trial of reduced-intensity busulfan/
transplantation for hematologic malignancies using nonmyeloablative clofarabine conditioning with allogeneic hematopoietic stem cell transplantation
conditioning and high-dose, posttransplantation cyclophosphamide. Biol Blood for patients with acute myeloid leukemia, myelodysplastic syndromes, and acute
Marrow Transplant 2008;14:641-650. lymphoid leukemia. Biol Blood Marrow Transplant 2016;22:80-85.
30 Choe HK, Gergis U, Mayer SA, et al. The addition of low-dose total 40 Kirschbaum MH, Stein AS, Popplewell L, et al. A phase I study in adults
body irradiation to fludarabine and melphalan conditioning in haplocord of clofarabine combined with high-dose melphalan as reduced-intensity
transplantation for high-risk hematological malignancies. Transplantation conditioning for allogeneic transplantation. Biol Blood Marrow Transplant
2017;101:e34-e38. 2012;18:432-440.
31 Ciurea SO, Saliba R, Rondon G, et al. Reduced-intensity conditioning 41 Spitzer B, Perales MA, Kernan NA, et al. Second allogeneic stem cell
using fludarabine, melphalan and thiotepa for adult patients undergoing transplantation for acute leukemia using a chemotherapy-only cytoreduction
haploidentical SCT. Bone Marrow Transplant 2010;45:429-436. with clofarabine, melphalan, and thiotepa. Biol Blood Marrow Transplant
32 Gaballa S, Ge I, El Fakih R, et al. Results of a 2-arm, phase 2 clinical trial 2016;22:1449-1454.
using post-transplantation cyclophosphamide for the prevention of graft- 42 Krakow EF, Gyurkocza B, Storer BE, et al. Phase I/II multisite trial of optimally
versus-host disease in haploidentical donor and mismatched unrelated donor dosed clofarabine and low-dose TBI for hematopoietic cell transplantation in
hematopoietic stem cell transplantation. Cancer 2016;122:3316-3326. acute myeloid leukemia. Am J Hematol 2020;95:48-56.
33 Sharma P, Pollyea DA, Smith CA, et al. Thiotepa-based intensified 43 Chevallier P, Peterlin P, Garnier A, et al. Clofarabine-based reduced
reduced-intensity conditioning adult double-unit cord blood hematopoietic intensity conditioning regimen with peripheral blood stem cell graft and post-
stem cell transplantation results in decreased relapse rate and improved transplant cyclophosphamide in adults with myeloid malignancies. Oncotarget
survival compared with transplantation following standard reduced-intensity 2018;9:33528-33535.
conditioning: A retrospective cohort comparison. Biol Blood Marrow Transplant 44 Saito T, Kanda Y, Kami M, et al. Therapeutic potential of a reduced-intensity
2018;24:1671-1677. preparative regimen for allogeneic transplantation with cladribine, busulfan, and
antithymocyte globulin against advanced/refractory acute leukemia/lymphoma.
Clin Cancer Res 2002;8:1014-1120.
Continued
Note: All recommendations are category 2A unless otherwise indicated.
HCT-A
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REFERENCES
45 Saito T, Kanda Y, Nakai K, et al. Immune reconstitution following reduced- 55 Frankiewicz A, Saduś-Wojciechowska M, Najda J, et al. Comparable safety
intensity transplantation with cladribine, busulfan, and antithymocyte globulin: profile of BeEAM (bendamustine, etoposide, cytarabine, melphalan) and BEAM
serial comparison with conventional myeloablative transplantation. Bone Marrow (carmustine, etoposide, cytarabine, melphalan) as conditioning before autologous
Transplant 2003;32:601-608. haematopoietic cell transplantation. Contemp Oncol (Pozn) 2018;22:113-117.
46 Markova M, Barker JN, Miller JS, et al. Fludarabine vs cladribine plus busulfan 56 Child JA, Morgan GJ, Davies FE, et al. High-dose chemotherapy with
and low-dose TBI as reduced intensity conditioning for allogeneic hematopoietic hematopoietic stem-cell rescue for multiple myeloma. N Engl J Med
stem cell transplantation: a prospective randomized trial. Bone Marrow 2003;348:1875-1883.
Transplant 2007;39:193-199. 57 Badros A, Barlogie B, Siegel E, et al. Results of autologous stem cell transplant in
47 Hallemeier C, Girgis M, Blum W, et al. Outcomes of adults with acute multiple myeloma patients with renal failure. Br J Haematol 2001;114:822-829.
myelogenous leukemia in remission given 550 cGy of single-exposure total body 58 Kumar SK, Dingli D, Lacy MQ, et al. Autologous stem cell transplantation in
irradiation, cyclophosphamide, and unrelated donor bone marrow transplants. patients of 70 years and older with multiple myeloma: Results from a matched
Biol Blood Marrow Transplant 2004;10:310-319. pair analysis. Am J Hematol 2008;83:614-617.
48 Mills W, Chopra R, McMillan A, et al. BEAM chemotherapy and autologous bone 59 Bashir Q, Chamoun K, Milton DR, et al. Outcomes of autologous hematopoietic
marrow transplantation for patients with relapsed or refractory non-Hodgkin's cell transplantation in myeloma patients aged ≥75 years. Leuk Lymphoma
lymphoma. J Clin Oncol 1995;13:588-595. 2019;60:3536-3543.
49 Geisler CH, Kolstad A, Laurell A, et al. Nordic MCL2 trial update: six-year 60 Bashir Q, Thall PF, Milton DR, et al. Conditioning with busulfan plus melphalan
follow-up after intensive immunochemotherapy for untreated mantle cell versus melphalan alone before autologous haemopoietic cell transplantation for
lymphoma followed by BEAM or BEAC + autologous stem-cell support: still very multiple myeloma: an open-label, randomised, phase 3 trial. Lancet Haematol
long survival but late relapses do occur [published correction appears in Br J 2019;6:e266-e275.
Haematol 2012;158:815-816]. Br J Haematol 2012;158:355-362. 61 Adra N, Abonour R, Althouse SK, et al. High-dose chemotherapy and autologous
50 Jo JC, Kang BW, Jang G, et al. BEAC or BEAM high-dose chemotherapy peripheral-blood stem-cell transplantation for relapsed metastatic germ cell
followed by autologous stem cell transplantation in non-Hodgkin's lymphoma tumors: The Indiana University experience. J Clin Oncol 2017;35:1096-1102.
patients: comparative analysis of efficacy and toxicity. Ann Hematol 2008;87:43- 62 Feldman DR, Sheinfeld J, Bajorin DF, et al. TI-CE high-dose chemotherapy for
48. patients with previously treated germ cell tumors: results and prognostic factor
51 Sakellari I, Gavriilaki E, Bouziana S, et al. BEAC (carmustine, etoposide, analysis. J Clin Oncol 2010;28:1706-1713.
cytarabine, and cyclophosphamide) in autologous hematopoietic cell 63 Yanada M, Tsuzuki M, Fujita H, et al. Phase 2 study of arsenic trioxide followed
transplantation: a safe and effective alternative conditioning regimen for Hodgkin by autologous hematopoietic cell transplantation for relapsed acute promyelocytic
and non-Hodgkin lymphoma. Bone Marrow Transplant 2019;54:921-923. leukemia. Blood 2013;121:3095-3102.
52 Ferreri AJ, Illerhaus G. The role of autologous stem cell transplantation in 64 Linker CA, Owzar K, Powell B, et al. Auto-SCT for AML in second remission:
primary central nervous system lymphoma. Blood 2016;127:1642-1649. CALGB study 9620. Bone Marrow Transplant 2009;44:353-359.
53 Hyung J, Hong JY, Yoon DH, et al. Thiotepa, busulfan, and cyclophosphamide or 65 de Botton S, Fawaz A, Chevret S, et al. Autologous and allogeneic stem-cell
busulfan, cyclophosphamide, and etoposide high-dose chemotherapy followed transplantation as salvage treatment of acute promyelocytic leukemia initially
by autologous stem cell transplantation for consolidation of primary central treated with all-trans-retinoic acid: a retrospective analysis of the European acute
nervous system lymphoma. Ann Hematol 2019;98:1657-1664. promyelocytic leukemia group. J Clin Oncol 2005;23:120-126.
54 Sellner L, Boumendil A, Finel H, et al. Thiotepa-based high-dose therapy for 66 Bubalo J, Carpenter PA, Majhail N, et al. Conditioning chemotherapy dose
autologous stem cell transplantation in lymphoma: a retrospective study from the adjustment in obese patients: a review and position statement by the American
EBMT. Bone Marrow Transplant 2016;51:212-218. Society for Blood and Marrow Transplantation practice guideline committee. Biol
Blood Marrow Transplant 2014;20:600-616.

Note: All recommendations are category 2A unless otherwise indicated.

HCT-A
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DIAGNOSIS/WORKUP OF GVHD
WORKUP GRADE
• Additional tests as clinically indicated
to rule out non-GVHD causesa,b,c
• Organ-directed biopsy, as clinically Grade Id
indicated, to support acute GVHD Management of Grade I Acute
(Mild acute GVHD; skin stage 1–2,
diagnosis GVHD (GVHD-2)
<50% BSA non-bullous rash only)
Skin rash: consider biopsy of
suspicious skin sites
Acute Diarrhea: lower gastrointestinal (GI)
GVHD biopsya
suspected Nausea/vomiting: consider upper GI
biopsya
Liver abnormalitiesb: Consider liver Grade II–IVd Management of Grade II–IV
biopsy if elevated liver-associated (Moderate to severe acute GVHD) Acute GVHD (GVHD-3)
enzymes or total/direct bilirubin
and no evidence of acute GVHD
elsewherec
• Determine acute GVHD grade (see
Acute GVHD Grading Criteria, GVHD-A)

Chronic Confirm chronic GVHDe

Determine chronic GVHD grade Management of Chronic
GVHD See Signs and Symptoms
See Chronic GVHD: Grading (GVHD-C) GVHD (GVHD-4)
suspected of Chronic GVHD (GVHD-B)

a GI biopsy (esophagogastroduodenoscopy, colonoscopy, and/or flexible sigmoidoscopy) as clinically indicated to support the diagnosis of GI acute GVHD. Stool testing
may be used to rule out infectious etiology of diarrhea.
b Consider imaging as clinically indicated to evaluate the etiology of LFT abnormalities (eg, ultrasound and/or CT scan of the abdomen).
c Liver biopsy and/or viral reactivation testing may be used to rule out non-GVHD causes of liver dysfunction (ie, VOD/SOS, infection, effects of preparatory regimen,
drug toxicity). Transjugular approach may be preferred, especially if thrombocytopenia or coagulopathy is present.
d Acute GVHD Grading Criteria (GVHD-A).
e While a biopsy may be done to confirm chronic GVHD, a biopsy is not always feasible and is not mandatory if the patient has at least one of the diagnostic findings of
chronic GVHD (Jagasia MH, et al. Biol Blood Marrow Transplant 2015;21:389-401).

Note: All recommendations are category 2A unless otherwise indicated.

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MANAGEMENT OF ACUTE GVHD

FIRST-LINE THERAPYf

Responsei
Taper immunosuppressive
Continue (resolution of
agent(s) as clinically feasible
or consider symptoms/rash)
restarting original
immunosuppressive
agent(s) Clinical trialj
No responsei or
and Continue topical steroidsg,h
Acute GVHD
Grade Id
Topical steroidsg,h
(skin 1–2, <50% BSA Progressiond and/or
until resolution of
non-bullous rash only) Symptomatic (ie, pruritus,
rash Acute GVHD Grade II–IV (GVHD-3)
pain, sloughing, increasing
or BSA involvement)i
Observe if
asymptomatic or if
rash is stable

Acute GVHD
GVHD-3
Grade II–IVd

d Acute GVHD Grading Criteria (GVHD-A).

f For recommendations on antibiotic prophylaxis during immunosuppressive therapy, see NCCN Guidelines for Prevention and Treatment of Cancer-Related Infections.
g Topical steroids (eg, triamcinolone, clobetasol) and/or topical tacrolimus. Medium to high potency formulations are recommended except on the face or intertriginous
areas where low potency hydrocortisone can be used.
h Antihistamines may be used for symptoms (eg, itching), as needed.
i GVHD Steroid Response Definitions/Criteria (GVHD-D).
j Enrollment in well-designed clinical trials should be encouraged since
no standard, effective therapy for steroid-refractory GVHD has been identified. The selection
of therapy for steroid-refractory GVHD should be based on physician experience, agent's toxicity profile, the effect of prior treatment, drug interactions, convenience/
accessibility, and patient tolerability.

Note: All recommendations are category 2A unless otherwise indicated.

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MANAGEMENT OF ACUTE GVHD

FIRST-LINE THERAPY ADDITIONAL
THERAPY
Clinical triali
or
Systemic corticosteroidsk ±
topical steroidsg,l Taper steroids
Continue or consider
• Upper GI only: Responseo as clinically
restarting original
0.5–1 mg/kg/day feasiblep
immunosuppressive
methylprednisolone (or
agent (or escalate
prednisone dose equivalent)
Acute dose to achieve
+ topical steroidsl
GVHD therapeutic Clinical trialj
• Skin/lower GI/liver:
Grade II–IV blood level if or
1–2 mg/kg/day
GVHD developed Addition of
methylprednisolonem (or
during tapering of systemic agent to
prednisone dose equivalent)
immunosuppressive corticosteroids with
± topical steroidsg (consider
therapy) steroid taper as
1 mg/kg for grade II)
or No responsei clinically feasiblep
Consider sirolimus for (steroid-refractory disease) See Suggested
standard-risk acute GVHDn Systemic Agents for
Steroid-Refractory
GVHD (GVHD-E)

l In a phase III randomized controlled trial, initial treatment with systemic prednisone
at 0.5 mg/kg/day in conjunction with GI topical steroids (beclomethasone
g Topical steroids (eg, triamcinolone, clobetasol) and/or topical tacrolimus. dipropionate [available as a compounded agent] ± budesonide) was safe and
Medium to high potency formulations are recommended except on the face or effective for upper GI symptoms (ie, nausea, vomiting, anorexia), with or without
intertriginous areas where low potency hydrocortisone can be used. skin involvement (<50% BSA), in patients with diarrhea volumes of <1000 mL/day
i GVHD Steroid Response Definitions/Criteria (GVHD-D). (Mielcarek M, et al. Haematologica 2015;100:842-848). Of note, budesonide is less
j Enrollment in well-designed clinical trials should be encouraged since no effective at treating the upper GI tract.
standard, effective therapy for steroid-refractory GVHD has been identified. m There is no role for escalation of methylprednisolone dose beyond 2 mg/kg/day.
The selection of therapy for steroid-refractory GVHD should be based on n Standard-risk acute GVHD as defined by clinical risk score and biomarker status.
physician experience, agent's toxicity profile, the effect of prior treatment, (CTN1501 trial: Pidala J, et al. Blood 2020;135:97-107.)
drug interactions, convenience/accessibility, and patient tolerability. o Complete resolution of GVHD or improvement in at least one organ without any
k Addition of other systemic agents in conjunction with systemic steroids as progression in any other organs.
initial therapy for acute GVHD should not be done outside the context of a p If response, taper systemic steroids to mitigate long-term steroid side effects and
well-designed clinical trial. risk of infection, as clinically feasible.

Note: All recommendations are category 2A unless otherwise indicated.

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Graft-Versus-Host Disease Discussion

MANAGEMENT OF CHRONIC GVHD

FIRST-LINE THERAPY ADDITIONAL THERAPY
Clinical triali
or
Taper steroids as
Continue or consider restarting original Responsei
clinically feasiblep
immunosuppressive agent
and/or
Systemic corticosteroids
Chronic 0.5–1 mg/kg/dayr methylprednisolone
GVHDq (or prednisone dose equivalent)
or
Sirolimus + prednisones Clinical trialj
± or
Addition of systemic agent to
Topical steroids as clinically indicatedt No responsei
corticosteroids with steroid taper
(steroid-refractory disease)
as clinically feasiblep
and/or See Suggested Systemic Agents for
Steroid-Refractory GVHD (GVHD-E)
Inhaled steroidu + azithromycinv +
montelukast for lung involvementw,x
(eg, FAM [fluticasone, azithromycin,
and montelukast])
i GVHD Steroid Response Definitions/Criteria (GVHD-D). t Topical steroids (eg, triamcinolone, clobetasol), topical estrogen (vulvovaginal
j Enrollment in well-designed clinical trials should be encouraged since no GVHD), topical tacrolimus, or dexamethasone oral rinse (oral GVHD). Medium- to
standard, effective therapy for steroid-refractory GVHD has been identified. The high-potency formulations are recommended except on the face or intertriginous
selection of therapy for steroid-refractory GVHD should be based on physician areas where low-potency hydrocortisone can be used.
experience, agent's toxicity profile, the effect of prior treatment, drug interactions, u Examples of acceptable inhaled steroids include budesonide or fluticasone.
convenience/accessibility, and patient tolerability. v Azithromycin should only be used for treatment of bronchiolitis obliterans
p If response, taper systemic steroids to mitigate long-term steroid side effects and syndrome (BOS), not for prophylaxis, due to a suggestion of an increased risk
risk of infection, as clinically feasible. of leukemic relapse or secondary neoplasms in recent clinical trials. Bergeron A,
q Multidisciplinary care aimed at avoiding organ damage and preserving function et al. JAMA 2017;318:557-566. Cheng GS, et al. Biol Blood Marrow Transplant
is recommended. 2020;26:392-400.
r Initial dose may vary depending on organs involved, GVHD severity, patient w Patients with progression/worsening of lung chronic GVHD following 2–3 lines of
comorbidities, and overlapping syndromes. therapy may be evaluated for lung transplant.
s Carpenter PA, et al. Haematologica 2018;103:1915-1924. x PFT at onset of chronic GVHD and subsequently as clinically indicated.

Note: All recommendations are category 2A unless otherwise indicated.

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ACUTE GVHD: STAGING AND GRADING

Commonly used criteria for the staging/grading of adults with acute GVHD include:
• Keystone (modified Glucksberg) criteria (see below)
• MAGIC criteria (GVHD-A, 2 of 2)
• Minnesota criteriaa

Modified Glucksberg Criteria: Staging and Grading of Acute GVHD*

Extent of Organ Involvement
Skin Liver Gut
Stage
1 Rash on <25% of skinb Bilirubin 2–3 mg/dlc Diarrhea >500 ml/dayd or
persistent nauseae
2 Rash on 25–50% of skin Bilirubin 3–6 mg/dl Diarrhea >1000 ml/day
3 Rash on >50% of skin Bilirubin 6–15 mg/dl Diarrhea >1500 ml/day
4 Generalized erythroderma with Bilirubin >15 mg/dl Severe abdominal pain with
bullous formation or without ileus
Gradef
I Stage 1–2 None None
II Stage 3 Stage 1 Stage 1
III — Stage 2–3 Stage 2–4
IVg Stage 4 Stage 4 —
*Used with permission: Przepiorka D, Weisdorf D, Martin P, et al. 1994 Consensus Conference on Acute GVHD Grading.
Bone Marrow Transplant 1995;15:825-828.

a MacMillan ML, et al. Biol Blood Marrow Transplant 2015;21:761-767; https://z.umn.edu/MNAcuteGVHDRiskScore

b Use 'Rule of Nines' or burn chart to determine extent of rash.
c Range given as total bilirubin. Downgrade one stage if an additional cause of elevated bilirubin has been documented.
d Volume of diarrhea applies to adults. For pediatric patients, the volume of diarrhea should be based on BSA. Gut staging criteria for pediatric patients was not
discussed at the consensus conference. Downgrade one stage if an additional cause of diarrhea has been documented.
e Persistent nausea with histologic evidence of GVHD in the stomach or duodenum.
f Criteria for grading given as minimum degree of organ involvement required to confer that grade.
g Grade IV may also include lesser organ involvement but with extreme decrease in performance status.

Note: All recommendations are category 2A unless otherwise indicated.

GVHD-A
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ACUTE GVHD: STAGING AND GRADING

MAGIC Criteria: Acute GVHD Target Organ Staging & Overall Clinical Gradeh
Stage Skin (active erythema only) Liver (bilirubin) Upper GI Lower GI (stool output/day)
0 No active (erythematous) <2 mg/dL No or intermittent nausea, Adult: <500 mL/day or <3 episodes/day
GVHD rash vomiting, or anorexia Child: <10 mL/kg/day or <4 episodes/day
1 Maculopapular rash 2–3 mg/dL Persistent nausea, Adult: 500–999 mL/day or 3–4 episodes/day
<25% BSA vomiting or anorexia Child: 10–19.9 mL/kg/day or 4–6 episodes/day
2 Maculopapular rash 3.1–6 mg/dL Adult: 1000–1500 mL/day or 5–7 episodes/day
25%–50% BSA Child: 20–30 mL/kg/day or 7–10 episodes/day
3 Maculopapular rash 6.1–15 mg/dL Adult: >1500 mL/day or >7 episodes/day
>50% BSA Child: >30 mL/kg/day or >10 episodes/day
4 Generalized erythroderma >15 mg/dL Severe abdominal pain with or without ileus or
(>50% BSA) plus bullous formation grossly bloody stool (regardless of stool volume)
and desquamation >5% BSA

Grade (based on most severe target organ involvement)

0 No stage 1–4 of any organ.
I Stage 1–2 skin without liver, upper GI, or lower GI involvement.
II Stage 3 rash and/or stage 1 liver and/or stage 1 upper GI and/or stage 1 lower GI.
III Stage 2–3 liver and/or stage 2–3 lower GI, with stage 0–3 skin and/or stage 0–1 upper GI.
IV Stage 4 skin, liver, or lower GI involvement, with stage 0–1 upper GI

h Reproduced with permission from Elsevier: Harris AC, Young R, Devine S, et al. International, Multicenter Standardization of Acute Graft-versus-Host Disease
Clinical Data Collection: A Report from the Mount Sinai Acute GVHD International Consortium. Biol Blood Marrow Transplant 2016;22(1):4-10. DOI: 10.1016/j.
bbmt.2015.09.001. This article is published under the terms of the Creative Commons Attribution-NonCommercial-No Derivatives License (CC BY NC ND).

Note: All recommendations are category 2A unless otherwise indicated.

GVHD-A
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CHRONIC GVHD: DIAGNOSIS

Signs and Symptoms of Chronic GVHDa

Organ Site Diagnostic Distinctiveb Other features for Commond
(sufficient to establish the (seen in chronic GVHD, but insufficient unclassified entitiesc (seen with both acute
diagnosis of chronic GVHD) to establish a diagnosis) and chronic GVHD)
Skin • Poikiloderma • Depigmentation • Sweat impairment • Erythema
• Lichen planus-like features • Papulosquamous lesions • Ichthyosis • Maculopapular rash
• Sclerotic features • Keratosis pilaris • Pruritus
• Morphea-like features • Hypopigmentation
• Lichen sclerosus-like features • Hyperpigmentation
Nails • Dystrophy
• Longitudinal ridging, splitting or brittle
features
• Onycholysis
• Pterygium unguis
• Nail loss (usually symmetric, affects most
nails)
Scalp and • New onset of scarring or non-scarring • Thinning scalp hair, typically
Body Hair scalp alopecia (after recovery from patchy, coarse, or dull (not
chemoradiotherapy) explained by endocrine or other
• Loss of body hair causes)
• Scaling • Premature gray hair
Mouth • Lichen planus-like changes • Xerostomia • Gingivitis
• Mucoceles • Mucositis
• Mucosal atrophy • Erythema
• Ulcers • Pain
• Pseudomembranes
Eyes • New onset dry, gritty, or painful eyes • Photophobia
• Cicatricial conjunctivitis • Periorbital hyperpigmentation
• Keratoconjunctivitis sicca • Blepharitis (erythema of the eye
• Confluent areas of punctate keratopathy lids with edema)

a Jagasia MH, Greinix HT, Arora M, et al. National Institutes of Health b In all cases, infection, drug effect, malignancy, or other causes must be excluded.
Consensus Development Project on Criteria for Clinical Trials in Chronic c Can be acknowledged as part of the chronic GVHD manifestations if diagnosis is
Graft-versus-Host Disease: I. The 2014 Diagnosis and Staging Working confirmed.
Group Report. Biol Blood Marrow Transplant 2015;21:389-401. d Common refers to shared features by both acute and chronic GVHD.
Continued
Note: All recommendations are category 2A unless otherwise indicated.
GVHD-B
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CHRONIC GVHD: DIAGNOSIS

Signs and Symptoms of Chronic GVHDa
Organ Site Diagnostic Distinctiveb Other features for Commond
(sufficient to establish the diagnosis of (seen in chronic GVHD, but unclassified entitiesc (seen with both acute and
chronic GVHD) insufficient to establish a diagnosis) chronic GVHD)
Genitalia • Lichen planus-like features • Erosions
• Lichen sclerosus-like features • Fissures
• Vaginal scarring or clitoral/labial • Ulcers
agglutination
• Phimosis or urethral/meatus scarring
or stenosis
GI Tract • Esophageal web • Exocrine pancreatic • Anorexia
• Strictures or stenosis in the upper to insufficiency • Nausea
mid third of the esophagus • Vomiting
• Diarrhea
• Weight loss
• Failure to thrive (infants and children)
Liver • Total bilirubin, alkaline phosphatase
(AP) > 2 × upper limit of normal
(ULN)
• Alanine transaminase (ALT) > 2 ×
ULN
Lung • Bronchiolitis obliterans diagnosed with • Air trapping and bronchiectasis • Cryptogenic organizing
lung biopsy on chest CT pneumonia (COP)f
• BOSe • Restrictive lung diseasef

1. Forced
 expiratory volume in the first second (FEV1)/vital capacity (VC) ratio <0.7 or the fifth percentile
a Jagasia MH, Greinix HT, Arora M, et al. National Institutes predicted.
of Health Consensus Development Project on Criteria for 2. FEV1
 <75% of predicted with ≥10% decline within 2 years. FEV1 should not be corrected to >75% of
Clinical Trials in Chronic Graft-versus-Host Disease: I. The predicted after albuterol inhalation, and the absolute decline for the corrected values should still remain at
2014 Diagnosis and Staging Working Group Report. Biol ≥10% over 2 years.
Blood Marrow Transplant 2015;21:389-401. 3. Absence
 of infection in the respiratory tract, documented with investigations directed by clinical
b In all cases, infection, drug effect, malignancy, or other symptoms, such as chest radiographs, CT scans, or microbiologic cultures (sinus aspiration, upper
causes must be excluded. respiratory tract viral screen, sputum culture, bronchoalveolar lavage).
c Can be acknowledged as part of the chronic GVHD 4. One
 of the 2 supporting features of BOS: Evidence of air trapping by expiratory CT or small airway
manifestations if diagnosis is confirmed. thickening or bronchiectasis by high-resolution chest CT; or evidence of air trapping by PFT: residual
d Common refers to shared features by both acute and chronic volume >120% of predicted or residual volume/total lung capacity elevated outside the 90% confidence
GVHD. interval.
e BOS can be diagnostic for lung chronic GVHD only if distinctive If a patient already carries the diagnosis of chronic GVHD by virtue of organ involvement elsewhere, then
signs or symptoms of chronic GVHD are present in another only the first 3 criteria above are necessary to document chronic GVHD lung involvement.
organ. BOS diagnosis requires the following criteria: f Pulmonary entities under investigation or unclassified.
Continued
Note: All recommendations are category 2A unless otherwise indicated.
GVHD-B
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Graft-Versus-Host Disease Discussion

CHRONIC GVHD: DIAGNOSIS

Signs and Symptoms of Chronic GVHDa

Organ Site Diagnostic Distinctiveb Other features for Commond
(sufficient to establish the (seen in chronic GVHD, but unclassified entitiesc (seen with both acute and
diagnosis of chronic GVHD) insufficient to establish a diagnosis) chronic GVHD)
Muscles, • Fasciitis • Myositis or polymyositisg • Edema
Fascia, • Joint stiffness or contractures • Muscle cramps
Joints secondary to fasciitis or sclerosis • Arthralgia or arthritis

Hematopoietic • Thrombocytopenia
and Immune • Eosinophilia
• Lymphopenia
• Hypo- or hyper-
gammaglobulinemia
• Autoantibodies (autoimmune
hemolytic anemia [AIHA],
immune thrombocytopenia [ITP])
• Raynaud’s phenomenon
Other • Pericardial or pleural effusions
• Ascites
• Peripheral neuropathy
• Nephrotic syndrome
• Myasthenia gravis
• Cardiac conduction abnormality
or cardiomyopathy

a Jagasia MH, Greinix HT, Arora M, et al. National Institutes of Health Consensus Development Project on Criteria for Clinical Trials in Chronic Graft-versus-Host
Disease: I. The 2014 Diagnosis and Staging Working Group Report. Biol Blood Marrow Transplant 2015;21:389-401.
b In all cases, infection, drug effect, malignancy, or other causes must be excluded.
c Can be acknowledged as part of the chronic GVHD manifestations if diagnosis is confirmed.
d Common refers to shared features by both acute and chronic GVHD.
g Diagnosis of chronic GVHD requires biopsy.

Note: All recommendations are category 2A unless otherwise indicated.

GVHD-B
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CHRONIC GVHD: GRADING

Organ Scoring of Chronic GVHDa

Score 0 Score 1 Score 2 Score 3
Performance Score: Asymptomatic and fully Symptomatic, fully ambulatory, Symptomatic, ambulatory, Symptomatic, limited self-care,
KPS ECOG (circle one) active (ECOG 0, KPS restricted only in physically capable of self-care, >50% >50% of waking hours in bed
100%) strenuous activity (ECOG 1, of waking hours out of bed (ECOG 3–4, KPS <60%)
KPS 80–90%) (ECOG 2, KPS 60–70%)
Skinb
Score % BSA: No BSA involved 1–18% BSA 19–50% BSA >50% BSA
GVHD features to be scored by BSA
(check all that apply):
{ Maculopapular rash/erythema
{ Lichen planus-like features
{ Sclerotic features
{ Papulosquamous lesions or ichthyosis
{ Keratosis pilaris-like GVHD

Skin Features No sclerotic features Superficial sclerotic features Check all that apply:
Score: "not hidebound" (able to { Deep sclerotic features
pinch) { "Hidebound" (unable to
pinch)
{ Impaired mobility
{ Ulceration
Other skin GVHD features, NOT scored by BSA (check all that apply):
{ Hyperpigmentation
{ Hypopigmentation
{ Poikiloderma
{ Severe or generalized pruritus
{ Hair involvement
{ Nail involvement
{ Abnormality present but explained entirely by non-GVHD documented cause (specify):

a Jagasia MH, Greinix HT, Arora M, et al. National Institutes of Health Consensus Development Project on Criteria for Clinical Trials in Chronic Graft-versus-Host
Disease: I. The 2014 Diagnosis and Staging Working Group Report. Biol Blood Marrow Transplant 2015;21:389-401.
b Skin scoring should use both percentage of BSA involved by disease signs and the cutaneous features scales. When a discrepancy exists between the percentage of
BSA score and the skin feature score, OR if superficial sclerotic features are present (Score 2), but there is impaired mobility or ulceration (Score 3), the higher level
should be used for the final skin scoring.
Continued
Note: All recommendations are category 2A unless otherwise indicated.
GVHD-C
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CHRONIC GVHD: GRADING

Organ Scoring of Chronic GVHDa

Score 0 Score 1 Score 2 Score 3
Mouth
No symptoms Mild symptoms with disease Moderate symptoms with Severe symptoms with disease
Lichen planus-like features present: signs but not limiting oral disease signs with partial signs on examination with
{ Yes intake significantly limitation of oral intake major limitation of oral intake
{ No
{ Abnormality present but explained entirely by non-GVHD documented cause (specify):
Eyes
Keratoconjunctivitis sicca (KCS) confirmed No symptoms Mild dry eye symptoms not Moderate dry eye symptoms Severe dry eye symptoms
by ophthalmologist affecting ADL (requirement partially affecting ADL significantly affecting ADL
{ Yes of lubricant eye drops ≤ 3 x (requiring lubricant eye drops (special eyeware to relieve
{ No per day) > 3 x per day or punctal pain) OR unable to work
{ Not examined plugs), WITHOUT new vision because of ocular symptoms
impairment due to KCS OR loss of vision due to KCS
{ Abnormality present but explained entirely by non-GVHD documented cause (specify):
GI Tract
Check all that apply: No symptoms Symptoms without Symptoms associated with Symptoms associated with
{ Esophageal web/proximal stricture or ring significant weight lossc mild to moderate weight significant weight lossc >15%,
{ Dysphagia (<5%) lossc (5–15%) OR moderate requires nutritional supplement
{ Anorexia diarrhea without significant for most calorie needs OR
{ Nausea interference with daily living esophageal dilation OR severe
{ Vomiting diarrhea with significant
{ Diarrhea interference with daily living
{ Weight loss ≥5%c
{ Failure to thrive
{ Abnormality present but explained entirely by non-GVHD documented cause (specify):

a Jagasia MH, Greinix HT, Arora M, et al. National Institutes of Health Consensus Development Project on Criteria for Clinical Trials in Chronic Graft-versus-Host
Disease: I. The 2014 Diagnosis and Staging Working Group Report. Biol Blood Marrow Transplant 2015;21:389-401.
c Weight loss within 3 months. Continued

Note: All recommendations are category 2A unless otherwise indicated.

GVHD-C
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CHRONIC GVHD: GRADING

Organ Scoring of Chronic GVHDa
Score 0 Score 1 Score 2 Score 3
Liver
Normal total bilirubin and Normal total bilirubin with ALT Elevated total bilirubin but ≤3 Elevated total bilirubin
ALT or AP < 3 x ULN ≥ 3 to 5 x ULN or AP ≥ 3 x ULN mg/dL or ALT > 5 x ULN >3 mg/dL
{ Abnormality present but explained entirely by non-GVHD documented cause (specify):
Lungsd
Symptom score: No symptoms Mild symptoms (shortness of Moderate symptoms Severe symptoms
breath after climbing one flight of (shortness of breath after (shortness of breath at
steps) walking on flat ground) rest; requiring O2)

Lung score: % FEV1 FEV1 ≥80% FEV1 60–79% FEV1 40–59% FEV1 ≤39%
Pulmonary function tests:
Not performed
{ Abnormality present but explained entirely by non-GVHD documented cause (specify):
Joints and Fascia
P-ROM score (see GVHD-C, 5 of 5) No symptoms Mild tightness of arms or legs, Tightness of arms or legs OR Contractures WITH
Shoulder (1-7): normal or mild decreased range of joint contractures, erythema significant decrease of
Elbow (1-7): motion (ROM) AND not affecting thought due to fasciitis, ROM AND significant
Wrist/finger (1-7): ADL moderate decrease ROM AND limitation of ADL (unable
Ankle (1-4): mild to moderate limitation of to tie shoes, button
{ Abnormality present but explained entirely by non-GVHD documented cause (specify): ADL shirts, dress self, etc)

Genital Tracte
{ Not examined No signs Mild signse and females with or Moderate signse and Severe signse with or
Currently sexually active: without discomfort on exam may have symptoms with without symptoms
{ Yes discomfort on exam
{ No
{ Abnormality present but explained entirely by non-GVHD documented cause (specify):

a Jagasia MH, Greinix HT, Arora M, et al. National Institutes d Lung scoring should be performed using both the symptoms and FEV1 scores whenever
of Health Consensus Development Project on Criteria for possible. FEV1 should be used in the final lung scoring where there is discrepancy between
Clinical Trials in Chronic Graft-versus-Host Disease: I. symptoms and FEV1 scores.
The 2014 Diagnosis and Staging Working Group Report. e Referral and close surveillance by a specialist is recommended for early detection of chronic
Biol Blood Marrow Transplant 2015;21:389-401. GVHD and full assessment of disease.
Continued
Note: All recommendations are category 2A unless otherwise indicated.
GVHD-C
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CHRONIC GVHD: GRADING

Organ Scoring of Chronic GVHDa
Other indicators, clinical features or complications related to chronic GVHD (check all that apply and assign a score to severity (0–3) based on functional impact
where applicable none – 0, mild – 1, moderate – 2, severe – 3)
{ Ascites (serositis) { Polymyositis
{ Pericardial effusion { Weight loss >5% without GI symptoms
{ Pleural effusion(s) { Eosinophilia >500/μl
{ Nephrotic syndrome { Platelets <100,000/μl
{ Myasthenia gravis { Others (specify):
{ Peripheral neuropathy
Overall GVHD Severity
Opinion of the evaluator: { No GVHD { Mild { Moderate { Severe

NIH Global Severity of Chronic GVHDa

Mild chronic GVHD Moderate chronic GVHD Severe chronic GVHD
1 or 2 organs involved with no more than score 1 3 or more organs involved with no more than score 1 At least 1 organ with a score of 3
plus OR OR
Lung score 0 At least 1 organ (not lung) with a score of 2 Lung score of 2 or 3
OR
Lung score 1

Key points:
1. In skin: higher of the two scores to be used for calculating global severity.
2. In lung: FEV1 is used instead of clinical score for calculating global severity.
3. If the entire abnormality in an organ is noted to be unequivocally explained by a non-GVHD documented cause, that organ is not included for
calculation of the global severity.
4. If the abnormality in an organ is attributed to multifactorial causes (GVHD plus other causes) the scored organ will be used for calculation of the
global severity regardless of the contributing causes (no downgrading of organ severity score).

a Jagasia MH, Greinix HT, Arora M, et al. National Institutes of Health Consensus Development Project on Criteria for Clinical Trials in Chronic Graft-versus-Host
Disease: I. The 2014 Diagnosis and Staging Working Group Report. Biol Blood Marrow Transplant 2015;21:389-401.
Continued
Note: All recommendations are category 2A unless otherwise indicated.
GVHD-C
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CHRONIC GVHD: GRADING

Photographic Range of Motion (P-ROM)a

a Jagasia MH, Greinix HT, Arora M, et al. National Institutes of Health Consensus Development Project on Criteria for Clinical Trials in Chronic Graft-versus-Host
Disease: I. The 2014 Diagnosis and Staging Working Group Report. Biol Blood Marrow Transplant 2015;21:389-401.

Note: All recommendations are category 2A unless otherwise indicated.

GVHD-C
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GVHD STEROID RESPONSE DEFINITIONS/CRITERIA

Response Criteria for GVHD Clinical Trialsa

Acute GVHD Steroid Response Chronic GVHD Steroid Response
Steroid Progression of acute GVHD within 3–5 days of Chronic GVHD progression while on prednisone at
Refractoriness therapy onset with ≥2 mg/kg/day of prednisone ≥1 mg/kg/day for 1–2 weeks
or Resistance OR OR
Failure to improve within 5–7 days of treatment Stable GVHD disease while on ≥0.5 mg/kg/day (or 1
initiation mg/kg every other day) of prednisone
OR for 1–2 months
Incomplete response after more than 28 days of
immunosuppressive treatment including steroids

Steroid Inability to taper prednisone below 2 mg/kg/day Inability to taper prednisone below 0.25 mg/kg/
Dependence OR day (or >0.5 mg/kg every other day) in at least two
A recurrence of acute GVHD activity during steroid unsuccessful attempts separated by at least 8 weeks
taper

Steroid Emergence of unacceptable toxicity due to the use of corticosteroids

Intolerance

Chronic GVHD Response Criteria (GVHD-D, 2 of 2)

a Schoemans HM, Lee SJ, Ferrara JL, et al. EBMT−NIH−CIBMTR Task Force position statement on standardized terminology & guidance for graft-versus-host disease
assessment. Bone Marrow Transplant 2018;53:1401-1415.

Note: All recommendations are category 2A unless otherwise indicated.

GVHD-D
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GVHD STEROID RESPONSE DEFINITIONS/CRITERIA

Chronic GVHD Response Criteriab
Organ Complete Response Partial Response Progression
Skin NIH Skin Score 0 after previous Decrease in NIH Skin Score by 1 or more Increase in NIH Skin Score by 1 or more
involvement points points, except 0 to 1
Eyes NIH Eye Score 0 after previous Decrease in NIH Eye Score by 1 or more Increase in NIH Eye Score by 1 or more
involvement points points, except 0 to 1

Mouth NIH Modified Oral Mucosa Rating Score 0 Decrease in NIH Modified Oral Mucosa Increase in NIH Modified Oral Mucosa
after previous involvement Rating Score of 2 or more points Rating Score of 2 or more points
Esophagus NIH Esophagus Score 0 after previous Decrease in NIH Esophagus Score by 1 Increase in NIH Esophagus Score by 1 or
involvement or more points more points, except 0 to 1
Upper GI NIH Upper GI Score 0 after previous Decrease in NIH Upper GI Score by 1 or Increase in NIH Upper GI Score by 1 or
involvement more points more points, except 0 to 1
Lower GI NIH Lower GI Score 0 after previous Decrease in NIH Lower GI Score by 1 or Increase in NIH Lower GI Score by 1 or
involvement more points more points, except from 0 to 1
Liver Normal ALT, alkaline phosphatase, and Decrease by 50% Increase by 2x ULN
total bilirubin after previous elevation of
one or more
Lungs -Normal %FEV1 after previous -Increase by 10% predicted absolute -Decrease by 10% predicted absolute
involvement value of %FEV1 value of %FEV1
-If PFTs not available, NIH Lung Symptom -If PFTs not available, decrease in NIH -If PFTs not available, increase in NIH
Score 0 after previous involvement Lung Symptom Score by 1 or more Lung Symptom Score by 1 or more
points points, except 0 to 1
Joints and Both NIH Joint and Fascia Score 0 Decrease in NIH Joint and Fascia Score Increase in NIH Joint and Fascia Score by
Fascia and P-ROM score 25 after previous by 1 or more points or increase in P-ROM 1 or more points or decrease in P-ROM
involvement by at least one measure score by 1 point for any site score by 1 point for any site
Global Clinician overall severity score 0 Clinician overall severity score decreases Clinician overall severity score increases
by 2 or more points on a 0–10 scale by 2 or more points on a 0–10 scale

b Lee SJ, Wolff D, Kitko C, et al. Measuring therapeutic response in chronic graft-versus-host disease: National Institutes of Health Consensus Development Project on
Criteria for Clinical Trials in Chronic Graft-Versus-Host Disease: IV. The 2014 Response Criteria Working Group Report. Biol Blood Marrow Transplant 2015;21:984-
999.

Note: All recommendations are category 2A unless otherwise indicated.

GVHD-D
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SUGGESTED SYSTEMIC AGENTS FOR STEROID-REFRACTORY GVHD

• Participation in clinical trials is encouraged.
• The following systemic agents are used in conjunction with corticosteroids for steroid-refractory GVHD. There is insufficient evidence to recommend one systemic
agent as preferred over another. However, these are the most commonly used agents among the NCCN Member Institutions.
• The selection of systemic agent should be based on institutional preferences, physician experience, agent's toxicity profile, the effect of prior treatment, drug
interactions, convenience/accessibility, and patient tolerability.
Suggested Systemic Agents for Steroid-Refractory GVHDa,b
Acute GVHD1 Chronic GVHD
The following agents are often used in conjunction with the While the following systemic agents may be used to treat chronic GVHD
original immunosuppressive agent. in any organ, some agents are used more commonly for certain sites
involved with chronic GVHD based on available data (see Discussion).
FDA-approved category 1 agents
• Ruxolitinib (category 1)c,2 FDA-approved category 1 agents
• Ruxolitinib (category 1)c,24-26
Alternative agents (listed in alphabetical order)
• Alemtuzumab3,4 Other FDA-approved agents (listed in order by FDA approval date)
• Alpha-1 antitrypsin5 • Ibrutinibe,27,28
• ATG6 • Belumosudilf,29
• Basiliximab7 • Axatilimab-csfrg,30
• Calcineurin inhibitors (CNIs) (eg, tacrolimus,
cyclosporine) Alternative agents (listed in alphabetical order)
• Etanercept8 • Abatacept31
• Extracorporeal photopheresis (ECP)d,9 • Alemtuzumab32,33
• Infliximab10 • CNIs (eg, tacrolimus, cyclosporine)
• mTOR inhibitors (eg, sirolimus)11,12 • Etanercept34
• Mycophenolate mofetil13,14 • ECPd,9
• Pentostatin15-17 • Hydroxychloroquine35
• Tocilizumab18-21 • Imatinib36,37
• Urinary-derived human chorionic gonadotropin/ • Interleukin-2 (IL-2)38
epidermal growth factor (uhCG/EGF)22 • Low-dose methotrexate39-41
• Vedolizumab23 • mTOR inhibitors (eg, sirolimus)42-44
• Mycophenolate mofetil45
• Pentostatin46-48
• Rituximab49

a For patients receiving immunosuppressive agents for GVHD, see NCCN Guidelines for
Prevention and Treatment of Cancer-Related Infections.
b An FDA-approved biosimilar is an appropriate substitute for any recommended systemic e Ibrutinib is FDA approved for the treatment of adult and pediatric patients ≥1 year with chronic
biologic therapy in the NCCN Guidelines. GVHD after failure of one or more lines of systemic therapy. Ibrutinib should be used with
c Ruxolitinib is FDA approved for the treatment of adult and pediatric patients (age ≥12 years) caution in patients with a history of heart arrhythmias or heightened risk of bleeding.
with either steroid-refractory acute GVHD, or chronic GVHD after failure of one or two lines of f Belumosudil is FDA approved for the treatment of adult and pediatric patients (age ≥12 years)
systemic therapy. with chronic GVHD after failure of two or more prior lines of systemic therapy.
d Psoralen and ultraviolet A irradiation (PUVA) may be used for sclerotic or cutaneous GVHD if g Axatilimab-csfr is FDA approved for the treatment of adult and pediatric patients weighing
ECP is not available or feasible. ≥40 kg with chronic GVHD after failure of at least two prior lines of systemic therapy.
References
Note: All recommendations are category 2A unless otherwise indicated.
GVHD-E
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SUGGESTED SYSTEMIC AGENTS FOR STEROID-REFRACTORY GVHD

REFERENCES
1 Martin, PJ, Rizzo JD, Wingard JR, et al. First- and second-line systemic 13 Pidala J, Kim J, Perkins J, et al. Mycophenolate mofetil for the management
treatment of acute graft-versus-host disease: recommendations of the American of steroid-refractory acute graft vs host disease. Bone Marrow Transplant
Society of Blood and Marrow Transplantation. Biol Blood Marrow Transplant 2010;45:919-924.
2012;18:1150-1163. 14 Furlong T, Martin P, Flowers ME, et al. Therapy with mycophenolate mofetil for
2 Zeiser R, von Bubnoff N, Butler J, et al. Ruxolitinib for glucocorticoid-refractory refractory acute and chronic GVHD. Bone Marrow Transplant 2009;44:739-748.
acute graft-versus-host disease. N Engl J Med 2020;382:1800-1810. 15 Ragon BK, Mehta RS, Gulbis AM, et al. Pentostatin therapy for steroid-refractory
3 Gomez-Almaguer D, Ruiz-Arguelles GJ, del Carmen Tarin-Arzaga L, et al. acute graft versus host disease: identifying those who may benefit. Bone Marrow
Alemtuzumab for the treatment of steroid-refractory acute graft-versus-host Transplant 2018;53:315-325.
disease. Biol Blood Marrow Transplant 2008;14:10-15. 16 Schmitt T, Luft T, Hegenbart U, et al. Pentostatin for treatment of steroid-
4 Schnitzler M, Hasskarl J, Egger M, et al. Successful treatment of severe acute refractory acute GVHD: a retrospective single-center analysis. Bone Marrow
intestinal graft-versus-host resistant to systemic and topical steroids with Transplant 2011;46:580-585.
alemtuzumab. Biol Blood Marrow Transplant 2009;15:910-918. 17 Bolanos-Meade J, Jacobsohn DA, Margolis J, et al. Pentostatin in steroid-
5 Magenau JM, Goldstein SC, Peltier D, et al. alpha1-Antitrypsin infusion refractory acute graft-versus-host disease. J Clin Oncol 2005;23:2661-2668.
for treatment of steroid-resistant acute graft-versus-host disease. Blood 18 Roddy JV, Haverkos BM, McBride A, et al. Tocilizumab for steroid refractory
2018;131:1372-1379. acute graft-versus-host disease. Leuk Lymphoma 2016;57:81-85.
6 MacMillan ML, Weisdorf DJ, Davies SM, et al. Early antithymocyte globulin 19 Drobyski WR, Pasquini M, Kovatovic K, et al. Tocilizumab for the treatment
therapy improves survival in patients with steroid-resistant acute graft-versus- of steroid refractory graft-versus-host disease. Biol Blood Marrow Transplant
host disease. Biol Blood Marrow Transplant 2002;8:40-46. 2011;17:1862-1868.
7 Schmidt-Hieber M, Fietz T, Knauf W, et al. Efficacy of the interleukin-2 receptor 20 Ganetsky A, Frey NV, Hexner EO, et al. Tocilizumab for the treatment of severe
antagonist basiliximab in steroid-refractory acute graft-versus-host disease. Br J steroid-refractory acute graft-versus-host disease of the lower gastrointestinal
Haematol 2005;130:568-574. tract. Bone Marrow Transplant 2019;54:212-217.
8 Busca A, Locatelli F, Marmont F, et al. Recombinant human soluble tumor 21 Yucebay F, Matthews C, Puto M, et al. Tocilizumab as first-line therapy for
necrosis factor receptor fusion protein as treatment for steroid refractory graft- steroid-refractory acute graft-versus-host-disease: analysis of a single-center
versus-host disease following allogeneic hematopoietic stem cell transplantation. experience. Leuk Lymphoma 2019;60:2223-2229.
Am J Hematol 2007;82:45-52. 22 Holtan SG, Hoeschen A, Cao Q, et al. Phase II, open-label clinical trial of
9 Abu-Dalle
 I, Reljic T, Nishihori T, et al. Extracorporeal photopheresis in steroid- urinary-derived human chorionic gonadotropin/epidermal growth factor for life-
refractory acute or chronic graft-versus-host disease: results of a systematic threatening acute graft-versus-host disease. Transplant Cell Ther 2023;29:509.
review of prospective studies. Biol Blood Marrow Transplant 2014;20:1677-1686. e1-509.e8.
10 Couriel D, Saliba R, Hicks K, et al. Tumor necrosis factor-alpha blockade for the 23 Li ACW, Dong C, Tay ST, et al. Vedolizumab for acute gastrointestinal graft
treatment of acute GVHD. Blood 2004;104:649-654. versus-host disease: A systematic review and meta-analysis. Front Immunol
11 Hoda
 D, Pidala J, Salgado-Vila N, et al. Sirolimus for treatment of steroid- 2022;13:1025350.
refractory acute graft-versus-host disease. Bone Marrow Transplant 24 Khoury HJ, Langston AA, Kota VK, et al. Ruxolitinib: a steroid sparing agent in
2010;45:1347-1351. chronic graft-versus-host disease. Bone Marrow Transplant 2018;53:826-831.
12 Pidala J, Kim J, Anasetti C. Sirolimus as primary treatment of acute graft- 25 Modi B, Hernandez-Henderson M, Yang D, et al. Ruxolitinib as salvage
versus-host disease following allogeneic hematopoietic cell transplantation. Biol therapy for chronic graft-versus-host disease. Biol Blood Marrow Transplant
Blood Marrow Transplant 2009;15:881-885. 2019;25:265-269.
26 Zeiser R, Polverelli N, Ram R, et al. Ruxolitinib for glucocorticoid-refractory
chronic graft-versus-host disease. N Engl J Med 2021;385:228-238.
Continued

Note: All recommendations are category 2A unless otherwise indicated.

GVHD-E
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SUGGESTED SYSTEMIC AGENTS FOR STEROID-REFRACTORY GVHD

REFERENCES
27 Miklos D, Cutler CS, Arora M, et al. Ibrutinib for chronic graft-versus-host 39 Giaccone L, Martin P, Carpenter P, et al. Safety and potential efficacy of low-dose
disease after failure of prior therapy. Blood 2017;30:2243-2250. methotrexate for treatment of chronic graft-versus-host disease. Bone Marrow
28 Carpenter PA, Kang HJ, Yoo KH, et al. Ibrutinib treatment of pediatric chronic Transplantation 2005;36:337-341.
graft-versus-host disease: Primary results from the Phase 1/2 iMAGINE study. 40 de Lavallade H, Mohty M, Faucher C, et al. Low-dose methotrexate as
Transplant Cell Ther 2022;28:771.e1-771.e10. salvage therapy for refractory graft-versus-host disease after reduced-intensity
29 Cutler CS, Lee SJ, Arai S, et al. Belumosudil for chronic graft-versus-host conditioning allogeneic stem cell transplantation. Haematologica 2006;91:1438-
disease (cGVHD) after 2 or more prior lines of therapy: The ROCKstar Study. 1440.
Blood 2021;138:2278-2289. 41 Huang XJ, Jiang Q, Chen H, et al. Low-dose methotrexate for the treatment of
30 Wolff D, Cutler C, Lee SJ, et al. Safety and efficacy of axatilimab at 3 different graft-versus-host disease after allogeneic hematopoietic stem cell transplantation.
doses in patients with chronic graft-versus-host disease (AGAVE-201). Blood Bone Marrow Transplant 2005;36:343-348.
2023;142:(Supplement 1):1. 42 Couriel DR, Saliba R, Escalon MP, et al. Sirolimus in combination with tacrolimus
31 Nahas MR, Soiffer RJ, Kim HT, et al. Phase 1 clinical trial evaluating abatacept and corticosteroids for the treatment of resistant chronic graft-versus-host
in patients with steroid-refractory chronic graft-versus-host disease. Blood disease. Br J Haematol 2005;130:409-417.
2018;131:2836-2845. 43 Johnston LJ, Brown J, Shizuru JA, et al. Rapamycin (sirolimus) for treatment of
32 Nikiforow S, Kim HT, Bindra B, et al. Phase I study of alemtuzumab for therapy chronic graft-versus-host disease. Biol Blood Marrow Transplant 2005;11:47-55.
of steroid-refractory chronic graft-versus-host disease. Biol Blood Marrow 44 Jurado M, Vallejo C, Perez-Simon JA, et al. Sirolimus as part of
Transplant 2013;19:804-811. immunosuppressive therapy for refractory chronic graft-versus-host disease. Biol
33 Gutierrez-Aguirre CH, Cantu-Rodriguez OG, Borjas-Almaguer OD, et Blood Marrow Transplant 2007;13:701-706.
al. Effectiveness of subcutaneous low-dose alemtuzumab and rituximab 45 Lopez F, Parker P, Nademanee A, et al. Efficacy of mycophenolate mofetil in the
combination therapy for steroid-resistant chronic graft-versus-host disease. treatment of chronic graft-versus-host disease. Biol Blood Marrow Transplant
Haematologica 2012;97:717-722. 2005;11:307-313.
34 Yanik GA, Mineishi S, Levine JE, et al. Soluble tumor necrosis factor receptor: 46 Goldberg JD, Jacobsohn DA, Margolis J, et al. Pentostatin for the treatment
enbrel (etanercept) for subacute pulmonary dysfunction following allogeneic of chronic graft-versus-host disease in children. J Pediatr Hematol Oncol
stem cell transplantation. Biol Blood Marrow Transplant 2012;18:1044-1054. 2003;25:584-588.
35 Gilman AL, Chan KW, Mogul A, et al. Hydroxychloroquine for the treatment of 47 Jacobsohn DA, Chen AR, Zahurak M, et al. Phase II study of pentostatin in
chronic graft-versus-host disease. Biol Blood Marrow Transplant 2000;6:327- patients with corticosteroid-refractory chronic graft-versus-host disease. J Clin
334. Oncol 2007;25:4255-4261.
36 Olivieri A, Cimminiello M, Corradini P, et al. Long-term outcome and 48 Saven A, Piro L. Newer purine analogues for the treatment of hairy-cell leukemia.
prospective validation of NIH response criteria in 39 patients receiving imatinib N Engl J Med 1994;330:691-697.
for steroid-refractory chronic GVHD. Blood 2013;122:4111-4118. 49 Kharfan-Dabaja MA, Mhaskar AR, Djulbegovic B, et al. Efficacy of rituximab in
37 Arai S, Pidala J, Pusic I, et al. A randomized phase II crossover study the setting of steroid-refractory chronic graft-versus-host disease: a systematic
of imatinib or rituximab for cutaneous sclerosis after hematopoietic cell review and meta-analysis. Biol Blood Marrow Transplant 2009;15:1005-1013.
transplantation. Clin Cancer Res 2016;22:319-327.
38 Koreth J, Kim HT, Jones KT, et al. Efficacy, durability, and response predictors
of low-dose interleukin-2 therapy for chronic graft-versus-host disease. Blood
2016;128:130-137.

Note: All recommendations are category 2A unless otherwise indicated.

GVHD-E
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Graft-Versus-Host Disease Discussion

GVHD SUPPORTIVE CARE

All Patients • GI Tract (continued)

• Supportive care is essential for patients with GVHD.1 Cautious use of octreotide is recommended for diarrhea control. It should be
• Special attention is required for the following issues: stopped once diarrhea resolves, or after 7 days of treatment (risk of ileus).
Appropriate antimicrobial prophylaxis should be used with escalating Prolonged oral beclomethasonea or budesonide may cause adrenal
immunosuppressive therapy. See NCCN Guidelines for Prevention and insufficiency. Monitor for symptoms and evaluate as clinically necessary.
Treatment of Cancer-Related Infections. • Nutrition
Surveillance for CMV reactivation is recommended in appropriate Patients may suffer from malnutrition and protein-losing enteropathy with
patients. Additional viral surveillance may be considered. deficiency of trace elements (eg, magnesium, zinc) and vitamins (eg, thiamine,
Vaccination: vitamins B12 and D).
◊ Avoid live vaccines if patient is on immunosuppressive therapy or has Total parenteral nutrition and bowel rest should be considered in patients with
active GVHD. voluminous diarrhea or poor tolerance to oral intake.
◊ COVID-19 re-vaccination is recommended in all patients 3 months Monitoring for thiamine deficiency should be considered for patients with
post-transplant. See the CDC for Use of COVID-19 Vaccines in the US. altered mental status.
IV immunoglobulin (IVIG) replacement: There may be subsets of patients
where prophylactic immunoglobulin replacement after bone marrow Chronic GVHD
transplant may be considered, such as in recipients of a UCB transplant, • Oral
in children undergoing transplantation for inherited or acquired disorders Sialagogues (eg, cevimeline) may be considered with severe xerostomia.
associated with B-cell deficiency, and in patients with chronic GVHD with Dental/oral surgery assessment is recommended for suspicious oral lesions
recurrent sinopulmonary infections.2 (risk of malignancy).
HD steroid therapy may be associated with glucose intolerance, Consider dexamethasone or CNI mouth rinses (swish and spit).
hypertension, adrenal insufficiency, poor wound healing, myopathy, Monitor for oral thrush and use appropriate antifungal topical therapy as
osteoporosis, vitamin D deficiency, and mood swings. indicated.
◊ Vitamin D and calcium supplementation should be considered for • Eyes
patients on HD steroid. Monitoring of vitamin D level is recommended. Ophthalmologic assessment is recommended.
DEXA scan (in particular for patients with either current or past exposure Patients may benefit from artificial tears, autologous serum drops, punctal
to HD steroids) with treatment and repeat imaging as indicated based on plugs, or gas-permeable scleral lenses.
results. Patients with severe ocular sicca may benefit from cholinergic agents
Dermatologic, dental, and ophthalmologic evaluation at appropriate (cevimeline or pilocarpine).
intervals beginning 6–12 months post-transplant. • GI Tract
Ursodiol for patients with liver GVHD may be considered.3,4 GI consultation is recommended for patients with esophageal stricture (may
benefit from periodic dilatation).
Acute GVHD Workup is recommended for malabsorption from prolonged diarrhea (patients
• Skin with pancreatic atrophy may benefit from oral pancreatic enzymes).
Avoid direct sunlight, use sunscreen, and avoid photosensitizing agents. • Genital Tract
Dermatologic assessment is recommended for advanced disease. Concerns around genitourinary symptoms (eg, urinary issues, erectile
• GI Tract dysfunction, vulvovaginal symptoms) should be addressed with referrals as
Cautious use of opioid medications is recommended for severe appropriate (ie, dermatology, urology, gynecology).
abdominal pain (risk of ileus). • Physical therapy may help patients with musculoskeletal, sclerotic, or
neuromuscular disease.
Footnote and
References on
GVHD-F (2 of 2)
Note: All recommendations are category 2A unless otherwise indicated.
GVHD-F
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Graft-Versus-Host Disease Discussion

GVHD SUPPORTIVE CARE

FOOTNOTE AND REFERENCES
Footnote
a Oral beclomethasone is available as a compounded agent.

References
1 Carpenter P, Kitko C, Elad S, et al. National Institutes of Health Consensus Development Project on Criteria for Clinical Trials in Chronic Graft versus-Host Disease: V.
The 2014 Ancillary Therapy and Supportive Care Working Group Report. Biol Blood Marrow Transplant 2015;21:1167-1187.
2 Bhella S, Majhail NS, Betcher J, et al. Choosing Wisely BMT: American Society for Blood and Marrow Transplantation and Canadian Blood and Marrow Transplant
Group's List of 5 Tests and Treatments to Question in Blood and Marrow Transplantation. Biol Blood Marrow Transplant 2018;24:909-913.
3 Ruutu T, Juvonen E, Remberger M, et al. Improved survival with ursodeoxycholic acid prophylaxis in allogeneic stem cell transplantation: long-term follow-up of a
randomized study. Biol Blood Marrow Transplant 2014;20:135-138.
4 Ruutu T, Eriksson B, Remes K, et al. Ursodeoxycholic acid for the prevention of hepatic complications in allogeneic stem cell transplantation. Blood 2002;100:1977-
1983.

Note: All recommendations are category 2A unless otherwise indicated.

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ABBREVIATIONS

ADL activities of daily living G-CSF granulocyte colony-stimulating NHL non-Hodgkin lymphoma
AIHA autoimmune hemolytic anemia factor NMA non-myeloablative
GI gastrointestinal NRM non-relapse mortality
ALT alanine transaminase
GVHD graft-versus-host disease
AP alkaline phosphatase
ATG antithymocyte globulin PFT pulmonary function test
HBV hepatitis B virus P-ROM photographic range of motion
AUC area under the curve
HCT hematopoietic cell transplant PTCy post-transplant
HCT-CI HCT Comorbidity Index cyclophosphamide
BOS bronchiolitis obliterans syndrome
HCV hepatitis C virus PUVA psoralen and ultraviolet A
BSA body surface area irradiation
HD high-dose
HIV human immunodeficiency virus
CMV cytomegalovirus RIC reduced-intensity conditioning
HL Hodgkin lymphoma
CNI calcineurin inhibitor ROM range of motion
HLA human leukocyte antigen
COP cryptogenic organizing HSV herpes simplex virus
pneumonia STR short tandem repeat
ITP immune thrombocytopenia
DEXA dual-energy x-ray absorptiometry TBI total body irradiation
IVIG intravenous immunoglobulin
DLCO diffusing capacity of the lungs for
carbon monoxide
KCS keratoconjunctivitis sicca UCB umbilical cord blood
KPS Karnofsky Performance Status ULN upper limit of normal
ECOG Eastern Cooperative Oncology
Group uhCG/EGF urinary-derived human
chorionic gonadotropin/
ECP extracorporeal photopheresis LFT liver function test epidermal growth factor
LVEF left ventricular ejection fraction
FEV1 forced expiratory volume in the VC vital capacity
first second MA myeloablative VOD/SOS veno-occlusive disease/
sinusoidal obstruction
syndrome
VZV varicella zoster virus

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NCCN Categories of Evidence and Consensus

Category 1 Based upon high-level evidence (≥1 randomized phase 3 trials or high-quality, robust meta-analyses), there is
uniform NCCN consensus (≥85% support of the Panel) that the intervention is appropriate.
Category 2A Based upon lower-level evidence, there is uniform NCCN consensus (≥85% support of the Panel) that the
intervention is appropriate.
Category 2B Based upon lower-level evidence, there is NCCN consensus (≥50%, but <85% support of the Panel) that the
intervention is appropriate.
Category 3 Based upon any level of evidence, there is major NCCN disagreement that the intervention is appropriate.
All recommendations are category 2A unless otherwise indicated.

NCCN Categories of Preference

Interventions that are based on superior efficacy, safety, and evidence; and, when appropriate,
Preferred intervention affordability.
Other recommended Other interventions that may be somewhat less efficacious, more toxic, or based on less mature data;
intervention or significantly less affordable for similar outcomes.
Useful in certain
Other interventions that may be used for selected patient populations (defined with recommendation).
circumstances
All recommendations are considered appropriate.

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This discussion corresponds to the NCCN Guidelines for Acute Graft-Versus-Host Disease ................................................................. 10
Discussion Hematopoietic Cell Transplantation. Last updated August 30,
2024. Diagnosis and Grading ............................................................................. 10
Table of Contents
First-Line Therapy of aGVHD ................................................................... 11
Overview ............................................................................................................. 2
Chronic Graft-Versus-Host Disease ............................................................. 12
Guidelines Update Methodology ......................................................................... 3
Diagnosis and Grading ............................................................................. 12
Literature Search Criteria .................................................................................... 3
First-Line Therapy of cGVHD .................................................................... 13
Sensitive/Inclusive Language Usage .................................................................. 3
Steroid-Refractory GVHD ............................................................................. 13
Autologous Hematopoietic Cell Transplant ......................................................... 3
Suggested Agents for Steroid-Refractory aGVHD .................................... 13
Allogeneic Hematopoietic Cell Transplant .......................................................... 4
Suggested Agents for Steroid-Refractory cGVHD .................................... 20
Indications for Transplantation ............................................................................ 5
GVHD Supportive Care ................................................................................ 27
Pre-Transplant Recipient Evaluation ................................................................... 5
Summary .......................................................................................................... 29
Hematopoietic Cell Mobilization .......................................................................... 5
References ....................................................................................................... 30
Hematopoietic Cell Mobilization for Autologous Donors .................................. 5

Dosing and Administration .......................................................................... 6

Additional Therapy ...................................................................................... 7

Hematopoietic Cell Mobilization for Allogeneic Donors ................................... 7

Dosing and Administration .......................................................................... 7

Additional Therapy ...................................................................................... 7

Principles of Conditioning for HCT ...................................................................... 8

Conditioning Regimens Without Fludarabine .................................................. 9

Post-Transplant Follow-Up ................................................................................. 9

Management of Graft-Versus-Host Disease ..................................................... 10

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Overview socioeconomic status, and non-white race to be associated with reduced

access to HCT.3
Hematopoietic cell transplantation (HCT) involves the infusion of
hematopoietic cells after preparation with cytotoxic conditioning regimens Outcomes of HCT vary according to the type and stage of the disease
in order to eradicate disease and establish adequate hematopoietic and being treated, the overall health and comorbidities of the patient, and for
immune function.1 HCT is potentially curative for patients with certain allogeneic HCT, the degree of HLA-mismatch between donor and
types of hematologic malignancies and is also used to support patients recipient, the source of the hematopoietic cells, and the
undergoing high-dose chemotherapy for the treatment of certain solid immunosuppressive regimen given post-transplant to prevent graft-versus-
tumors. HCT is classified as autologous or allogeneic based on the origin host disease (GVHD), a common complication of allogeneic HCT.1,4
of hematopoietic cells. An autologous HCT uses the patient’s own cells Hematopoietic cells can be obtained from peripheral blood, bone marrow,
while an allogeneic HCT uses hematopoietic cells from a human leukocyte or umbilical cord blood (UCB). Several clinical factors should be
antigen (HLA)-compatible related or unrelated donor. Prior to HCT, most considered when determining the optimal graft source for an individual
patients receive chemotherapy, immunotherapy, and/or radiation therapy patient, including disease type, disease stage, patient comorbidities, and
for pre-transplant conditioning (conditioning regimen). In allogeneic HCT, the urgency for transplantation.5 The use of peripheral blood progenitor
conditioning regimens are administered in order to eradicate malignant cells (PBPCs) has largely replaced the use of bone marrow grafts (in
cells in the bone marrow (if using a myeloablative [MA] regimen) and to particular for autologous HCT) due to the ease of collection, avoidance of
immunosuppress the recipient so that engraftment of healthy donor cells general anesthesia, more rapid engraftment rates and reduced risk of graft
can occur.1 In autologous HCT, MA conditioning regimens are used to failure.6-8 However, allogeneic PBPC transplants are associated with an
treat the malignancy. This is followed by rescue infusion of the patient’s increased risk of chronic graft-versus-host disease (cGVHD) compared to
own cells, which are collected and stored before high-dose therapy, in bone marrow transplants.8-10
order to restore hematopoiesis and reconstitute the immune system.1
Advantages of using UCB grafts include rapid cell procurement, lower
The Center for International Blood and Marrow Transplant Research incidence of cGVHD, and less stringent HLA-matching requirements;
(CIBMTR) estimates that 8295 allogeneic transplants and 11,434 however, use of UCB is limited by the cell doses that can be achieved in
autologous transplants were performed in the United States in 2021.2 recipients with high body weight and is also associated with delayed
Acute myeloid leukemia (AML), acute lymphocytic leukemia (ALL), engraftment, higher risk for graft failure, higher rates of infectious
myelodysplastic syndromes (MDS), and myeloproliferative neoplasms complications, and higher costs for procurement.11 Therefore, UCB
(MPN) were the most common malignancies treated with allogeneic HCT, transplantation is typically reserved for patients without an HLA-matched
while autologous HCT was used most frequently in multiple myeloma donor and should be performed in centers with expertise in this procedure.
(MM)/plasma cell disorders, non-Hodgkin lymphoma (NHL), and Hodgkin Patients without an HLA-matched donor may also be candidates for HCT
lymphoma (HL).2 Difficult logistics and high costs create significant barriers from a haploidentical, or half HLA-matched, related donor. Advantages of
to access for many patients. A systematic review found older age, lower haploidentical HCT include lower costs for procurement and rapid

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availability of the cell products, while disadvantages include increased risk the Discussion section. Recommendations for which high-level evidence is
of graft failure and GVHD as compared to HLA-matched HCT.12 The use of lacking are based on the Panel’s review of lower-level evidence and
post-transplant cyclophosphamide has been shown to reduce the expert opinion.
incidence of GVHD in haploidentical HCT recipients.13 Several
investigators have also advocated for the use of bone marrow grafts for Sensitive/Inclusive Language Usage
haploidentical HCT and HLA-mismatched unrelated donor HCT to reduce NCCN Guidelines strive to use language that advances the goals of
the risk of GVHD.9,10,14 equity, inclusion, and representation. NCCN Guidelines endeavor to use
language that is person-first; not stigmatizing; anti-racist, anti-classist,
Guidelines Update Methodology anti-misogynist, anti-ageist, anti-ableist, and anti-weight-biased; and
The complete details of the Development and Update of the NCCN inclusive of individuals of all sexual orientations and gender identities.
Guidelines are available at www.NCCN.org. NCCN Guidelines incorporate non-gendered language, instead focusing
on organ-specific recommendations. This language is both more accurate
Literature Search Criteria and more inclusive and can help fully address the needs of individuals of
all sexual orientations and gender identities. NCCN Guidelines will
Prior to the update of the NCCN Clinical Practice Guidelines in Oncology
continue to use the terms men, women, female, and male when citing
(NCCN Guidelines®) for Hematopoietic Cell Transplantation, an electronic
statistics, recommendations, or data from organizations or sources that do
search of the PubMed database was performed to obtain key literature in
not use inclusive terms. Most studies do not report how sex and gender
hematopoietic cell transplantation published since the previous Guidelines
data are collected and use these terms interchangeably or inconsistently.
update, using the following search terms: hematopoietic stem cell
If sources do not differentiate gender from sex assigned at birth or organs
transplant; allogeneic cell transplant; autologous cell transplant; and graft-
present, the information is presumed to predominantly represent cisgender
versus-host disease. The PubMed database was chosen as it remains the
individuals. NCCN encourages researchers to collect more specific data in
most widely used resource for medical literature and indexes peer-
future studies and organizations to use more inclusive and accurate
reviewed biomedical literature.15
language in their future analyses.
The search results were narrowed by selecting studies in humans
published in English. Results were confined to the following types: Clinical Autologous Hematopoietic Cell Transplant
Trial, Phase II; Clinical Trial, Phase III; Clinical Trial, Phase IV; Guideline; Autologous HCT is performed to replace or “rescue” hematopoietic cells
Practice Guideline; Meta-Analysis; Randomized Controlled Trial; damaged by the high-dose chemotherapy used to treat certain advanced
Systematic Reviews; and Validation Studies. or high-risk hematologic malignancies and solid tumors. Hematopoietic
cells collected from the patient prior to receipt of high-dose chemotherapy
The data from key PubMed articles as well as articles from additional
are infused back into the patient after administration of the preparative
sources deemed as relevant to these Guidelines as discussed by the
regimen.1 High-dose chemotherapy with autologous HCT is an effective
Panel during the Guidelines update have been included in this version of

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treatment for several hematologic malignancies, including MM,16-20 matched unrelated donors for several diseases.39,40 When a patient has no
relapsed/refractory HL,21,22 and relapsed/refractory NHL.23-25 However, HLA-matched related or unrelated donors, a haploidentical donor or UCB
while autologous HCT may prolong PFS and OS for patients with MM, it is may be used. A haploidentical donor is a first-degree relative who matches
not curative.26 Autologous HCT is also used in patients receiving high- at half of the HLA loci of the patient. Emerging data suggest that
dose chemotherapy for the treatment of certain solid tumors, including haploidentical HCT with post-transplant cyclophosphamide (PTCy) for
testicular germ cell tumors27-30 and some central nervous system tumors,31- GVHD prophylaxis may yield comparable outcomes to HLA-matched
35
for whom hematologic toxicity would otherwise limit chemotherapy HCT.41,42 Of note, a retrospective multi-center analysis found that use of
administration. Additionally, autologous HCT is sometimes used as haploidentical donors beyond first-degree relatives may negatively affect
consolidation therapy for certain patients with AML.36 survival.43 UCB transplant was first reported to cure a child with Fanconi
anemia,44 and has been subsequently used successfully in patients with
Since autologous HCT uses the patient’s own cells, these patients do not hematologic malignancies.45,46 Although the outcomes of UCB transplants
typically develop GVHD. Additionally, these patients often have a lower have been comparable to HLA-matched transplants in some reports,39,47-50
risk of infectious complications since they do not receive post-transplant delayed engraftment and delayed immune reconstitution often result in
immunosuppression. While autologous HCT is associated with less increased risks of infectious complications. Additionally, the high degree of
morbidity and mortality than allogeneic HCT, risk of disease relapse is HLA disparity that typically occurs with haploidentical or UCB donors has
often higher with autologous HCT when compared to allogeneic HCT.1 been associated with an increased risk of graft failure.39,47-51
There is no benefit of graft purging (ex vivo manipulation to eliminate
residual neoplastic cells) prior to autologous HCT. 37,38 Allogeneic HCT improves outcomes in patients with many subtypes of
AML52 and ALL,53 patients with MDS,54 patients with relapsed and/or
Allogeneic Hematopoietic Cell Transplant refractory HL55 and NHL,56 and certain patients with chronic myeloid
Allogeneic HCT is performed to replace malignant (or defective) leukemia (CML),57 such as those with advanced phase disease and those
hematopoietic cells using those from a healthy donor. A preparative whose disease is refractory to tyrosine kinase inhibitor therapy, including
regimen consisting of chemotherapy (often high-dose), immunotherapy, patients with certain high risk ABL kinase mutations. Allogeneic HCT has
and/or total body (or lymphoid) irradiation is given prior to allogeneic HCT also been offered to some patients with chronic lymphocytic leukemia
to eliminate residual malignant cells and to suppress the recipient’s (CLL),58 MM,59 and primary and secondary myelofibrosis,60 although
immune system, which is necessary to allow for engraftment of the donor- benefits for these patients are less clear and toxicity may be higher.
derived cells and to prevent graft rejection. There are three potential donor Decisions regarding allogeneic HCT are always complex and should be
sources for hematopoietic cells: related donor (family members), unrelated carefully weighed as part of shared decision-making between the
volunteers (from donor registries), and UCB units.1 HLA matching is the transplant team and patient. Donor-derived immune cells often exert an
most imperative factor when choosing a donor. An HLA-matched sibling immune-mediated cytotoxic effect against the recipient’s neoplastic cells
remains the preferred donor source, although post-transplant survival is (ie, graft-versus-tumor effect). This phenomenon was described several
comparable among patients receiving hematopoietic cells from HLA- decades ago and its clinical impact was demonstrated in a seminal

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CIBMTR study of more than 2000 patients that showed a reduced relapse transplant.72,73 Furthermore, an updated composite-age HCT-CI has also
risk among patients with GVHD.61 The graft-versus-tumor effect is been shown to have the same utility.74 Detailed clinical assessment of
considered a major mechanism for sustained response following HCT-CI has been published.75 For specific information on pre-transplant
allogeneic HCT, in particular with reduced intensity or non-MA (NMA) donor evaluation and HLA typing, refer to Foundation for the Accreditation
HCT.62,63 of Cellular Therapy and Joint Accreditation Committee- International
Society for Cell and Gene Therapy (ISCT) and European Society for Blood
Indications for Transplantation and Marrow Transplantation (EBMT) (JACIE) International Standards, 8th
Indications for HCT (allogeneic or autologous) vary by disease type and edition.76 For more information regarding pre-transplant recipient
remission status. Information on indications for HCT can be found in evaluation, see Pre-Transplant Recipient Evaluation in the algorithm.
disease-specific NCCN Guidelines, available at www.NCCN.org. The
Hematopoietic Cell Mobilization
American Society for Transplantation and Cellular Therapy (ASTCT) has
also published clinical practice guidelines on indications for autologous Granulocyte-colony stimulating factors (G-CSF), including filgrastim, tbo-
and allogeneic HCT.5 filgrastim, pegfilgrastim, and filgrastim/pegfilgrastim biosimilars, are
commonly administered in the HCT setting for mobilization of PBPCs.
Pre-Transplant Recipient Evaluation Mobilization of PBPCs by G-CSF has largely replaced use of bone marrow
The pre-transplant recipient evaluation generates data to estimate the grafts due to the ease of collection, avoidance of general anesthesia, more
risks of relapse, non-relapse mortality (NRM), and overall survival. It also rapid engraftment rates, and lower transplant-related mortality (TRM).6-8
generates information that may inform other transplant related decisions. For donor evaluation and follow-up recommendations, refer to the FACT-
Physiological age, as measured by performance/functional status and use JACIE International Standards, 8th edition
of geriatric assessments, rather than chronological age, should be used to (https://www.factglobal.org/ctstandards/).76
determine eligibility for HCT.5,64 Selected patients who are older with Hematopoietic Cell Mobilization for Autologous Donors
limited comorbidities and good functional status can safely receive HCT
with a relatively low risk of NRM.65-68 Studies such as the recently Effective mobilization regimens for autologous donors include G-CSF plus
completed BMT CTN 1704, are assessing the utility of geriatric plerixafor, G-CSF plus cyclophosphamide with or without plerixafor,
assessment tools in predicting outcome of HCT in patients who are older granulocyte-macrophage colony-stimulating factor (GM-CSF) plus
(Clinical Trial ID: NCT03992352). Determining functional status cyclophosphamide with or without plerixafor, pegfilgrastim plus plerixafor,
(Karnofsky’s or ECOG performance status) and HCT-Comorbidity Index G-CSF alone, G-CSF plus disease-specific chemotherapy with or without
(HCT-CI) score69 are essential to determine candidacy for HCT (in plerixafor, and G-CSF plus motixafortide (for patients with MM). Adequate
particular for allogeneic HCT). HCT-CI score has been validated to predict PBPC collection depends on individual patient- and disease-related
the risk of NRM and estimated survival after allogeneic transplant.70,71 factors. The minimum target yield for PBPC collection is 2 to 5 x 106
HCT-CI has also been shown to predict survival after autologous CD34+ cells/kg, with a target of 4 to 5 x 106 CD34+ cells/kg.77 Yields <2 x

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106 CD34+ cells/kg may result in delayed engraftment, while larger cell required substantially more apheresis days (12.5 vs. 4.2 days; P < .001),
doses have been associated with a more rapid time to platelet and with higher total cost ($19,614 vs. $16,852; P = .003).94 In a study of
neutrophil recovery.77 patients with MM comparing cyclophosphamide plus G-CSF to plerixafor
plus G-CSF, the cyclophosphamide group had significantly lower total
Single-agent G-CSF (filgrastim, tbo-filgrastim, or filgrastim biosimilars) is CD34+ collection yields (median 7 × 106/kg vs. 11.6 × 106/kg; P = .001)
effective in mobilizing PBPCs in the autologous setting.78-82 The addition of and higher mobilization failure rates (8.1% vs. 0), but significantly lower
the CXCR4 inhibitor plerixafor to G-CSF mobilization accelerates the rise costs ($19,626.5 vs. $28,980; P < .0001).83 Another study showed no
in PBPC count.83-91 In a phase III trial, the addition of plerixafor to G-CSF difference in mobilization efficacy between G-CSF plus cyclophosphamide
improved PBPC collection yields and reduced mobilization failure rates in and GM-CSF (sargramostim) plus cyclophosphamide in patients with
patients with heavily pre-treated NHL, with 59% of patients in the G-CSF NHL.95 Therefore, G-CSF or GM-CSF plus cyclophosphamide with or
plus plerixafor group collecting ≥5 × 106 CD34+ cells/kg in ≤4 apheresis without plerixafor are recommended regimens for PBPC mobilization in
days compared to 20% of patients in the G-CSF alone group (P < .001).89 the autologous setting. Chemomobilization regimens using other
Another phase III trial found similar results in patients with multiple chemotherapy agents with disease-specific activity are also appropriate.
myeloma, with 71.6% of patients in the plerixafor plus G-CSF group
collecting ≥6 × 106 CD34+ cells/kg in ≤2 apheresis days compared to Although there are limited high-quality data supporting the use of
34.4% of patients in the G-CSF alone group (P < .001).90 Therefore, G- pegfilgrastim in this setting, some small studies suggest that pegfilgrastim
CSF plus plerixafor as well as single-agent G-CSF are recommended for may have similar efficacy to filgrastim for mobilization.96-101 Therefore,
PBPC mobilization in the autologous setting. The addition of a novel pegfilgrastim or pegfilgrastim biosimilars plus plerixafor are also
cyclic-peptide CXCR4 inhibitor, motixafortide, to G-CSF may also improve appropriate options for mobilization in the autologous setting.
PBPC collection yields in patients with MM, with 92.5% of patients in the
motixafortide plus G-CSF group collecting ≥6 × 106 CD34+ cells/kg in ≤2 Dosing and Administration
apheresis days compared to 26.2% of patients in the G-CSF alone group The NCCN Panel recommends administration of filgrastim, tbo-filgrastim,
(P < .0001).92 Therefore, G-CSF plus motixafortide is a recommended or a filgrastim biosimilar as single agents, or as part of a
PBPC mobilization option for patients with MM in the autologous setting. chemomobilization regimen for 4 to 5 days after the completion of
cyclophosphamide (or other disease-directed therapy), at a dose of 10
The addition of chemotherapy agents such as cyclophosphamide to G-
mcg/kg body weight per day in daily or twice daily (split) dosing by
CSF may also result in higher PBPC collection yields with fewer days of
subcutaneous injection. Sargramostim should be administered at a dose
apheresis compared to G-CSF alone and may reduce the burden of
of 250 mcg/m2 per day either by intravenous infusion over 24 hours or by
residual tumor.93,94 In a trial comparing chemotherapy + G-CSF to G-CSF
subcutaneous injection once daily for 4 to 5 days. Pegfilgrastim is given as
alone, the addition of chemotherapy resulted in higher total cells collected
a single dose of 6 mg by subcutaneous injection on day 1. Apheresis
(18.6 × 106/kg vs. 7.0 × 106/kg, P < .001), fewer days of apheresis (2.0 vs.
usually commences on the fourth or fifth day following initiation of growth
2.9; P < .001), and fewer re-mobilizations (1.06 vs. 1.2; P = .01) but also
factor. Plerixafor is generally administered by subcutaneous injection 11

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hours prior to hematopoietic cell collection. Plerixafor dosing is based on sparse. Some studies have suggested that filgrastim biosimilars are
patient body weight and estimated creatinine clearance. Clinical judgment effective for mobilization in healthy donors with no short-term safety
should be used when the white blood cell count is >50,000; these patients issues,120-124 but long-term data are needed. In a study by the World
should be monitored carefully for splenic pain due to rare cases of Marrow Donor Association (WMDA), mobilization of CD34+ cells and
splenomegaly or splenic rupture. incidence of treatment-related adverse events were found to be similar
between filgrastim biosimilars and reference filgrastim in 1287 healthy
Additional Therapy volunteers,125 although the authors cite a lack of long-term follow-up for
If CD34+ cell yield is inadequate (<2 x 106 CD34+ cells/kg), consider both. Tbo-filgrastim has also been shown to effectively mobilize PBPCs for
increasing G-CSF dose or changing dose schedule. If not administered allogeneic transplantation in healthy donors.82,126,127 Based on these data,
prior to cell collection, the addition of plerixafor to G-CSF or chemotherapy the NCCN Panel endorses the use of filgrastim, tbo-filgrastim, and
plus G-CSF is also recommended. The addition of plerixafor as a filgrastim biosimilars for the mobilization of PBPCs in healthy allogeneic
preemptive (“just in time”) strategy in patients with poor mobilization after donors, but cautions physicians to closely follow patients receiving tbo-
administration of G-CSF with or without chemotherapy has been highly filgrastim or filgrastim biosimilars during the follow-up period in order to
successful.85,86,102-104 Risk factors associated with poor mobilization include identify any potential complications or unexpected outcomes. The
older age, extensive prior therapy, prior radiation to marrow-containing minimum target yield for PBPC collection in allogeneic donors is 4 to 5 x
regions, low white blood cell count (<4000), or multiple cycles of certain 106 CD34+ cells/kg.77
agents such as fludarabine or lenalidomide.87,105-114 Additional studies have
Dosing and Administration
suggested there may also be genetic parameters that contribute to
mobilization outcome.115 However, predicting mobilization failure based on Single-agent filgrastim, tbo-filgrastim, or a filgrastim biosimilar should be
baseline patient characteristics or risk factors has historically been highly administered at a dose of 10 mcg/kg per day in daily or twice daily (split)
inaccurate.87 Bone marrow harvest can also be considered in the setting of dosing by subcutaneous injection for 4 to 5 days. Apheresis usually
poor mobilization.116 For bone marrow harvest recommendations, refer to commences on the fourth or fifth day following mobilization initiation.
the National Marrow Donor Program/Be the Match. If feasible, consider
rest for 2 to 4 weeks before a remobilization attempt. Additional Therapy
If CD34+ cell yield is inadequate (<4 × 106 CD34+ cells/kg), consider
Hematopoietic Cell Mobilization for Allogeneic Donors
addition of plerixafor to G-CSF. Bone marrow harvest is an alternative
G-CSF alone should be used to mobilize allogeneic donors. Initially, there option.116 For bone marrow harvest recommendations, refer to the National
were concerns about using G-CSF for mobilization in the allogeneic Marrow Donor Program/Be the Match.
setting due to toxicity for the donor and the risk for GVHD in the recipient.
However, studies have demonstrated filgrastim to be well-tolerated by
donors without an effect on long-term survival in the recipient.117-119 Data
supporting the use of filgrastim biosimilars in the allogeneic setting are
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Principles of Conditioning for HCT derived from a single cord blood unit, has been shown to shorten the time
to engraftment and reduce the risk of some infections.131 In a phase III trial,
Conditioning regimens are categorized into three groups based on their median time to neutrophil engraftment for UCB transplantation with
intensity.128 MA regimens cause irreversible (or near irreversible)
omidubicel-onlv was 12 days compared to 22 days for standard UCB
pancytopenia. Hematopoietic cell support is required to rescue marrow transplantation (P < .001).131 Similarly, platelet recovery was shorter in the
function and prevent aplasia-related death. Regimens that include total
omidubicel-onlv arm (55% vs. 35% recovery at 42 days; P = .028). Grade
body irradiation (TBI) (≥5 Gy single dose or ≥8 Gy fractionated) or 2–3 bacterial or invasive fungal infections were also less common in the
busulfan (Bu) >8 mg/kg orally (>6.4 mg/kg IV) or Bu plasma exposure unit
omidubicel-onlv arm (37% vs. 57%; P = .027).
(BPEU) equivalent are MA regimens.129 NMA conditioning regimens
produce moderate-to-minimal cytopenia, and graft rejection, if it occurred, NMA or RIC regimens may be preferred for patients undergoing allogeneic
would be followed by autologous hematopoietic recovery. Examples HCT for treatment of lymphoma (NHL or HL), CLL and plasma cell
include TBI ≤2 Gy ± purine analog, fludarabine + cyclophosphamide ± disorders such as MM and plasma cell leukemia. NMA/RIC regimens may
antithymocyte globulin (ATG), fludarabine + cytarabine + idarubicin, also be preferred for patients who have received a prior autologous HCT
cladribine + cytarabine, and total lymphoid irradiation + ATG. A reduced- and patients who are not candidates for MA regimens. See HCT-A 3 of 9
intensity conditioning (RIC) regimen is one that does not fulfill the criteria for a non-exhaustive list of NMA regimens commonly used in allogeneic
for either an MA or NMA regimen. transplant and HCT-A 4 of 9 for a non-exhaustive list of RIC regimens
commonly used in allogeneic and UCB transplants. Conditioning regimens
The choice among an MA, NMA, or RIC regimen is a nuanced decision commonly used in autologous transplants are listed by disease type on
that should be made by the transplant team at the time of pre-transplant HCT-A 6 of 9). Suggested dose modifications by weight for many of the
recipient evaluation or upon review of pre-transplant organ testing, drugs commonly used in conditioning regimens are given in the Principles
frailty/geriatric assessment, or other evaluation. The selection of of Conditioning for Hematopoietic Cell Transplant: Suggested
conditioning regimen intensity depends on many factors including patient Doses/Modifications by Weight section of the algorithm.132
age (chronologic and physiologic),74 performance status, HCT-CI score,75
disease type, remission status (including measurable residual disease), There are certain special situations that warrant more caution. For
and history of prior HCT. In patients who are young and fit, MA regimens example, use of high-dose Bu, BCNU, or high-dose TBI in patients with
may be preferred for ALL, AML, CML, and MDS.130 See HCT-A 3 of 9 for a significant pulmonary dysfunction should be carefully considered due to
non-exhaustive list of MA regimens commonly used in autologous, the substantial additional risk to the lungs.133-135 The use of high-dose Bu
allogeneic, and UCB transplants. and high-dose TBI has been associated with an increased risk of
sinusoidal obstruction syndrome (SOS) in patients with significant liver
If UCB transplant is being used, referral to a center with experience in dysfunction.136 An increased risk of SOS has also been associated with the
UCB transplants is strongly recommended. If a myeloablative conditioning use of dual alkylator-based regimens with pre-transplant inotuzumab or
regimen is planned for a recipient of UCB, omidubicel-onlv, an ex vivo gemtuzumab.137 Additionally, the alkylating agent thiotepa can be excreted
nicotinamide modified allogeneic hematopoietic progenitor cell therapy
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through the skin and requires special skin care.138 The combination of Post-Transplant Follow-Up
sirolimus and tacrolimus may be also associated with higher risk of SOS
and thrombotic microangiopathy (TMA), especially if used with MA Advances in HCT methods and supportive care have led to improved
survival following HCT.154 However, disease relapse and post-transplant
regimens.139-142 Importantly, an increased risk of GVHD has been
associated with treatment with immune checkpoint inhibitors (pre- or post- complications continue to pose a major threat to HCT survivors. Disease
relapse is more frequent in patients with advanced disease and in those
HCT) and mogamulizumab.143-146Therefore, the panel recommends
receiving NMA conditioning regimens.155 Intensive supportive care is
considering a minimum 8- to 12-week window between these treatments
and the start of transplant conditioning if clinically feasible. required for all post-transplant recipients until engraftment occurs. Post-
transplant complications are common after both allogeneic and autologous
Conditioning Regimens Without Fludarabine HCT and are often caused by the conditioning regimen,156,157 delayed
immune reconstitution, and/or GVHD (for allogeneic HCT and very rarely
There have been intermittent shortages of fludarabine, which is a
autologous HCT). The risk and type of complications are also influenced
component of many conditioning regimens.147 To address this, the panel
by patient-related factors such as age, performance status, and
has developed recommendations for non-fludarabine RIC regimens for
comorbidities.40,158,159 Early complications (generally occurring within the
use during times of shortage (see Principles of Conditioning for
first 100 days post-HCT) include prolonged cytopenia/delayed
Hematopoietic Cell Transplant: Conditioning Regimens Without
engraftment, infections, SOS, and other organ toxicities such as
Fludarabine in the algorithm for a non-inclusive list).The panel suggests
cardiomyopathy or idiopathic pneumonia syndrome (IPS).156,160 Late
that the choice of regimen should be based on institutional preference and
complications (after the first 100 days) include infections; late radiation-
experience due to the lack of comparative data with fludarabine-based
related toxicities (eg, cataracts and hypothyroidism); late chemotherapy-
regimens.
related toxicities (eg, heart failure); organ dysfunction; secondary
Some of the regimens recommended by the panel are associated with malignancies including therapy-related myeloid neoplasms, breast and
certain adverse events. For example, a systemic inflammatory syndrome thyroid cancer, melanoma and non-melanoma skin cancers;
has been reported with the use of clofarabine-based regimens, although endocrinopathies and infertility; among others.156,160 Allogeneic HCT
concomitant steroid use may mitigate this risk.148 Additionally, use of recipients may also develop acute and/or chronic GVHD, in which the
certain cladribine-based regimens may be associated with increased risk donor lymphocytes recognize the recipient’s tissues as foreign, resulting in
of graft failure.149-151 The pentostatin + Bu + cyclophosphamide regimen immune-mediated cellular injury of several organs, such as the skin,
was reported with primary immunodeficiency disorders using post- gastrointestinal (GI) tract, and liver.
transplant cyclophosphamide152 and pentostatin + TBI 4 Gy was reported
Common causes of NRM after allogeneic HCT include GVHD, infections,
for second transplant after engraftment failure.153
cardiovascular disease, secondary malignancies, and organ toxicity.161-164
Common causes of NRM after autologous HCT include organ toxicity,
cardiovascular disease, and infectious complications.165-167 Therefore, post-

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transplant care plans, including optimal supportive and survivorship care, diagnostic, and all biopsies may help exclude other diagnostic
are essential to optimize long-term outcomes in both autologous and considerations.
allogeneic HCT recipients.
Diagnosis and Grading
Management of Graft-Versus-Host Disease If aGVHD is suspected, organ-appropriate additional tests such as stool
The development of acute and/or chronic GVHD is a common infectious disease testing, imaging studies, and/or viral testing should be
complication of allogeneic HCT and may be associated with significant performed to rule out non-GVHD causes of the symptoms. Organ-directed
morbidities and NRM in allogeneic HCT recipients.168-170 The incidence of biopsies can then be performed as clinically indicated to support the
GVHD has been increasing in recent years, primarily due to the increased presence of aGVHD or to exclude other diagnoses. GI biopsy (via
use of unrelated and/or HLA-mismatched donors and G-CSF–mobilized esophagogastroduodenoscopy [EGD], colonoscopy, and/or flexible
PBPCs, among other factors.8,171-173 Mild manifestations limited to a single sigmoidoscopy) is recommended, whenever possible, for the diagnosis of
organ are often managed with close observation, topical treatment, or by GI aGVHD, particularly if stool testing is unrevealing. Rectosigmoid
slowing the tapering of immunosuppressive agents.174 More severe biopsies were shown in one study to have higher sensitivity and negative
manifestations or multi-organ involvement typically requires systemic predictive value than biopsies at other sites, whether the patient presented
corticosteroid treatment; addition of secondary agents may be required for with diarrhea, nausea, or vomiting.177 Liver function tests (LFTs) should be
patients who do not experience response to initial steroid therapy.170 routinely monitored after allogeneic HCT for early detection of hepatic
Management of GVHD can be optimized by providing coordinated care aGVHD, which is often asymptomatic and can manifest with elevated
from a multidisciplinary team, preferably in medical centers with access to transaminases without elevated bilirubin. Liver biopsy may be considered
specialized transplant services. in patients presenting with unexplained abnormal LFTs without evidence
of aGVHD elsewhere if the information obtained would inform treatment.
Acute Graft-Versus-Host Disease Once the diagnosis of aGVHD is made, the organ staging and overall
Despite prophylaxis with immunosuppressive agents, 20% to 80% of grade of aGVHD should be determined to guide choice of therapy and
allogeneic HCT recipients develop acute graft-versus-host disease disease monitoring.
(aGVHD). Risk factors include degree of HLA-matching, donor type, and
The clinical grade of aGVHD is predictive of survival. Glucksberg aGVHD
graft source.170 The skin, GI tract (upper and lower), and liver are the three
grading criteria were first proposed in 1974.178 Modified Glucksberg
organs primarily affected by aGVHD, which is characterized by
(consensus or Keystone) criteria were developed in 1994 (see Acute
maculopapular rash, GI symptoms such as nausea, vomiting, and
GVHD: Staging and Grading in the algorithm for modified Glucksberg
diarrhea, and hyperbilirubinemia.175,176 Pathologic confirmation of aGVHD
grading criteria).168 IBMTR Severity Index was subsequently developed,179
should be considered whenever possible, especially before escalating
and was shown to be more predictive of HCT outcome when compared
systemic immunosuppression. Although skin biopsy is not absolutely
with the original Glucksberg criteria.180 Minnesota criteria have also been
sensitive or diagnostic, biopsy of the GI tract and liver are usually
devised to identify patients with “high-risk” aGVHD who could benefit from

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early escalated therapy.181,182 More recently, MAGIC (Mount Sinai Acute Grades II–IV
GVHD International Consortium) criteria were developed (see Acute
Enrollment in a well-designed clinical trial is encouraged for all patients
GVHD: Staging and Grading in the algorithm for MAGIC grading
presenting with grade II–IV aGVHD. The original immunosuppressive
criteria).183 A joint task force of the EBMT, National Institutes of Health
agent(s) should be restarted, continued, or escalated (with or without
(NIH), and CIBMTR has published a position statement on standardized
therapeutic drug monitoring) if aGVHD developed during tapering of
terminology for GVHD.184 Furthermore, blood biomarkers are being
immunosuppressive therapy. Administration of systemic corticosteroids (±
investigated for their utility as a predictive tool in aGVHD.185-188
topical steroids) is the standard first-line treatment option (unless
First-Line Therapy of aGVHD contraindicated or associated with severe intolerance) for patients with
grades II–IV aGVHD.175,176,189 A phase III randomized controlled trial
Grade I showed that initial treatment with low-dose systemic prednisone (0.5
mg/kg/day) in conjunction with GI topical steroids (beclomethasone
Grade I aGVHD affects only the skin (stage 1–2, <50% body surface area
dipropionate ± budesonide) was safe and effective for managing upper GI
[BSA] non-bullous rash), with no GI or liver involvement.168 First-line
symptoms (ie, nausea, vomiting, anorexia) in patients with grade II
therapy options for these patients include continuing (or restarting) the
aGVHD, with or without skin involvement (<50% BSA), with diarrhea
original immunosuppressive agent(s) and administering topical steroids
volumes <1000 mL/day.189 Of note, budesonide alone is less effective at
(eg, triamcinolone, clobetasol) and/or topical tacrolimus. Medium- to high-
treating the upper GI tract. In patients with higher grade aGVHD, use of
potency topical steroid formulations are recommended, except on the face
low-dose prednisone was associated with an increased risk of requiring
or intertriginous areas where low-potency hydrocortisone is to be used (to
secondary immunosuppressive therapy, but with no difference in survival.
avoid skin atrophy, telangiectasia, and acneiform eruptions).
Thus, patients with grade II aGVHD may be treated with 0.5–1 mg/kg/day
Antihistamines may be used for symptomatic relief of itching as needed.
of methylprednisone (or prednisone dose equivalent). Patients with higher
Alternatively, the patient can be observed without treatment if the rash is
grade aGVHD should be treated with higher doses of systemic steroids
asymptomatic and stable. If there is a response to first-line therapy, as
(1–2 mg/kg/day methylprednisolone or prednisone dose equivalent). There
indicated by a resolution of the rash and associated symptoms, the
is no role for escalation of methylprednisolone above 2 mg/kg/day.190 The
immunosuppressive agent(s) should be tapered as clinically feasible and
addition of other systemic agents in conjunction with systemic
topical steroids can be discontinued. Options for patients with no response
corticosteroids as first-line therapy for aGVHD should only be done in the
to first-line therapy include enrollment in a well-designed clinical trial or
context of a well-designed clinical trial. Patients on high-dose steroids
continuing topical steroids. Patients with progression and/or symptomatic
require significant supportive care (see Supportive Care for All Patients
rash (eg, pruritus, pain, sloughing, increasing BSA involvement) should be
with GVHD).
treated according to the recommendations for grade II–IV aGVHD.
The randomized phase II BMT CTN 1501 trial compared sirolimus to
prednisone as initial treatment in 122 patients with standard-risk aGVHD
as defined by the Minnesota GVHD Risk Score and Ann Arbor (AA1/2)
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biomarker status.191 At day 28, the overall response rate (ORR) for If there is a response to first-line therapy, as indicated by a complete
sirolimus and prednisone was similar (65% vs. 73%) and there were no resolution of GVHD or improvement in at least one organ without any
differences in steroid-refractory aGVHD, disease-free survival, relapse, progression in any other organs, the steroids should be tapered as
NRM, or overall survival (OS). Patients in the sirolimus group encountered clinically feasible. Options for patients with no response to first-line therapy
less hyperglycemia and had reduced risk of infections but were at an include enrollment in a well-designed clinical trial194 or the addition of other
increased risk for TMA as compared to patients in the prednisone group systemic agent(s) to the corticosteroids, with steroid taper as clinically
(10% vs. 1.6%). Thus, sirolimus can be considered as an alternative to feasible. See Suggested Agents for Steroid-Refractory aGVHD below for
systemic corticosteroids as first-line therapy for patients with standard risk more information.
aGVHD, as defined by clinical risk score and biomarker status.
Chronic Graft-Versus-Host Disease
Alternative regimens have been investigated as first-line therapy for cGVHD is the leading cause of NRM after allogeneic HCT and has a
aGVHD. BMT CTN 0302 was a randomized 4-arm phase II clinical trial (n profound impact on quality of life.164,195 cGVHD usually develops within the
= 180) that compared different agents (etanercept, mycophenolate mofetil first year after HCT in most patients, but it can also develop many years
[MMF], denileukin diftitox, and pentostatin) in combination with later.170 cGVHD affects multiple organ systems and is characterized by
methylprednisolone at 2 mg/kg per day (or prednisone dose equivalent) for fibrosis and variable clinical features resembling autoimmune disorders.196
treatment of newly diagnosed aGVHD.192 The day 28 ORRs were The NIH Consensus Development Project has published detailed
etanercept 26%, MMF 60%, denileukin diftitox 53%, and pentostatin 38%. recommendations for the management of cGVHD including diagnosis,
The corresponding 9-month OS rates were 47%, 64%, 49%, and 47%, assessment of organ involvement, monitoring response to treatment, and
respectively. Risk of severe infections were etanercept 48%, MMF 44%, supportive care interventions.174,197-200 A thorough understanding of the
denileukin 62%, and pentostatin 57%. These results suggested that MMF various clinical manifestations of cGVHD is essential for the early
plus corticosteroids would be a potentially promising regimen for initial recognition of signs and symptoms. Multidisciplinary care aimed at
therapy of aGVHD. Accordingly, a phase III multicenter double-blinded avoiding organ damage and preserving function is strongly recommended.
clinical trial (BMT CTN 0802) was initiated comparing the combination of
methylprednisolone at 1.6 mg/kg per day (or prednisone dose equivalent) Diagnosis and Grading
plus MMF versus methylprednisolone plus placebo as first-line therapy for
In all cases of suspected cGVHD, additional tests are often performed to
aGVHD.193 A futility rule for GVHD-free survival at day 56 was met at a
rule out non-GVHD causes of the symptoms, such as infection, drug-
planned interim analysis after 235 patients (of 372) were enrolled.
induced injury or toxicity, malignancy, or other causes. While a biopsy may
Outcomes of both arms were equivalent in OS, 1-year incidence of
be done to confirm the presence of cGVHD, this is not always feasible and
cGVHD, and infection risk. Therefore, MMF provided no benefit when
is not mandatory if the patient has at least one of the diagnostic findings of
added to corticosteroids as first-line therapy for aGVHD.
cGVHD defined by the NIH Consensus Development Project (see GVHD-
B in the algorithm for diagnostic signs and symptoms of cGVHD).174
Manifestations of cGVHD include bronchiolitis obliterans syndrome (BOS),
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an inflammatory lung condition. Unless it is pathologically diagnosed (via If there is a response to first-line therapy according to the NIH Response
lung biopsy), clinical characteristics of BOS (assessed by pulmonary Criteria,184 steroids should be tapered as clinically feasible to mitigate long-
function tests [PFTs]) are only diagnostic of lung cGVHD if distinctive term side effects and risk of infection. Options for patients with no
features of cGVHD are present in another organ (see GVHD-B 2 of 3 in response to first-line therapy include enrollment in a well-designed clinical
the algorithm for the complete criteria required for diagnosis of BOS). trial194 or the addition of other systemic agent(s) to the corticosteroids, with
cGVHD grading is done according to the NIH Consensus Development steroid taper as clinically feasible. See Suggested Agents for Steroid-
Project criteria (see Chronic GVHD: Grading in the algorithm).174 A Refractory cGVHD below for more information. Supportive care
predictive score including day +100 levels of gamma-glutamyl transferase interventions for controlling organ-specific symptoms or complications
(GGT), creatinine, cholinesterase, and albumin is being investigated for its should be an integral part in the long-term management of patients with
utility as a predictive tool for cGVHD, though it requires further cGVHD.198
validation.201
Steroid-Refractory GVHD
First-Line Therapy of cGVHD Approximately 40% to 50% of patients with acute or chronic GVHD
Enrollment in a well-designed clinical trial is encouraged for all patients present with steroid-refractory disease, which is associated with high
presenting with cGVHD. Options for first-line therapy include restarting, mortality.175,204 The NIH has defined criteria for steroid-refractory acute and
continuing, or escalating the original immunosuppressive agent(s) and/or chronic GVHD (see GVHD Steroid Response Definitions/Criteria in the
administration of systemic corticosteroids (0.5–1 mg/kg/day algorithm).184 Enrollment in a well-designed clinical trial is strongly
methylprednisolone or prednisone dose equivalent). The initial encouraged for these patients. The selection of therapy for steroid-
corticosteroid dose may vary depending on the organs involved, the refractory GVHD should be based on institutional preferences, physician
severity of GVHD, and patient comorbidities. Topical steroids, such as experience, the agent’s toxicity profile, the effects of prior treatments, drug
triamcinolone or clobetasol, topical estrogen (for vulvovaginal cGVHD), interactions, convenience/accessibility, and patient tolerability. Agent
topical tacrolimus, or dexamethasone oral rinse (for oral cGVHD) may be selection may also depend on organ involvement and overall grade of
used as clinically indicated. Patients with lung involvement should receive cGVHD.
inhaled steroids (eg, budesonide or fluticasone) ± montelukast ±
Suggested Agents for Steroid-Refractory aGVHD
azithromycin (eg, FAM [fluticasone, azithromycin, and montelukast]).
Azithromycin should be used only for the treatment of BOS and not for The following systemic agents, listed in alphabetical order (except for the
BOS prophylaxis due to data suggesting increased risks for leukemic category 1 recommendation), can be used in conjunction with the original
relapse and secondary neoplasms in patients undergoing HCT receiving immunosuppressive agent(s) and corticosteroids (typical first-line therapy)
azithromycin for BOS prophylaxis.202,203 Patients with progressive or for steroid-refractory aGVHD. Slow taper of systemic corticosteroids is
worsening lung cGVHD following two to three lines of therapy may be recommended if deemed ineffective therapy. In patients with steroid-
evaluated for lung transplant. dependent disease, corticosteroid therapy may be continued until an
alternative steroid-sparing agent induces a response. The following are
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the most commonly used agents among NCCN Member Institutions. GVHD prophylaxis.209,210 The safety and efficacy of alemtuzumab for the
Currently, ruxolitinib is the only therapy approved by the U.S. Food and treatment of steroid-refractory aGVHD was evaluated in a prospective
Drug Administration (FDA) for treatment of steroid-refractory aGVHD.205 clinical study of 18 patients with grade II–IV steroid-refractory aGVHD
treated subcutaneously with 10 mg alemtuzumab daily for 5 consecutive
Ruxolitinib days.211 The ORR to alemtuzumab was 83%, with 33% of patients
Ruxolitinib is a selective inhibitor of JAK1 and JAK2, which are intracellular achieving CR. Importantly, univariate analyses of clinical characteristics
tyrosine kinases that play critical roles in cytokine signaling as well as the between those who experienced response and those who did not
development and function of several types of immune cells.206 In 2019, the experience response showed no differences in the main organ involved,
FDA approved ruxolitinib for the treatment of steroid-refractory aGVHD in grade of GVHD, or time between HCT and GVHD onset. After a median
adult and pediatric patients aged ≥12 years based on data from the single- follow-up of 9 months, 78% of patients had one or more infectious
arm phase II REACH1 trial in which 71 patients with grade II–IV steroid- episodes. In a retrospective analysis of 20 patients with steroid-refractory
refractory aGVHD were treated with 5 mg ruxolitinib twice daily with an grade III–IV aGVHD receiving 10 mg of intravenous alemtuzumab weekly,
optional increase to 10 mg.205,207 The ORR at day 28 was 55%, with 27% of the ORR was 70% with a CR of 35%.212 One-year OS was 50%. Although
patients achieving a complete response (CR). Responses were seen infectious complications were common, infection was not a significant
across the skin (61%), GI tract (46%), and liver (27%). The randomized predictor of survival in this study. These data suggest that alemtuzumab
phase III REACH2 trial compared ruxolitinib (10 mg twice daily) to has favorable activity in the treatment of steroid-refractory aGVHD and
investigator’s choice of regimen in 309 patients with steroid-refractory emphasizes the need for anti-infective prophylaxis and close monitoring
aGVHD.208 The ORR at day 28 was significantly higher in the ruxolitinib for patients receiving this therapy. Currently in the United States,
group compared to the control group (62% vs. 39%; P < .001). Similar alemtuzumab is only available via the Campath Distribution Program and
results were observed for the durable ORRs at day 56 (40% vs. 22%; P = drug supply is patient-specific.
.001). Median failure-free survival and median OS were substantially
Alpha-1 Antitrypsin
longer with ruxolitinib than with control (5 vs. 1 month; hazard ratio [HR],
0.46 and 11 vs. 6.5 months; HR, 0.83). The most common adverse events Alpha-1 antitrypsin (AAT) (also known as alpha-1 proteinase inhibitor) is a
in the ruxolitinib group were thrombocytopenia (33%), anemia (30%), and circulating protease inhibitor that inactivates serine proteases from
cytomegalovirus infection (26%). Based on these data, ruxolitinib is a neutrophils and macrophages to protect tissues from proteolytic
category 1 recommended option for patients with steroid-refractory degradation.213 AAT is most commonly used to treat patients with AAT
aGVHD. deficiency, an inherited condition that causes lung and liver damage.214
The safety and efficacy of AAT to treat steroid-refractory aGVHD was
Alemtuzumab evaluated in a prospective, multicenter phase II trial of 40 patients treated
Alemtuzumab is a humanized anti-CD52 monoclonal antibody that has with intravenous AAT twice weekly for up to 4 weeks at a dose of 60
been successfully used as part of a pre-transplant preparative regimen for mg/kg/day.213 The ORR and CR rate at 28 days were 65% and 35%,
respectively. After 60 days, responses were maintained in 73% of patients.
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OS at 6 months was 45% and did not differ by grade or site of organ in the aforementioned study, skin aGVHD was more responsive (96% of
involvement. Infectious mortality was 10% at 6 months. No infusion patients) than GI (46%) or liver aGVHD (36%). Common adverse events
reactions or drug-related grade 3–4 toxicities were reported. These data included hepatic dysfunction (25%), viral infections (26%), fungal
suggest that AAT is an effective treatment option for patients with steroid- infections (32%), and bacteremia (21%). Of the 36 original patients
refractory aGVHD. enrolled in the study, only 2 (6%) were alive 34 months post-HCT. A more
recent retrospective analysis of 11 patients with steroid-refractory aGVHD
Anti-Thymocyte Globulin reported an ORR of 55% for rabbit ATG administered at a median dose of
Anti-thymocyte globulin is a T-cell–depleting antibody that has been 3 mg/kg/day, and a median of 2 doses (range105).227 In this study, high
commonly used for immunosuppression in the solid organ transplant response rates were observed in patients with skin (100%) and GI (83%)
setting and for GVHD prophylaxis.215-222 Two non-interchangeable ATG aGVHD as compared to those with liver aGVHD (25%). One-year OS and
products are currently approved by the FDA: anti-thymocyte globulin TRM were 55% and 45%, respectively. These data suggest that ATG may
(rabbit), a polyclonal immunoglobulin G (IgG) derived from rabbits, and be an effective treatment option for patients with steroid-refractory
anti-thymocyte globulin (equine), a polyclonal IgG derived from aGVHD, especially for those with skin involvement. However, long-term
horses.223,224 An early retrospective study analyzed the clinical response survival appears to be low, even in those who experience response.226 A
and survival outcomes of 79 patients with steroid-refractory aGVHD comprehensive review on the use of ATG for GVHD treatment has been
treated with 1 to 5 courses of equine ATG at a dose of 15 mg/kg/day twice published.228
daily for 5 days.225 At day 28 of treatment, the ORR was 54% with 20% of
Basiliximab
patients achieving a durable CR. Response to ATG was not associated
with the initial grade of GVHD; however, it was associated with the site of Basiliximab is a chimeric monoclonal antibody that functions as an
GVHD. Patients with skin aGVHD were more likely to experience immunosuppressive agent by binding to and blocking the interleukin-2 (IL-
response to ATG. Of the 64 patients with skin involvement, 61% achieved 2) receptor.229 IL-2 plays a key role in the development of aGVHD by
a CR or partial response compared to 27% without skin involvement (P = stimulating the activation of donor T cells in the graft, which can attack the
.02). The probability of survival at 1 year for all patients was 32% (95% CI, cells and tissues of the recipient.230 The efficacy and feasibility of
22%–42%). Bacterial, viral, and fungal infections occurred in 37%, 10%, basiliximab for the treatment of steroid-refractory aGVHD was evaluated in
and 18% of patients, respectively. Another early retrospective study a prospective phase II trial of 23 patients treated with intravenous
analyzed the efficacy of rabbit ATG in 36 patients with steroid-refractory basiliximab at a dose of 20 mg on days 1 and 4.230 The ORR was 83% with
GVHD treated at a single institution.226 Patients, most of whom (89%) had 18% of patients achieving a CR. The percentage of patients achieving a
grade III–IV aGVHD, received rabbit ATG at 2.5 mg/kg/day for either 4 to 6 minimum one-grade reduction in aGVHD varied with organ involvement
consecutive days (group 1; n = 13) or on days 1, 3, 5, and 7 (group 2; n = (77% of patients with skin GVHD, 14% of patients with liver involvement,
21). The ORR was 59%, with a CR rate of 38%. The response rate was and 67% of patients with GI involvement). While administration of
higher in patients in group 1 (77%) compared to patients in group 2 (48%); basiliximab did not cause any infusion-related toxicity, infections occurred
however, this difference was not statistically significant (P = .15). As seen in 65% of patients. The rates of malignancy recurrence and 1-year
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treatment-related mortality were 10% and 45%, respectively, following proinflammatory cytokine that acts as the master regulator of immune
immunosuppression with basiliximab. Therefore, basiliximab appears to response and is a major mediator in the pathogenesis of aGVHD.243 The
have some activity in the treatment of steroid-refractory aGVHD. efficacy of etanercept for the treatment of steroid-refractory aGVHD was
retrospectively evaluated in a cohort of 13 patients.244 Etanercept at 25 mg
Calcineurin Inhibitors was given subcutaneously twice weekly for 4 weeks followed by 25 mg
Calcineurin inhibitors (CNI), such as tacrolimus and cyclosporine, are weekly for 4 weeks. The ORR was 46%, with 4 patients achieving CR.
immunosuppressive agents that inhibit the action of calcineurin, an Responses correlated with the overall grade of aGVHD, with patients with
enzyme involved in the activation of T cells. CNI are commonly used for grade II aGVHD showing higher response rates than those with grades III–
the prevention and initial treatment of GVHD, often in conjunction with IV aGVHD, and were most commonly observed in patients with GI
other agents.142,231-239 However, limited data exist for their use in the involvement (64% of clinical responses). No immediate treatment-related
treatment of steroid-refractory aGVHD. In a small phase II trial, 18 patients side effects were observed; however, bacterial and fungal infections
with aGVHD that developed or progressed during therapy with occurred in 14% and 19% of patients, respectively. At a median follow-up
cyclosporine and/or other immunosuppressive agents were treated with of 429 days, OS was 67%. These results suggest that etanercept has
tacrolimus at an initial dose of 0.05 mg/kg intravenously or 0.15 mg/kg favorable activity in steroid-refractory aGVHD.
orally twice daily (targe trough 15-25 ng/mL).240 In the 13 patients with
Extracorporeal Photopheresis
evaluable data, the ORR was 54%. The most common adverse events
were renal toxicity (53% of patients), followed by nausea and vomiting Extracorporeal photopheresis (ECP) is a form of immunotherapy that
(31%). A retrospective analysis involving 42 patients with steroid-refractory involves ex vivo exposure of mononuclear cells obtained by apheresis to
aGVHD treated with tacrolimus (target concentration 4-8 ng/mL) in the photosensitizing agent 8-methoxypsoralen and ultraviolet A (UVA)
combination with sirolimus reported an ORR of 49% (CR rate = 42%) for light, followed by reinfusion of the cells back into the patient.245 The clinical
patients treated in the second-line (n = 31) and an ORR of 27% (CR = 0) activity of ECP is thought to be mediated by the immunomodulatory effects
for patients treated in the third-line (n = 11).241 One-year OS was 42% in of UV light.246 The exact mechanism by which ECP ameliorates GVHD
patients treated in the second-line and 0% in patients treated in the third- (acute or chronic) is unclear, but may involve the normalization of
line. Infectious complications occurred in 90% of patients. Therefore, CNI CD4+/CD8+ lymphocyte populations, an increase in the number of CD3-
may be a reasonable option for the treatment of patients with steroid- /CD56+ natural killer (NK) cells, and/or a decrease in circulating dendritic
refractory aGVHD, including when they have not been used in prophylaxis cells.245,247
or initial therapy.
A phase II trial in patients with grade II–IV steroid-refractory aGVHD found
Etanercept that weekly ECP therapy resulted in complete resolution of aGVHD
symptoms in 82% of patients with skin involvement and 61% of patients
Etanercept is a recombinant tumor necrosis factor-alpha (TNF-α) receptor
with liver or GI involvement.248 In a prospective single-center study
fusion protein.242 Etanercept acts by inhibiting the activity of TNF-α, a
involving 21 patients with grade III–IV aGVHD, second- or third-line
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treatment with ECP resulted in an ORR of 84%.249 After a median follow- complications.253 These data suggest that infliximab is active in the
up of 17 months, 1-year OS was 53% and was independently associated treatment of steroid-refractory aGVHD; however, the potential for
with a higher number of ECP sessions. A systematic review of prospective excessive infections should be evaluated.
studies reported a pooled ORR of 69% for ECP in the treatment of steroid-
refractory aGVHD.245 The ORR for skin manifestations was highest at mTOR Inhibitors
84%, followed by 65% for GI involvement. Reported rates of ECP-related Sirolimus (rapamycin) is a macrolide compound derived from the bacteria
mortality were extremely low. Another systematic review largely reached Streptomyces hygroscopicus that possesses immunosuppressive,
the same conclusions, reporting a pooled ORR of 71% and ORRs of 86%, antibiotic, and antitumor properties. Sirolimus functions as a potent
60%, and 68% for skin, liver, and GI involvement, respectively.250 These immunosuppressant by inhibiting the activity of mTOR, a serine/threonine
data suggest that ECP is an effective therapy for steroid-refractory kinase that acts as a master regulator of cell growth, proliferation,
aGVHD, especially for patients with skin involvement. If ECP is not metabolism, and survival.254,255 By inhibiting mTOR, sirolimus disrupts the
available or feasible, the NCCN Panel recommends the use of psoralen cytokine signaling that promotes the growth and differentiation of T cells.256
plus UVA (PUVA) irradiation as an alternative treatment option for sclerotic Sirolimus is also used for GVHD prophylaxis, often in conjunction with the
or cutaneous steroid-refractory GVHD. CNI tacrolimus.142,236,237,257-260 The safety and efficacy of sirolimus in the
treatment of steroid-refractory aGVHD was evaluated in a phase I trial
Infliximab
involving 21 patients with grade III–IV steroid-refractory aGVHD.261 The
Infliximab is a genetically constructed immunoglobulin G1 (IgG1) chimeric ORR was 57%, with a CR rate of 24%. However, only 11 patients
monoclonal antibody that binds to membrane-bound TNF-α, blocking its completed the full course of treatment due primarily to extensive toxicities
activity and triggering lysis of TNF-α–producing cells.243,251 In a including cytopenias, hyperlipidemia, severe TMA, and renal failure. In a
retrospective evaluation of 21 patients with steroid-refractory aGVHD who retrospective analysis of 31 patients with steroid-refractory aGVHD treated
had received treatment with single-agent infliximab (10 mg/kg once weekly with sirolimus (target therapeutic range 4-12 ng/mL) in combination with
for at least 4 doses), the ORR was 67%, with 62% of patients achieving tacrolimus, the ORR was 76% and 42% of patients achieved CR.262
CR.243 No toxic reactions to infliximab were observed; however, bacterial, Median OS was 5.6 months and 1-year OS was 44%. TMA and
fungal, and viral infections occurred in 81%, 48%, and 67% of patients, hyperlipidemia occurred in 21% and 44% of patients, respectively, but
respectively. OS was 38% at a median follow-up of 21 months. Another were manageable. Another retrospective study involving 22 patients with
retrospective analysis of 32 patients with steroid-refractory aGVHD treated steroid-refractory aGVHD treated with sirolimus (target therapeutic range
with infliximab administered intravenously at the dose of 10 mg/kg once 7-13 ng/mL) reported similar results.263 The ORR was 72% and OS was
weekly for a median of three courses reported an ORR of 59%.252 41% after a median follow-up of 13 months. TMA occurred in 36% of
Infections developed in 72% of patients. A third, more recent retrospective patients when sirolimus was combined with tacrolimus or other CNI. A
analysis involving 35 patients with steroid-refractory aGVHD reported an third, more recent retrospective analysis involving 42 patients with steroid-
ORR of 40% for infliximab administered intravenously at 10 mg/kg weekly refractory aGVHD treated with sirolimus (target concentration 4-8 ng/mL)
for a median of four doses, with 83% of patients developing infectious and tacrolimus reported an ORR of 48.5% (CR rate = 42%) for patients
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treated in the second-line (n = 31) and an ORR of 27% for patients treated with lower grade GVHD (40% for grades I–II vs. 8% for grades III–IV).
in the third-line (n = 11).241 For patients treated in the second-line, 1-year These data suggest that MMF has some efficacy for treating steroid-
OS was 42% (0% for patients treated in the third-line). Infectious refractory aGVHD, especially in those with lower grade GVHD at the start
complications were common (90% of patients). These data suggest that of treatment.
sirolimus is an effective option for the treatment of patients with steroid-
refractory aGVHD, but may result in significant toxicities. Pentostatin
Pentostatin is a purine analogue that acts as an immunosuppressant by
Mycophenolate Mofetil
inducing lymphocyte apoptosis through inhibition of adenosine
MMF is a prodrug of mycophenolic acid (MPA) that acts as an deaminase.269 A large retrospective analysis of 60 patients treated with
immunosuppressant by inducing apoptosis in lymphocytes through pentostatin for steroid-refractory aGVHD reported an ORR of 33% and a
inhibition of the de novo synthesis of purines.264 MMF is indicated for the CR rate of 18%.270 All patients received pentostatin at a dose of 1.5 mg/m2
prevention of organ rejection in solid organ transplants and is a standard on days 1 to 3, repeated every 2 weeks, for a median of three courses. OS
component of GVHD prophylaxis regimens.265 In a prospective phase II at 18 months was 21% and NRM was 72%. Stratified analysis revealed
trial completed in the mid-1990s, Furlong et al reported an ORR of 47% that patients <60 years of age with isolated lower GI GVHD had the best
and a CR rate of 31% in 19 patients with steroid-refractory aGVHD treated outcomes with an ORR of 48% and 18-month OS of 42%. An earlier
with MMF at an initial dose of 1 g twice daily for 35 days.266 OS at 6 and 12 retrospective study reported similar results, with an ORR of 38% and 2-
months was 37% and 16%, respectively. MMF treatment was discontinued year OS of 17% in 24 patients treated with pentostatin at a daily dose of 1
in 4 patients because of toxicities including neutropenia, abdominal pain, mg/m2 given intravenously on 3 consecutive days.271 A smaller
and pulmonary infiltrate. The same group conducted a retrospective retrospective analysis of 12 patients reported a higher ORR of 50% and a
analysis of more recent patients with steroid-refractory aGVHD (n = 29) CR rate of 33%.272 Discrepancies in the results of these studies may be
and found a similar ORR to MMF therapy (48%).266 However, OS at 6 and attributed to variability in the patient populations, pentostatin doses and
12 months was much higher (55% and 52%, respectively). Possible number of treatment cycles, use of additional therapies, or the assessment
explanations for the improved OS may include improved management of of treatment response.270
GVHD and longer experience with the use of MMF. In another
retrospective analysis of 13 patients with steroid-refractory aGVHD, the A phase I dose-escalation study involving 22 patients with steroid-
ORR to MMF (1.5 or 2 g daily) was 31% and the estimated 2-year OS rate refractory aGVHD reported a high CR rate of 63%.273 However, late
was 33%.267 Responses were observed in 31% of cases with skin infections observed at the 2 mg/m2/day dose used in the study were
involvement, 44% of cases with liver involvement, and 23% of cases with considered to be dose-limiting toxicities. In a follow-up phase II study of
GI involvement. Another retrospective study reported a 3-year OS rate of eight patients receiving a lower dose of 1.5 mg/m2/day of pentostatin, four
40% and a CR rate of 26% in 27 patients with steroid-refractory aGVHD patients died from progressive hepatic GVHD and three patients died from
treated with MMF at a dose of 1–1.5 g twice daily orally or intravenously.268 sepsis secondary to infections, pancytopenia, progressive hepatic GVHD,
The CR rates observed with MMF therapy were typically higher in patients and/or acute renal failure.274 Two patients with renal insufficiency
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demonstrated excessive pentostatin exposure, as determined by previous studies. Patients with skin and/or GI involvement had the
measurement of the area under the curve (AUC), despite a 50% reduction greatest response, while those with liver involvement demonstrated no
in pentostatin dose. Although this trial was terminated before efficacy response. Another retrospective study conducted at a different institution
could be assessed, the data suggest that pentostatin is ineffective in reported a CR rate of 63% to tocilizumab (8 mg/kg given every 2 weeks) in
treating liver manifestations of GVHD and may be inappropriate for 16 patients with steroid-refractory aGVHD of the lower GI tract.278 These
patients with renal insufficiency. The limited available data suggest activity data suggest that tocilizumab has activity in the treatment of patients with
for pentostatin in the treatment of steroid-refractory aGVHD without liver steroid-refractory aGVHD, especially in patients with skin or GI
involvement; however, serious adverse events have been reported. The involvement. An FDA-approved biosimilar is an appropriate substitute for
renal function of patients receiving pentostatin should be monitored tocilizumab.
throughout the course of treatment.
Vedolizumab
Tocilizumab
Vedolizumab is a monoclonal antibody that is currently FDA approved for
Tocilizumab is a humanized anti-IL-6 receptor antibody that functions as the treatment of moderate to severe inflammatory bowel disease.283
an immunosuppressive agent by blocking IL-6 signaling.275 IL-6 is a pro- Vedolizumab inhibits trafficking of T-cells to the GI mucosa by blocking the
inflammatory cytokine produced by a variety of cell types that plays a key activation of α4β7 integrin, a process involved in the pathogenesis of GI
role in the development of aGVHD. Elevations of IL-6 have been detected aGVHD.284-286
in the serum of patients with GVHD, and polymorphisms that result in
increased IL-6 production have been associated with an increase in GVHD Several studies have investigated the safety and efficacy of vedolizumab
severity.276,277 The efficacy of tocilizumab for the treatment of steroid- for steroid-refractory GI aGVHD.284-286 In a small retrospective study that
refractory aGVHD was evaluated in several studies.278-282 A small study of analyzed the outcomes of 29 patients, the ORR following vedolizumab
eight patients (6 patients had aGVHD, the majority of whom had grade IV) was 79%, with a CR rate of 29% and a PR rate of 52%.285 ORR was 100%
showed an ORR of 67%, with a CR rate of 33%.282 Tocilizumab was when vedolizumab was given as a second-line agent, compared to 63%
administered intravenously at a dose of 8 mg/kg once every 3 to 4 when given as third-line or later (P = .012) When given early, vedolizumab
weeks. The most common adverse event in this study was infectious was also associated with a greater likelihood of coming off of
complications (69% were bacterial in origin). A retrospective study of nine immunosuppression (69% vs. 19%; P = .007) as well as fewer fatal
patients with grade III–IV steroid-refractory aGVHD treated with the same infections (38% vs. 88%; P = .0006) In another small retrospective study
dose and schedule of tocilizumab reported a lower ORR of 44% and a CR analyzing the outcomes of 29 patients with steroid refractory GI aGVHD,
rate of 22%.281 Another retrospective analysis of 15 patients conducted at ORR was 64% at 6 to 10 weeks following vedolizumab administration.286
the same institution reported improved results with the use of tocilizumab At 6 months, OS was 54%. There were 29 serious adverse events (SAEs),
for steroid-refractory aGVHD, with a CR rate of 40%.280 In this study, the 12 of which were infectious in nature (3 possibly related to vedolizumab)
patients received tocilizumab every 2 to 3 weeks (majority received and 13 of which were fatal (1 possibly related to vedolizumab). In a more
tocilizumab every 2 weeks), compared to every 3 to 4 weeks as in the recent meta-analysis, the use of vedolizumab for GI aGVHD was
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associated with significantly improved pooled ORR at 14 days (60.53%), cGVHD were 25 months and 5.6 months, respectively. The most common
28 days (50%), and 12 months (76.92%).284 While improvement in CR grade 3 or higher adverse events were thrombocytopenia (15% in the
rates at 14 and 28 days were not significant, improvement at 12 months ruxolitinib group and 10% in the control group) and anemia (13% and 8%,
was significant (pooled CR, 27.27%). respectively). Based on these data and the FDA approval, ruxolitinib is a
category 1 recommended option for patients with steroid-refractory
Suggested Agents for Steroid-Refractory cGVHD cGVHD.
The following systemic agents, listed in alphabetical order (except for the
category 1 recommendation and FDA approved recommendations), can Ibrutinib
be used in conjunction with corticosteroids for steroid-refractory cGVHD. Ibrutinib is a potent and irreversible inhibitor of Bruton’s tyrosine kinase
Although prolonged systemic corticosteroid therapy is better avoided, (BTK), which regulates B-cell survival.287 It also inhibits IL-2–inducible T-
some patients may require prolonged steroid therapy (preferably using cell kinase (ITK), which is involved in the selective activation of T-cell
≤0.5 mg/kg/day) for steroid-dependent cGVHD. The following are the most subsets.291 In 2017, ibrutinib was approved by the FDA for the treatment of
commonly used agents among NCCN Member Institutions. Currently, adult patients with cGVHD after failure of one or more lines of systemic
ruxolitinib, ibrutinib, and belumosudil are the only FDA-approved agents therapy and in 2022 was approved for pediatric patients ≥1 year of age
for treatment of steroid-refractory cGVHD.287-289 While the following agents with the same indication.292, 2022 #624 The initial approval in adults was based
may be used in any site, some agents are more commonly used with on data from a single-arm multicenter trial that included 42 patients with
particular organ involvement. steroid-refractory cGVHD.287 Patients received 420 mg ibrutinib daily until
cGVHD progression. The majority of patients (88%) had at least two
Ruxolitinib organs involved at baseline, the most common being mouth (86%), skin
In 2021, the FDA approved ruxolitinib for the treatment of steroid- (81%), and GI tract (33%). At a median follow-up of 14 months, the ORR
refractory cGVHD after failure or one or two lines of systemic therapy in was 67% and the most commonly reported adverse events were fatigue,
adult and pediatric patients aged ≥12 years.290 The approval was based on bleeding/bruising, diarrhea, muscle spasms, nausea, thrombocytopenia,
data from the randomized phase III REACH3 trial, which compared and anemia. After a median follow-up of 26 months, the ORR was 69%,
ruxolitinib (10 mg twice daily) to investigator’s choice of best available with 31% of patients achieving a CR.293 Sustained responses of ≥44 weeks
therapy in 329 patients with steroid-refractory or steroid-dependent were seen in 55% of the those who experienced response. Of the patients
cGVHD.288 At week 24, the ORR was higher in patients in the ruxolitinib with multiorgan involvement, 73% of those with ≥2 organs involved
group compared to those in the control group (50% vs. 26%; P < .001). showed responses in ≥2 organs and 60% of those with ≥3 organs involved
Ruxolitinib also led to longer median failure-free survival (>19 vs. 6 showed responses in ≥3 organs. Corticosteroid dose was reduced to
months; HR = .37; P < .001) and higher symptom response (24% vs. 11%; <0.15 mg/kg/day in 64% of patients and was completely discontinued in
P = .001) than control. The median durations of response were 4.2 months 19% of patients. The most common grade 3 adverse events were
and 2.1 months for the ruxolitinib and control arms, respectively. The pneumonia, fatigue, and diarrhea. These data suggest that ibrutinib is
median times from first response to death or new systemic therapies for effective and may produce durable responses in patients with steroid-
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refractory cGVHD. However, ibrutinib should be used with caution in based on data from the randomized, multicenter phase II AGAVE-201
patients with a history of heart arrhythmias, due to a heightened risk of study, which investigated the efficacy and safety of 3 different doses (0.3
atrial fibrillation, and in patients on anticoagulation or antiplatelet therapy, mg/kg every 2 weeks, 1 mg/kg every 2 weeks, or 3 mg/kg every 3 weeks)
due to a heightened risk of bleeding. Given the high risk of bleeding, of axatilimab-csfr in 239 patients with recurrent or refractory cGVHD.296
patients should hold ibrutinib for 3 to 7 days prior to and after surgical Simultaneous use of corticosteroids, CNIs, or mTOR inhibitors was
procedures. permitted. Median duration of response was not reached at any dose, with
60%, 60%, and 53% of patients at doses of 0.3 mg/kg, 1 mg/kg, and 3
Belumosudil mg/kg maintaining response at 12 months, respectively. However, ORR
In 2021, belumosudil was approved by the FDA for the treatment of adult was superior in the 0.3 mg/kg arm, at 74%, compared to 67% and 50%
and pediatric patients aged ≥12 years with cGVHD after failure of two or with the 1 mg/kg and 3 mg/kg doses, respectively. Treatment-related
more lines of systemic therapy.294 This approval was based on data from adverse events, including fatal events, were also less common in the 0.3
the randomized, multicenter phase II ROCKstar study, which evaluated mg/kg arm. The most common treatment-related adverse events included
the efficacy of belumosudil 200 mg taken once or twice daily in patients headache, elevation in LFTs and CPK, and infections. Of note, there are
with cGVHD who had received two to five prior lines of therapy.289 After a currently no randomized data comparing axatilimab-csfr with other agents
median follow-up of 14 months, the ORR was 76%, with 5% of patients utilized for steroid-refractory cGVHD.
achieving a CR. Response, including CR, was observed in all organs,
Abatacept
including pulmonary GVHD. The median duration of response was 54
weeks and 44% of patients remained on belumosudil therapy for more Abatacept is a T-cell costimulatory inhibitor. It is a recombinant soluble
than 1 year. Adverse events were consistent with those observed in fusion protein composed of the extracellular domain of cytotoxic T-
patients with cGVHD receiving immunosuppressants and included lymphocyte–associated antigen 4 (CTLA-4) linked to the modified
infections, asthenia, nausea, diarrhea, dyspnea, cough, edema, fragment crystallizable (Fc) region of IgG1.297,298 Abatacept acts as an
hemorrhage, abdominal pain, and musculoskeletal pain. Sixteen patients immunomodulatory drug by selectively inhibiting T-cell activation via
(12%) discontinued belumosudil due to possible drug-related adverse binding to (blocking) the costimulation receptors (CD80 and CD86) on
events. These data suggest that belumosudil is a promising therapy for antigen-presenting cells (costimulation blockade). The safety and efficacy
steroid-refractory cGVHD that is well tolerated and produces clinically of abatacept in the treatment of steroid-refractory cGVHD were evaluated
meaningful responses. in a phase I clinical trial involving 16 patients.297 The study followed a 3+3
design with two escalating abatacept doses to determine the maximum
Axatilimab-csfr tolerated dose (MTD). The partial response rate to abatacept was 44%
In August 2024, axatilimab-csfr was approved by the FDA for the and no dose-limiting toxicities were observed at the MTD of 10 mg/kg. The
treatment of pediatric and adult patients with cGVHD weighing ≥40 kg affected sites with greatest improvement were the mouth, GI tract, joints,
after failure of at least two prior lines of systemic therapy.295 Approval was skin, eyes, and lungs. The most common adverse events were pulmonary
infections (all of which resolved), diarrhea, and fatigue. Importantly,
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treatment with abatacept resulted in a 51% reduction in prednisone usage. hypomagnesemia, hypertension, and tremors. In a phase II trial, 31
These data suggest that abatacept is an effective treatment option for patients with cGVHD that developed or progressed during therapy with
patients with steroid-refractory cGVHD. cyclosporine and/or other immunosuppressive agents were treated with
tacrolimus at an initial dose of 0.05 mg/kg intravenously or 0.15 mg/kg
Alemtuzumab orally twice daily (target trough 15-25 ng/mL). In the 26 patients with
The safety and efficacy of alemtuzumab for the treatment of steroid- evaluable data, the ORR was 46%.240 Another trial evaluated the efficacy
refractory cGVHD was evaluated in a phase I dose-escalation trial of tacrolimus administered at 0.15 mg/kg twice daily orally or 0.15
involving 13 patients.299 Six patients had moderate and seven patients had mg/kg/day intravenously in 17 patients with severe steroid-refractory
severe cGVHD per NIH consensus global scoring criteria; all patients had cGVHD.301 The ORR was 35% and OS was 65% at a median follow-up of
involvement of skin and subcutaneous tissues. Alemtuzumab dosing was 8.4 months. The greatest responses were observed in the skin, liver, and
investigated in a 3+3 study design. The MTD of alemtuzumab was 3 GI tract; musculoskeletal and lung cGVHD showed no response to
mg×1, then 10 mg×5 administered over 4 weeks. The most common treatment. Commonly reported adverse events included renal toxicity,
adverse events were infections and hematologic toxicities. Of the 10 hypertension, and infections. In a third report, 39 patients with cGVHD
patients evaluable for response, the ORR was 70%, with a 30% CR rate. refractory to cyclosporine and prednisone were treated with tacrolimus.302
The median decrease in steroid dose at 1 year was 62%. A prospective The ORR was 21% with a CR rate of 13%. However, 56% of patients
study of 15 patients with steroid-refractory cGVHD treated with one cycle discontinued tacrolimus due to progression/persistence of cGVHD or
of subcutaneous alemtuzumab at 10 mg/day for 3 days followed by 100 treatment-related toxicity and 23% died during continued tacrolimus
mg intravenous rituximab on days +4, +11, +18, and +25 reported an ORR treatment. Infectious complications were the most common adverse event
of 100% and a CR rate of 33% at day +30 evaluation.300 At day +90 followed by renal toxicity, which led to treatment discontinuation in two
evaluation, the partial response rate was 50%, the CR rate was 28%, and patients. Three-year estimated OS was 64% and 41% of patients had
21% of patients had relapsed cGVHD. Of the five patients with evaluable discontinued all immunosuppressive treatment at 3 years post-HCT.
data at 1 year, two (40%) had a partial response, two had a CR, and one Therefore, CNI may provide clinical benefit for steroid-refractory cGVHD,
experienced cGVHD progression. These data indicate that alemtuzumab in particular when they have not been used for GVHD prophylaxis or initial
is active in steroid-refractory cGVHD. Currently in the United States, therapy.
alemtuzumab is only available via the Campath Distribution Program and
Etanercept
the drug supply is patient-specific.
The efficacy of etanercept for the treatment of steroid-refractory cGVHD
Calcineurin Inhibitors was retrospectively evaluated in a cohort of eight patients treated with
Limited data exist for the efficacy of CNI, such as tacrolimus and subcutaneous etanercept at 25 mg twice weekly for 4 weeks followed by
cyclosporine, for the treatment of steroid-refractory cGVHD. The most 25 mg once weekly for 4 weeks.244 Patients were also continued on CNI,
common adverse events typically seen with CNI use are renal toxicity, MMF, and/or sirolimus. The ORR was 62%, with one patient achieving
CR. Three of the eight patients (37%) treated with etanercept died of
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progressive disease or sepsis. In three of the five patients who compared to 0% of patients in the control group (P = .04).304 Treatment
experienced response to etanercept, corticosteroids were reduced by with ECP resulted in an ORR of 61% in a retrospective analysis of 71
>50%. In a phase II trial, 34 patients with either obstructive (n = 25) or patients with severe steroid-refractory cGVHD; the best responses were
restrictive (n = 9) lung dysfunction following allogeneic HCT were treated seen in the skin, liver, oral mucosa, and eyes.305 A systematic review of
with etanercept subcutaneously at 0.4 mg/kg/dose twice weekly for 4 prospective studies reported a pooled ORR of 64% for ECP in the
(group A) or 12 (group B) weeks.303 Obstructive lung dysfunction is treatment of steroid-refractory cGVHD.245 Similar response rates were
commonly associated with cGVHD, with BOS being the most common seen with skin and GI involvement; however, the ORR for cGVHD with
histopathology reported. All patients had clinical signs or symptoms of lung involvement was only 15%, suggesting that ECP may not effectively
cGVHD at the onset of treatment with diffuse skin, oral mucosal, ocular, treat lung manifestations of cGVHD. Reported rates of ECP-related
and/or hepatic involvement. All patients received concurrent mortality were extremely low. Another systematic review largely reached
immunosuppressive therapy with either CNI alone (n = 5), CNI plus the same conclusions, reporting a pooled ORR of 64% and pooled
corticosteroids ± MMF (n = 22), MMF ± corticosteroids (n = 5), or response rates of 74% and 48% for skin and lung involvement,
sirolimus (n = 2). Clinical response, defined as a ≥10% improvement in the respectively.306 This review also reported activity for ECP in treating
absolute value for forced expiratory volume (FEV1; for obstructive defects) cGVHD with GI involvement (ORR = 53%). These data suggest that ECP
or forced vital capacity (FVC; for restrictive defects), was obtained in 32% is an effective therapy for steroid-refractory cGVHD, especially in those
of patients. There was no difference in ORR based on the duration of with skin involvement. If ECP is not available or feasible, the NCCN Panel
treatment (29% in group A vs. 35% in group B; P = .99) or the presence of recommends the use of PUVA irradiation as an alternative treatment
restrictive or obstructive lung dysfunction (33% vs. 32%, respectively; P = option for sclerotic or cutaneous steroid-refractory cGVHD.
.73). No bacterial or viral infections were observed. Thus, etanercept
seems to be effective for treating steroid-refractory cGVHD of the lung Hydroxychloroquine
(especially if associated with BOS). Hydroxychloroquine is a 4-aminoquinoline immunosuppressive and anti-
parasitic agent that is commonly used for the treatment of malaria.307
Extracorporeal Photopheresis
Hydroxychloroquine is believed to exert its immunomodulatory effects by
In a prospective single-center study involving 88 patients with extensive interfering with cytokine production and antigen processing and
cGVHD, second- or third-line treatment with ECP resulted in an ORR of presentation.308,309 The efficacy of hydroxychloroquine for the treatment of
73%.249 Cutaneous and sclerotic manifestations were associated with steroid-refractory cGVHD was evaluated in a phase II trial involving 40
higher response rates. After a median follow-up of 68 months, 5-year OS patients treated with hydroxychloroquine at 800 mg (12 mg/kg) per day.309
was 65% and was independently associated with a higher number of ECP The ORR was 53% among the 32 patients with evaluable data, with three
sessions and cutaneous manifestations. A multicenter randomized phase patients achieving a CR. All patients who experienced response tolerated
II trial involving 95 patients with cutaneous manifestations of steroid- a >50% reduction in their steroid dose while receiving hydroxychloroquine.
refractory cGVHD found that 8% of patients receiving ECP therapy The highest response rates were observed in patients with skin, oral,
experienced at least a 25% reduction in total skin score from baseline
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and/or liver involvement; efficacy in the treatment of GI manifestations was (36%) had a partial response, 7 (50%) had stable disease, and 2 (14%)
limited. had progressive disease. After treatment with imatinib for 6 months, range
of motion (ROM) deficit was improved in 79% of patients by an average of
One of the most serious adverse events reported with the long-term use 24%. Common adverse events included hypophosphatemia, fatigue,
(>2 years) of hydroxychloroquine is chloroquine retinopathy, a form of nausea, diarrhea, and disrupted fluid homeostasis leading to edema. A
toxic retinopathy caused by the binding of hydroxychloroquine to melanin randomized phase II crossover study compared imatinib (200 mg daily) to
in the retinal pigment epithelium, which can result in vision loss. The rituximab (375 mg/m2 intravenously weekly for 4 weeks) for the treatment
retinal toxicity of hydroxychloroquine was evaluated in a cohort of 12 of patients (n = 35) with cutaneous sclerosis associated with cGVHD.314
patients with cGVHD treated with 800 mg hydroxychloroquine per day for Significant clinical response, defined as quantitative improvement in skin
a median duration of 22.8 months.310 Seven patients developed vortex sclerosis or joint ROM, was observed in 26% of patients randomized to
keratopathy and three patients developed retinal toxicity; retinal structure imatinib and 27% of patients randomized to rituximab. Treatment success,
and color vision were abnormal in two of the three patients. These data defined as significant clinical response at 6 months without crossover,
suggest that hydroxychloroquine is an effective treatment option for recurrent malignancy, or death, was achieved in 17% of patients on
patients with steroid-refractory cGVHD, especially in those with skin or oral imatinib and 14% of patients on rituximab. In a prospective trial of 39
involvement, but may not be appropriate for long-term use due to the risk patients with steroid-refractory cGVHD treated with imatinib, the partial
of retinal toxicity. Periodic ophthalmologic assessment is recommended response rate was 36%.315 The best responses were seen in the skin
during treatment. (32%), GI tract (50%), and lungs (35%). After a median follow-up of 40
months, the 3-year OS and event-free survival rates were 72% and 46%,
Imatinib
respectively. These data suggest that low-dose imatinib (200 mg) is active
Imatinib is a small molecule tyrosine kinase inhibitor indicated for the in the treatment of patients with steroid-refractory cGVHD, especially in
treatment of several types of cancer, including CML.311 Imatinib has activity those with cutaneous sclerosis.
against several tyrosine kinase enzymes, including platelet-derived growth
factor receptor (PDGFR), which is implicated in skin fibrosis.312 Stimulatory Interleukin-2
antibodies against PDGFR have been identified in patients with cGVHD IL-2 is a naturally occurring pleiotropic cytokine that regulates the growth
with cutaneous sclerosis; however, neither anti-PDGFR antibody level, nor of T cells and is a key mediator of immune response.316 The efficacy of IL-
phosphorylation of tissue PDGFR, correlated with response to imatinib in 2 in the treatment of steroid-refractory cGVHD was evaluated in a phase I
patients with cGVHD.313 The efficacy of imatinib to treat sclerotic study involving 29 patients.317 Patients received daily subcutaneous IL-2 at
manifestations of cutaneous steroid-refractory cGVHD was assessed in a escalating dose levels for 8 weeks. The MTD was determined to be 1×106
pilot phase II trial involving 20 patients.312 Eight patients received a IU/m2. Of the 23 patients evaluable for a response, 12 had a significant
standard dose of 400 mg daily while 12 patients underwent a dose clinical response involving multiple organs. Clinical responses were
escalation study due to poor tolerability (100 mg daily initial dose up to 200 sustained in patients who received IL-2 for an extended period, allowing
mg daily maximum). Of the 14 patients evaluable for primary response, 5 their corticosteroid dose to be tapered by a mean of 60%. In a follow-up
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phase II trial, 35 patients with steroid-refractory cGVHD were treated with steroid-refractory cGVHD reported an ORR of 76% in patients treated with
IL-2 at 1×106 IU/m2 for 12 weeks.316 The ORR in 33 patients with evaluable low-dose methotrexate (5 or 10 mg/m2 infusion every 3–4 days).322 The
data was 61%. There were CRs and three patients developed progressive response rates were particularly high in patients with extensive cGVHD
cGVHD. All those who experienced response experienced improvement in (ORR = 92%) and were significantly higher in patients with skin
multiple sites of cGVHD, including the liver, skin, GI tract, lungs, and involvement (92%) compared to those with liver involvement (43%; P =
joints/muscle/fascia. Extended IL-2 therapy for up to 2 years was well .009). Among patients with cGVHD in a single organ (skin or liver), 58%
tolerated and resulted in durable clinical responses in most patients. experienced response compared to 100% of patients with ≥2 organs
However, two patients in this study withdrew and five required dose involved. Although this trial reported severe hematologic toxicities
reductions of IL-2 due to adverse events including thrombocytopenia, associated with methotrexate, these toxicities were reversible and did not
fatigue, flu-like symptoms, malaise, and thrombocytopenia. A phase I result in treatment discontinuation. These data suggest that low-dose
dose-escalation trial showed that escalation above the previously defined methotrexate is active in the treatment of patients with steroid-refractory
MTD did not improve clinical response in 10 patients with steroid- cGVHD, especially in those with skin and oral manifestations.
refractory cGVHD.318 These data suggest that low-dose IL-2 has durable
clinical activity in treating steroid-refractory cGVHD and is generally safe mTOR Inhibitors
for long-term use. The safety and efficacy of sirolimus for the treatment of steroid-refractory
cGVHD was evaluated in a phase II trial involving 35 patients.323 Patients
Low-Dose Methotrexate
with steroid-refractory cGVHD received sirolimus at a loading dose of 6
Methotrexate is an antimetabolite that exerts immunosuppressive effects mg orally followed by a maintenance dose of 2 mg/day targeting a
by inhibiting the activity of dihydrofolic acid reductase, resulting in impaired concentration between 7-12 ng/mL while continuing immunosuppressive
DNA synthesis and lymphocyte proliferation.319 In a retrospective study of treatment with tacrolimus and methylprednisolone. The ORR was 63%,
14 patients who had received low-dose methotrexate (7.5 mg/m2/week for with six patients achieving CR. The highest response rates were observed
3–50 weeks) for the treatment of steroid-refractory cGVHD, 71% of in patients with sclerotic skin involvement (73%) and involvement of the
patients were able to reduce their prednisone dose to <1 mg/kg every oral mucosa (75%), but responses were also observed in the lower GI
other day without the addition of other agents.320 In this study, the most tract (67%), liver (33%), and eyes (64%). Major adverse events included
frequently involved sites were the oral mucosa (n = 14) and skin (n = 11) hyperlipidemia, renal dysfunction, cytopenias, TMA, and infectious
and no grade 3 or higher toxicities were observed. The steroid-sparing complications. Median survival was 15 months and estimated actuarial
effects of methotrexate were also observed in a prospective study of eight survival at 2 years was 41%. In another phase II trial, 19 patients with
patients with steroid-refractory cGVHD, which reported a reduction in steroid-refractory cGVHD were treated with sirolimus, CNI, and
corticosteroid dose in the range of 25% to 80% in patients treated with prednisone.324 Sirolimus was administered orally at a loading dose of 10
low-dose methotrexate (5 mg/m2/infusion).321 The ORR was 75% and few mg followed by a daily dose of 5 mg without a defined target range. Of the
toxicities were observed, the most serious being grade 3–4 cytopenias 16 patients with evaluable data, 15 had an initial clinical response to this
reported in two patients. Another retrospective review of 21 patients with regimen. However, five patients discontinued treatment due to renal
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toxicity. Of the 10 patients who continued with this regimen, three had a decreased by a median of 50% by the end of the 6-month observation
prolonged response and were able to successfully taper off period. The most common adverse events were abdominal cramps (which
immunosuppressive agents. A retrospective study analyzed 47 patients resulted in discontinuation of MMF in 3 patients) and infections. At a
with steroid-refractory cGVHD treated with sirolimus (2 mg/day, target median follow-up of 24 months, 83% of patients were alive. In a
concentration 5-10 ng/mL) in combination with other immunosuppressive prospective phase II trial involving 23 patients with steroid-refractory
agents (CNI [n = 33], MMF [n = 9], or prednisone [n = 5]).325 The ORR was cGVHD, the cumulative incidence of disease resolution and withdrawal of
81%, with a CR rate of 38%. The main toxicity was mild impairment of all immunosuppressive treatment was 26% at 36 months after starting
renal function, which was more common in patients receiving sirolimus treatment with MMF (initial dose of 1 g twice daily).266 After a median
and CNI (33%) compared to sirolimus and other immunosuppressive follow-up of 9.5 years, 52% of patients remained alive with only one
agents (7%). Estimated 3-year OS in all patients was 57%. These data patient requiring continued treatment with immunosuppressive agents. In
suggest that sirolimus is an effective agent for the treatment of patients another retrospective analysis of 13 patients with steroid-refractory
with steroid-refractory cGVHD and should be investigated further to find cGVHD, the ORR to MMF (1.5 or 2 g daily) was 77% and the estimated 2-
the best dose schedule and combination of additional agents to optimize year OS rate was 54%. The most common adverse events were GI
clinical response while limiting toxicity. disturbances (27%) and infectious complications (23%). These data
suggest that MMF is an effective therapy option for patients with steroid-
Although it has not been studied extensively, the sirolimus derivative refractory cGVHD.
everolimus has shown activity in the treatment of steroid-refractory
cGVHD. Preliminary data from two retrospective studies showed that Pentostatin
treatment with everolimus resulted in significant improvement in the NIH
In a phase II trial involving 58 patients with steroid-refractory cGVHD,
Severity Score and patient-reported quality of life.326,327 However, more
treatment with pentostatin at 4 mg/m2 given intravenously every 2 weeks
data are necessary to confirm the role of everolimus in the treatment of
for a median of 12 doses resulted in an ORR of 55%.329 Most patients had
steroid-refractory cGVHD.
skin involvement and more than half had oral and GI involvement. The
Mycophenolate Mofetil highest response rates were observed in patients with lichenoid cutaneous
manifestations (69%) followed by patients with oral involvement (62%); the
The safety and efficacy of MMF for the treatment of steroid-refractory lowest response rates were seen in patients with liver involvement. A total
cGVHD was evaluated in a retrospective study of 24 patients treated with of 11 grade 3–4 infections were reported and four patients withdrew from
MMF at a dose of 500 mg twice daily (escalated to 1 g twice daily if treatment due to adverse events including nausea/vomiting, renal toxicity,
tolerated) in combination with cyclosporine, tacrolimus, and/or and fatigue. OS at 1 and 2 years was 78% and 70%, respectively. In a
prednisone.328 The ORR was 75%, with a CR rate of 21%. Only two retrospective analysis of 18 patients with steroid-refractory cGVHD, 12 of
patients experienced progressive disease. The highest response rates whom had severe cGVHD, treatment with pentostatin at 4 mg/m2 every 2
were seen in patients with involvement of the skin or oral mucosa. Of the weeks resulted in an ORR of 56%; CR was achieved in one patient.272
22 patients receiving prednisone, 14 (64%) had their prednisone dose Activity was observed in all affected organs, with CRs observed in GI (CR
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= 3), skin (CR = 4), and muscle/fascia (CR = 1) manifestations. The GVHD Supportive Care
median decrease in corticosteroid dose over 24 months after pentostatin Supportive Care for All Patients with GVHD
initiation was 38% and median OS was 5 months. Estimated 1-year OS
was 34%. Common adverse events included renal toxicity and infections. Supportive care is essential for all patients with GVHD. Special attention is
These data suggest that pentostatin is active in the treatment of steroid- required for prevention of infection, as infection is the most common cause
refractory cGVHD. of death in those with cGVHD.198 The NCCN Panel recommends initiation
of appropriate antimicrobial prophylaxis with escalating
Rituximab immunosuppressive therapy as outlined in the NCCN Guidelines for
Prevention and Treatment of Cancer-Related Infections. Surveillance for
Rituximab is an anti-CD20 chimeric monoclonal antibody used to treat
cytomegalovirus reactivation, which is associated with significant morbidity
NHL and CLL that exerts immunosuppressive effects by binding to CD20
and mortality among allogeneic HCT recipients,198,332 is also recommended
on the surface of B cells, facilitating their destruction.330 Since B cells are
in appropriate patients. Consideration can be made for additional viral
implicated in the pathogenesis of cGVHD, the efficacy of rituximab in the
surveillance. Live vaccines should be avoided for all patients on
treatment of steroid-refractory cGVHD has been evaluated in several
immunosuppressive therapy or those with active GVHD.198 Re-vaccination
studies.308,331 In a systematic review and meta-analysis of seven studies (3
for COVID-19 is recommended in all allogeneic HCT recipients, though
prospective and 4 retrospective) including 111 patients, the pooled ORR to
with a delay until 3 months post-transplant given the likelihood of a blunted
rituximab was 66%.331 The majority of studies used rituximab at a dose of
immune response affecting the efficacy of vaccination prior to this time
375 mg/m2 once per week for 4 to 8 infusions, although similar results
point.333 Routine use of prophylactic intravenous immunoglobulin (IVIG)
were reported with rituximab administered at 50 mg/m2 per week for 4
replacement is not recommended given lack of clear evidence of benefit,
weeks (ORR = 69%). The pooled ORR for patients with skin cGVHD was
higher risks of SOS and thrombosis, and possible reduced efficacy of
60%, compared to 36% for oral mucosal cGVHD, 29% for liver cGVHD,
vaccinations post-transplant; however, there may be subsets of patients
and 30% for lung cGVHD, suggesting that skin manifestations of cGVHD
where prophylactic IVIG may be considered, such as in UCB transplant
are particularly susceptible to rituximab treatment. However, it should be
recipients, in children undergoing transplantation for inherited or acquired
noted that the site-specific response rates varied greatly among studies.
disorders associated with B-cell deficiency, and in patients with cGVHD
Administration of rituximab facilitated corticosteroid dose reductions in the
with recurrent sinopulmonary infections.334
range of 75% to 86%, depending on the study. The steroid-sparing effect
of rituximab was more pronounced in patients with skin and oral mucosal The use of high-dose steroid therapy for management of GVHD may be
GVHD. The most common adverse events were related to infusion associated with infections (including viral, fungal, and bacterial), glucose
reactions or infectious complications. Therefore, rituximab is an effective intolerance, hypertension, adrenal insufficiency, poor wound healing,
treatment option for patients with steroid-refractory cGVHD, especially in myopathy, osteoporosis, vitamin D deficiency, insomnia, anxiety, and
those with skin involvement. An FDA-approved biosimilar is an appropriate mood swings.335 Vitamin D and calcium supplementation should be
substitute for rituximab. considered for patients on high-dose steroids. 335 Allogeneic HCT, even

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without the use of high-dose steroids, is associated with bone resorption given the risk of ileus should be stopped once diarrhea resolves, or after 7
and decreased bone formation, which can lead to osteoporosis. Thus, days of treatment.341
monitoring of vitamin D levels and measurement of bone mineral density
by dual-energy x-ray absorptiometry (DEXA) scans is recommended for Patients with aGVHD of the gut may suffer from malnutrition and protein-
those with current or past exposure to high-dose steroids and those with losing enteropathy with deficiency of trace elements (eg, magnesium and
cGVHD, with treatment and repeat imaging as indicated based on zinc) and vitamins (eg, thiamine, and vitamins B12 and D).340,342 In
results.198 addition, bowel rest is a critical component of supportive care for high
grade aGVHD of the GI tract. Total parenteral nutrition should be
Dermatology, dental, and ophthalmology exams are recommended at considered in patients with voluminous diarrhea or poor tolerance to oral
baseline and at appropriate intervals beginning 6-12 months post- intake.340,342 Monitoring for thiamine deficiency should be considered for
transplant for all patients with GVHD for both GVHD-related symptoms patients with altered mental status.
and other increased risk factors, such as increased risks of skin cancer
and oral squamous cell carcinoma in those with cGVHD.198 GI topical steroids such as oral beclomethasone or budesonide are
frequently administered in the setting of aGVHD of the gut, but prolonged
For patients with liver GVHD, prophylaxis with ursodiol, a hydrophilic bile use can lead to adrenal insufficiency. Thus, it is critical for providers to be
acid, can be considered. In a randomized trial, ursodiol was found to familiar with symptoms of adrenal insufficiency and to keep a high index of
reduce the incidence of bilirubin elevation, severe aGVHD, liver GVHD, suspicion in the setting of non-specific symptoms, such as fatigue,
and GI GVHD, as well as improve survival.336,337 malaise, and muscle aches.343

Supportive Care for Acute GVHD Supportive Care for cGVHD

Acute GVHD of the Skin Chronic Oral GVHD

Supportive care recommendations for aGVHD of the skin include Xerostomia is a common complication of oral cGVHD. Sialogogues such
avoidance of direct sunlight and photosensitizing agents, such as as cevimeline can be considered for severe xerostomia in the absence of
voriconazole, as well as the use of sunscreen.338 Those with advanced contraindications.198 Patients with oral cGVHD are also at higher risk of
skin aGVHD should be evaluated by a dermatologist.339 developing oral squamous cell carcinoma198; thus, all suspicious oral
lesions should be examined by a dentist or oral surgeon, in addition to
Acute GVHD of the GI Tract routine surveillance dental examinations. Dexamethasone mouth rinses
Acute GVHD of the GI tract can lead to symptoms such as severe (swish and spit) can be considered198; patients should be monitored for
abdominal pain and diarrhea. Abdominal pain from aGVHD can be difficult oral thrush and appropriate anti-fungal topical therapy should be initiated
to treat and opioids are often required, though should be used with caution as indicated.
given the increased risk of ileus associated with their use.340 Similarly, the
use of octreotide can be considered for control of severe diarrhea, though Chronic Ocular GVHD

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Supportive care for ocular cGVHD centers around increasing ocular cGVHD of the Nervous System
surface moisture to reduce dry eye and reduction of inflammation.198 Physical therapy consultation may be beneficial for patients experiencing
Autologous serum drops may improve ocular surface inflammation but are myopathy and/or neuropathy from cGVHD, especially when symptoms
not widely available. Methods to alleviate dry eye include artificial tears such as muscle pain, weakness, or wasting or paresthesias limit activities
and, in severe cases, punctal plugs or gas-permeable scleral lenses. of daily living or impair quality of life.198 Patients with limited ROM from
Assessment and follow-up by an ophthalmologist, ideally with experience sclerotic skin changes may also benefit from physical therapy consultation.
in GVHD, is recommended.
Summary
Chronic Gut GVHD
Although diarrhea is a well-known symptom of gut cGVHD, a workup for The NCCN Guidelines ® for Hematopoietic Cell Transplantation provide
malabsorption is indicated in patients with prolonged diarrhea. Pancreatic an evidence- and consensus-based approach for the use of HCT for the
atrophy leading to fat malabsorption may occur in the setting of gut management of malignant disease in adult patients. HCT is a potentially
cGVHD and oral pancreatic enzyme supplementation may be curative treatment option for patients with certain types of malignancies.
beneficial.198,344 However, disease relapse and transplant-related complications often
limit the long-term survival of HCT recipients. The leading cause of NRM
Upper intestinal cGVHD is associated with the development of esophageal in allogeneic HCT recipients is the development of GVHD. 164 Despite
webs and strictures, for which GI consultation for endoscopic esophageal treatment with systemic corticosteroids, approximately 50% of patients
dilation may be beneficial.198 with GVHD develop steroid-refractory disease. 204 Steroid-refractory
GVHD is associated with high mortality and no standard, effective
cGVHD of the Genitalia therapy has yet been identified. Therefore, the NCCN Panel strongly
Vulvovaginal cGVHD often presents with symptoms of dryness, encourages patients with steroid-refractory acute or cGVHD to
tenderness, dysuria, and dyspareunia.198 All patients with vulvovaginal participate in well-designed clinical trials to enable further advancements
symptoms should be assessed by a gynecologist. Urology and for the management of these diseases and ultimately increase the long-
dermatology assessment may also be required for genitourinary term survival of HCT recipients.
symptoms or sclerotic changes. Differential diagnosis includes post-
menopausal changes and consideration may be given to starting topical
estrogen or systemic estrogen/progestin-combined hormone therapy (or
referral to gynecology for further evaluation).345

Foreskin and penile cGVHD are uncommon but may lead to lichenoid skin
lesions and erectile dysfunction.198,346 Appropriate referrals to urology
and/or dermatology are recommended.

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References 2012;367:1487-1496. Available at:

https://www.ncbi.nlm.nih.gov/pubmed/23075175.
1. Copelan EA. Hematopoietic stem-cell transplantation. N Engl J Med
2006;354:1813-1826. Available at: 9. Lee SJ, Logan B, Westervelt P, et al. Comparison of patient-reported
https://www.ncbi.nlm.nih.gov/pubmed/16641398. outcomes in 5-year survivors who received bone marrow vs peripheral
blood unrelated donor transplantation: long-term follow-up of a
2. Current use and outcome of hematopoietic stem cell transplantation: randomized clinical trial. JAMA Oncol 2016;2:1583-1589. Available at:
CIBMTR summary slides, 2022. 2022. Available at: https://www.ncbi.nlm.nih.gov/pubmed/27532508.
https://cibmtr.org/CIBMTR/Resources/Summary-Slides-Reports.
Accessed July 6, 2023. 10. Alousi A, Wang T, Hemmer MT, et al. Peripheral blood versus bone
marrow from unrelated donors: bone marrow allografts have improved
3. Flannelly C, Tan BE, Tan JL, et al. Barriers to hematopoietic cell long-term overall and graft-versus-host disease-free, relapse-free
transplantation for adults in the united states: a systematic review with a survival. Biol Blood Marrow Transplant 2019;25:270-278. Available at:
focus on age. Biol Blood Marrow Transplant 2020;26:2335-2345. https://www.ncbi.nlm.nih.gov/pubmed/30292009.
Available at: https://www.ncbi.nlm.nih.gov/pubmed/32961375.
11. Kindwall-Keller TL, Ballen KK. Umbilical cord blood: The promise and
4. Timofeeva OA, Philogene MC, Zhang QJ. Current donor selection the uncertainty. Stem Cells Transl Med 2020;9:1153-1162. Available at:
strategies for allogeneic hematopoietic cell transplantation. Hum https://www.ncbi.nlm.nih.gov/pubmed/32619330.
Immunol 2022;83:674-686. Available at:
https://www.ncbi.nlm.nih.gov/pubmed/36038413. 12. Ballen KK, Spitzer TR. The great debate: haploidentical or cord blood
transplant. Bone Marrow Transplant 2011;46:323-329. Available at:
5. Majhail NS, Farnia SH, Carpenter PA, et al. Indications for autologous https://www.ncbi.nlm.nih.gov/pubmed/21042314.
and allogeneic hematopoietic cell transplantation: guidelines from the
American Society for Blood and Marrow Transplantation. Biol Blood 13. Al-Homsi AS, Roy TS, Cole K, et al. Post-transplant high-dose
Marrow Transplant 2015;21:1863-1869. Available at: cyclophosphamide for the prevention of graft-versus-host disease. Biol
https://www.ncbi.nlm.nih.gov/pubmed/26256941. Blood Marrow Transplant 2015;21:604-611. Available at:
https://www.ncbi.nlm.nih.gov/pubmed/25240817.
6. Hosing C. Hematopoietic stem cell mobilization with G-CSF. Methods
Mol Biol 2012;904:37-47. Available at: 14. Luznik L, O'Donnell PV, Symons HJ, et al. HLA-haploidentical bone
http://www.ncbi.nlm.nih.gov/pubmed/22890920. marrow transplantation for hematologic malignancies using
nonmyeloablative conditioning and high-dose, posttransplantation
7. Bensinger WI, Martin PJ, Storer B, et al. Transplantation of bone cyclophosphamide. Biol Blood Marrow Transplant 2008;14:641-650.
marrow as compared with peripheral-blood cells from HLA-identical Available at: https://www.ncbi.nlm.nih.gov/pubmed/18489989.
relatives in patients with hematologic cancers. N Engl J Med
2001;344:175-181. Available at: 15. U.S. National Library of Medicine-Key MEDLINE® Indicators.
https://www.ncbi.nlm.nih.gov/pubmed/11172139. Available at: https://pubmed.ncbi.nlm.nih.gov/about/.

8. Anasetti C, Logan BR, Lee SJ, et al. Peripheral-blood stem cells

versus bone marrow from unrelated donors. N Engl J Med
MS-30
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Hematopoietic Cell Transplantation

16. Palumbo A, Cavallo F, Gay F, et al. Autologous transplantation and 23. Philip T, Guglielmi C, Hagenbeek A, et al. Autologous bone marrow
maintenance therapy in multiple myeloma. N Engl J Med 2014;371:895- transplantation as compared with salvage chemotherapy in relapses of
905. Available at: https://www.ncbi.nlm.nih.gov/pubmed/25184862. chemotherapy-sensitive non-Hodgkin's lymphoma. N Engl J Med
1995;333:1540-1545. Available at:
17. Child JA, Morgan GJ, Davies FE, et al. High-dose chemotherapy with https://www.ncbi.nlm.nih.gov/pubmed/7477169.
hematopoietic stem-cell rescue for multiple myeloma. N Engl J Med
2003;348:1875-1883. Available at: 24. Oliansky DM, Czuczman M, Fisher RI, et al. The role of cytotoxic
https://www.ncbi.nlm.nih.gov/pubmed/12736280. therapy with hematopoietic stem cell transplantation in the treatment of
diffuse large B cell lymphoma: update of the 2001 evidence-based
18. Fermand JP, Katsahian S, Divine M, et al. High-dose therapy and review. Biol Blood Marrow Transplant 2011;17:20-47 e30. Available at:
autologous blood stem-cell transplantation compared with conventional https://www.ncbi.nlm.nih.gov/pubmed/20656046.
treatment in myeloma patients aged 55 to 65 years: long-term results of
a randomized control trial from the Group Myelome-Autogreffe. J Clin 25. Oliansky DM, Gordon LI, King J, et al. The role of cytotoxic therapy
Oncol 2005;23:9227-9233. Available at: with hematopoietic stem cell transplantation in the treatment of follicular
https://www.ncbi.nlm.nih.gov/pubmed/16275936. lymphoma: an evidence-based review. Biol Blood Marrow Transplant
2010;16:443-468. Available at:
19. Attal M, Harousseau JL, Stoppa AM, et al. A prospective, https://www.ncbi.nlm.nih.gov/pubmed/20114084.
randomized trial of autologous bone marrow transplantation and
chemotherapy in multiple myeloma. Intergroupe Francais du Myelome. N 26. Mahajan S, Tandon N, Kumar S. The evolution of stem-cell
Engl J Med 1996;335:91-97. Available at: transplantation in multiple myeloma. Ther Adv Hematol 2018;9:123-133.
https://www.ncbi.nlm.nih.gov/pubmed/8649495. Available at: https://www.ncbi.nlm.nih.gov/pubmed/29713445.

20. Shah N, Callander N, Ganguly S, et al. Hematopoietic stem cell 27. Einhorn LH, Williams SD, Chamness A, et al. High-dose
transplantation for multiple myeloma: guidelines from the American chemotherapy and stem-cell rescue for metastatic germ-cell tumors. N
Society for Blood and Marrow Transplantation. Biol Blood Marrow Engl J Med 2007;357:340-348. Available at:
Transplant 2015;21:1155-1166. Available at: https://www.ncbi.nlm.nih.gov/pubmed/17652649.
https://www.ncbi.nlm.nih.gov/pubmed/25769794.
28. Hamid AA, Markt SC, Vicier C, et al. Autologous stem-cell
21. Schmitz N, Pfistner B, Sextro M, et al. Aggressive conventional transplantation outcomes for relapsed metastatic germ-cell tumors in the
chemotherapy compared with high-dose chemotherapy with autologous modern era. Clin Genitourin Cancer 2019;17:58-64. Available at:
haemopoietic stem-cell transplantation for relapsed chemosensitive https://www.ncbi.nlm.nih.gov/pubmed/30309761.
Hodgkin's disease: a randomised trial. Lancet 2002;359:2065-2071.
Available at: https://www.ncbi.nlm.nih.gov/pubmed/12086759. 29. Feldman DR, Sheinfeld J, Bajorin DF, et al. TI-CE high-dose
chemotherapy for patients with previously treated germ cell tumors:
22. Perales MA, Ceberio I, Armand P, et al. Role of cytotoxic therapy results and prognostic factor analysis. J Clin Oncol 2010;28:1706-1713.
with hematopoietic cell transplantation in the treatment of Hodgkin Available at: http://www.ncbi.nlm.nih.gov/pubmed/20194867.
lymphoma: guidelines from the American Society for Blood and Marrow
Transplantation. Biol Blood Marrow Transplant 2015;21:971-983. 30. Kilari D, D'Souza A, Fraser R, et al. Autologous hematopoietic stem
Available at: https://www.ncbi.nlm.nih.gov/pubmed/25773017. cell transplantation for male germ cell tumors: improved outcomes over 3
MS-31
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decades. Biol Blood Marrow Transplant 2019;25:1099-1106. Available 37. De Rosa L, Lalle M, Pandolfi A, et al. Autologous bone marrow
at: https://www.ncbi.nlm.nih.gov/pubmed/30794931. transplantation with negative immunomagnetic purging for aggressive B-
cell non-Hodgkin's lymphoma in first complete remission. Ann Hematol
31. Dunkel IJ, Gardner SL, Garvin JH, Jr., et al. High-dose carboplatin, 2002;81:575-581. Available at:
thiotepa, and etoposide with autologous stem cell rescue for patients https://www.ncbi.nlm.nih.gov/pubmed/12424539.
with previously irradiated recurrent medulloblastoma. Neuro Oncol
2010;12:297-303. Available at: 38. Bierman PJ, Sweetenham JW, Loberiza FR, Jr., et al. Syngeneic
https://www.ncbi.nlm.nih.gov/pubmed/20167818. hematopoietic stem-cell transplantation for non-Hodgkin's lymphoma: a
comparison with allogeneic and autologous transplantation--The
32. Illerhaus G, Muller F, Feuerhake F, et al. High-dose chemotherapy Lymphoma Working Committee of the International Bone Marrow
and autologous stem-cell transplantation without consolidating Transplant Registry and the European Group for Blood and Marrow
radiotherapy as first-line treatment for primary lymphoma of the central Transplantation. J Clin Oncol 2003;21:3744-3753. Available at:
nervous system. Haematologica 2008;93:147-148. Available at: https://www.ncbi.nlm.nih.gov/pubmed/12963703.
https://www.ncbi.nlm.nih.gov/pubmed/18166803.
39. Weisdorf D, Eapen M, Ruggeri A, et al. Alternative donor
33. Kasenda B, Ihorst G, Schroers R, et al. High-dose chemotherapy transplantation for older patients with acute myeloid leukemia in first
with autologous haematopoietic stem cell support for relapsed or complete remission: a Center for International Blood and Marrow
refractory primary CNS lymphoma: a prospective multicentre trial by the Transplant Research-Eurocord analysis. Biol Blood Marrow Transplant
German Cooperative PCNSL study group. Leukemia 2017;31:2623- 2014;20:816-822. Available at:
2629. Available at: https://www.ncbi.nlm.nih.gov/pubmed/28559537. https://www.ncbi.nlm.nih.gov/pubmed/24582782.
34. DeFilipp Z, Li S, El-Jawahri A, et al. High-dose chemotherapy with 40. Servais S, Porcher R, Xhaard A, et al. Pre-transplant prognostic
thiotepa, busulfan, and cyclophosphamide and autologous stem cell factors of long-term survival after allogeneic peripheral blood stem cell
transplantation for patients with primary central nervous system transplantation with matched related/unrelated donors. Haematologica
lymphoma in first complete remission. Cancer 2017;123:3073-3079. 2014;99:519-526. Available at:
Available at: https://www.ncbi.nlm.nih.gov/pubmed/28369839. https://www.ncbi.nlm.nih.gov/pubmed/24241489.
35. Soussain C, Hoang-Xuan K, Taillandier L, et al. Intensive 41. Rashidi A, Hamadani M, Zhang MJ, et al. Outcomes of haploidentical
chemotherapy followed by hematopoietic stem-cell rescue for refractory vs matched sibling transplantation for acute myeloid leukemia in first
and recurrent primary CNS and intraocular lymphoma: Societe Francaise complete remission. Blood Adv 2019;3:1826-1836. Available at:
de Greffe de Moelle Osseuse-Therapie Cellulaire. J Clin Oncol https://www.ncbi.nlm.nih.gov/pubmed/31201170.
2008;26:2512-2518. Available at:
https://www.ncbi.nlm.nih.gov/pubmed/18413641. 42. Meybodi MA, Cao W, Luznik L, et al. HLA-haploidentical vs matched-
sibling hematopoietic cell transplantation: a systematic review and meta-
36. Gorin NC. History and development of autologous stem cell analysis. Blood Adv 2019;3:2581-2585. Available at:
transplantation for acute myeloid leukemia. Clin Hematol Int 2021;3:83- https://www.ncbi.nlm.nih.gov/pubmed/31484635.
95. Available at: https://www.ncbi.nlm.nih.gov/pubmed/34820613.
43. Bazarbachi A, Boumendil A, Finel H, et al. Influence of donor type,
stem cell source and conditioning on outcomes after haploidentical
MS-32
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transplant for lymphoma - a LWP-EBMT study. Br J Haematol leukemia. N Engl J Med 2004;351:2276-2285. Available at:
2020;188:745-756. Available at: https://www.ncbi.nlm.nih.gov/pubmed/15564544.
https://www.ncbi.nlm.nih.gov/pubmed/31498883.
51. Khaddour K, Mewawalla P. Hematopoietic stem cell transplantation.
44. Gluckman E, Broxmeyer HA, Auerbach AD, et al. Hematopoietic StatPearls. Treasure Island (FL); 2019.
reconstitution in a patient with Fanconi's anemia by means of umbilical-
cord blood from an HLA-identical sibling. N Engl J Med 1989;321:1174- 52. Othus M, Appelbaum FR, Petersdorf SH, et al. Fate of patients with
1178. Available at: https://www.ncbi.nlm.nih.gov/pubmed/2571931. newly diagnosed acute myeloid leukemia who fail primary induction
therapy. Biol Blood Marrow Transplant 2015;21:559-564. Available at:
45. Wagner JE, Rosenthal J, Sweetman R, et al. Successful https://www.ncbi.nlm.nih.gov/pubmed/25536215.
transplantation of HLA-matched and HLA-mismatched umbilical cord
blood from unrelated donors: analysis of engraftment and acute graft- 53. Yanada M, Matsuo K, Suzuki T, Naoe T. Allogeneic hematopoietic
versus-host disease. Blood 1996;88:795-802. Available at: stem cell transplantation as part of postremission therapy improves
https://www.ncbi.nlm.nih.gov/pubmed/8704232. survival for adult patients with high-risk acute lymphoblastic leukemia: a
metaanalysis. Cancer 2006;106:2657-2663. Available at:
46. Barker JN, Weisdorf DJ, DeFor TE, et al. Transplantation of 2 https://www.ncbi.nlm.nih.gov/pubmed/16703597.
partially HLA-matched umbilical cord blood units to enhance engraftment
in adults with hematologic malignancy. Blood 2005;105:1343-1347. 54. de Witte T, Bowen D, Robin M, et al. Allogeneic hematopoietic stem
Available at: https://www.ncbi.nlm.nih.gov/pubmed/15466923. cell transplantation for MDS and CMML: recommendations from an
international expert panel. Blood 2017;129:1753-1762. Available at:
47. Warlick ED, Peffault de Latour R, Shanley R, et al. Allogeneic https://www.ncbi.nlm.nih.gov/pubmed/28096091.
hematopoietic cell transplantation outcomes in acute myeloid leukemia:
similar outcomes regardless of donor type. Biol Blood Marrow Transplant 55. Sureda A, Robinson S, Canals C, et al. Reduced-intensity
2015;21:357-363. Available at: conditioning compared with conventional allogeneic stem-cell
https://www.ncbi.nlm.nih.gov/pubmed/25452032. transplantation in relapsed or refractory Hodgkin's lymphoma: an
analysis from the Lymphoma Working Party of the European Group for
48. Laughlin MJ, Eapen M, Rubinstein P, et al. Outcomes after Blood and Marrow Transplantation. J Clin Oncol 2008;26:455-462.
transplantation of cord blood or bone marrow from unrelated donors in Available at: https://www.ncbi.nlm.nih.gov/pubmed/18086796.
adults with leukemia. N Engl J Med 2004;351:2265-2275. Available at:
https://www.ncbi.nlm.nih.gov/pubmed/15564543. 56. Rezvani AR, Norasetthada L, Gooley T, et al. Non-myeloablative
allogeneic haematopoietic cell transplantation for relapsed diffuse large
49. Marks DI, Woo KA, Zhong X, et al. Unrelated umbilical cord blood B-cell lymphoma: a multicentre experience. Br J Haematol
transplant for adult acute lymphoblastic leukemia in first and second 2008;143:395-403. Available at:
complete remission: a comparison with allografts from adult unrelated https://www.ncbi.nlm.nih.gov/pubmed/18759762.
donors. Haematologica 2014;99:322-328. Available at:
https://www.ncbi.nlm.nih.gov/pubmed/24056817. 57. Barrett J. Allogeneic stem cell transplantation for chronic myeloid
leukemia. Semin Hematol 2003;40:59-71. Available at:
50. Rocha V, Labopin M, Sanz G, et al. Transplants of umbilical-cord https://www.ncbi.nlm.nih.gov/pubmed/12563612.
blood or bone marrow from unrelated donors in adults with acute
MS-33
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58. Kharfan-Dabaja MA, Kumar A, Hamadani M, et al. Clinical practice 65. Muffly L, Pasquini MC, Martens M, et al. Increasing use of allogeneic
recommendations for use of allogeneic hematopoietic cell transplantation hematopoietic cell transplantation in patients aged 70 years and older in
in chronic lymphocytic leukemia on behalf of the Guidelines Committee the United States. Blood 2017;130:1156-1164. Available at:
of the American Society for Blood and Marrow Transplantation. Biol https://www.ncbi.nlm.nih.gov/pubmed/28674027.
Blood Marrow Transplant 2016;22:2117-2125. Available at:
https://www.ncbi.nlm.nih.gov/pubmed/27660167. 66. Ciurea SO, Shah MV, Saliba RM, et al. Haploidentical transplantation
for older patients with acute myeloid leukemia and myelodysplastic
59. Bruno B, Rotta M, Patriarca F, et al. Nonmyeloablative allografting for syndrome. Biol Blood Marrow Transplant 2018;24:1232-1236. Available
newly diagnosed multiple myeloma: the experience of the Gruppo at: https://www.ncbi.nlm.nih.gov/pubmed/28918304.
Italiano Trapianti di Midollo. Blood 2009;113:3375-3382. Available at:
https://www.ncbi.nlm.nih.gov/pubmed/19064724. 67. Mohyuddin GR, Romanelli N, Shune L, et al. Autologous
hematopoietic stem cell transplant is safe for elderly lymphoma patients.
60. Shanavas M, Messner HA, Atenafu EG, et al. Allogeneic Hematol Oncol Stem Cell Ther 2019;12:124-125. Available at:
hematopoietic cell transplantation for myelofibrosis using fludarabine-, https://www.ncbi.nlm.nih.gov/pubmed/30075096.
intravenous busulfan- and low-dose TBI-based conditioning. Bone
Marrow Transplant 2014;49:1162-1169. Available at: 68. Antonioli E, Nozzoli C, Buda G, et al. Autologous stem cell
https://www.ncbi.nlm.nih.gov/pubmed/24978138. transplantation is safe in selected elderly multiple myeloma patients. Eur
J Haematol 2020;104:138-144. Available at:
61. Horowitz MM, Gale RP, Sondel PM, et al. Graft-versus-leukemia https://www.ncbi.nlm.nih.gov/pubmed/31762088.
reactions after bone marrow transplantation. Blood 1990;75:555-562.
Available at: https://www.ncbi.nlm.nih.gov/pubmed/2297567. 69. Sorror ML, Maris MB, Storb R, et al. Hematopoietic cell
transplantation (HCT)-specific comorbidity index: a new tool for risk
62. Corradini P, Dodero A, Zallio F, et al. Graft-versus-lymphoma effect assessment before allogeneic HCT. Blood 2005;106:2912-2919.
in relapsed peripheral T-cell non-Hodgkin's lymphomas after reduced- Available at: https://www.ncbi.nlm.nih.gov/pubmed/15994282.
intensity conditioning followed by allogeneic transplantation of
hematopoietic cells. J Clin Oncol 2004;22:2172-2176. Available at: 70. Sorror ML, Logan BR, Zhu X, et al. Prospective validation of the
https://www.ncbi.nlm.nih.gov/pubmed/15169805. predictive power of the hematopoietic cell transplantation comorbidity
index: a Center for International Blood and Marrow Transplant research
63. Weisdorf D, Zhang MJ, Arora M, et al. Graft-versus-host disease study. Biol Blood Marrow Transplant 2015;21:1479-1487. Available at:
induced graft-versus-leukemia effect: greater impact on relapse and https://www.ncbi.nlm.nih.gov/pubmed/25862591.
disease-free survival after reduced intensity conditioning. Biol Blood
Marrow Transplant 2012;18:1727-1733. Available at: 71. ElSawy M, Storer BE, Pulsipher MA, et al. Multi-centre validation of
https://www.ncbi.nlm.nih.gov/pubmed/22766220. the prognostic value of the haematopoietic cell transplantation- specific
comorbidity index among recipient of allogeneic haematopoietic cell
64. Artz AS. Biologic vs physiologic age in the transplant candidate. transplantation. Br J Haematol 2015;170:574-583. Available at:
Hematology Am Soc Hematol Educ Program 2016;2016:99-105. https://www.ncbi.nlm.nih.gov/pubmed/25945807.
Available at: https://www.ncbi.nlm.nih.gov/pubmed/27913468.
72. Saad A, Mahindra A, Zhang MJ, et al. Hematopoietic cell transplant
comorbidity index is predictive of survival after autologous hematopoietic
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NCCN Guidelines Version 1.2025

Hematopoietic Cell Transplantation

cell transplantation in multiple myeloma. Biol Blood Marrow Transplant 80. Trifilio S, Zhou Z, Galvin J, et al. Filgrastim versus TBO-filgrastim to
2014;20:402-408 e401. Available at: reduce the duration of neutropenia after autologous hematopoietic stem
https://www.ncbi.nlm.nih.gov/pubmed/24342394. cell transplantation: TBO, or not TBO, that is the question. Clin
Transplant 2015;29:1128-1132. Available at:
73. Berro M, Arbelbide JA, Rivas MM, et al. Hematopoietic cell https://www.ncbi.nlm.nih.gov/pubmed/26493022.
transplantation-specific comorbidity index predicts morbidity and
mortality in autologous stem cell transplantation. Biol Blood Marrow 81. Neme K, Henkin D, Mikulandric N, et al. Outcomes of tbo-filgrastim,
Transplant 2017;23:1646-1650. Available at: filgrastim-sndz or filgrastim for mobilization in patients undergoing an
https://www.ncbi.nlm.nih.gov/pubmed/28669923. autologous hematopoietic stem cell transplant: A single center
experience. Journal of Clinical Oncology 2019;37:e19000-e19000.
74. Sorror ML, Storb RF, Sandmaier BM, et al. Comorbidity-age index: a Available at:
clinical measure of biologic age before allogeneic hematopoietic cell https://ascopubs.org/doi/abs/10.1200/JCO.2019.37.15_suppl.e19000.
transplantation. J Clin Oncol 2014;32:3249-3256. Available at:
https://www.ncbi.nlm.nih.gov/pubmed/25154831. 82. Schmitt M, Hoffmann JM, Lorenz K, et al. Mobilization of autologous
and allogeneic peripheral blood stem cells for transplantation in
75. Sorror ML. How I assess comorbidities before hematopoietic cell haematological malignancies using biosimilar G-CSF. Vox Sang
transplantation. Blood 2013;121:2854-2863. Available at: 2016;111:178-186. Available at:
https://www.ncbi.nlm.nih.gov/pubmed/23355537. https://www.ncbi.nlm.nih.gov/pubmed/27509033.

76. Foundation for the Accreditation of Cellular Therapy and Joint 83. Chaudhary L, Awan F, Cumpston A, et al. Peripheral blood stem cell
Accreditation Committee-ISCT and EBMT. FACT-JACIE International mobilization in multiple myeloma patients treat in the novel therapy-era
Standards for Hematopoietic Cellular Therapy Product Collection, with plerixafor and G-CSF has superior efficacy but significantly higher
Processing, and Administration (8th edition). 2021. Available at: costs compared to mobilization with low-dose cyclophosphamide and G-
https://www.factglobal.org/ctstandards/. CSF. J Clin Apher 2013;28:359-367. Available at:
http://www.ncbi.nlm.nih.gov/pubmed/23765597.
77. Jillella AP, Ustun C. What is the optimum number of CD34+
peripheral blood stem cells for an autologous transplant? Stem Cells Dev 84. Dugan MJ, Maziarz RT, Bensinger WI, et al. Safety and preliminary
2004;13:598-606. Available at: efficacy of plerixafor (Mozobil) in combination with chemotherapy and G-
https://www.ncbi.nlm.nih.gov/pubmed/15684827. CSF: an open-label, multicenter, exploratory trial in patients with multiple
myeloma and non-Hodgkin's lymphoma undergoing stem cell
78. Kroger N, Zeller W, Fehse N, et al. Mobilizing peripheral blood stem mobilization. Bone Marrow Transplant 2010;45:39-47. Available at:
cells with high-dose G-CSF alone is as effective as with Dexa-BEAM http://www.ncbi.nlm.nih.gov/pubmed/19483760.
plus G-CSF in lymphoma patients. Br J Haematol 1998;102:1101-1106.
Available at: https://www.ncbi.nlm.nih.gov/pubmed/9734664. 85. Gopal AK, Karami M, Mayor J, et al. The effective use of plerixafor as
a real-time rescue strategy for patients poorly mobilizing autologous
79. Elayan MM, Horowitz JG, Magraner JM, et al. Tbo-filgrastim versus CD34(+) cells. J Clin Apher 2012;27:81-87. Available at:
filgrastim during mobilization and neutrophil engraftment for autologous https://www.ncbi.nlm.nih.gov/pubmed/22298418.
stem cell transplantation. Biol Blood Marrow Transplant 2015;21:1921-
1925. Available at: https://www.ncbi.nlm.nih.gov/pubmed/26033279.
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NCCN Guidelines Version 1.2025

Hematopoietic Cell Transplantation

86. Milone G, Tripepi G, Martino M, et al. Early measurement of CD34+ multiple myeloma: a randomized phase 3 trial. Nat Med 2023;29:869-
cells in peripheral blood after cyclophosphamide and granulocyte colony- 879. Available at: https://www.ncbi.nlm.nih.gov/pubmed/37069359.
stimulating factor treatment predicts later CD34+ mobilisation failure and
is a possible criterion for guiding "on demand" use of plerixafor. Blood 93. Haynes A, Hunter A, McQuaker G, et al. Engraftment characteristics
Transfus 2013;11:94-101. Available at: of peripheral blood stem cells mobilised with cyclophosphamide and the
https://www.ncbi.nlm.nih.gov/pubmed/23114516. delayed addition of G-CSF. Bone Marrow Transplant 1995;16:359-363.
Available at: https://www.ncbi.nlm.nih.gov/pubmed/8535307.
87. Giralt S, Costa L, Schriber J, et al. Optimizing autologous stem cell
mobilization strategies to improve patient outcomes: consensus 94. Chao NJ, Grima DT, Carrum G, et al. Chemo-mobilization provides
guidelines and recommendations. Biol Blood Marrow Transplant superior mobilization and collection in autologous stem cell transplants
2014;20:295-308. Available at: but with less predictability and at a higher cost. Blood 2011;118:4040-
https://www.ncbi.nlm.nih.gov/pubmed/24141007. 4048. Available at:
https://ashpublications.org/blood/article/118/21/4048/68992/Chemo-
88. Becker PS. Optimizing stem cell mobilization: lessons learned. J Natl Mobilization-Provides-Superior-Mobilization.
Compr Canc Netw 2014;12:1443-1449. Available at:
https://www.ncbi.nlm.nih.gov/pubmed/25313183. 95. Gazitt Y, Callander N, Freytes CO, et al. Peripheral blood stem cell
mobilization with cyclophosphamide in combination with G-CSF, GM-
89. DiPersio JF, Micallef IN, Stiff PJ, et al. Phase III prospective CSF, or sequential GM-CSF/G-CSF in non-Hodgkin's lymphoma
randomized double-blind placebo-controlled trial of plerixafor plus patients: a randomized prospective study. J Hematother Stem Cell Res
granulocyte colony-stimulating factor compared with placebo plus 2000;9:737-748. Available at:
granulocyte colony-stimulating factor for autologous stem-cell https://www.ncbi.nlm.nih.gov/pubmed/11091498.
mobilization and transplantation for patients with non-Hodgkin's
lymphoma. J Clin Oncol 2009;27:4767-4773. Available at: 96. Kobbe G, Bruns I, Fenk R, et al. Pegfilgrastim for PBSC mobilization
https://www.ncbi.nlm.nih.gov/pubmed/19720922. and autologous haematopoietic SCT. Bone Marrow Transplant
2009;43:669-677. Available at:
90. DiPersio JF, Stadtmauer EA, Nademanee A, et al. Plerixafor and G- http://www.ncbi.nlm.nih.gov/pubmed/19308043.
CSF versus placebo and G-CSF to mobilize hematopoietic stem cells for
autologous stem cell transplantation in patients with multiple myeloma. 97. Costa LJ, Kramer C, Hogan KR, et al. Pegfilgrastim- versus
Blood 2009;113:5720-5726. Available at: filgrastim-based autologous hematopoietic stem cell mobilization in the
https://www.ncbi.nlm.nih.gov/pubmed/19363221. setting of preemptive use of plerixafor: efficacy and cost analysis.
Transfusion 2012;52:2375-2381. Available at:
91. Duong HK, Savani BN, Copelan E, et al. Peripheral blood progenitor http://www.ncbi.nlm.nih.gov/pubmed/22404694.
cell mobilization for autologous and allogeneic hematopoietic cell
transplantation: guidelines from the American Society for Blood and 98. Herbert KE, Demosthenous L, Wiesner G, et al. Plerixafor plus
Marrow Transplantation. Biol Blood Marrow Transplant 2014;20:1262- pegfilgrastim is a safe, effective mobilization regimen for poor or
1273. Available at: https://www.ncbi.nlm.nih.gov/pubmed/24816581. adequate mobilizers of hematopoietic stem and progenitor cells: a phase
I clinical trial. Bone Marrow Transplant 2014;49:1056-1062. Available at:
92. Crees ZD, Rettig MP, Jayasinghe RG, et al. Motixafortide and G-CSF https://www.ncbi.nlm.nih.gov/pubmed/24887382.
to mobilize hematopoietic stem cells for autologous transplantation in
MS-36
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NCCN Guidelines Version 1.2025

Hematopoietic Cell Transplantation

99. Abid MB, De Mel S, Abid MA, et al. Pegylated filgrastim versus 106. Kuittinen T, Nousiainen T, Halonen P, et al. Prediction of
filgrastim for stem cell mobilization in multiple myeloma after novel agent mobilisation failure in patients with non-Hodgkin's lymphoma. Bone
induction. Clin Lymphoma Myeloma Leuk 2018;18:174-179. Available at: Marrow Transplant 2004;33:907-912. Available at:
https://www.ncbi.nlm.nih.gov/pubmed/29398647. https://www.ncbi.nlm.nih.gov/pubmed/15034543.

100. Herbert KE, Gambell P, Link EK, et al. Pegfilgrastim compared with 107. Kumar S, Giralt S, Stadtmauer EA, et al. Mobilization in myeloma
filgrastim for cytokine-alone mobilization of autologous haematopoietic revisited: IMWG consensus perspectives on stem cell collection following
stem and progenitor cells. Bone Marrow Transplant 2013;48:351-356. initial therapy with thalidomide-, lenalidomide-, or bortezomib-containing
Available at: https://www.ncbi.nlm.nih.gov/pubmed/22858510. regimens. Blood 2009;114:1729-1735. Available at:
https://www.ncbi.nlm.nih.gov/pubmed/19561323.
101. Partanen A, Valtola J, Ropponen A, et al. Preemptive plerixafor
injection added to pegfilgrastim after chemotherapy in non-Hodgkin 108. Micallef IN, Apostolidis J, Rohatiner AZ, et al. Factors which predict
lymphoma patients mobilizing poorly. Ann Hematol 2017;96:1897-1906. unsuccessful mobilisation of peripheral blood progenitor cells following
Available at: https://www.ncbi.nlm.nih.gov/pubmed/28879595. G-CSF alone in patients with non-Hodgkin's lymphoma. Hematol J
2000;1:367-373. Available at:
102. Micallef IN, Stiff PJ, DiPersio JF, et al. Successful stem cell https://www.ncbi.nlm.nih.gov/pubmed/11920216.
remobilization using plerixafor (mozobil) plus granulocyte colony-
stimulating factor in patients with non-hodgkin lymphoma: results from 109. Hosing C, Saliba RM, Ahlawat S, et al. Poor hematopoietic stem
the plerixafor NHL phase 3 study rescue protocol. Biol Blood Marrow cell mobilizers: a single institution study of incidence and risk factors in
Transplant 2009;15:1578-1586. Available at: patients with recurrent or relapsed lymphoma. Am J Hematol
https://www.ncbi.nlm.nih.gov/pubmed/19896082. 2009;84:335-337. Available at:
https://www.ncbi.nlm.nih.gov/pubmed/19384931.
103. Li J, Hamilton E, Vaughn L, et al. Effectiveness and cost analysis of
"just-in-time" salvage plerixafor administration in autologous transplant 110. Wuchter P, Ran D, Bruckner T, et al. Poor mobilization of
patients with poor stem cell mobilization kinetics. Transfusion hematopoietic stem cells-definitions, incidence, risk factors, and impact
2011;51:2175-2182. Available at: on outcome of autologous transplantation. Biol Blood Marrow Transplant
https://www.ncbi.nlm.nih.gov/pubmed/21492180. 2010;16:490-499. Available at:
https://www.ncbi.nlm.nih.gov/pubmed/19925876.
104. Worel N, Fritsch G, Agis H, et al. Plerixafor as preemptive strategy
results in high success rates in autologous stem cell mobilization failure. 111. Paripati H, Stewart AK, Cabou S, et al. Compromised stem cell
J Clin Apher 2017;32:224-234. Available at: mobilization following induction therapy with lenalidomide in myeloma.
https://www.ncbi.nlm.nih.gov/pubmed/27578390. Leukemia 2008;22:1282-1284. Available at:
https://www.ncbi.nlm.nih.gov/pubmed/18216870.
105. Tournilhac O, Cazin B, Lepretre S, et al. Impact of frontline
fludarabine and cyclophosphamide combined treatment on peripheral 112. Mazumder A, Kaufman J, Niesvizky R, et al. Effect of lenalidomide
blood stem cell mobilization in B-cell chronic lymphocytic leukemia. therapy on mobilization of peripheral blood stem cells in previously
Blood 2004;103:363-365. Available at: untreated multiple myeloma patients. Leukemia 2008;22:1280-1281;
https://www.ncbi.nlm.nih.gov/pubmed/12969985. author reply 1281-1282. Available at:
https://www.ncbi.nlm.nih.gov/pubmed/18033320.
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NCCN Guidelines Version 1.2025

Hematopoietic Cell Transplantation

113. Waterman J, Rybicki L, Bolwell B, et al. Fludarabine as a risk factor 120. Azar N, Choquet S, Garnier A. Use of a biosimilar G-CSF in
for poor stem cell harvest, treatment-related MDS and AML in follicular allogeneic stem cell mobilisation. Bone Marrow Transplant 2012;47:S316
lymphoma patients after autologous hematopoietic cell transplantation. (P727). Available at:
Bone Marrow Transplant 2012;47:488-493. Available at: http://www.nature.com/bmt/journal/v47/n1s/pdf/bmt201237a.pdf.
https://www.ncbi.nlm.nih.gov/pubmed/21572461.
121. Antelo M, Zabalza A, Sanchez P. Safety and efficacy of a G-CSF
114. Ogunniyi A, Rodriguez M, Devlin S, et al. Upfront use of plerixafor biosimilar (Zarzio(R)) for haematopoietic progenitor cell mobilization in
and granulocyte-colony stimulating factor (GCSF) for stem cell allogeneic healthy donors. Bone Marrow Transplant 2013;48:S102
mobilization in patients with multiple myeloma: efficacy and analysis of (P491). Available at:
risk factors associated with poor stem cell collection efficiency. Leuk http://www.nature.com/bmt/journal/v48/n2s/pdf/bmt201323a.pdf.
Lymphoma 2017;58:1123-1129. Available at:
https://www.ncbi.nlm.nih.gov/pubmed/27735212. 122. Becker P, Schwebig A, Brauninger S, et al. Healthy donor
hematopoietic stem cell mobilization with biosimilar granulocyte-colony-
115. Shin S, Kim J, Kim-Wanner SZ, et al. A novel association between stimulating factor: safety, efficacy, and graft performance. Transfusion
relaxin receptor polymorphism and hematopoietic stem cell yield after 2016;56:3055-3064. Available at:
mobilization. PLoS One 2017;12:e0179986. Available at: https://www.ncbi.nlm.nih.gov/pubmed/27633122.
https://www.ncbi.nlm.nih.gov/pubmed/28666004.
123. Antelo ML, Zabalza A, Sanchez Anton MP, et al. Mobilization of
116. Kanate AS, Watkins K, Cumpston A, et al. Salvage bone marrow hematopoietic progenitor cells from allogeneic healthy donors using a
harvest in patients failing plerixafor-based stem cell mobilization attempt: new biosimilar G-CSF (Zarzio(R)). J Clin Apher 2016;31:48-52. Available
feasibility and autologous transplantation outcomes. Biol Blood Marrow at: http://www.ncbi.nlm.nih.gov/pubmed/26011178.
Transplant 2013;19:1133-1135. Available at:
https://www.ncbi.nlm.nih.gov/pubmed/23635452. 124. Farhan R, Urbanowska E, Zborowska H, et al. Biosimilar G-CSF
versus filgrastim and lenograstim in healthy unrelated volunteer
117. Bensinger WI, Weaver CH, Appelbaum FR, et al. Transplantation of hematopoietic stem cell donors. Ann Hematol 2017;96:1735-1739.
allogeneic peripheral blood stem cells mobilized by recombinant human Available at: https://www.ncbi.nlm.nih.gov/pubmed/28801752.
granulocyte colony-stimulating factor. Blood 1995;85:1655-1658.
Available at: https://www.ncbi.nlm.nih.gov/pubmed/7534140. 125. Pahnke S, Egeland T, Halter J, et al. Current use of biosimilar G-
CSF for haematopoietic stem cell mobilisation. Bone Marrow Transplant
118. Cavallaro AM, Lilleby K, Majolino I, et al. Three to six year follow-up 2019;54:858-866. Available at:
of normal donors who received recombinant human granulocyte colony- https://www.ncbi.nlm.nih.gov/pubmed/30283148.
stimulating factor. Bone Marrow Transplant 2000;25:85-89. Available at:
https://www.ncbi.nlm.nih.gov/pubmed/10654020. 126. Schmitt M, Xu X, Hilgendorf I, et al. Mobilization of PBSC for
allogeneic transplantation by the use of the G-CSF biosimilar XM02 in
119. Rinaldi C, Savignano C, Pasca S, et al. Efficacy and safety of healthy donors. Bone Marrow Transplant 2013;48:922-925. Available at:
peripheral blood stem cell mobilization and collection: a single-center http://www.ncbi.nlm.nih.gov/pubmed/23318540.
experience in 190 allogeneic donors. Transfusion 2012;52:2387-2394.
Available at: https://www.ncbi.nlm.nih.gov/pubmed/22452363. 127. Danylesko I, Sareli R, Bloom-Varda N, et al. Biosimilar filgrastim
(Tevagrastim, XMO2) for allogeneic hematopoietic stem cell mobilization
MS-38
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Hematopoietic Cell Transplantation

and transplantation in patients with acute myelogenous 135. Vogel J, Hui S, Hua CH, et al. Pulmonary toxicity after total body
leukemia/myelodysplastic syndromes. Biol Blood Marrow Transplant irradiation - critical review of the literature and recommendations for
2016;22:277-283. Available at: toxicity reporting. Front Oncol 2021;11:708906. Available at:
https://www.ncbi.nlm.nih.gov/pubmed/26343949. https://www.ncbi.nlm.nih.gov/pubmed/34513689.

128. Bacigalupo A, Ballen K, Rizzo D, et al. Defining the intensity of 136. Mohty M, Malard F, Abecassis M, et al. Sinusoidal obstruction
conditioning regimens: working definitions. Biol Blood Marrow Transplant syndrome/veno-occlusive disease: current situation and perspectives-a
2009;15:1628-1633. Available at: position statement from the European Society for Blood and Marrow
https://www.ncbi.nlm.nih.gov/pubmed/19896087. Transplantation (EBMT). Bone Marrow Transplant 2015;50:781-789.
Available at: https://www.ncbi.nlm.nih.gov/pubmed/25798682.
129. McCune JS, Quinones CM, Ritchie J, et al. Harmonization of
Busulfan Plasma Exposure Unit (BPEU): A Community-Initiated 137. Ladha A, Mannis G, Muffly L. Hepatic veno-occlusive disease in
Consensus Statement. Biol Blood Marrow Transplant 2019;25:1890- allogeneic stem cell transplant recipients with prior exposure to
1897. Available at: https://www.ncbi.nlm.nih.gov/pubmed/31136799. gemtuzumab ozogamicin or inotuzumab ozogamicin. Leuk Lymphoma
2021;62:257-263. Available at:
130. Scott BL, Pasquini MC, Logan BR, et al. Myeloablative versus https://www.ncbi.nlm.nih.gov/pubmed/32988266.
reduced-intensity hematopoietic cell transplantation for acute myeloid
leukemia and myelodysplastic syndromes. J Clin Oncol 2017;35:1154- 138. Van Schandevyl G, Bauters T. Thiotepa-induced cutaneous toxicity
1161. Available at: https://www.ncbi.nlm.nih.gov/pubmed/28380315. in pediatric patients: Case report and implementation of preventive care
guidelines. J Oncol Pharm Pract 2019;25:689-693. Available at:
131. Horwitz ME, Stiff PJ, Cutler C, et al. Omidubicel vs standard https://www.ncbi.nlm.nih.gov/pubmed/30185131.
myeloablative umbilical cord blood transplantation: results of a phase 3
randomized study. Blood 2021;138:1429-1440. Available at: 139. Pidala J, Kim J, Jim H, et al. A randomized phase II study to
https://www.ncbi.nlm.nih.gov/pubmed/34157093. evaluate tacrolimus in combination with sirolimus or methotrexate after
allogeneic hematopoietic cell transplantation. Haematologica
132. Bubalo J, Carpenter PA, Majhail N, et al. Conditioning 2012;97:1882-1889. Available at:
chemotherapy dose adjustment in obese patients: a review and position https://www.ncbi.nlm.nih.gov/pubmed/22689677.
statement by the American Society for Blood and Marrow
Transplantation practice guideline committee. Biol Blood Marrow 140. Khimani F, Kim J, Chen L, et al. Predictors of overall survival
Transplant 2014;20:600-616. Available at: among patients treated with sirolimus/tacrolimus vs
https://www.ncbi.nlm.nih.gov/pubmed/24462742. methotrexate/tacrolimus for GvHD prevention. Bone Marrow Transplant
2017;52:1003-1009. Available at:
133. Hagenburg J, Savale L, Lechartier B, et al. Pulmonary hypertension https://www.ncbi.nlm.nih.gov/pubmed/28368376.
associated with busulfan. Pulm Circ 2021;11:20458940211030170.
Available at: https://www.ncbi.nlm.nih.gov/pubmed/34616544. 141. Cutler C, Stevenson K, Kim HT, et al. Sirolimus is associated with
veno-occlusive disease of the liver after myeloablative allogeneic stem
134. Till BG, Madtes DK. BCNU-associated pneumonitis: portrait of a cell transplantation. Blood 2008;112:4425-4431. Available at:
toxicity. Leuk Lymphoma 2012;53:1019-1020. Available at: https://www.ncbi.nlm.nih.gov/pubmed/18776081.
https://www.ncbi.nlm.nih.gov/pubmed/22220936.
MS-39
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Hematopoietic Cell Transplantation

142. Cutler C, Logan B, Nakamura R, et al. Tacrolimus/sirolimus vs 149. Saito T, Kanda Y, Kami M, et al. Therapeutic potential of a reduced-
tacrolimus/methotrexate as GVHD prophylaxis after matched, related intensity preparative regimen for allogeneic transplantation with
donor allogeneic HCT. Blood 2014;124:1372-1377. Available at: cladribine, busulfan, and antithymocyte globulin against
https://www.ncbi.nlm.nih.gov/pubmed/24982504. advanced/refractory acute leukemia/lymphoma. Clin Cancer Res
2002;8:1014-1020. Available at:
143. Ijaz A, Khan AY, Malik SU, et al. Significant Risk of Graft-versus- https://www.ncbi.nlm.nih.gov/pubmed/11948108.
Host Disease with Exposure to Checkpoint Inhibitors before and after
Allogeneic Transplantation. Biol Blood Marrow Transplant 2019;25:94- 150. Saito T, Kanda Y, Nakai K, et al. Immune reconstitution following
99. Available at: https://www.ncbi.nlm.nih.gov/pubmed/30195074. reduced-intensity transplantation with cladribine, busulfan, and
antithymocyte globulin: serial comparison with conventional
144. Merryman RW, Kim HT, Zinzani PL, et al. Safety and efficacy of myeloablative transplantation. Bone Marrow Transplant 2003;32:601-
allogeneic hematopoietic stem cell transplant after PD-1 blockade in 608. Available at: https://www.ncbi.nlm.nih.gov/pubmed/12953133.
relapsed/refractory lymphoma. Blood 2017;129:1380-1388. Available at:
https://www.ncbi.nlm.nih.gov/pubmed/28073785. 151. Markova M, Barker JN, Miller JS, et al. Fludarabine vs cladribine
plus busulfan and low-dose TBI as reduced intensity conditioning for
145. Kamada Y, Arima N, Hayashida M, et al. Prediction of the risk for allogeneic hematopoietic stem cell transplantation: a prospective
graft versus host disease after allogeneic hematopoietic stem cell randomized trial. Bone Marrow Transplant 2007;39:193-199. Available
transplantation in patients treated with mogamulizumab. Leuk Lymphoma at: https://www.ncbi.nlm.nih.gov/pubmed/17220905.
2022;63:1701-1707. Available at:
https://www.ncbi.nlm.nih.gov/pubmed/35225126. 152. Dimitrova D, Gea-Banacloche J, Steinberg SM, et al. Prospective
Study of a Novel, Radiation-Free, Reduced-Intensity Bone Marrow
146. Merryman RW, Castagna L, Giordano L, et al. Allogeneic Transplantation Platform for Primary Immunodeficiency Diseases. Biol
transplantation after PD-1 blockade for classic Hodgkin lymphoma. Blood Marrow Transplant 2020;26:94-106. Available at:
Leukemia 2021;35:2672-2683. Available at: https://www.ncbi.nlm.nih.gov/pubmed/31493539.
https://www.ncbi.nlm.nih.gov/pubmed/33658659.
153. Gvajaia A, Langston A, Esiashvil N , et al. Pentotstatin/TBI
147. Maziarz RT, Diaz A, Miklos DB, Shah NN. Perspective: An Conditioning Is Well-Tolerated and Permits Engraftment of a Second
International Fludarabine Shortage: Supply Chain Issues Impacting Allogeneic Stem Cell Transplant Following Primary or Secondary
Transplantation and Immune Effector Cell Therapy Delivery. Rejection of an Allogeneic Hematopoietic Stem Graft [abstract]. Blood
Transplantation and Cellular Therapy, Official Publication of the 2019;134 (Suppl 1):Abstract 5657. Available at:
American Society for Transplantation and Cellular Therapy 2022;28:723- https://ashpublications.org/blood/article/134/Supplement_1/5657/425387/
726. Available at: https://doi.org/10.1016/j.jtct.2022.08.002. Pentotstatin-TBI-Conditioning-Is-Well-Tolerated?
148. Chevallier P, Peterlin P, Garnier A, et al. Clofarabine-based 154. McDonald GB, Sandmaier BM, Mielcarek M, et al. Survival,
reduced intensity conditioning regimen with peripheral blood stem cell nonrelapse mortality, and relapse-related mortality after allogeneic
graft and post-transplant cyclophosphamide in adults with myeloid hematopoietic cell transplantation: comparing 2003-2007 versus 2013-
malignancies. Oncotarget 2018;9:33528-33535. Available at: 2017 cohorts. Ann Intern Med 2020;172:229-239. Available at:
https://www.ncbi.nlm.nih.gov/pubmed/30323896. https://www.ncbi.nlm.nih.gov/pubmed/31958813.

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Hematopoietic Cell Transplantation

155. Levine JE, Uberti JP, Ayash L, et al. Lowered-intensity preparative 2010;363:2091-2101. Available at:
regimen for allogeneic stem cell transplantation delays acute graft- https://www.ncbi.nlm.nih.gov/pubmed/21105791.
versus-host disease but does not improve outcome for advanced
hematologic malignancy. Biol Blood Marrow Transplant 2003;9:189-197. 163. Tanaka Y, Kurosawa S, Tajima K, et al. Analysis of non-relapse
Available at: https://www.ncbi.nlm.nih.gov/pubmed/12652470. mortality and causes of death over 15 years following allogeneic
hematopoietic stem cell transplantation. Bone Marrow Transplant
156. Majhail NS, Rizzo JD, Lee SJ, et al. Recommended screening and 2016;51:553-559. Available at:
preventive practices for long-term survivors after hematopoietic cell https://www.ncbi.nlm.nih.gov/pubmed/26752142.
transplantation. Biol Blood Marrow Transplant 2012;18:348-371.
Available at: https://www.ncbi.nlm.nih.gov/pubmed/22178693. 164. Wingard JR, Majhail NS, Brazauskas R, et al. Long-term survival
and late deaths after allogeneic hematopoietic cell transplantation. J Clin
157. Jim HS, Syrjala KL, Rizzo D. Supportive care of hematopoietic cell Oncol 2011;29:2230-2239. Available at:
transplant patients. Biol Blood Marrow Transplant 2012;18:S12-16. https://www.ncbi.nlm.nih.gov/pubmed/21464398.
Available at: https://www.ncbi.nlm.nih.gov/pubmed/22226095.
165. D'Souza A, Fretham C, Lee SJ, et al. Current use of and trends in
158. Giebel S, Labopin M, Socie G, et al. Improving results of allogeneic hematopoietic cell transplantation in the United States. Biol Blood
hematopoietic cell transplantation for adults with acute lymphoblastic Marrow Transplant 2020;26:e177-e182. Available at:
leukemia in first complete remission: an analysis from the Acute https://www.ncbi.nlm.nih.gov/pubmed/32438042.
Leukemia Working Party of the European Society for Blood and Marrow
Transplantation. Haematologica 2017;102:139-149. Available at: 166. Marchesi F, Pimpinelli F, Di Domenico EG, et al. Association
https://www.ncbi.nlm.nih.gov/pubmed/27686376. between CMV and invasive fungal infections after autologous stem cell
transplant in lymphoproliferative malignancies: opportunistic partnership
159. Ribera JM. Allogeneic stem cell transplantation for adult acute or cause-effect relationship? Int J Mol Sci 2019;20. Available at:
lymphoblastic leukemia: when and how. Haematologica 2011;96:1083- https://www.ncbi.nlm.nih.gov/pubmed/30893777.
1086. Available at: https://www.ncbi.nlm.nih.gov/pubmed/21810970.
167. Jantunen E, Itala M, Lehtinen T, et al. Early treatment-related
160. Trajkovska I, Georgievski B, Cevreska L, et al. Early and late mortality in adult autologous stem cell transplant recipients: a nation-
complications in patients with allogeneic transplantation of hematopoietic wide survey of 1482 transplanted patients. Eur J Haematol 2006;76:245-
stem cell. Open Access Maced J Med Sci 2017;5:340-343. Available at: 250. Available at: https://www.ncbi.nlm.nih.gov/pubmed/16412136.
https://www.ncbi.nlm.nih.gov/pubmed/28698754.
168. Przepiorka D, Weisdorf D, Martin P, et al. 1994 consensus
161. Bacigalupo A, Sormani MP, Lamparelli T, et al. Reducing conference on acute GVHD grading. Bone Marrow Transplant
transplant-related mortality after allogeneic hematopoietic stem cell 1995;15:825-828. Available at:
transplantation. Haematologica 2004;89:1238-1247. Available at: https://www.ncbi.nlm.nih.gov/pubmed/7581076.
https://www.ncbi.nlm.nih.gov/pubmed/15477210.
169. Filipovich AH, Weisdorf D, Pavletic S, et al. National Institutes of
162. Gooley TA, Chien JW, Pergam SA, et al. Reduced mortality after Health Consensus Development Project on criteria for clinical trials in
allogeneic hematopoietic-cell transplantation. N Engl J Med chronic graft-versus-host disease: I. Diagnosis and staging working

MS-41
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group report. Biol Blood Marrow Transplant 2005;11:945-956. Available 177. Ross WA, Ghosh S, Dekovich AA, et al. Endoscopic biopsy
at: https://www.ncbi.nlm.nih.gov/pubmed/16338616. diagnosis of acute gastrointestinal graft-versus-host disease:
rectosigmoid biopsies are more sensitive than upper gastrointestinal
170. Flowers ME, Martin PJ. How we treat chronic graft-versus-host biopsies. Am J Gastroenterol 2008;103:982-989. Available at:
disease. Blood 2015;125:606-615. Available at: https://www.ncbi.nlm.nih.gov/pubmed/18028511.
https://www.ncbi.nlm.nih.gov/pubmed/25398933.
178. Glucksberg H, Storb R, Fefer A, et al. Clinical manifestations of
171. Arai S, Arora M, Wang T, et al. Increasing incidence of chronic graft-versus-host disease in human recipients of marrow from HL-A-
graft-versus-host disease in allogeneic transplantation: a report from the matched sibling donors. Transplantation 1974;18:295-304. Available at:
Center for International Blood and Marrow Transplant Research. Biol https://www.ncbi.nlm.nih.gov/pubmed/4153799.
Blood Marrow Transplant 2015;21:266-274. Available at:
https://www.ncbi.nlm.nih.gov/pubmed/25445023. 179. Rowlings PA, Przepiorka D, Klein JP, et al. IBMTR Severity Index
for grading acute graft-versus-host disease: retrospective comparison
172. Jagasia M, Arora M, Flowers ME, et al. Risk factors for acute GVHD with Glucksberg grade. Br J Haematol 1997;97:855-864. Available at:
and survival after hematopoietic cell transplantation. Blood https://www.ncbi.nlm.nih.gov/pubmed/9217189.
2012;119:296-307. Available at:
https://www.ncbi.nlm.nih.gov/pubmed/22010102. 180. Martino R, Romero P, Subira M, et al. Comparison of the classic
Glucksberg criteria and the IBMTR Severity Index for grading acute graft-
173. Flowers ME, Inamoto Y, Carpenter PA, et al. Comparative analysis versus-host disease following HLA-identical sibling stem cell
of risk factors for acute graft-versus-host disease and for chronic graft- transplantation. International Bone Marrow Transplant Registry. Bone
versus-host disease according to National Institutes of Health consensus Marrow Transplant 1999;24:283-287. Available at:
criteria. Blood 2011;117:3214-3219. Available at: https://www.ncbi.nlm.nih.gov/pubmed/10455367.
https://www.ncbi.nlm.nih.gov/pubmed/21263156.
181. MacMillan ML, DeFor TE, Weisdorf DJ. What predicts high risk
174. Jagasia MH, Greinix HT, Arora M, et al. National Institutes of Health acute graft-versus-host disease (GVHD) at onset?: Identification of those
Consensus Development Project on criteria for clinical trials in chronic at highest risk by a novel acute GVHD risk score. Br J Haematol
graft-versus-host disease: I. The 2014 diagnosis and staging working 2012;157:732-741. Available at:
group report. Biol Blood Marrow Transplant 2015;21:389-401 e381. https://www.ncbi.nlm.nih.gov/pubmed/22486355.
Available at: https://www.ncbi.nlm.nih.gov/pubmed/25529383.
182. MacMillan ML, Robin M, Harris AC, et al. A refined risk score for
175. Zeiser R, Blazar BR. Acute graft-versus-host disease - biologic acute graft-versus-host disease that predicts response to initial therapy,
process, prevention, and therapy. N Engl J Med 2017;377:2167-2179. survival, and transplant-related mortality. Biol Blood Marrow Transplant
Available at: https://www.ncbi.nlm.nih.gov/pubmed/29171820. 2015;21:761-767. Available at:
https://www.ncbi.nlm.nih.gov/pubmed/25585275.
176. Martin PJ, Rizzo JD, Wingard JR, et al. First- and second-line
systemic treatment of acute graft-versus-host disease: recommendations 183. Harris AC, Young R, Devine S, et al. International, multicenter
of the American Society of Blood and Marrow Transplantation. Biol Blood standardization of acute graft-versus-host disease clinical data
Marrow Transplant 2012;18:1150-1163. Available at: collection: a report from the Mount Sinai Acute GVHD International
https://www.ncbi.nlm.nih.gov/pubmed/22510384.
MS-42
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Hematopoietic Cell Transplantation

Consortium. Biol Blood Marrow Transplant 2016;22:4-10. Available at: 191. Pidala J, Hamadani M, Dawson P, et al. Randomized multicenter
https://www.ncbi.nlm.nih.gov/pubmed/26386318. trial of sirolimus vs prednisone as initial therapy for standard-risk acute
GVHD: the BMT CTN 1501 trial. Blood 2020;135:97-107. Available at:
184. Schoemans HM, Lee SJ, Ferrara JL, et al. EBMT-NIH-CIBMTR https://www.ncbi.nlm.nih.gov/pubmed/31738834.
Task Force position statement on standardized terminology & guidance
for graft-versus-host disease assessment. Bone Marrow Transplant 192. Alousi AM, Weisdorf DJ, Logan BR, et al. Etanercept,
2018;53:1401-1415. Available at: mycophenolate, denileukin, or pentostatin plus corticosteroids for acute
https://www.ncbi.nlm.nih.gov/pubmed/29872128. graft-versus-host disease: a randomized phase 2 trial from the Blood and
Marrow Transplant Clinical Trials Network. Blood 2009;114:511-517.
185. Major-Monfried H, Renteria AS, Pawarode A, et al. MAGIC Available at: https://www.ncbi.nlm.nih.gov/pubmed/19443659.
biomarkers predict long-term outcomes for steroid-resistant acute GVHD.
Blood 2018;131:2846-2855. Available at: 193. Bolanos-Meade J, Logan BR, Alousi AM, et al. Phase 3 clinical trial
https://www.ncbi.nlm.nih.gov/pubmed/29545329. of steroids/mycophenolate mofetil vs steroids/placebo as therapy for
acute GVHD: BMT CTN 0802. Blood 2014;124:3221-3227; quiz 3335.
186. Ali AM, DiPersio JF, Schroeder MA. The role of biomarkers in the Available at: https://www.ncbi.nlm.nih.gov/pubmed/25170121.
diagnosis and risk stratification of acute graft-versus-host disease: a
systematic review. Biol Blood Marrow Transplant 2016;22:1552-1564. 194. Martin PJ, Inamoto Y, Flowers ME, Carpenter PA. Secondary
Available at: https://www.ncbi.nlm.nih.gov/pubmed/27158050. treatment of acute graft-versus-host disease: a critical review. Biol Blood
Marrow Transplant 2012;18:982-988. Available at:
187. Levine JE, Braun TM, Harris AC, et al. A prognostic score for acute https://www.ncbi.nlm.nih.gov/pubmed/22510383.
graft-versus-host disease based on biomarkers: a multicentre study.
Lancet Haematol 2015;2:e21-29. Available at: 195. Csanadi M, Agh T, Tordai A, et al. A systematic literature review of
https://www.ncbi.nlm.nih.gov/pubmed/26687425. incidence, mortality, and relapse of patients diagnosed with chronic graft
versus host disease. Expert Rev Hematol 2019;12:311-323. Available at:
188. Socie G, Niederwieser D, von Bubnoff N, et al. Prognostic value of https://www.ncbi.nlm.nih.gov/pubmed/30955381.
blood biomarkers in steroid-refractory or steroid-dependent acute graft-
versus-host disease: a REACH2 analysis. Blood 2023;141:2771-2779. 196. Pidala J, Kurland B, Chai X, et al. Patient-reported quality of life is
Available at: https://www.ncbi.nlm.nih.gov/pubmed/36827620. associated with severity of chronic graft-versus-host disease as
measured by NIH criteria: report on baseline data from the Chronic
189. Mielcarek M, Furlong T, Storer BE, et al. Effectiveness and safety of GVHD Consortium. Blood 2011;117:4651-4657. Available at:
lower dose prednisone for initial treatment of acute graft-versus-host https://www.ncbi.nlm.nih.gov/pubmed/21355084.
disease: a randomized controlled trial. Haematologica 2015;100:842-
848. Available at: https://www.ncbi.nlm.nih.gov/pubmed/25682602. 197. Lee SJ, Wolff D, Kitko C, et al. Measuring therapeutic response in
chronic graft-versus-host disease. National Institutes of Health
190. Van Lint MT, Uderzo C, Locasciulli A, et al. Early treatment of acute Consensus Development Project on criteria for clinical trials in chronic
graft-versus-host disease with high- or low-dose 6-methylprednisolone: a graft-versus-host disease: IV. The 2014 response criteria working group
multicenter randomized trial from the Italian Group for Bone Marrow report. Biol Blood Marrow Transplant 2015;21:984-999. Available at:
Transplantation. Blood 1998;92:2288-2293. Available at: https://www.ncbi.nlm.nih.gov/pubmed/25796139.
https://www.ncbi.nlm.nih.gov/pubmed/9746766.
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Hematopoietic Cell Transplantation

198. Carpenter PA, Kitko CL, Elad S, et al. National Institutes of Health 205. Jagasia M, Perales MA, Schroeder MA, et al. Ruxolitinib for the
Consensus Development Project on criteria for clinical trials in chronic treatment of steroid-refractory acute GVHD (REACH1): a multicenter,
graft-versus-host disease: V. The 2014 ancillary therapy and supportive open-label phase 2 trial. Blood 2020;135:1739-1749. Available at:
care working group report. Biol Blood Marrow Transplant 2015;21:1167- https://www.ncbi.nlm.nih.gov/pubmed/32160294.
1187. Available at: https://www.ncbi.nlm.nih.gov/pubmed/25838185
206. Jagasia M, Zeiser R, Arbushites M, et al. Ruxolitinib for the
199. Shulman HM, Cardona DM, Greenson JK, et al. NIH Consensus treatment of patients with steroid-refractory GVHD: an introduction to the
Development Project on criteria for clinical trials in chronic graft-versus- REACH trials. Immunotherapy 2018;10:391-402. Available at:
host disease: II. The 2014 pathology working group report. Biol Blood https://www.ncbi.nlm.nih.gov/pubmed/29316837.
Marrow Transplant 2015;21:589-603. Available at:
https://www.ncbi.nlm.nih.gov/pubmed/25639770. 207. U.S. Food and Drug Administration. FDA approves ruxolitinib for
acute graft-versus-host disease. 2019. Available at:
200. Paczesny S, Hakim FT, Pidala J, et al. National Institutes of Health https://www.fda.gov/drugs/resources-information-approved-drugs/fda-
Consensus Development Project on criteria for clinical trials in chronic approves-ruxolitinib-acute-graft-versus-host-disease. Accessed January
graft-versus-host disease: III. The 2014 biomarker working group report. 24, 2020.
Biol Blood Marrow Transplant 2015;21:780-792. Available at:
https://www.ncbi.nlm.nih.gov/pubmed/25644957. 208. Zeiser R, von Bubnoff N, Butler J, et al. Ruxolitinib for
glucocorticoid-refractory acute graft-versus-host disease. N Engl J Med
201. Metafuni E, Cavattoni IM, Lamparelli T, et al. The day 100 score 2020;382:1800-1810. Available at:
predicts moderate to severe cGVHD, transplant mortality, and survival https://www.ncbi.nlm.nih.gov/pubmed/32320566.
after hematopoietic cell transplantation. Blood Adv 2022;6:2309-2318.
Available at: https://www.ncbi.nlm.nih.gov/pubmed/34920451. 209. Prescribing information for alemtuzumab injection, for intravenous
use. 2023. Available at:
202. Bergeron A, Chevret S, Granata A, et al. Effect of azithromycin on https://www.accessdata.fda.gov/drugsatfda_docs/label/2023/103948s518
airflow decline-free survival after allogeneic hematopoietic stem cell 8lbl.pdf. Accessed July 28, 2023.
transplant: the ALLOZITHRO randomized clinical trial. JAMA
2017;318:557-566. Available at: 210. Khouri IF, Albitar M, Saliba RM, et al. Low-dose alemtuzumab
https://www.ncbi.nlm.nih.gov/pubmed/28787506. (Campath) in myeloablative allogeneic stem cell transplantation for
CD52-positive malignancies: decreased incidence of acute graft-versus-
203. Cheng GS, Bondeelle L, Gooley T, et al. Azithromycin use and host-disease with unique pharmacokinetics. Bone Marrow Transplant
increased cancer risk among patients with bronchiolitis obliterans after 2004;33:833-837. Available at:
hematopoietic cell transplantation. Biol Blood Marrow Transplant https://www.ncbi.nlm.nih.gov/pubmed/14755312.
2020;26:392-400. Available at:
https://www.ncbi.nlm.nih.gov/pubmed/31682980. 211. Gomez-Almaguer D, Ruiz-Arguelles GJ, del Carmen Tarin-Arzaga
L, et al. Alemtuzumab for the treatment of steroid-refractory acute graft-
204. Pidala J, Anasetti C. Glucocorticoid-refractory acute graft-versus- versus-host disease. Biol Blood Marrow Transplant 2008;14:10-15.
host disease. Biol Blood Marrow Transplant 2010;16:1504-1518. Available at: https://www.ncbi.nlm.nih.gov/pubmed/18158956.
Available at: https://www.ncbi.nlm.nih.gov/pubmed/20096359.

MS-44
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Hematopoietic Cell Transplantation

212. Schnitzler M, Hasskarl J, Egger M, et al. Successful treatment of 219. Kumar A, Reljic T, Hamadani M, et al. Antithymocyte globulin for
severe acute intestinal graft-versus-host resistant to systemic and topical graft-versus-host disease prophylaxis: an updated systematic review and
steroids with alemtuzumab. Biol Blood Marrow Transplant 2009;15:910- meta-analysis. Bone Marrow Transplant 2019;54:1094-1106. Available
918. Available at: https://www.ncbi.nlm.nih.gov/pubmed/19589480. at: https://www.ncbi.nlm.nih.gov/pubmed/30446739.

213. Magenau JM, Goldstein SC, Peltier D, et al. alpha1-Antitrypsin 220. Ziakas PD, Zervou FN, Zacharioudakis IM, Mylonakis E. Graft-
infusion for treatment of steroid-resistant acute graft-versus-host versus-host disease prophylaxis after transplantation: a network meta-
disease. Blood 2018;131:1372-1379. Available at: analysis. PLoS One 2014;9:e114735. Available at:
https://www.ncbi.nlm.nih.gov/pubmed/29437593. https://www.ncbi.nlm.nih.gov/pubmed/25485632.

214. Pye A, Turner AM. Experimental and investigational drugs for the 221. Cho BS, Min GJ, Park SS, et al. Low-dose thymoglobulin for
treatment of alpha-1 antitrypsin deficiency. Expert Opin Investig Drugs prevention of chronic graft-versus-host disease in transplantation from an
2019;28:891-902. Available at: HLA-matched sibling donor. Am J Hematol 2021;96:1441-1449.
https://www.ncbi.nlm.nih.gov/pubmed/31550938. Available at: https://www.ncbi.nlm.nih.gov/pubmed/34390504.

215. Arai Y, Jo T, Matsui H, et al. Efficacy of antithymocyte globulin for 222. Khanolkar RA, Kalra A, Kinzel M, et al. A biomarker-guided,
allogeneic hematopoietic cell transplantation: a systematic review and prospective, phase 2 trial of pre-emptive graft-versus-host disease
meta-analysis. Leuk Lymphoma 2017;58:1840-1848. Available at: therapy using anti-thymocyte globulin. Cytotherapy 2021;23:1007-1016.
https://www.ncbi.nlm.nih.gov/pubmed/27951736. Available at: https://www.ncbi.nlm.nih.gov/pubmed/34373186.

216. Alousi AM, Brammer JE, Saliba RM, et al. Phase II trial of graft- 223. Prescribing information for anti-thymocyte globulin (rabbit) for
versus-host disease prophylaxis with post-transplantation intravenous use. 1998. Available at:
cyclophosphamide after reduced-intensity busulfan/fludarabine https://www.fda.gov/media/74641/download. Accessed September 21,
conditioning for hematological malignancies. Biol Blood Marrow 2023.
Transplant 2015;21:906-912. Available at:
https://www.ncbi.nlm.nih.gov/pubmed/25667989. 224. Prescribing information for lymphocyte immune globulin, anti-
thymocyte globulin (equine), sterile solution for intravenous use only.
217. Czerw T, Labopin M, Giebel S, et al. Anti-thymocyte globulin 1981. Available at: https://www.fda.gov/media/78206/download.
improves survival free from relapse and graft-versus-host disease after Accessed September 21, 2023.
allogeneic peripheral blood stem cell transplantation in patients with
Philadelphia-negative acute lymphoblastic leukemia: An analysis by the 225. MacMillan ML, Weisdorf DJ, Davies SM, et al. Early antithymocyte
Acute Leukemia Working Party of the EBMT. Cancer 2018;124:2523- globulin therapy improves survival in patients with steroid-resistant acute
2533. Available at: https://www.ncbi.nlm.nih.gov/pubmed/29603136. graft-versus-host disease. Biol Blood Marrow Transplant 2002;8:40-46.
Available at: https://www.ncbi.nlm.nih.gov/pubmed/11858189.
218. Kroger N, Solano C, Wolschke C, et al. Antilymphocyte globulin for
prevention of chronic graft-versus-host disease. N Engl J Med 226. McCaul KG, Nevill TJ, Barnett MJ, et al. Treatment of steroid-
2016;374:43-53. Available at: resistant acute graft-versus-host disease with rabbit antithymocyte
https://www.ncbi.nlm.nih.gov/pubmed/26735993. globulin. J Hematother Stem Cell Res 2000;9:367-374. Available at:
https://www.ncbi.nlm.nih.gov/pubmed/10894358.
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Hematopoietic Cell Transplantation

227. Nishimoto M, Nakamae H, Koh H, et al. Response-guided therapy 2016;51:103-109. Available at:
for steroid-refractory acute GVHD starting with very-low-dose https://www.ncbi.nlm.nih.gov/pubmed/26437063.
antithymocyte globulin. Exp Hematol 2015;43:177-179. Available at:
https://www.ncbi.nlm.nih.gov/pubmed/25584866. 235. Mielcarek M, Furlong T, O'Donnell PV, et al. Posttransplantation
cyclophosphamide for prevention of graft-versus-host disease after HLA-
228. Ali R, Ramdial J, Algaze S, Beitinjaneh A. The role of anti- matched mobilized blood cell transplantation. Blood 2016;127:1502-
thymocyte globulin or alemtuzumab-based serotherapy in the 1508. Available at: https://www.ncbi.nlm.nih.gov/pubmed/26764356.
prophylaxis and management of graft-versus-host disease. Biomedicines
2017;5:67. Available at: https://www.ncbi.nlm.nih.gov/pubmed/29186076. 236. Torlen J, Ringden O, Garming-Legert K, et al. A prospective
randomized trial comparing cyclosporine/methotrexate and
229. Prescribing information for basiliximab. 2003. Available at: tacrolimus/sirolimus as graft-versus-host disease prophylaxis after
https://www.accessdata.fda.gov/drugsatfda_docs/label/2003/basnov0102 allogeneic hematopoietic stem cell transplantation. Haematologica
03LB.htm. Accessed July 28, 2023. 2016;101:1417-1425. Available at:
https://www.ncbi.nlm.nih.gov/pubmed/27662016.
230. Schmidt-Hieber M, Fietz T, Knauf W, et al. Efficacy of the
interleukin-2 receptor antagonist basiliximab in steroid-refractory acute 237. Al-Kadhimi Z, Gul Z, Abidi M, et al. Low incidence of severe cGvHD
graft-versus-host disease. Br J Haematol 2005;130:568-574. Available and late NRM in a phase II trial of thymoglobulin, tacrolimus and
at: https://www.ncbi.nlm.nih.gov/pubmed/16098072. sirolimus for GvHD prevention. Bone Marrow Transplant 2017;52:1304-
1310. Available at: https://www.ncbi.nlm.nih.gov/pubmed/28581472.
231. Prescribing information for tacrolimus capsules, for oral use;
injection, for intravenous use; granules (tacrolimus for oral suspension). 238. Gao L, Liu J, Zhang Y, et al. Low incidence of acute graft-versus-
2022. Available at: host disease with short-term tacrolimus in haploidentical hematopoietic
https://www.accessdata.fda.gov/drugsatfda_docs/label/2022/050708s054 stem cell transplantation. Leuk Res 2017;57:27-36. Available at:
,050709s047,204096s010lbl.pdf. Accessed July 28, 2023. https://www.ncbi.nlm.nih.gov/pubmed/28273549.

232. Prescribing information for cyclosporine, capsules; oral solution; 239. Deeg HJ, Loughran TP, Jr., Storb R, et al. Treatment of human
injection. 2015. Available at: acute graft-versus-host disease with antithymocyte globulin and
https://www.accessdata.fda.gov/drugsatfda_docs/label/2015/050573s041 cyclosporine with or without methylprednisolone. Transplantation
,050574s051,050625s055lbl.pdf. Accessed July 28, 2023. 1985;40:162-166. Available at:
https://www.ncbi.nlm.nih.gov/pubmed/3895622.
233. Moiseev IS, Pirogova OV, Alyanski AL, et al. Graft-versus-host
disease prophylaxis in unrelated peripheral blood stem cell 240. Kanamaru A, Takemoto Y, Kakishita E, et al. FK506 treatment of
transplantation with post-transplantation cyclophosphamide, tacrolimus, graft-versus-host disease developing or exacerbating during prophylaxis
and mycophenolate mofetil. Biol Blood Marrow Transplant 2016;22:1037- and therapy with cyclosporin and/or other immunosuppressants.
1042. Available at: https://www.ncbi.nlm.nih.gov/pubmed/26970381. Japanese FK506 BMT Study Group. Bone Marrow Transplant
1995;15:885-889. Available at:
234. Kanda Y, Kobayashi T, Mori T, et al. A randomized controlled trial of https://www.ncbi.nlm.nih.gov/pubmed/7581086.
cyclosporine and tacrolimus with strict control of blood concentrations
after unrelated bone marrow transplantation. Bone Marrow Transplant
MS-46
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241. Xhaard A, Launay M, Sicre de Fontbrune F, et al. A monocentric severe acute graft-versus-host disease. Haematologica 2006;91:405-
study of steroid-refractory acute graft-versus-host disease treatment with 408. Available at: https://www.ncbi.nlm.nih.gov/pubmed/16531267.
tacrolimus and mTOR inhibitor. Bone Marrow Transplant 2020;55:86-92.
Available at: https://www.ncbi.nlm.nih.gov/pubmed/31413313. 249. Sakellari I, Gavriilaki E, Batsis I, et al. Favorable impact of
extracorporeal photopheresis in acute and chronic graft versus host
242. Prescribing information for etanercept injection, for subcutaneous disease: prospective single-center study. J Clin Apher 2018;33:654-660.
use. 2023. Available at: Available at: https://www.ncbi.nlm.nih.gov/pubmed/30394564.
https://www.accessdata.fda.gov/drugsatfda_docs/label/2023/103795s559
4lbl.pdf. Accessed July 28, 2023. 250. Zhang H, Chen R, Cheng J, et al. Systematic review and meta-
analysis of prospective studies for ECP treatment in patients with steroid-
243. Couriel D, Saliba R, Hicks K, et al. Tumor necrosis factor-alpha refractory acute GVHD. Patient Prefer Adherence 2015;9:105-111.
blockade for the treatment of acute GVHD. Blood 2004;104:649-654. Available at: https://www.ncbi.nlm.nih.gov/pubmed/25653504.
Available at: https://www.ncbi.nlm.nih.gov/pubmed/15069017.
251. Prescribing information for infliximab for injection, for intravenous
244. Busca A, Locatelli F, Marmont F, et al. Recombinant human soluble use. 2021. Available at:
tumor necrosis factor receptor fusion protein as treatment for steroid https://www.accessdata.fda.gov/drugsatfda_docs/label/2021/103772s540
refractory graft-versus-host disease following allogeneic hematopoietic 1lbl.pdf. Accessed July 28, 2023.
stem cell transplantation. Am J Hematol 2007;82:45-52. Available at:
https://www.ncbi.nlm.nih.gov/pubmed/16937391. 252. Patriarca F, Sperotto A, Damiani D, et al. Infliximab treatment for
steroid-refractory acute graft-versus-host disease. Haematologica
245. Abu-Dalle I, Reljic T, Nishihori T, et al. Extracorporeal 2004;89:1352-1359. Available at:
photopheresis in steroid-refractory acute or chronic graft-versus-host https://www.ncbi.nlm.nih.gov/pubmed/15531458.
disease: results of a systematic review of prospective studies. Biol Blood
Marrow Transplant 2014;20:1677-1686. Available at: 253. Yalniz FF, Hefazi M, McCullough K, et al. Safety and efficacy of
https://www.ncbi.nlm.nih.gov/pubmed/24867779. infliximab therapy in the setting of steroid-refractory acute graft-versus-
host disease. Biol Blood Marrow Transplant 2017;23:1478-1484.
246. Smith EP, Sniecinski I, Dagis AC, et al. Extracorporeal Available at: https://www.ncbi.nlm.nih.gov/pubmed/28495641.
photochemotherapy for treatment of drug-resistant graft-vs.-host
disease. Biol Blood Marrow Transplant 1998;4:27-37. Available at: 254. Goral S, Helderman JH. Chapter 36 - Current and emerging
https://www.ncbi.nlm.nih.gov/pubmed/9701389. maintenance immunosuppressive therapy. In: Himmelfarb J, Sayegh MH,
eds. Chronic Kidney Disease, Dialysis, and Transplantation (Third
247. Alcindor T, Gorgun G, Miller KB, et al. Immunomodulatory effects of Edition). Philadelphia: W.B. Saunders; 2010:516-525.
extracorporeal photochemotherapy in patients with extensive chronic
graft-versus-host disease. Blood 2001;98:1622-1625. Available at: 255. Hsieh A. mTOR: The master regulator. Cell 2012;149:955-957.
https://www.ncbi.nlm.nih.gov/pubmed/11520818. Available at:
http://www.sciencedirect.com/science/article/pii/S0092867412005855.
248. Greinix HT, Knobler RM, Worel N, et al. The effect of intensified
extracorporeal photochemotherapy on long-term survival in patients with

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256. Dumont FJ, Su Q. Mechanism of action of the immunosuppressant 263. Ghez D, Rubio MT, Maillard N, et al. Rapamycin for refractory acute
rapamycin. Life Sci 1996;58:373-395. Available at: graft-versus-host disease. Transplantation 2009;88:1081-1087. Available
https://www.ncbi.nlm.nih.gov/pubmed/8594303. at: https://www.ncbi.nlm.nih.gov/pubmed/19898203.

257. Armand P, Kim HT, Sainvil MM, et al. The addition of sirolimus to 264. Allison AC, Eugui EM. Mycophenolate mofetil and its mechanisms
the graft-versus-host disease prophylaxis regimen in reduced intensity of action. Immunopharmacology 2000;47:85-118. Available at:
allogeneic stem cell transplantation for lymphoma: a multicentre https://www.ncbi.nlm.nih.gov/pubmed/10878285.
randomized trial. Br J Haematol 2016;173:96-104. Available at:
https://www.ncbi.nlm.nih.gov/pubmed/26729448. 265. Prescribing information for mycophenolate mofetil. 2022. Available
at:
258. Kornblit B, Maloney DG, Storer BE, et al. A randomized phase II https://www.accessdata.fda.gov/drugsatfda_docs/label/2022/050722s050
trial of tacrolimus, mycophenolate mofetil and sirolimus after non- ,050723s050,050758s048,050759s055lbl.pdf. Accessed July 28, 2023.
myeloablative unrelated donor transplantation. Haematologica
2014;99:1624-1631. Available at: 266. Furlong T, Martin P, Flowers ME, et al. Therapy with
https://www.ncbi.nlm.nih.gov/pubmed/25085357. mycophenolate mofetil for refractory acute and chronic GVHD. Bone
Marrow Transplant 2009;44:739-748. Available at:
259. Pidala J, Kim J, Alsina M, et al. Prolonged sirolimus administration https://www.ncbi.nlm.nih.gov/pubmed/19377515.
after allogeneic hematopoietic cell transplantation is associated with
decreased risk for moderate-severe chronic graft-versus-host disease. 267. Kim JG, Sohn SK, Kim DH, et al. Different efficacy of
Haematologica 2015;100:970-977. Available at: mycophenolate mofetil as salvage treatment for acute and chronic GVHD
https://www.ncbi.nlm.nih.gov/pubmed/25840599. after allogeneic stem cell transplant. Eur J Haematol 2004;73:56-61.
Available at: https://www.ncbi.nlm.nih.gov/pubmed/15182339.
260. Wang L, Gu Z, Zhai R, et al. The efficacy and safety of sirolimus-
based graft-versus-host disease prophylaxis in patients undergoing 268. Pidala J, Kim J, Perkins J, et al. Mycophenolate mofetil for the
allogeneic hematopoietic stem cell transplantation: a meta-analysis of management of steroid-refractory acute graft vs host disease. Bone
randomized controlled trials. Transfusion 2015;55:2134-2141. Available Marrow Transplant 2010;45:919-924. Available at:
at: https://www.ncbi.nlm.nih.gov/pubmed/25857725. https://www.ncbi.nlm.nih.gov/pubmed/19767783.

261. Benito AI, Furlong T, Martin PJ, et al. Sirolimus (rapamycin) for the 269. Prescribing information for pentostatin for injection. 2019. Available
treatment of steroid-refractory acute graft-versus-host disease. at:
Transplantation 2001;72:1924-1929. Available at: https://www.accessdata.fda.gov/drugsatfda_docs/label/2019/020122s015
https://www.ncbi.nlm.nih.gov/pubmed/11773890. lbl.pdf. Accessed July 28, 2023.

262. Hoda D, Pidala J, Salgado-Vila N, et al. Sirolimus for treatment of 270. Ragon BK, Mehta RS, Gulbis AM, et al. Pentostatin therapy for
steroid-refractory acute graft-versus-host disease. Bone Marrow steroid-refractory acute graft versus host disease: identifying those who
Transplant 2010;45:1347-1351. Available at: may benefit. Bone Marrow Transplant 2018;53:315-325. Available at:
https://www.ncbi.nlm.nih.gov/pubmed/19966849. https://www.ncbi.nlm.nih.gov/pubmed/29269797.

MS-48
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Hematopoietic Cell Transplantation

271. Schmitt T, Luft T, Hegenbart U, et al. Pentostatin for treatment of 278. Ganetsky A, Frey NV, Hexner EO, et al. Tocilizumab for the
steroid-refractory acute GVHD: a retrospective single-center analysis. treatment of severe steroid-refractory acute graft-versus-host disease of
Bone Marrow Transplant 2011;46:580-585. Available at: the lower gastrointestinal tract. Bone Marrow Transplant 2019;54:212-
https://www.ncbi.nlm.nih.gov/pubmed/20562925. 217. Available at: https://www.ncbi.nlm.nih.gov/pubmed/29795429.

272. Pidala J, Kim J, Roman-Diaz J, et al. Pentostatin as rescue therapy 279. Gergis U, Arnason J, Yantiss R, et al. Effectiveness and safety of
for glucocorticoid-refractory acute and chronic graft-versus-host disease. tocilizumab, an anti-interleukin-6 receptor monoclonal antibody, in a
Ann Transplant 2010;15:21-29. Available at: patient with refractory GI graft-versus-host disease. J Clin Oncol
https://www.ncbi.nlm.nih.gov/pubmed/21183872. 2010;28:e602-604. Available at:
https://www.ncbi.nlm.nih.gov/pubmed/20713858.
273. Bolanos-Meade J, Jacobsohn DA, Margolis J, et al. Pentostatin in
steroid-refractory acute graft-versus-host disease. J Clin Oncol 280. Yucebay F, Matthews C, Puto M, et al. Tocilizumab as first-line
2005;23:2661-2668. Available at: therapy for steroid-refractory acute graft-versus-host-disease: analysis of
https://www.ncbi.nlm.nih.gov/pubmed/15837980. a single-center experience. Leuk Lymphoma 2019;60:2223-2229.
Available at: https://www.ncbi.nlm.nih.gov/pubmed/30764681.
274. Poi MJ, Hofmeister CC, Johnston JS, et al. Standard pentostatin
dose reductions in renal insufficiency are not adequate: selected patients 281. Roddy JV, Haverkos BM, McBride A, et al. Tocilizumab for steroid
with steroid-refractory acute graft-versus-host disease. Clin refractory acute graft-versus-host disease. Leuk Lymphoma 2016;57:81-
Pharmacokinet 2013;52:705-712. Available at: 85. Available at: https://www.ncbi.nlm.nih.gov/pubmed/26140610.
https://www.ncbi.nlm.nih.gov/pubmed/23588536.
282. Drobyski WR, Pasquini M, Kovatovic K, et al. Tocilizumab for the
275. Prescribing information for tocilizumab injection, for intravenous or treatment of steroid refractory graft-versus-host disease. Biol Blood
subcutaneous use. 2022. Available at: Marrow Transplant 2011;17:1862-1868. Available at:
https://www.accessdata.fda.gov/drugsatfda_docs/label/2022/125276s138 https://www.ncbi.nlm.nih.gov/pubmed/21745454.
lbl.pdf. Accessed July 28, 2023.
283. Prescribing information for vedlizumab for injection. 2023. Available
276. Imamura M, Hashino S, Kobayashi H, et al. Serum cytokine levels at:
in bone marrow transplantation: synergistic interaction of interleukin-6, https://www.accessdata.fda.gov/drugsatfda_docs/label/2023/125476s057
interferon-gamma, and tumor necrosis factor-alpha in graft-versus-host lbl.pdf. Accessed November 13, 2023.
disease. Bone Marrow Transplant 1994;13:745-751. Available at:
https://www.ncbi.nlm.nih.gov/pubmed/7920309. 284. Li AC, Dong C, Tay ST, et al. Vedolizumab for acute gastrointestinal
graft-versus-host disease: A systematic review and meta-analysis. Front
277. Cavet J, Dickinson AM, Norden J, et al. Interferon-gamma and Immunol 2022;13:1025350. Available at:
interleukin-6 gene polymorphisms associate with graft-versus-host https://www.ncbi.nlm.nih.gov/pubmed/36439135.
disease in HLA-matched sibling bone marrow transplantation. Blood
2001;98:1594-1600. Available at: 285. Danylesko I, Bukauskas A, Paulson M, et al. Anti-alpha4beta7
https://www.ncbi.nlm.nih.gov/pubmed/11520812. integrin monoclonal antibody (vedolizumab) for the treatment of steroid-
resistant severe intestinal acute graft-versus-host disease. Bone Marrow

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Hematopoietic Cell Transplantation

Transplant 2019;54:987-993. Available at: 293. Waller EK, Miklos D, Cutler C, et al. Ibrutinib for chronic graft-
https://www.ncbi.nlm.nih.gov/pubmed/30356163. versus-host disease after failure of prior therapy: 1-year update of a
phase 1b/2 study. Biol Blood Marrow Transplant 2019;25:2002-2007.
286. Floisand Y, Lazarevic VL, Maertens J, et al. Safety and Available at: https://www.ncbi.nlm.nih.gov/pubmed/31260802.
effectiveness of vedolizumab in patients with steroid-refractory
gastrointestinal acute graft-versus-host disease: a retrospective record 294. Prescribing information for belumosudil tablets, for oral use. 2021.
review. Biol Blood Marrow Transplant 2019;25:720-727. Available at: Available at:
https://www.ncbi.nlm.nih.gov/pubmed/30468919. https://www.accessdata.fda.gov/drugsatfda_docs/label/2021/214783s000
lbl.pdf. Accessed July 28, 2023.
287. Miklos D, Cutler CS, Arora M, et al. Ibrutinib for chronic graft-
versus-host disease after failure of prior therapy. Blood 2017;130:2243- 295. Prescribing information for axatilimab-csfr injection, for intravenous
2250. Available at: https://www.ncbi.nlm.nih.gov/pubmed/28924018. use. 2024. Available at:
https://www.accessdata.fda.gov/drugsatfda_docs/label/2024/761411s000
288. Zeiser R, Polverelli N, Ram R, et al. Ruxolitinib for glucocorticoid- lbl.pdf. Accessed August 16, 2024.
refractory chronic graft-versus-host disease. N Engl J Med
2021;385:228-238. Available at: 296. Wolff D, Cutler C, Lee SJ, et al. Safety and efficacy of axatilimab at
https://www.ncbi.nlm.nih.gov/pubmed/34260836. 3 different doses in patients with chronic graft-versus-host disease
(AGAVE-201). Blood 2023;142:1-1. Available at:
289. Cutler CS, Lee SJ, Arai S, et al. Belumosudil for Chronic Graft- https://doi.org/10.1182/blood-2023-186963.
versus-Host Disease After 2 or More Prior Lines of Therapy: The
ROCKstar Study. Blood 2021;138:2278-2289. Available at: 297. Nahas MR, Soiffer RJ, Kim HT, et al. Phase 1 clinical trial
https://www.ncbi.nlm.nih.gov/pubmed/34265047. evaluating abatacept in patients with steroid-refractory chronic graft-
versus-host disease. Blood 2018;131:2836-2845. Available at:
290. U.S. Food and Drug Administration. FDA approves ruxolitinib for https://www.ncbi.nlm.nih.gov/pubmed/29549175.
chronic graft-versus-host disease. 2021. Available at:
https://www.fda.gov/drugs/resources-information-approved-drugs/fda- 298. Prescribing information for abatacept injection. 2021. Available at:
approves-ruxolitinib-chronic-graft-versus-host- https://www.accessdata.fda.gov/drugsatfda_docs/label/2021/125118s240
disease#:~:text=On%20September%2022%2C%202021%2C%20the,pat lbl.pdf. Accessed July 28, 2023.
ients%2012%20years%20and%20older. Accessed January 7, 2022.
299. Nikiforow S, Kim HT, Bindra B, et al. Phase I study of alemtuzumab
291. Dubovsky JA, Beckwith KA, Natarajan G, et al. Ibrutinib is an for therapy of steroid-refractory chronic graft-versus-host disease. Biol
irreversible molecular inhibitor of ITK driving a Th1-selective pressure in Blood Marrow Transplant 2013;19:804-811. Available at:
T lymphocytes. Blood 2013;122:2539-2549. Available at: https://www.ncbi.nlm.nih.gov/pubmed/23416855.
https://www.ncbi.nlm.nih.gov/pubmed/23886836.
300. Gutierrez-Aguirre CH, Cantu-Rodriguez OG, Borjas-Almaguer OD,
292. Prescribing information for ibrutinib capsules, for oral use. 2014. et al. Effectiveness of subcutaneous low-dose alemtuzumab and
Available at: rituximab combination therapy for steroid-resistant chronic graft-versus-
https://www.accessdata.fda.gov/drugsatfda_docs/label/2014/205552Orig host disease. Haematologica 2012;97:717-722. Available at:
2lbl.pdf. Accessed July 28, 2023. https://www.ncbi.nlm.nih.gov/pubmed/22133770.
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Hematopoietic Cell Transplantation

301. Tzakis AG, Abu-Elmagd K, Fung JJ, et al. FK 506 rescue in chronic 2011;17:1-17. Available at:
graft-versus-host-disease after bone marrow transplantation. Transplant https://www.ncbi.nlm.nih.gov/pubmed/20685255.
Proc 1991;23:3225-3227. Available at:
https://www.ncbi.nlm.nih.gov/pubmed/1721416. 309. Gilman AL, Chan KW, Mogul A, et al. Hydroxychloroquine for the
treatment of chronic graft-versus-host disease. Biol Blood Marrow
302. Carnevale-Schianca F, Martin P, Sullivan K, et al. Changing from Transplant 2000;6:327-334. Available at:
cyclosporine to tacrolimus as salvage therapy for chronic graft-versus- https://www.ncbi.nlm.nih.gov/pubmed/10905770.
host disease. Biol Blood Marrow Transplant 2000;6:613-620. Available
at: https://www.ncbi.nlm.nih.gov/pubmed/11128811. 310. Navajas EV, Krema H, Hammoudi DS, et al. Retinal toxicity of high-
dose hydroxychloroquine in patients with chronic graft-versus-host
303. Yanik GA, Mineishi S, Levine JE, et al. Soluble tumor necrosis disease. Can J Ophthalmol 2015;50:442-450. Available at:
factor receptor: Enbrel (etanercept) for subacute pulmonary dysfunction https://www.ncbi.nlm.nih.gov/pubmed/26651304.
following allogeneic stem cell transplantation. Biol Blood Marrow
Transplant 2012;18:1044-1054. Available at: 311. Prescribing information for imatinib mesylate tablets, for oral use.
https://www.ncbi.nlm.nih.gov/pubmed/22155140. 2022. Available at:
https://www.accessdata.fda.gov/drugsatfda_docs/label/2022/021588s062
304. Flowers ME, Apperley JF, van Besien K, et al. A multicenter lbl.pdf. Accessed July 28, 2023.
prospective phase 2 randomized study of extracorporeal photopheresis
for treatment of chronic graft-versus-host disease. Blood 2008;112:2667- 312. Baird K, Comis LE, Joe GO, et al. Imatinib mesylate for the
2674. Available at: https://www.ncbi.nlm.nih.gov/pubmed/18621929. treatment of steroid-refractory sclerotic-type cutaneous chronic graft-
versus-host disease. Biol Blood Marrow Transplant 2015;21:1083-1090.
305. Couriel DR, Hosing C, Saliba R, et al. Extracorporeal Available at: https://www.ncbi.nlm.nih.gov/pubmed/25771402.
photochemotherapy for the treatment of steroid-resistant chronic GVHD.
Blood 2006;107:3074-3080. Available at: 313. Chen GL, Arai S, Flowers ME, et al. A phase 1 study of imatinib for
https://www.ncbi.nlm.nih.gov/pubmed/16368882. corticosteroid-dependent/refractory chronic graft-versus-host disease:
response does not correlate with anti-PDGFRA antibodies. Blood
306. Malik MI, Litzow M, Hogan W, et al. Extracorporeal photopheresis 2011;118:4070-4078. Available at:
for chronic graft-versus-host disease: a systematic review and meta- https://www.ncbi.nlm.nih.gov/pubmed/21828142.
analysis. Blood Res 2014;49:100-106. Available at:
https://www.ncbi.nlm.nih.gov/pubmed/25025011. 314. Arai S, Pidala J, Pusic I, et al. A randomized phase II crossover
study of imatinib or rituximab for cutaneous sclerosis after hematopoietic
307. Prescribing information for hydroxycloroquine sulfate tablets, for cell transplantation. Clin Cancer Res 2016;22:319-327. Available at:
oral use. 2023. Available at: https://www.ncbi.nlm.nih.gov/pubmed/26378033.
https://www.accessdata.fda.gov/drugsatfda_docs/label/2023/009768s060
lbl.pdf. Accessed July 28, 2023. 315. Olivieri A, Cimminiello M, Corradini P, et al. Long-term outcome and
prospective validation of NIH response criteria in 39 patients receiving
308. Wolff D, Schleuning M, von Harsdorf S, et al. Consensus imatinib for steroid-refractory chronic GVHD. Blood 2013;122:4111-4118.
conference on clinical practice in chronic GVHD: second-line treatment Available at: https://www.ncbi.nlm.nih.gov/pubmed/24152907.
of chronic graft-versus-host disease. Biol Blood Marrow Transplant
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Hematopoietic Cell Transplantation

316. Koreth J, Kim HT, Jones KT, et al. Efficacy, durability, and response 324. Johnston LJ, Brown J, Shizuru JA, et al. Rapamycin (sirolimus) for
predictors of low-dose interleukin-2 therapy for chronic graft-versus-host treatment of chronic graft-versus-host disease. Biol Blood Marrow
disease. Blood 2016;128:130-137. Available at: Transplant 2005;11:47-55. Available at:
https://www.ncbi.nlm.nih.gov/pubmed/27073224. https://www.ncbi.nlm.nih.gov/pubmed/15625544.

317. Koreth J, Matsuoka K, Kim HT, et al. Interleukin-2 and regulatory T 325. Jurado M, Vallejo C, Perez-Simon JA, et al. Sirolimus as part of
cells in graft-versus-host disease. N Engl J Med 2011;365:2055-2066. immunosuppressive therapy for refractory chronic graft-versus-host
Available at: https://www.ncbi.nlm.nih.gov/pubmed/22129252. disease. Biol Blood Marrow Transplant 2007;13:701-706. Available at:
https://www.ncbi.nlm.nih.gov/pubmed/17531780.
318. Whangbo JS, Kim HT, Mirkovic N, et al. Dose-escalated interleukin-
2 therapy for refractory chronic graft-versus-host disease in adults and 326. Lutz M, Kapp M, Einsele H, et al. Improvement of quality of life in
children. Blood Adv 2019;3:2550-2561. Available at: patients with steroid-refractory chronic graft-versus-host disease treated
https://www.ncbi.nlm.nih.gov/pubmed/31471324. with the mTOR inhibitor everolimus. Clin Transplant 2014;28:1410-1415.
Available at: https://www.ncbi.nlm.nih.gov/pubmed/25287756.
319. Prescribing information for methotrexate injection, for intravenous
use. 2022. Available at: 327. Mielke S, Lutz M, Schmidhuber J, et al. Salvage therapy with
https://www.accessdata.fda.gov/drugsatfda_docs/label/2022/214121s001 everolimus reduces the severity of treatment-refractory chronic GVHD
lbl.pdf. Accessed July 28, 2023. without impairing disease control: a dual center retrospective analysis.
Bone Marrow Transplant 2014;49:1412-1418. Available at:
320. Giaccone L, Martin P, Carpenter P, et al. Safety and potential https://www.ncbi.nlm.nih.gov/pubmed/25089598.
efficacy of low-dose methotrexate for treatment of chronic graft-versus-
host disease. Bone Marrow Transplant 2005;36:337-341. Available at: 328. Lopez F, Parker P, Nademanee A, et al. Efficacy of mycophenolate
https://www.ncbi.nlm.nih.gov/pubmed/15968296. mofetil in the treatment of chronic graft-versus-host disease. Biol Blood
Marrow Transplant 2005;11:307-313. Available at:
321. de Lavallade H, Mohty M, Faucher C, et al. Low-dose methotrexate https://www.ncbi.nlm.nih.gov/pubmed/15812396.
as salvage therapy for refractory graft-versus-host disease after reduced-
intensity conditioning allogeneic stem cell transplantation. Haematologica 329. Jacobsohn DA, Chen AR, Zahurak M, et al. Phase II study of
2006;91:1438-1440. Available at: pentostatin in patients with corticosteroid-refractory chronic graft-versus-
https://www.ncbi.nlm.nih.gov/pubmed/16963392. host disease. J Clin Oncol 2007;25:4255-4261. Available at:
https://www.ncbi.nlm.nih.gov/pubmed/17878478.
322. Huang XJ, Jiang Q, Chen H, et al. Low-dose methotrexate for the
treatment of graft-versus-host disease after allogeneic hematopoietic 330. Prescribing information for rituximab injection, for intravenous use.
stem cell transplantation. Bone Marrow Transplant 2005;36:343-348. 2021. Available at:
Available at: https://www.ncbi.nlm.nih.gov/pubmed/15968295. https://www.accessdata.fda.gov/drugsatfda_docs/label/2021/103705s546
7lbl.pdf. Accessed July 28, 2023.
323. Couriel DR, Saliba R, Escalon MP, et al. Sirolimus in combination
with tacrolimus and corticosteroids for the treatment of resistant chronic 331. Kharfan-Dabaja MA, Mhaskar AR, Djulbegovic B, et al. Efficacy of
graft-versus-host disease. Br J Haematol 2005;130:409-417. Available rituximab in the setting of steroid-refractory chronic graft-versus-host
at: https://www.ncbi.nlm.nih.gov/pubmed/16042691. disease: a systematic review and meta-analysis. Biol Blood Marrow
MS-52
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Transplant 2009;15:1005-1013. Available at: treatment. Am J Clin Dermatol 2018;19:33-50. Available at:
https://www.ncbi.nlm.nih.gov/pubmed/19660713. https://www.ncbi.nlm.nih.gov/pubmed/28656563.

332. Stern L, Withers B, Avdic S, et al. Human cytomegalovirus latency 339. Ziemer M. Graft-versus-host disease of the skin and adjacent
and reactivation in allogeneic hematopoietic stem cell transplant mucous membranes. J Dtsch Dermatol Ges 2013;11:477-495. Available
recipients. Front Microbiol 2019;10:1186. Available at: at: https://www.ncbi.nlm.nih.gov/pubmed/23721594.
https://www.ncbi.nlm.nih.gov/pubmed/31191499.
340. Naymagon S, Naymagon L, Wong SY, et al. Acute graft-versus-host
333. ASH-ASTCT COVID-19 vaccination for HCT and CAR T cell disease of the gut: considerations for the gastroenterologist. Nat Rev
recipients: Frequently asked questions. 2022. Available at: Gastroenterol Hepatol 2017;14:711-726. Available at:
https://www.hematology.org/covid-19/ash-astct-covid-19-vaccination-for- https://www.ncbi.nlm.nih.gov/pubmed/28951581.
hct-and-car-t-cell-recipients. Accessed July 10, 2023.
341. Peeters M, Van den Brande J, Francque S. Diarrhea and the
334. Bhella S, Majhail NS, Betcher J, et al. Choosing wisely BMT: rationale to use Sandostatin. Acta Gastroenterol Belg 2010;73:25-36.
American Society for Blood and Marrow Transplantation and Canadian Available at: https://www.ncbi.nlm.nih.gov/pubmed/20458847.
Blood and Marrow Transplant Group's list of 5 tests and treatments to
question in blood and marrow transplantation. Biol Blood Marrow 342. van der Meij BS, de Graaf P, Wierdsma NJ, et al. Nutritional support
Transplant 2018;24:909-913. Available at: in patients with GVHD of the digestive tract: state of the art. Bone
https://www.ncbi.nlm.nih.gov/pubmed/29360515. Marrow Transplant 2013;48:474-482. Available at:
https://www.ncbi.nlm.nih.gov/pubmed/22773121.
335. Liu D, Ahmet A, Ward L, et al. A practical guide to the monitoring
and management of the complications of systemic corticosteroid therapy. 343. Borresen SW, Klose M, Glintborg D, et al. Approach to the patient
Allergy Asthma Clin Immunol 2013;9:30. Available at: with glucocorticoid-induced adrenal insufficiency. J Clin Endocrinol
https://www.ncbi.nlm.nih.gov/pubmed/23947590. Metab 2022;107:2065-2076. Available at:
https://www.ncbi.nlm.nih.gov/pubmed/35302603.
336. Ruutu T, Eriksson B, Remes K, et al. Ursodeoxycholic acid for the
prevention of hepatic complications in allogeneic stem cell 344. Moenen FC, Bakers FC, Bos GM. Pancreatic atrophy after
transplantation. Blood 2002;100:1977-1983. Available at: allogeneic peripheral blood stem cell transplantation. Br J Haematol
https://www.ncbi.nlm.nih.gov/pubmed/12200355. 2016;172:155. Available at:
https://www.ncbi.nlm.nih.gov/pubmed/26303722.
337. Ruutu T, Juvonen E, Remberger M, et al. Improved survival with
ursodeoxycholic acid prophylaxis in allogeneic stem cell transplantation: 345. Frey Tirri B, Häusermann P, Bertz H, et al. Clinical guidelines for
long-term follow-up of a randomized study. Biol Blood Marrow Transplant gynecologic care after hematopoietic SCT. Report from the international
2014;20:135-138. Available at: consensus project on clinical practice in chronic GVHD. Bone Marrow
https://www.ncbi.nlm.nih.gov/pubmed/24141008. Transplant 2015;50:3-9. Available at:

338. Strong Rodrigues K, Oliveira-Ribeiro C, de Abreu Fiuza Gomes S, 346. Jain NA, Venkatesan K, Anandi P, et al. A rare consequence of
Knobler R. Cutaneous graft-versus-host disease: Diagnosis and chronic graft versus host disease - peyronie's disease. Arch Cancer Res
2015;3. Available at: https://www.ncbi.nlm.nih.gov/pubmed/26770907.

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