NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®)

Chronic Myeloid Leukemia

Version 1.2024 — August 1, 2023

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Table of Contents
Chronic Myeloid Leukemia Discussion

*Neil P. Shah, MD, PhD/Chair ‡ Lori Maness, MD ‡ Kendra L. Sweet, MD, MS ‡ † Þ

UCSF Helen Diller Family Fred and Pamela Buffett Cancer Center Moffitt Cancer Center
Comprehensive Cancer Center Leland Metheny, MD ‡ ξ Moshe Talpaz, MD †
*Ravi Bhatia, MD/Vice-Chair ‡ Case Comprehensive Cancer Center University of Michigan
O'Neal Comprehensive University Hospitals Seidman Cancer Center Rogel Cancer Center
Cancer Center at UAB and Cleveland Clinic Taussig Cancer Institute Tiffany N. Tanaka, MD ‡
Jessica K. Altman, MD ‡ Sanjay Mohan, MD, MSCI ‡ UC San Diego Moores Cancer Center
Robert H. Lurie Comprehensive Cancer Vanderbilt-Ingram Cancer Center Srinivas Tantravahi, MBBS ‡
Center of Northwestern University Joseph O. Moore, MD † Huntsman Cancer Institute
Maria Amaya, MD, PhD ‡ Duke Cancer Institute at the University of Utah
University of Colorado Cancer Center *Vivian Oehler, MD ‡ James Thompson, MD, MS ‡
Kebede H. Begna, MD ‡ Fred Hutchinson Cancer Center Roswell Park Comprehensive
Mayo Clinic Comprehensive Cancer Center Keith Pratz, MD † Cancer Center
Ellin Berman, MD ‡ † Þ Abramson Cancer Center Steven Tsai, MD ‡ ξ
Memorial Sloan Kettering Cancer Center at the University of Pennsylvania UCLA Jonsson Comprehensive
Robert H. Collins, Jr., MD ‡ Iskra Pusic, MD, MSCI † Cancer Center
UT Southwestern Simmons Siteman Cancer Center at Barnes- Jennifer Vaughn, MD, MSPH ‡
Comprehensive Cancer Center Jewish Hospital and Washington The Ohio State University Comprehensive
Peter T. Curtin, MD † ‡ ξ University School of Medicine Cancer Center - James Cancer Hospital
City of Hope National Medical Center Michal G. Rose, MD † and Solove Research Institute

Daniel J. DeAngelo, MD, PhD ‡ † Yale Cancer Center/ Jeanna Welborn, MD †

Dana-Farber/Brigham and Women’s Smilow Cancer Hospital UC Davis Comprehensive Cancer Center
Cancer Center William Shomali, MD ‡ David T. Yang, MD ≠
Gabriela Hobbs, MD ‡ † Stanford Cancer Institute University of Wisconsin
Massachusetts General Hospital B. Douglas Smith, MD † Þ Carbone Cancer Center
Cancer Center The Sidney Kimmel Comprehensive NCCN
Hagop M. Kantarjian, MD ‡ Cancer Center at Johns Hopkins Kristina Gregory, RN, MSN, OCN
The University of Texas Michael Styler, MD ‡ † Hema Sundar, PhD
MD Anderson Cancer Center Fox Chase Cancer Center
ξ Hematopoietic cell transplantation
‡ Hematology/Hematology oncology
Þ Internal medicine

NCCN Guidelines Panel Disclosures Continue † Medical oncology

≠ Pathology
* Discussion Section Writing Committee

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Table of Contents
Chronic Myeloid Leukemia Discussion

NCCN Chronic Myeloid Leukemia Panel Members

Summary of Guidelines Updates Clinical Trials: NCCN believes that
the best management for any patient
with cancer is in a clinical trial.
Workup (CML-1)
Participation in clinical trials is
Chronic Phase CML (CML-2) especially encouraged.
Early Treatment Response Milestones, Clinical Considerations, and Recommendations (CML-3)
Find an NCCN Member Institution:
Advanced Phase CML (CML-4) https://www.nccn.org/home/member-
Treatment Recommendations Based on BCR::ABL1 Mutation Profile (CML-5) institutions.
Allogeneic Hematopoietic Cell Transplantation (CML-6) NCCN Categories of Evidence and
Consensus: All recommendations
Risk Calculation Table (CML-A) are category 2A unless otherwise
Definitions of Advanced Phase CML (CML-B) indicated.
Management of CML During Pregnancy (CML-C) See NCCN Categories of Evidence
Criteria for Response and Relapse (CML-D) and Consensus.
Monitoring Response to TKI Therapy and Mutational Analysis (CML-E) NCCN Categories of Preference:
Discontinuation of TKI Therapy (CML-F) All recommendations are considered
Management of Asciminib Toxicity (CML-G 1 of 9) appropriate.
Management of Bosutinib Toxicity (CML-G 2 of 9) See NCCN Categories of
Management of Dasatinib Toxicity (CML-G 3 of 9) Preference.
Management of Imatinib Toxicity (CML-G 4 of 9)
Management of Nilotinib Toxicity (CML-G 5 of 9)
Management of Omacetaxine Toxicity (CML-G 6 of 9)
Management of Ponatinib Toxicity (CML-G 7 of 9)
Drug Interactions of TKIs (CML-G 8 of 9)

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. ©2023.

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NCCN Guidelines Version 1.2024 NCCN Guidelines Index

Table of Contents
Chronic Myeloid Leukemia Discussion

Terminologies in all NCCN Guidelines are being actively modified to advance the goals of equity, inclusion, and representation.
Updates in Version 1.2024 of the NCCN Guidelines for Chronic Myeloid Leukemia from Version 2.2023 include:
CML-1
• Workup; Bullet 3 modified: Chemistry profile, including uric acid
• Chronic phase CML; Additional Evaluation
Consider myeloid mutational analysis added with a category 2B designation
• Footnote a added: Hydroxyurea is the preferred option (until the initiation of TKI therapy) to lower very high white blood cell (WBC) counts.
Leukapheresis is rarely indicated, except for high-risk indications (eg, persistent priapism, shortness of breath, transient ischemic attack).
• Footnote b modified: Bone marrow cytogenetics with a minimum of 20 metaphases evaluation should be done for the initial workup, to provide
morphologic review, and also is useful to detect chromosomal abnormalities in addition to the Ph chromosome. The presence of major route additional
chromosomal abnormalities (ACAs) in Ph-positive cells (trisomy 8, isochromosome 17q, second Ph, trisomy 19, and chromosome 3 abnormalities)
may have a negative prognostic impact on survival in patients with accelerated phase. Fluorescence in situ hybridization (FISH) on the bone marrow or
peripheral blood can be used if bone marrow cytogenetic evaluation is not possible.
• Footnote content moved to the algorithm: Consider myeloid mutation panel for patients with accelerated phase or blast phase.
CML-2
• Treatment considerations independent of risk score: Age added.
• Footnote f modified: If treatment is needed during pregnancy, it is preferable to initiate treatment with interferons (interferon alfa-2a; in the United States,
peginterferon alfa-2a is the only interferon available for clinical use or peginterferon alfa-2a). Interferon alfa-2a/2b and peginterferon alfa-2b have been
discontinued. Peginterferon alfa-2a may be substituted for other interferon preparations. TKI therapy, particularly during the first trimester, should be
avoided because of teratogenic risk. See Management of CML During Pregnancy (CML-C). (also applies to CML-4A)
• Footnote i; Reference added: Kantarjian H et al. Lancet Haematol 2022;9:e854-e861. (also applies to CML-4A)
CML-3
• TKI-resistant disease; Clinical Considerations
Bullet 3 added: Consider bone marrow cytogenetic analysis to assess ACAs
• TKI-resistant disease; Recommendations
Switch to alternate TKI (CML-5) (other than imatinib)
• Possible TKI Resistance; Recommendations
Continue same TKI (other than imatinib)
• Footnote p added: Switching to an alternate TKI for intolerance is appropriate for patients with disease responding to TKI therapy.
• Footnote r modified: Achievement of response milestones must be interpreted within the clinical context. Patients with more than 50% reduction
compared to baseline or minimally above the 10% cutoff can continue the same dose of dasatinib, nilotinib, or bosutinib TKI for another 3 months.
Continuation of imatinib 400 mg is not recommended.
• Footnote s modified: Switching from imatinib to a 2G TKI improves response, but is may be associated with increased toxicity.
CML-4
• Accelerated phase
The following added after treatment: Lack of response or Disease progression
• Blast phase
The following added after treatment: For patients in remission: Consolidation chemotherapy and TKI maintenance for non-candidates for allogeneic
HCT.
Continued

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NCCN Guidelines Version 1.2024 NCCN Guidelines Index

Table of Contents
Chronic Myeloid Leukemia Discussion

Updates in Version 1.2024 of the NCCN Guidelines for Chronic Myeloid Leukemia from Version 2.2023 include:

CML-4A
• Footnote u modified: The presence of major route ACAs in Ph-positive cells (trisomy 8, isochromosome 17q, second Ph, and trisomy 19, and
chromosome 3 abnormalities) may have a negative prognostic impact on survival. Patients who present with accelerated phase at diagnosis should be
treated with a TKI at the FDA-approved dose for accelerated phase, followed by evaluation for allogeneic HCT, based on response to therapy. Consider
evaluation for allogeneic HCT if response milestones are not achieved at 3, 6, and 12 months as outlined on CML-3.
CML-5
• Bullet 2 modified: Patients with disease resistant to primary treatment with bosutinib, dasatinib, or nilotinib can be treated with an alternate TKI (other
than imatinib) in the second line setting, taking into account BCR::ABL1 kinase domain mutation status. Subsequent therapy with an alternate 2G TKI
would be effective only in patients with identifiable BCR::ABL1 mutations that confer resistance to TKI therapy. Ponatinib is preferred for patients with
no identifiable BCR::ABL1 mutations. The durability of these responses is frequently limited.
Ponatinib is the preferred treatment option for patients with a T315I mutation in any phase. It is also a treatment option for CP-CML with resistance or
intolerance to at least two prior TKIs or for patients with AP-CML or BP-CML for whom no other TKI is indicated. (this was a previous footnote)
Asciminib is a treatment option for CP-CML patients with the T315I mutation and/or CP-CML with resistance or intolerance to at least two prior TKIs.
(this was a previous footnote)
• Therapy: Clinical trial removed from row 5.
• Contraindicated Mutations: F359V/I/C added for asciminib.
• Footnote bb modified: Ponatinib is the preferred treatment option for patients with a T315I mutation. It is also a treatment option for CP-CML with
resistance or intolerance to at least two prior TKIs or for patients with AP-CML or BP-CML for whom no other TKI is indicated. There are compound
mutations (defined as harboring ≥2 mutations in the same BCR::ABL1 allele) that can cause resistance to ponatinib, but those are uncommon following
treatment with bosutinib, dasatinib, or nilotinib. (also applies to CML-6)
CML-6
• Footnote cc replaced footnote bb: Ponatinib is the preferred treatment option for patients with a T315I mutation. It is also a treatment option for CP-
CML with resistance or intolerance to at least two prior TKIs or for patients with AP-CML or BP-CML for whom no other TKI is indicated. Ponatinib is
the preferred treatment option for patients with a T315I mutation in any phase. It is also a treatment option for patients with for CP-CML with resistance
or intolerance to at least two prior TKIs or for patients with AP-CML or BP-CML for whom no other TKI is indicated. There are compound mutations
(defined as harboring ≥2 mutations in the same BCR::ABL allele) that can cause resistance to ponatinib, but those are uncommon following treatment
with bosutinib, dasatinib, or nilotinib.
CML-B
• Definitions of ACCELERATED Advanced Phase CML
Statement added: Clinical trials in the TKI era have mostly utilized the modified MDACC criteria or the IBMTR criteria. The use of the International
Consensus Classification (ICC) or the World Health Organization (WHO) criteria for the diagnosis of AP-CML and BP-CML is not recommended.
Accelerated Phase
◊ Modified MD Anderson Cancer Center (MDACC) Criteria (most commonly used in clinical trials)
• References added:
Gambacorti-Passerini C, le Coutre P. Chronic myelogenous leukemia In: DeVita VT, Lawrence TS, Rosenburg SA, eds. DeVita, Hellman, and
Rosenberg's Cancer: Principles & Practice of Oncology (12th edition); 2022:1773-1784.
Arber DA, Orazi A, Hasserjian RP, et al. International consensus classification of myeloid neoplasms and acute leukemias: Integrating morphologic,
clinical, and genomic data. Blood 2022;140:1200-1228.
Khoury JD, Solary E, Abla O, et al. The 5th edition of the World Health Organization classification of haematolymphoid tumours: Myeloid Continued
and histiocytic/dendritic neoplasms. Leukemia 2022;36:1703-1719.
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® ® ®
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NCCN Guidelines Version 1.2024 NCCN Guidelines Index

Table of Contents
Chronic Myeloid Leukemia Discussion

Updates in Version 1.2024 of the NCCN Guidelines for Chronic Myeloid Leukemia from Version 2.2023 include:

CML-C 1 of 2
• TKI Therapy and Conception
Bullet 2 modified: TKI therapy during pregnancy in patients assigned female at birth has been associated with both a higher rate of miscarriage and
fetal abnormalities. A prolonged washout period prior to pregnancy, prompt consideration of holding TKI therapy (if pregnancy occurs while on TKI
therapy), and close monitoring should be considered. There are no data regarding how long a patient should be off therapy before trying to become
pregnant.
Bullet 3 modified: Discontinuation of TKI therapy because of pregnancy in patients who were are not in DMR (≥MR4.0; ≤0.01% BCR::ABL1 IS) has
only been reported in a small series of patients. Conception while on active TKI therapy is strongly discouraged due to the risk of fetal abnormalities.
There are no published guidelines regarding the optimal depth of molecular response that is considered “safe” to stop TKI therapy before attempting
pregnancy and the literature regarding this consists of case reports.
Bullet 4 modified: Prior to attempting pregnancy, patients of childbearing age and their partners should be counseled about the potential risks and
benefits of discontinuation of TKI therapy, and possible resumption of TKI therapy, and treatment options during pregnancy, should the CML recur
during pregnancy. Fertility preservation should be discussed with all patients of childbearing age prior to the initiation of TKI therapy. While sperm
banking can be performed prior to starting TKI therapy, there are no data regarding the quality of sperm in patients with untreated CML. Referral to a
CML specialty center and consultation with a high-risk obstetrician is recommended.
• Treatment and Monitoring During Pregnancy
Bullet 1 modified: As noted above, in patients assigned male at birth, TKI therapy need not be discontinued if a pregnancy is planned. Sperm banking
can also be performed prior to starting TKI therapy, although there are no data regarding the quality of sperm in patients with untreated CML.
Bullet 2 modified: In patients assigned female at birth, TKI therapy should be stopped prior to natural conception, and patients should remain off
therapy during pregnancy. Referral to an in vitro fertilization (IVF) center is recommended in coordination with the patient’s obstetrician. TKI should
be stopped prior to attempting a natural pregnancy or oocyte retrieval, but the optimal timing of discontinuation is unknown. There are no data to
recommend how long a patient should be off therapy before oocyte retrieval, although usually at least one month off therapy is recommended.
Bullet 3 modified: If treatment is needed during pregnancy, it is preferable to initiate treatment with interferons interferon alfa-2a; in the United States,
peginterferon alfa-2a is the only interferon available for clinical use. Both interferon alfa-2a or peginterferon alfa-2a have been used during pregnancy.
Most of the data using interferons during pregnancy have been reported in patients with essential thrombocythemia. If introduced earlier, the use of
interferon alfa-2a or peginterferon alfa-2a can preserve molecular remission after discontinuation of TKI. Interferon alfa-2a/2b and peginterferon alfa-
2b have been discontinued. Peginterferon alfa-2a may be substituted for other interferon preparations.
Bullet 4 modified: The use of TKI therapy, particularly during the first trimester, should be avoided because of teratogenic risk. If TKI therapy is
considered during pregnancy, the potential risks and benefits must be carefully evaluated in terms of maternal health and fetal risk on an individual
basis prior to initiation of TKI therapy during pregnancy.
Bullet 5 modified: The panel recommends against the use of hydroxyurea during pregnancy, especially in the first trimester, if possible.
Bullet 6 modified: Leukapheresis can be used for a rising white blood cell (WBC) count and/or platelet count, although there are no data that
recommend at what levels of WBC count leukapheresis and/or platelet pheresis should be initiated.
Bullet 8 modified: Monthly monitoring of CBC with differential and frequent monitoring with qPCR (every 1–3 mo) and initiating treatment if the
BCR::ABL1 IS increases to >1.0% is recommended would be helpful to guide the timing for initiation of TKI therapy.
CML-C 2 of 2
• Reference added: Berman E. Family planning and pregnancy in patients with chronic myeloid leukemia. Curr Hematol Malig Rep 2023;18:33-39.
Continued

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Table of Contents
Chronic Myeloid Leukemia Discussion

Updates in Version 1.2024 of the NCCN Guidelines for Chronic Myeloid Leukemia from Version 2.2023 include:

CML-D
• Relapse
Bullet 2 modified: Any sign of loss of CCyR or its molecular response correlate (MR2.0: BCR::ABL1 [IS]≤1%) – defined as an increase in BCR::ABL1
transcript to >1%
CML-E
• Bone Marrow Cytogenetics
Bullet 4 modified: Any sign of loss of CCyR or its molecular response correlate (MR2.0: BCR::ABL1 [IS] ≤1%) – defined as an increase in BCR::ABL1
transcript to >1%
• qPCR using IS
Bullet 2 modified: Every 3 months after initiating treatment. After BCR::ABL1 (IS) ≤1% (MR2.0) has been achieved, every 3 months for 2 years and
every 3–6 months thereafter
• BCR::ABL kinase domain mutation analysis
Bullet 1; Sub-bullet 2 modified: Any sign of loss of CCyR or its molecular response correlate (MR2.0: BCR::ABL1 [IS] ≤1%) – defined as an increase
in BCR::ABL1 transcript to >1%

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WORKUP CLINICAL PRESENTATION ADDITIONAL EVALUATION

• Determine risk score

(Risk Calculation
Chronic
Table CML-A)
phase CML CML-2
• Consider myeloid
(CP-CML)
mutational analysis
(category 2B)
Ph-positive
or
• H&P, including spleen size by
BCR::ABL1
palpation (cm below costal Accelerated • Flow cytometry to
positive
margin) phase CML determine cell lineage
• CBC with differentiala (AP-CML)e • Consider myeloid
• Chemistry profile, including Advanced mutational analysise
uric acid phase CML • Human leukocyte CML-4
• Bone marrow aspirate and antigen (HLA) testing, if
biopsy for morphologic review Blast phase
CML (BP-CML)e considering allogeneic
and cytogenetic evaluation hematopoietic cell
• Quantitative RT-PCR (qPCR) transplant (HCT) (CML-6)
using International Scale (IS)
for BCR::ABL1 (blood)b,c Ph-negative
Evaluate for diseases other than CML
• Hepatitis B paneld and
(NCCN Guidelines for
BCR::ABL1
Myeloproliferative Neoplasms)
negative

a Hydroxyurea is the preferred option (until the initiation of TKI therapy) to lower very high white blood cell (WBC) counts. Leukapheresis is rarely indicated, except for
high-risk indications (eg, persistent priapism, shortness of breath, transient ischemic attack).
b Bone marrow cytogenetics with a minimum of 20 metaphases is useful to detect chromosomal abnormalities in addition to the Ph chromosome. The presence of major
route additional chromosomal abnormalities (ACAs) in Ph-positive cells (trisomy 8, isochromosome 17q, second Ph, trisomy 19, and chromosome 3 abnormalities) may
have a negative prognostic impact on survival in patients with accelerated phase. Fluorescence in situ hybridization (FISH) on the bone marrow or peripheral blood can
be used if bone marrow cytogenetic evaluation is not possible.
c Consider qualitative reverse transcription polymerase chain reaction (RT-PCR) for the detection of atypical BCR::ABL1 transcripts. See Discussion. Referral to centers
with expertise in the management of rare hematologic malignancies is recommended.
d Hepatitis B virus reactivation has been reported in patients receiving tyrosine kinase inhibitor (TKI) therapy. However, it is not always possible to reliably estimate the
frequency or establish a relationship to drug exposure because these incidences are reported voluntarily from a population of uncertain size.
e Definitions of Advanced Phase CML (CML-B).

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

Clinical Trials: NCCN believes that the best management of any patient with cancer is in a clinical trial. Participation in clinical trials is especially encouraged.

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CML-1
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Chronic Myeloid Leukemia Discussion

CLINICAL PRESENTATION PRIMARY TREATMENTf,g,h

Preferred regimens
First-generation (1G) TKI (Imatinib 400 mg QD
[category 1])i
or Response
Low-risk score
Second-generation (2G) TKI (alphabetical order) Milestones
Treatment (Risk
(Bosutinib 400 mg QD [category 1] or and Treatment
considerations Calculation
Dasatinib 100 mg QD [category 1] or Options (CML-3)k,l
independent of risk Table CML-A)
Nilotinib 300 mg BID [category 1])
score
or
• Age
Chronic Clinical trial
• Comorbidities
phase Preferred regimens
• Toxicity profile of
CP-CML 2G TKI (alphabetical order)
tyrosine kinase
inhibitor (TKI) (Bosutinib 400 mg QD [category 1] or
Intermediate- or
• Possible drug Dasatinib 100 mg QD [category 1] or Response
high-risk score
interactions Nilotinib 300 mg BID [category 1]) Milestones
(Risk
• Patient preference or and Treatment
Calculation
Other recommended regimen Options (CML-3)k,l
Table CML-A)
1G TKI (Imatinib 400 mg QD)i,j
or
Clinical trial
f If treatment is needed during pregnancy, it is preferable to initiate treatment with interferon alfa-2a; in the United States, peginterferon alfa-2a is the only interferon
available for clinical use. TKI therapy, particularly during the first trimester, should be avoided because of teratogenic risk. See Management of CML During Pregnancy
(CML-C).
g Based on follow-up data from the BFORE, DASISION, and ENESTnd trials, 2G TKIs (bosutinib, dasatinib, or nilotinib) are preferred for patients with an intermediate-
or high-risk score. 2G TKIs should also be considered for specific subgroups (based on the assessment of treatment goals and benefit/risks), for example, younger
patients who are interested in ultimately discontinuing treatment and especially young patients assigned female at birth whose goal is to achieve a deep and rapid
molecular response and eventual discontinuation of TKI therapy for family planning purposes.
h Limited available evidence from small cohort studies suggests that initiation of first-line TKIs (bosutinib, dasatinib, or nilotinib) at lower doses (to minimize treatment-
related adverse events) and dose reduction (with close monitoring) in patients who achieve optimal responses are appropriate strategies to reduce the risk of long-
term toxicities. However, the minimum effective dose or optimal de-escalation of TKI (bosutinib, dasatinib, or nilotinib) has not yet been established in prospective
randomized clinical trials. See the Discussion section for Dose Modifications of TKI Therapy.
i Innovator and generic drugs approved by the regulatory authorities based on pharmacokinetic equivalence can be used interchangeably. An FDA-approved generic
version is an appropriate substitute for an innovator drug (imatinib) (Kantarjian H, et al. Lancet Haematol 2022;9:e854-e861). Generic versions of other TKIs are likely
to be marketed in the near future.
j Imatinib may be preferred for older patients with comorbidities such as cardiovascular disease.
k Criteria for Response and Relapse (CML-D).
l Monitoring Response to TKI Therapy and Mutational Analysis (CML-E).

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

Clinical Trials: NCCN believes that the best management of any patient with cancer is in a clinical trial. Participation in clinical trials is especially encouraged.

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CML-2
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Chronic Myeloid Leukemia Discussion

EARLY TREATMENT RESPONSE MILESTONES

CRITERIA FOR RESPONSE AND RELAPSE
BCR::ABL1 (IS) 3 months 6 months 12 monthsm
>10%n YELLOW RED
>1%–10% GREEN YELLOW
>0.1%–1% GREEN LIGHT GREEN
≤0.1% GREEN

COLOR CONCERN CLINICAL CONSIDERATIONSp RECOMMENDATIONSp

RED TKI-resistant • Evaluate patient adherence and drug interactions Switch to alternate TKI (CML-5) (other than imatinib)
diseaseo • Consider BCR::ABL1 kinase domain mutational analysisq and evaluate for allogeneic HCT
• Consider bone marrow cytogenetic analysis to assess
additional chromosomal abnormalities (ACAs)
YELLOW Possible TKI • Evaluate patient adherence and drug interactions Switch to alternate TKI (CML-5) or
resistanceo • Consider BCR::ABL1 kinase domain mutational analysisq Continue same TKI (CML-G)r
• Consider bone marrow cytogenetic analysis to assess for and Consider evaluation for allogeneic HCT
MCyR at 3 mo or CCyR at 12 mo
LIGHT TKI-sensitive • Evaluate patient adherence and drug interactions • If optimal: continue same TKI (CML-G)
GREEN disease • If treatment goal is long-term survival: ≤1% optimal • If not optimal: shared decision-making with
• If treatment goal is treatment-free remission: ≤0.1% optimal patiento,s
GREEN TKI-sensitive • Monitor response (CML-E) Continue same TKI (CML-G)t
disease • Evaluate patient adherence and drug interactions

m BCR::ABL1 ≤0.1% at 12 months is associated with a very low probability of subsequent loss of response and a high likelihood of achieving a subsequent deep
molecular response (DMR MR4.0; ≤0.01% BCR::ABL1 IS), which is a prerequisite for a trial of treatment-free remission (TFR).
n Patients with BCR::ABL1 only slightly >10% at 3 months and/or with a steep decline from baseline may achieve <10% at 6 months and have generally favorable
outcomes. Therefore, it is important to interpret the value at 3 months in this context before making drastic changes to the treatment strategy.
o Consider referral to a specialized CML center and/or enrollment in a clinical trial.
p Switching to an alternate TKI for intolerance is appropriate for patients with disease responding to TKI therapy.
q Consider myeloid mutation panel to identify BCR::ABL1–independent resistance mutations in patients with no BCR::ABL1 kinase domain mutations.
r Achievement of response milestones must be interpreted within the clinical context. Patients with more than 50% reduction compared to baseline or minimally above
the 10% cutoff can continue the same dose of TKI for another 3 months.
s Switching from imatinib to a 2G TKI improves response, but may be associated with increased toxicity.
t Discontinuation of TKI with careful monitoring is feasible in selected patients. See Discontinuation of TKI Therapy (CML-F).

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

Clinical Trials: NCCN believes that the best management of any patient with cancer is in a clinical trial. Participation in clinical trials is especially encouraged.

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CLINICAL PRESENTATION TREATMENTf

Clinical trial
or
Preferred regimens
• 2G TKI (alphabetical order)
(Bosutinib or Dasatinib or Lack of
Treatment considerations AP-CMLe,u Nilotinib) or third-generation Allogeneic
response
• Disease progression to (3G) TKI (Ponatinib) HCT
Useful in certain circumstances or
advanced phase while on Disease (CML-6)
TKI therapy has worse • 1G TKI (Imatinib; if 2G or 3G
TKI is contraindicated)i,w progression
prognosis than de novo
• Omacetaxinex
advanced phase CML.
• Evaluation for allogeneic
HCT as indicated.
Advanced • Selection of TKI is based Clinical trial
phase on prior therapy and/ or
CML or BCR::ABL1 mutation Preferred regimens
profile. • ALL-type induction
• Central nervous system chemotherapy
(CNS) involvement has Lymphoid (NCCN Guidelines for ALL)
been described in BP- + TKIi,y (CML-G)
CML. Lumbar puncture Useful in certain circumstances
• TKIi,y (CML-G) + steroids
and CNS prophylaxis is (if not a candidate for
recommended for lymphoid induction chemotherapy) For patients in remission:
BP-CML. BP-CMLe,v • Allogeneic HCT (CML-6)
• Consolidation
Clinical trial chemotherapy and TKIi,y
or (CML-G) maintenance
Preferred regimens for non-candidates for
• AML-type induction allogeneic HCT
chemotherapy
Myeloid (NCCN Guidelines for AML)
+ TKIi,y (CML-G)
Useful in certain circumstances
• TKIi,y (CML-G)
(if not a candidate for
induction chemotherapy)
Footnotes on CML-4A
Note: All recommendations are category 2A unless otherwise indicated.
Clinical Trials: NCCN believes that the best management of any patient with cancer is in a clinical trial. Participation in clinical trials is especially encouraged.

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FOOTNOTES FOR ADVANCED PHASE CML

e Definitions of Advanced Phase CML (CML-B).
f If treatment is needed during pregnancy, it is preferable to initiate treatment with interferon alfa-2a; in the United States, this is the only interferon available for clinical
use. TKI therapy, particularly during the first trimester, should be avoided because of teratogenic risk. See Management of CML During Pregnancy (CML-C).
i Innovator and generic drugs approved by the regulatory authorities based on pharmacokinetic equivalence can be used interchangeably. An FDA-approved generic
version is an appropriate substitute for an innovator drug (imatinib) (Kantarjian H, et al. Lancet Haematol 2022;9:e854-e861). Generic versions of other TKIs are likely
to be marketed in the near future.
u The presence of major route ACAs in Ph-positive cells (trisomy 8, isochromosome 17q, second Ph, trisomy 19, and chromosome 3 abnormalities) may have a negative
prognostic impact on survival. Patients who present with accelerated phase at diagnosis should be treated with a TKI at the FDA-approved dose for accelerated phase,
followed by evaluation for allogeneic HCT, based on response to therapy. Consider evaluation for allogeneic HCT if response milestones are not achieved at 3, 6, and
12 months as outlined on CML-3.
v TKI (alone or in combination with minimal chemotherapy or steroids) is less effective in BP-CML compared to Ph-positive ALL. Interphase FISH for the detection of
BCR::ABL1 transcript on blood granulocytes is recommended to differentiate between de novo BP-CML and de novo Ph-positive ALL.
w Imatinib is not recommended for patients with disease progression on prior TKI therapy.
x Omacetaxine is indicated for the treatment of AP-CML that is resistant and/or intolerant to two or more TKIs. Omacetaxine is a treatment option for patients with
disease progression to AP-CML. Omacetaxine is not a treatment option for patients who present with AP-CML.
y 2G or 3G TKI is preferred. Consider imatinib for patients with contraindications to 2G or 3G TKI.

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

Clinical Trials: NCCN believes that the best management of any patient with cancer is in a clinical trial. Participation in clinical trials is especially encouraged.

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TREATMENT RECOMMENDATIONS BASED ON BCR::ABL1 MUTATION PROFILE

• Patients with disease resistant to primary treatment with imatinib should be treated with a 2G TKI (bosutinib, dasatinib, or nilotinib) in the
second-line setting, taking into account BCR::ABL1 kinase domain mutation status.
• Patients with disease resistant to primary treatment with bosutinib, dasatinib, or nilotinib can be treated with an alternate TKI (other than
imatinib), taking into account BCR::ABL1 kinase domain mutation status. Subsequent therapy with an alternate 2G TKI would be effective
only in patients with identifiable BCR::ABL1 mutations that confer resistance to TKI therapy. Ponatinib is preferred for patients with no
identifiable BCR::ABL1 mutations.
Ponatinib is the preferred treatment option for patients with a T315I mutation in any phase. It is also a treatment option for CP-CML with
resistance or intolerance to at least two prior TKIs or for patients with AP-CML or BP-CML for whom no other TKI is indicated.
Asciminib is a treatment option for CP-CML patients with the T315I mutation and/or CP-CML with resistance or intolerance to at least two
prior TKIs.
• BCR::ABL1 kinase domain mutations that should NOT be treated with asciminib, bosutinib, dasatinib, or nilotinib are listed in the table
below.

THERAPY CONTRAINDICATED MUTATIONSz

Asciminib A337T, P465S, or F359V/I/C
Bosutinib T315I, V299L, G250E, or F317Laa
Dasatinib T315I/A, F317L/V/I/C, or V299L
Nilotinib T315I, Y253H, E255K/V, or F359V/C/I
Ponatinib, Omacetaxine,cc or allogeneic HCT (CML-6) Nonebb

z Mutations contraindicated for imatinib are too numerous to include. BCR::ABL35INS has been reported in patients with disease not responding to imatinib; however,
there are not enough data to confirm that 2G TKIs could overcome this resistance (Berman E, et al. Leuk Res 2016;49:108-112). See Discussion.
aa Bosutinib has minimal activity against F317L mutation. Nilotinib may be preferred over bosutinib in patients with F317L mutation.
bb There are compound mutations (defined as harboring ≥2 mutations in the same BCR::ABL1 allele) that can cause resistance to ponatinib, but those are uncommon
following treatment with bosutinib, dasatinib, or nilotinib.
cc Omacetaxine is a treatment option for patients with chronic or AP-CML that is resistant and/or intolerant to two or more TKIs.

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

Clinical Trials: NCCN believes that the best management of any patient with cancer is in a clinical trial. Participation in clinical trials is especially encouraged.

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ADDITIONAL THERAPY

Consider TKIi,ee therapy for at least 1 y in

Monitor with Negative
patients with prior AP-CML or BP-CMLff
qPCR (peripheral
CCyRk blood) every 3 mo
for 2 y, then every
Discuss options with transplant team:
3–6 mo thereafter Positive
TKIi,ee ± donor lymphocyte infusion (DLI)
Allogeneic (selection of TKI is based on prior therapy,
HCTdd BCR::ABL1 mutation profile, and post-HCT
morbidities)
Less than or
CCyR Omacetaxinecc
or in relapsek or
Clinical trial

i Innovator and generic drugs approved by the regulatory authorities based on pharmacokinetic equivalence can be used interchangeably. An FDA-approved generic
version is an appropriate substitute for an innovator drug (imatinib) (Kantarjian H, et al. Lancet Haematol 2022;9:e854-e861). Generic versions of other TKIs are likely
to be marketed in the near future.
k Criteria for Response and Relapse (CML-D).
cc Omacetaxine is a treatment option for patients with chronic or AP-CML that is resistant and/or intolerant to two or more TKIs.
dd Indications for allogeneic HCT: advanced phase CML at presentation or disease progression to blast phase. Outcomes of allogeneic HCT are dependent on age,
comorbidities, donor type, and transplant center.
ee Ponatinib is the preferred treatment option for patients with a T315I mutation in any phase. It is also a treatment option for patients with for CP-CML with resistance or
intolerance to at least two prior TKIs or for patients with AP-CML or BP-CML for whom no other TKI is indicated. There are compound mutations (defined as harboring
≥2 mutations in the same BCR::ABL allele) that can cause resistance to ponatinib, but those are uncommon following treatment with bosutinib, dasatinib, or nilotinib.
ff Carpenter PA, et al. Blood 2007;109:2791-2793; Olavarria E, et al. Blood 2007;110:4614-4617; DeFilipp Z, et al. Clin Lymphoma Myeloma Leuk 2016;16:466-471.

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

Clinical Trials: NCCN believes that the best management of any patient with cancer is in a clinical trial. Participation in clinical trials is especially encouraged.

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RISK CALCULATION TABLE

Risk Score Calculation Risk Category

Sokal score1 Exp 0.0116 x (age - 43.4) + 0.0345 x (spleen - 7.51) + 0.188 Low <0.8
x [(platelet count ÷ 700)2 - 0.563] + 0.0887 x (blasts - 2.10) Intermediate 0.8 – 1.2
High >1.2

Hasford Euro score2 (0.6666 x age [0 when age <50 years; 1, otherwise] + 0.042 Low ≤780
x spleen size [cm below costal margin] + 0.0584 × percent Intermediate >780 – ≤1480
blasts + 0.0413 × percent eosinophils + 0.2039 × basophils High >1480
[0 when basophils <3%; 1, otherwise] + 1.0956 × platelet
count [0 when platelets <1500 × 109/L; 1, otherwise]) × 1000

EUTOS long-term 0.0025 × (age/10)3 + 0.0615 × spleen size cm below costal Low ≤1.5680
survival (ELTS) score3 margin + 0.1052 × blasts in peripheral blood + 0.4104 × Intermediate >1.5680 but ≤2.2185
(platelet count/1000)-0.5 High >2.2185

Calculation of relative risk based on Sokal or Hasford (EURO) score can be found at:
https://www.leukemia net.org/content/leukemias/cml/euro__and_sokal_score/index_eng.html

Online calculator for the ELTS score can be found at: https://www.leukemia-net.org/content/leukemias/cml/elts_score/index_eng.html

1 Sokal J, Cox EB, Baccarani M, et al. Prognostic discrimination in "good-risk" chronic granulocytic leukemia. Blood 1984;63:789-799.
2 Hasford J, Pfirrmann M, Hehlmann R, et al. A new prognostic score for survival of patients with chronic myeloid leukemia treated with interferon alfa. Writing Committee
for the Collaborative CML Prognostic Factors Project Group. J Natl Cancer Inst 1998;90:850-858.
3 Pfirrman M, Baccarani M, Saussele S, et al. Prognosis of long-term survival considering disease-specific death in patients with chronic myeloid leukemia. Leukemia
2016;30:48-56.

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

Clinical Trials: NCCN believes that the best management of any patient with cancer is in a clinical trial. Participation in clinical trials is especially encouraged.

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DEFINITIONS OF ADVANCED PHASE CMLa

Clinical trials in the TKI era have mostly utilized the modified MD Anderson Cancer Center (MDACC) criteria1,2 or the International Bone
Marrow Transplant Registry (IBMTR) criteria.3 The use of the International Consensus Classification (ICC)4 or the World Health Organization
(WHO) criteria5 for the diagnosis of AP-CML and BP-CML is not recommended.

AP-CMLb BP-CML
Modified MDACC Criteria1,2 IBMTR criteria3
• Peripheral blood myeloblasts ≥15% and <30% • ≥30% blasts in the blood, marrow, or both
• Peripheral blood myeloblasts and promyelocytes combined ≥30% • Extramedullary infiltrates of leukemic cells
• Peripheral blood basophils ≥20%
• Platelet count ≤100 x 109/L unrelated to therapy
• Additional clonal cytogenetic abnormalities in Ph+ cellsc

a Any increase in lymphoblasts is concerning for (nascent) blast phase.

b Sokal criteria and IBMTR criteria are historically used when allogeneic HCT is the recommended treatment option.6,7
c The prognostic significance of ACAs in Ph‑positive cells (ACA/Ph+) is related to the specific chromosomal abnormality
and often other features of accelerated phase.
The presence of “major route” ACA/Ph+ (trisomy 8, isochromosome 17q, second Ph, trisomy 19, and chromosome 3 abnormalities) at diagnosis may have a negative
prognostic impact on survival.

1 Kantarjian HM, Deisseroth A, Kurzrock R, et al. Chronic myelogenous leukemia: A concise update. Blood 1993;82:691-703.
2 Talpaz M, Silver RT, Druker BJ, et al. Imatinib induces durable hematologic and cytogenetic responses in patients with accelerated phase chronic myeloid leukemia:
results of a phase 2 study. Blood 2002;99:1928-1937.
3 Gambacorti-Passerini C, le Coutre P. Chronic myelogenous leukemia In: DeVita VT, Lawrence TS, Rosenburg SA, eds. DeVita, Hellman, and Rosenberg's Cancer:
Principles & Practice of Oncology (12th edition); 2022:1773-1784.
4 Arber DA, Orazi A, Hasserjian RP, et al. International consensus classification of myeloid neoplasms and acute leukemias: Integrating morphologic, clinical, and
genomic data. Blood 2022;140:1200-1228.
5 Khoury JD, Solary E, Abla O, et al. The 5th edition of the World Health Organization classification of haematolymphoid tumours: Myeloid and histiocytic/dendritic
neoplasms. Leukemia 2022;36:1703-1719.
6 Sokal JE, Baccarani M, Russo D, Tura S. Staging and prognosis in chronic myelogenous leukemia. Semin Hematol 1988;25:49-61.
7 Savage DG, Szydlo RM, Chase A, et al. Bone marrow transplantation for chronic myeloid leukemia: The effects of differing criteria for defining chronic phase on
probabilities of survival and relapse. Br J Haematol 1997;99:30-35.

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

Clinical Trials: NCCN believes that the best management of any patient with cancer is in a clinical trial. Participation in clinical trials is especially encouraged.

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MANAGEMENT OF CML DURING PREGNANCY

TKI Therapy and Conception • If treatment is needed during pregnancy, it is preferable to initiate treatment
• TKI therapy appears to affect some male hormones at least transiently, but with interferon alfa-2a;16 in the United States, peginterferon alfa-2a
does not appear to have a deleterious effect on male fertility; miscarriage or is the only interferon available for clinical use. Most of the data using
fetal abnormality rate is not elevated in female partners of male patients on interferons during pregnancy have been reported in patients with essential
TKI therapy.1-5 thrombocythemia.17,18 If introduced earlier, the use of peginterferon alfa-2a
• TKI therapy during pregnancy has been associated with both a higher rate can preserve molecular remission after discontinuation of TKI.19
of miscarriage and fetal abnormalities. A prolonged washout period prior to • TKI therapy, particularly during the first trimester, should be avoided because
pregnancy, prompt consideration of holding TKI therapy (if pregnancy occurs of teratogenic risk. If TKI therapy is considered during pregnancy, the
while on TKI therapy), and close monitoring should be considered.6-10 There potential risks and benefits must be carefully evaluated in terms of maternal
are no data regarding how long a patient should be off therapy before trying health and fetal risk on an individual basis.
to become pregnant. • The panel recommends against the use of hydroxyurea during pregnancy,
• Discontinuation of TKI therapy because of pregnancy in patients who are not especially in the first trimester.20-22
in DMR (≤0.01% BCR::ABL1 IS) has only been reported in a small series of • Leukapheresis can be used for a rising white blood cell (WBC) count and/
patients.11-14 Conception while on active TKI therapy is strongly discouraged or platelet count, although there are no data that recommend at what levels
due to the risk of fetal abnormalities. There are no published guidelines leukapheresis and/or platelet pheresis should be initiated.23-26
regarding the optimal depth of molecular response that is considered “safe” • Low-dose aspirin or low-molecular-weight heparin can be considered for
to stop TKI therapy before attempting pregnancy and the literature regarding patients with thrombocytosis.27,28
this consists of case reports.15 • Monthly monitoring of CBC with differential and frequent monitoring with
• Prior to attempting pregnancy, patients of childbearing age and their partners qPCR (every 1–3 mo) would be helpful to guide the timing for initiation of TKI
should be counseled about the potential risks and benefits of discontinuation therapy.
of TKI therapy, possible resumption of TKI therapy, and treatment options Breastfeeding
during pregnancy, should the CML recur. Fertility preservation should be • TKI therapy can be restarted after delivery. However, patients should be
discussed with all patients of childbearing age prior to the initiation of TKI advised not to breastfeed while on TKI therapy, as TKIs pass into human
therapy. While sperm banking can be performed prior to starting TKI therapy, breast milk.29-32
there are no data regarding the quality of sperm in patients with untreated • Breastfeeding without TKI therapy may be safe with molecular monitoring,
CML. Referral to a CML specialty center and consultation with a high-risk but preferably in those patients with CML who have achieved durable DMR.
obstetrician is recommended. It may be acceptable to avoid TKIs for the short period of the first 2–5 days
Treatment and Monitoring During Pregnancy after labor to give the child colostrum.32,33
• As noted above, in patients assigned male at birth, TKI therapy need not • Close molecular monitoring is recommended for patients who extend the
be discontinued if a pregnancy is planned. Sperm banking can also be treatment-free period for breastfeeding. If the loss of MMR after treatment
performed prior to starting TKI therapy, although there are no data regarding cessation is confirmed, breastfeeding needs to be terminated and TKI
the quality of sperm in patients with untreated CML. therapy should be restarted.32
• In patients assigned female at birth, TKI therapy should be stopped prior
to natural conception, and patients should remain off therapy during
pregnancy.6-8 Referral to an in vitro fertilization (IVF) center is recommended
in coordination with the patient’s obstetrician. TKI should be stopped prior
to attempting oocyte retrieval, but the optimal timing of discontinuation is
unknown. There are no data to recommend how long a patient should be
off therapy before oocyte retrieval, although usually at least one month off
therapy is recommended.
References
Note: All recommendations are category 2A unless otherwise indicated. (CML-C 2 of 2)
Clinical Trials: NCCN believes that the best management of any patient with cancer is in a clinical trial. Participation in clinical trials is especially encouraged.
CML-C
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® ® ®
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MANAGEMENT OF CML DURING PREGNANCY – REFERENCES

1 Ramasamy K, Hayden J, Lim Z, et al. Successful pregnancies involving men with chronic 18 Beauverd Y, Radia D, Cargo C, et al. Pegylated interferon alpha-2a for essential
myeloid leukaemia on imatinib therapy. Br J Haematol 2007;137:374-375. thrombocythemia during pregnancy: outcome and safety. A case series. Haematologica
2 Breccia M, Cannella L, Montefusco E, et al. Male patients with chronic myeloid leukemia 2016;101:e182-184.
treated with imatinib involved in healthy pregnancies: report of five cases. Leuk Res 19 Abruzzese E, Turkina AG, Apperley JF, et al. Pregnancy management in CML patients: To
2008;32:519-520. treat or not to treat? Report of 224 outcomes of the European Leukemia Net (ELN) Database
3 Oweini H, Otrock ZK, Mahfouz RAR, Bazarbachi A. Successful pregnancy involving a man [abstract]. Blood 2019;134:Abstract 498.
with chronic myeloid leukemia on dasatinib. Arch Gynecol Obstet 2011;283:133-134. 20 Baykal C, Zengin N, Coskun F, et al. Use of hydroxyurea and alpha-interferon in chronic
4 Ghalaut VS, Prakash G, Bansal P, et al. Effect of imatinib on male reproductive hormones in myeloid leukemia during pregnancy: a case report. Eur J Gynaecol Oncol 2000;21:89-90.
BCR-ABL positive CML patients: A preliminary report. J Oncol Pharm Pract 2014;20:243-248. 21 Thauvin-Robinet C, Maingueneau C, Robert E, et al. Exposure to hydroxyurea during
5 Alizadeh H, Jaafar H, Rajnics P, et al. Outcome of pregnancy in chronic myeloid leukaemia pregnancy: a case series. Leukemia 2001;15:1309-1311.
patients treated with tyrosine kinase inhibitors: short report from a single centre. Leuk Res 22 Fadilah SA, Ahmad-Zailani H, Soon-Keng C, Norlaila M. Successful treatment of chronic
2015;39:47-51. myeloid leukemia during pregnancy with hydroxyurea. Leukemia 2002;16:1202-1203.
6 Pye SM, Cortes J, Ault P, et al. The effects of imatinib on pregnancy outcome. Blood 23 Koh LP, Kanagalingam D. Pregnancies in patients with chronic myeloid leukemia in the era of
2008;111:5505-5508. imatinib. Int J Hematol 2006;84:459-462.
7 Cortes JE, Abruzzese E, Chelysheva E, et al. The impact of dasatinib on pregnancy outcomes. 24 Ali R, Ozkalemkas F, Ozkocaman V, et al. Successful pregnancy and delivery in a patient with
Am J Hematol 2015;90:1111-1115. chronic myelogenous leukemia (CML), and management of CML with leukapheresis during
8 Barkoulas T, Hall PD. Experience with dasatinib and nilotinib use in pregnancy. J Oncol Pharm pregnancy: a case report and review of the literature. Jpn J Clin Oncol 2004;34:215-217.
Pract 2018;24:121-128. 28 Palani R, Milojkovic D, Apperley JF. Managing pregnancy in chronic myeloid leukaemia. Ann
9 Salem W, Li K, Krapp C, et al. Imatinib treatments have long-term impact on placentation and Hematol 2015;94 Suppl 2:S167-176.
embryo survival. Sci Rep 2019;9:2535. 26 Staley EM, Simmons SC, Feldman AZ, et al. Management of chronic myeloid leukemia in the
10 Madabhavi I, Sarkar M, Modi M, Kadakol N. Pregnancy outcomes in chronic myeloid setting of pregnancy: when is leukocytapheresis appropriate? A case report and review of the
leukemia: A single center experience. J Glob Oncol 2019;5:1-11. literature. Transfusion 2018;58:456-460.
11 Ault P, Kantarjian H, O'Brien S, et al. Pregnancy among patients with chronic myeloid 27 James AH, Brancazio LR, Price T. Aspirin and reproductive outcomes. Obstet Gynecol Surv
leukemia treated with imatinib. J Clin Oncol 2006;24:1204-1208. 2008;63:49-57.
12 Kuwabara A, Babb A, Ibrahim A, et al. Poor outcome after reintroduction of imatinib in patients 28 Deruelle P, Coulon C. The use of low-molecular-weight heparins in pregnancy--how safe are
with chronic myeloid leukemia who interrupt therapy on account of pregnancy without having they? Curr Opin Obstet Gynecol 2007;19:573-577.
achieved an optimal response. Blood 2010;116:1014-1016. 29 Russell MA, Carpenter MW, Akhtar MS, et al. Imatinib mesylate and metabolite
13 Lasica M, Willcox A, Burbury K, et al. The effect of tyrosine kinase inhibitor interruption and concentrations in maternal blood, umbilical cord blood, placenta and breast milk. J Perinatol
interferon use on pregnancy outcomes and long-term disease control in chronic myeloid 2007;27:241-243.
leukemia. Leuk Lymphoma 2019;60:1796-1802. 30 Ali R, Ozkalemkas F, Kimya Y, et al. Imatinib use during pregnancy and breast feeding: a
14 Stella S, Tirro E, Massimino M, et al. Successful management of a pregnant patient with case report and review of the literature. Arch Gynecol Obstet 2009;280:169-175.
chronic myeloid leukemia receiving standard dose imatinib. In Vivo 2019;33:1593-1598. 31 Drugs and Lactation Database (LactMed) [Internet]. Bethesda (MD): National Library of
15 Berman E. Family planning and pregnancy in patients with chronic myeloid leukemia. Medicine (US); 2006-.
Curr Hematol Malig Rep 2023;18:33-39. 32 Chelysheva E, Aleshin S, Polushkina E, et al. Breastfeeding in patients with chronic myeloid
16 Balsat M, Etienne M, Elhamri M, et al. Successful pregnancies in patients with BCR-ABL- leukaemia: Case series with measurements of drug concentrations in maternal milk and
positive leukemias treated with interferon-alpha therapy during the tyrosine kinase inhibitors literature review. Mediterr J Hematol Infect Dis 2018;10:e2018027.
era. Eur J Haematol 2018;101:774-780. 33 Abruzzese E, Trawinska MM, Perrotti AP, De Fabritiis P. Tyrosine kinase inhibitors and
17 Schrickel L, Heidel FH, Sadjadian P et al. Interferon alpha for essential thrombocythemia pregnancy. Mediterr J Hematol Infect Dis 2014;6:e2014028.
during 34 high-risk pregnancies: outcome and safety. J Cancer Res and Clin Oncol 2021:
147;1481-1491.

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

Clinical Trials: NCCN believes that the best management of any patient with cancer is in a clinical trial. Participation in clinical trials is especially encouraged.
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CRITERIA FOR RESPONSE AND RELAPSE

Response/Relapse Definition
Complete hematologic • Complete normalization of peripheral blood counts with leukocyte count <10 x 109/L
response (CHR)1 • Platelet count <450 x 109/L
• No immature cells, such as myelocytes, promyelocytes, or blasts in peripheral blood
• No signs and symptoms of disease with resolution of palpable splenomegaly
Cytogenetic response2,3,4 • Complete cytogenetic response (CCyR): No Ph-positive metaphases
• Major cytogenetic response (MCyR): 0%–35% Ph-positive metaphases
• Partial cytogenetic response (PCyR): 1%–35% Ph-positive metaphases
• Minor cytogenetic response: >35%–65% Ph-positive metaphases
Molecular response5,6,7 • Early molecular response (EMR): BCR::ABL1 (IS) ≤10% at 3 and 6 months
• Major molecular response (MMR): BCR::ABL1 (IS) ≤0.1% or ≥3-log reduction in BCR::ABL1 transcripts from the
standardized baseline, if qPCR (IS) is not available
• Deep molecular response (DMR): MR4.0: BCR::ABL1 (IS) ≤0.01% or MR4.5: BCR::ABL1 (IS) ≤0.0032%
Relapse • Any sign of loss of hematologic response
• Any sign of loss of CCyR or its molecular response correlate (MR2.0: BCR::ABL1 [IS] ≤1%) – defined as an increase
in BCR::ABL1 transcript to >1%
• 1-log increase in BCR::ABL1 transcript levels with loss of MMR8

1 Faderl S, Talpaz M, Estrov Z, Kantarjian HM. Chronic myelogenous leukemia: biology and therapy. Ann Intern Med 1999;131:207-219. The American College of
Physicians-American Society of Internal Medicine is not responsible for the accuracy of the translation.
2 A minimum of 20 metaphases should be examined.
3 O'Brien SG, Guilhot F, Larson RA, et al. Imatinib compared with interferon and low-dose cytarabine for newly diagnosed chronic-phase chronic myeloid leukemia. N
Engl J Med 2003;348:994-1004.
4 CCyR correlates with BCR::ABL1 (IS) ≤1% (MR2.0).
5 Hughes TP, Kaeda J, Branford S, et al. Frequency of major molecular responses to imatinib or interferon alfa plus cytarabine in newly diagnosed chronic myeloid
leukemia. N Engl J Med 2003;349:1423-1432.
6 Hughes T, Deininger M, Hochhaus A, et al. Monitoring CML patients responding to treatment with tyrosine kinase inhibitors: review and recommendations for
harmonizing current methodology for detecting BCR-ABL transcripts and kinase domain mutations and for expressing results. Blood 2006;108:28-37.
7 Cross NC, White HE, Müller MC, Saglio G, Hochhaus A. Standardized definitions of molecular response in chronic myeloid leukemia. Leukemia 2012;26:2172-2175.
8 The loss of MMR in the presence of a CCyR does not necessarily indicate inadequate response to treatment.

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

Clinical Trials: NCCN believes that the best management of any patient with cancer is in a clinical trial. Participation in clinical trials is especially encouraged.

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MONITORING RESPONSE TO TKI THERAPY AND MUTATIONAL ANALYSIS

Test Recommendation

Bone marrow • At diagnosis

cytogenetics1 • Response milestones not reached
• Any sign of loss of hematologic response
• Any sign of loss of CCyR or its molecular response correlate (MR2.0: BCR::ABL1 [IS] ≤1%) – defined as
an increase in BCR::ABL1 transcript to >1%

qPCR using IS • At diagnosis

• Every 3 months after initiating treatment. After BCR::ABL1 (IS) ≤1% (MR2.0)2 has been achieved, every 3
months for 2 years and every 3–6 months thereafter
• If there is a 1-log increase in BCR::ABL1 transcript levels with MMR, qPCR should be repeated in 1–3
months

BCR::ABL1 kinase domain • CP-CML

mutation analysis3 • Response milestones not reached
Any sign of loss of hematologic response
Any sign of loss of CCyR or its molecular response correlate (MR2.0: BCR::ABL1 [IS] ≤1%) – defined as
an increase in BCR::ABL1 transcript to >1%
1-log increase in BCR::ABL1 transcript levels and loss of MMR
• Disease progression to AP-CML or BP-CML3

1 FISH has been inadequately studied for monitoring response to treatment.

2 CCyR correlates with BCR::ABL1 (IS) ≤1% (MR2.0).
3 Consider myeloid mutation panel to identify BCR::ABL1–independent resistance mutations in patients with no BCR::ABL1 kinase domain mutations.

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

Clinical Trials: NCCN believes that the best management of any patient with cancer is in a clinical trial. Participation in clinical trials is especially encouraged.

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DISCONTINUATION OF TKI THERAPY

General Considerations
• Discontinuation of TKI therapy appears to be safe in select patients with CML.
• Consult with a CML specialist to review the appropriateness for TKI discontinuation and potential risks and benefits of treatment
discontinuation, including TKI withdrawal syndrome.
• Clinical studies that have evaluated the safety and efficacy of TKI discontinuation have employed strict eligibility criteria and have mandated
more frequent molecular monitoring than typically recommended for patients on TKI therapy.
• Some patients have experienced significant adverse events that are believed to be due to TKI discontinuation.
• Discontinuation of TKI therapy should only be performed in consenting patients after a thorough discussion of the potential risks and
benefits.
• Consultation with an NCCN Panel Member or center of expertise is recommended in the following circumstances:
Any significant adverse event is believed to be related to treatment discontinuation.
There is progression to AP-CML or BP-CML at any time.
MMR is not regained after 3 months following treatment reinitiation.
• Outside of a clinical trial, discontinuation of TKI therapy should be considered only if all of the criteria included in the list below are met.

Criteria for TKI Discontinuation

• Age ≥18 years.
• CP-CML. No prior history of AP-CML or BP-CML.
• On approved TKI therapy for at least 3 years.1,2
• Prior evidence of quantifiable BCR::ABL1 transcript.
• Stable molecular response (MR4; BCR::ABL1 ≤0.01% IS) for ≥2 years, as documented on at least 4 tests, performed at least 3 months apart.2
• Access to a reliable qPCR test with a sensitivity of detection of at least MR4.5 (BCR::ABL1 ≤0.0032% IS) and that provides results within 2
weeks.
• Molecular monitoring every 1–2 months for the first 6 months following discontinuation, bimonthly during months 7–12, and quarterly
thereafter (indefinitely) for patients who remain in MMR (MR3; BCR::ABL1 ≤0.1% IS).
• Prompt resumption of TKI within 4 weeks of a loss of MMR with monthly molecular monitoring until MMR is re-established, then every 3
months thereafter is recommended indefinitely for patients who have reinitiated TKI therapy after a loss of MMR. If MMR is not achieved after
3 months of TKI resumption, BCR::ABL1 kinase domain mutation testing should be performed, and monthly molecular monitoring should be
continued for another 6 months.

1 The feasibility of TFR following discontinuation of TKIs other than dasatinib, imatinib, or nilotinib has not yet been evaluated in clinical studies. It is reasonable to
assume that the likelihood of TFR following discontinuation would be similar irrespective of TKI in patients who have achieved and maintained DMR (MR4.0; ≤0.01%
BCR::ABL1 IS) for ≥2 years, based on the extrapolation of findings from the studies that have evaluated TFR following discontinuation of imatinib, dasatinib, or nilotinib.
2 Data from the EURO-SKI study suggest that MR4.0 (BCR::ABL1 ≤0.01% IS) for ≥3 years was the most significant predictor for successful discontinuation of imatinib.
Total duration of imatinib therapy for at least 6 years was also predictive of successful discontinuation (Saussele S, et al. Lancet Oncol 2018;19:747-757).

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

Clinical Trials: NCCN believes that the best management of any patient with cancer is in a clinical trial. Participation in clinical trials is especially encouraged.

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MANAGEMENT OF TOXICITIES AND DRUG INTERACTIONS

ASCIMINIB (CML-G 1 of 9)

BOSUTINIB (CML-G 2 of 9)

DASATINIB (CML-G 3 of 9)

IMATINIB (CML-G 4 of 9)

NILOTINIB (CML-G 5 of 9)

OMACETAXINE (CML-G 6 of 9)

PONATINIB (CML-G 7 of 9)

DRUG INTERACTIONS OF TKIs (CML-G 8 of 9)

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

Clinical Trials: NCCN believes that the best management of any patient with cancer is in a clinical trial. Participation in clinical trials is especially encouraged.

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MANAGEMENT OF ASCIMINIB TOXICITY1

Dosing:
• Asciminib should be taken orally without food. Patients should avoid food 2 hours before and 1 hour after taking asciminib.
• CP-CML (previously treated with ≥2 TKIs): The recommended initial dose is 80 mg orally once daily or 40 mg twice daily (at approximately 12-
hour intervals).
• CP-CML with T315I mutation: The recommended initial dose is 200 mg orally twice daily (at approximately 12-hour intervals).
Dose Adjustments:
Hematologic Toxicities
• ANC <1.0 x 10⁹/L, and/or platelets <50 x 10⁹/L: Hold asciminib until ANC ≥1.0 x 10⁹/L and/or platelets ≥50 x 10⁹/L. Resume asciminib at starting
dose (if resolved within 2 weeks) or at reduced dose (if resolved after 2 weeks).
• For recurrent severe thrombocytopenia and/or neutropenia, withhold asciminib until resolved to ANC ≥1.0 x 10⁹/L and platelets ≥50 x 10⁹/L,
then resume at reduced dose.
Non-Hematologic Toxicities
• Elevated serum amylase and/or lipase (>2.0 x institutional upper limit of normal [IULN]): Hold asciminib and resume asciminib at reduced
dose, after serum levels return to <1.5 x IULN. If events reoccur at reduced dose or if serum levels do not return to <1.5 x IULN, permanently
discontinue asciminib. Perform diagnostic tests to exclude pancreatitis.
• Hypertension: Monitor blood pressure and manage hypertension as clinically indicated. Interrupt, dose reduce, or permanently discontinue
asciminib if hypertension is not medically controlled.
• Hypersensitivity: May cause hypersensitivity reactions. Monitor patients for signs and symptoms and initiate appropriate treatment as
clinically indicated.
Grade ≥3: Hold asciminib until recovery to grade ≤1 and resume asciminib at reduced dose. If not resolved, permanently discontinue
asciminib.
• Cardiovascular toxicity: Monitor patients with history of cardiovascular risk factors for cardiovascular signs and symptoms. Initiate
appropriate treatment as clinically indicated.
Grade ≥3: Hold asciminib until recovery to grade ≤1 and resume asciminib at reduced dose. If not resolved, permanently discontinue
asciminib.w

1 Please refer to package insert for full prescribing information and monitoring of hematologic or biochemical abnormalities: https://www.accessdata.fda.gov/scripts/cder/daf/index.cfm.

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

Clinical Trials: NCCN believes that the best management of any patient with cancer is in a clinical trial. Participation in clinical trials is especially encouraged.
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MANAGEMENT OF BOSUTINIB TOXICITY1

Dosing:
Newly diagnosed CP-CML: The recommended initial dose is 400 mg once daily.
CP-CML, AP-CML, or BP-CML with resistance or intolerance to prior therapy: The recommended initial dose is 500 mg once daily.
Dose Adjustments:
Hematologic Toxicities
• Absolute neutrophil count (ANC) <1.0 x 109/L or platelets <50 x 109/L: Hold bosutinib until ANC ≥1.0 x 109/L and platelets ≥50 x 109/L. Resume
treatment with bosutinib at the same dose if recovery occurs within 2 weeks. If blood counts remain low for >2 weeks, upon recovery reduce
dose by 100 mg and resume treatment. If cytopenia recurs, reduce dose by an additional 100 mg upon recovery and resume treatment.
Doses <300 mg/day have not been evaluated.
• Growth factors can be used in combination with bosutinib for patients with persistent neutropenia and thrombocytopenia.
• Grade 3–4 anemia:2 Check reticulocyte count, ferritin, iron saturation, B12, folate, and correct nutritional deficiencies if present. Transfusion
support should be used if patient is symptomatic.
Non-Hematologic Toxicities
• Liver transaminases >5 x IULN: Hold bosutinib until recovery to ≤2.5 x IULN and resume dose at 400 mg once daily thereafter. If recovery
takes >4 weeks, discontinue bosutinib. If transaminase elevations ≥3 x IULN occur concurrently with bilirubin elevations >2 x IULN and
alkaline phosphatase <2 x IULN (Hy’s law case definition), discontinue bosutinib.
• Diarrhea: For NCI Common Terminology Criteria for Adverse Events (CTCAE) grade 3–4 diarrhea (increase of ≥7 stools/day over baseline/
pretreatment), withhold bosutinib until recovery to grade ≤1. Bosutinib may be resumed at 400 mg once daily.
• For other clinically significant, moderate, or severe non-hematologic toxicity, withhold bosutinib until the toxicity has resolved, then
consider resuming bosutinib at 400 mg once daily. If clinically appropriate, consider re-escalating the dose of bosutinib to 500 mg once daily.
Special Populations
• In patients with pre-existing mild, moderate, and severe hepatic impairment, the recommended dose of bosutinib is 200 mg daily. A daily
dose of 200 mg in patients with hepatic impairment is predicted to result in an area under the curve (AUC) similar to the AUC seen in patients
with normal hepatic function receiving 500 mg daily. However, there are no clinical data for efficacy at the dose of 200 mg once daily in
patients with hepatic impairment and CML.
• Monitoring renal function at baseline and during therapy is recommended with particular attention to those patients with preexisting renal
impairment or risk factors for renal dysfunction. Dose modification (as outlined in the prescribing information) should be considered for
patients with baseline and treatment-emergent renal impairment.
Specific Interventions
• Fluid retention events (ie, pulmonary and/or peripheral edema; pleural and pericardial effusion): Diuretics, supportive care.
• Gastrointestinal (GI) upset: Take medication with a meal and large glass of water.
• Rash: Topical or systemic steroids, dose reduction, dose interruption, or dose discontinuation.
1 Please refer to package insert for full prescribing information and monitoring of hematologic or biochemical abnormalities:
https://www.accessdata.fda.gov/scripts/cder/daf/index.cfm.
2 Although erythropoietin is effective, guidelines from the Centers for Medicare & Medicaid Services (CMS) and the U.S. Food and Drug Administration (FDA) do not
support the use of erythropoiesis-stimulating agents (ESAs) in myeloid malignancies.

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

Clinical Trials: NCCN believes that the best management of any patient with cancer is in a clinical trial. Participation in clinical trials is especially encouraged.
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MANAGEMENT OF DASATINIB TOXICITY1

Dosing:
• CP-CML: The recommended initial dose is 100 mg once daily.
• AP-CML and BP-CML: The recommended initial dose is 140 mg once daily.
Dose Adjustments:
Hematologic Toxicities
• CP-CML: ANC <0.5 x 109/L or platelets <50 x 109/L: Hold dasatinib until ANC ≥1.0 x 109/L and platelets ≥50 x 109/L, then resume dasatinib at
the starting dose if recovery occurs in ≤7 days. If platelets <25 x 109/L or recurrence of ANC <0.5 x 109/L for >7 days, hold drug until ANC
≥1.0 x 109/L and platelets ≥50 x 109/L, then resume dasatinib at reduced dose of 80 mg once daily for second episode. For third episode,
further reduce dose to 50 mg once daily (for newly diagnosed patients) or discontinue dasatinib (for patients with disease that is resistant or
intolerant to prior therapy including imatinib).
• AP-CML and BP-CML: ANC <0.5 x 109/L and/or platelets <10 x 109/L: Patients may have cytopenias related to disease. If cytopenia is
unrelated to disease, hold dasatinib until ANC ≥1.0 x 109/L and platelets ≥20 x 109/L, and resume at original starting dose. If recurrence, hold
dasatinib until ANC ≥1.0 x 109/L and platelets ≥20 x 109/L, and resume dasatinib at reduced dose of 100 mg once daily (second episode) or 80
mg once daily (third episode).
• Growth factors can be used in combination with dasatinib for patients with persistent neutropenia and thrombocytopenia.
• Grade 3–4 anemia:2 Check reticulocyte count, ferritin, iron saturation, B12, folate, and correct nutritional deficiencies if present. Transfusion
support should be used if patient is symptomatic.
Non-Hematologic Toxicities
• If a severe, non-hematologic, adverse reaction develops with dasatinib, treatment must be held until the event has resolved or improved.
Thereafter, treatment can be resumed as appropriate at a reduced dose depending on the initial severity of the event.
Rare But Serious Toxicities
• Pulmonary arterial hypertension (PAH): Dasatinib can cause PAH, which may occur any time after initiation, including after >1 year of
treatment. PAH may be reversible on discontinuation of dasatinib. Evaluate patients for signs and symptoms of underlying cardiopulmonary
disease prior to initiating dasatinib and during treatment. If PAH is confirmed, dasatinib should be permanently discontinued.
Specific Interventions
• Fluid retention events (ie, ascites, edema, pleural and pericardial effusion): Diuretics, supportive care.
• Pleural/pericardial effusion: Diuretics, dose interruption. If patient has significant symptoms, consider short course of steroids (prednisone
20–50 mg/day x 3–4 days, may taper with 20 mg/day x 3–4 days); when resolved, reduce one dose level.
• GI upset: Take medication with a meal and large glass of water.
• Rash: Topical or systemic steroids, dose reduction, dose interruption, or dose discontinuation.

1 Please refer to package insert for full prescribing information and monitoring of hematologic or biochemical abnormalities:
https://www.accessdata.fda.gov/scripts/cder/daf/index.cfm.
2 Although erythropoietin is effective, guidelines from CMS and the FDA do not support the use of ESAs in myeloid malignancies.

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

Clinical Trials: NCCN believes that the best management of any patient with cancer is in a clinical trial. Participation in clinical trials is especially encouraged.
CML-G
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MANAGEMENT OF IMATINIB TOXICITY1,3

Dosing:
• CP-CML: The recommended initial dose is 400 mg once daily.
• AP-CML and BP-CML: The recommended initial dose is 600 mg once daily.
Dose Adjustments:
Hematologic Toxicities
• CP-CML: ANC <1.0 x 109/L, and/or platelets <50 x 109/L: Hold imatinib until ANC ≥1.5 x 109/L and platelets ≥75 x 109/L, then resume imatinib at
the starting dose of 400 mg. If recurrence of ANC <1.0 x 109/L and/or platelets <50 x 109/L, hold drug until ANC ≥1.5 x 109/L and platelets ≥75 x
109/L, then resume imatinib at reduced dose of 300 mg.
• AP-CML and BP-CML: ANC <0.5 x 109/L and/or platelets <10 x 109/L: Patients may have cytopenias related to disease. If cytopenia is
unrelated to disease, reduce dose to 400 mg. If cytopenia persists for 2 weeks, reduce dose further to 300 mg. If cytopenia persists for 4
weeks, stop imatinib until ANC ≥1.0 x 109/L and platelet count ≥20 x 109/L and then resume treatment at 300 mg.
• Growth factors can be used in combination with imatinib for patients with persistent neutropenia.4
• Grade 3–4 anemia:2 Check reticulocyte count, ferritin, iron saturation, B12, folate, and correct nutritional deficiencies if present. Transfusion
support should be used if patient is symptomatic.
Non-Hematologic Toxicities
• Bilirubin >3 x IULN or liver transaminases >5 x IULN: Hold imatinib until bilirubin <1.5 x IULN and transaminase levels <2.5 x IULN. Resume
imatinib at a reduced daily dose (400–300 mg, 600–400 mg, or 800–600 mg).
• Severe hepatotoxicity or severe fluid retention: Hold imatinib until the event has resolved. Treatment can be resumed as appropriate
depending on the severity of the event.
• Patients with moderate renal impairment (creatinine clearance [CrCl] = 20–39 mL/min) should receive a 50% decrease in the recommended
starting dose and future doses can be increased as tolerated. Doses >600 mg are not recommended in patients with mild renal impairment
(CrCl = 40–59 mL/min). For patients with moderate renal impairment, doses >400 mg are not recommended. Imatinib should be used with
caution in patients with severe renal impairment.
Specific Interventions
• Fluid retention (ie, pleural effusion, pericardial effusion, edema, ascites): Diuretics, supportive care, dose reduction, interruption, or
discontinuation. Consider echocardiogram to check left ventricular ejection fraction (LVEF).
• GI upset: Take medication with a meal and large glass of water.
• Muscle cramps: Calcium supplement, tonic water.
• Rash: Topical or systemic steroids, dose reduction, dose interruption, or dose discontinuation.

1 Please refer to package insert for full prescribing information and monitoring of hematologic or biochemical abnormalities:
https://www.accessdata.fda.gov/scripts/cder/daf/index.cfm.
2 Although erythropoietin is effective, guidelines from CMS and the FDA do not support the use of ESAs in myeloid malignancies.
3 Many toxicities are self-limiting; consider re-escalating dose at a later time.
4 Quintas-Cardama A, Kantarjian H, O’Brien S, et al. Granulocyte-colony-stimulating factor (filgrastim) may overcome imatinib-induced neutropenia in patients with
chronic-phase chronic myelogenous leukemia. Cancer 2004;100:2592-2597.

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

Clinical Trials: NCCN believes that the best management of any patient with cancer is in a clinical trial. Participation in clinical trials is especially encouraged.
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MANAGEMENT OF NILOTINIB TOXICITY1

• Nilotinib prolongs the QT interval. Prior to administration of nilotinib and periodically, monitor for hypokalemia or hypomagnesemia and
correct deficiencies. Electrocardiograms (ECGs) should be obtained to monitor the QT interval at baseline, 7 days after initiation, and
periodically thereafter, as well as following any dose adjustments.
• Sudden deaths have been reported in patients receiving nilotinib.
• Avoid concomitant use of drugs known to prolong the QT interval and strong CYP3A4 inhibitors.
Dosing:
• Patients should avoid food 2 hours before and 1 hour after taking dose.
• Newly diagnosed CP-CML: The recommended initial dose is 300 mg twice daily.
• Resistant or intolerant CP-CML and AP-CML: The recommended initial dose is 400 mg twice daily.
• BP-CML: The recommended initial dose is 400 mg twice daily.
Dose Adjustments:
QT Interval Prolongation
• ECGs with a QT corrected for heart rate (QTc) >480 msec: Hold nilotinib. If serum potassium and magnesium levels are below lower limit of
normal, correct with supplements to within normal limits. Review concomitant medication usage. Resume within 2 weeks at prior dose if
QTc is <450 msec and within 20 msec of baseline. If QTc is between 450 and 480 msec after 2 weeks, resume at reduced dose (400 mg once
daily). Following dose reduction, if QTc returns to >480 msec, nilotinib should be discontinued. ECG should be obtained 7 days after any dose
adjustment to monitor QT interval.
Hematologic Toxicities
• CP-CML or AP-CML: ANC <1.0 x 109/L, and/or platelets <50 x 109/L: Hold nilotinib and monitor blood counts. Resume within 2 weeks at prior
dose if ANC >1.0 x 109/L and platelets >50 x 109/L. If blood counts remain low for >2 weeks, reduce dose to 400 mg once daily.
• Growth factors can be used in combination with nilotinib for patients with persistent neutropenia and thrombocytopenia.
• Grade 3–4 anemia:2 Check reticulocyte count, ferritin, iron saturation, B12, folate, and correct nutritional deficiencies if present. Transfusion
support should be used if patient is symptomatic.
Non-Hematologic Toxicities
• Elevated serum lipase, amylase, bilirubin, or hepatic transaminases grade ≥3: Hold nilotinib and monitor serum levels. Resume nilotinib at
400 mg once daily if serum levels return to grade ≤1.
• Hepatic Impairment: Consider alternate therapies. See prescribing information for dose adjustments related to hepatic impairment.
• Assess glucose levels before initiating treatment and monitor treatment as clinically indicated.
Rare But Serious Toxicities
• Peripheral arterial occlusive disease (PAOD): Nilotinib is associated with an increased risk of vascular adverse events, including PAOD, and
should be used with caution in patients with cardiovascular risk factors or a history of PAOD. Evaluate patients for a history of PAOD and for
vascular risk factors prior to initiating nilotinib and during treatment. If PAOD is confirmed, nilotinib should be permanently discontinued.
Specific Interventions
• Rash: Topical or systemic steroids, dose reduction, dose interruption, or dose discontinuation.
1 Please refer to package insert for full prescribing information and monitoring of hematologic or biochemical abnormalities:
https://www.accessdata.fda.gov/scripts/cder/daf/index.cfm.
2 Although erythropoietin is effective, guidelines from CMS and the FDA do not support the use of ESAs in myeloid malignancies.

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

Clinical Trials: NCCN believes that the best management of any patient with cancer is in a clinical trial. Participation in clinical trials is especially encouraged.
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MANAGEMENT OF OMACETAXINE TOXICITY1

Dosing:
• Resistant or intolerant CP-CML and AP-CML:
Induction dose: The recommended initial dose is 1.25 mg/m2 twice daily for 14 consecutive days of a 28-day cycle.
Maintenance dose: 1.25 mg/m2 twice daily for 7 consecutive days of a 28-day cycle.
Dose Adjustments:
Hematologic Toxicities
• CBCs should be performed weekly during induction and initial maintenance cycles. After initial maintenance cycles, monitor CBCs every 2
weeks or as clinically indicated. ANC <0.5 x 109/L or platelet count <50 x 109/L: Delay starting the next cycle until ANC ≥1.0 x 109/L and platelet
count ≥50 x 109/L and reduce the number of dosing days by 2 days for the next cycle.
Non-Hematologic Toxicities
• Grade 3 or 4 hyperglycemia: Monitor blood glucose levels frequently, especially in patients with diabetes mellitus (DM) or risk factors for DM.
Avoid omacetaxine in patients with poorly controlled DM until good glycemic control has been established.
• Manage other clinically significant non-hematologic toxicity symptomatically. Interrupt and/or delay omacetaxine until toxicity is resolved.

1 Please refer to package insert for full prescribing information and monitoring of hematologic or biochemical abnormalities:
https://www.accessdata.fda.gov/scripts/cder/daf/index.cfm.

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

Clinical Trials: NCCN believes that the best management of any patient with cancer is in a clinical trial. Participation in clinical trials is especially encouraged.
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MANAGEMENT OF PONATINIB TOXICITY1

• Arterial occlusive events (AOEs; including fatal myocardial infarction and stroke) and venous thromboembolic events (VTEs), have occurred in patients treated
with ponatinib. Monitor for evidence of thromboembolism and vascular occlusion. Interrupt or stop ponatinib immediately for vascular occlusion.
• Heart failure has occurred in patients treated with ponatinib. Monitor cardiac function. Interrupt or stop ponatinib for new or worsening heart failure.
• Hepatotoxicity: Hepatotoxicity, liver failure, and death have occurred in patients treated with ponatinib. Monitor hepatic function prior to and during treatment.
Interrupt ponatinib if hepatotoxicity is suspected.
• Cardiovascular risk: Identify and control traditional risk factors for atherosclerosis (eg, DM, hypertension, hyperlipidemia, smoking, estrogen use) before starting
ponatinib. Patients with cardiovascular risk factors should be referred to a cardiologist. Consider use of low-dose aspirin if there is no contraindication.
• Ponatinib is also associated with grade ≥3 skin rash and pancreatitis leading to dose modifications (dose delays or dose reductions).
Dosing: • Serum lipase elevation, grade 1 or 2 (asymptomatic): Consider dose
• CP-CML: The recommended initial dose is 45 mg once daily with a interruption or reduction. Serum lipase elevation, grade 3 or 4 (>2 x IULN)
reduction to 15 mg once daily upon achievement of BCR::ABL1 (IS) ≤1%. (asymptomatic) or asymptomatic radiologic pancreatitis: Hold drug until
In patients with a loss of response, the dose can be re-escalated to a serum levels are <1.5 x IULN. Resume at lower dose after recovery (30
previously tolerated dose of 30 mg or 45 mg once daily and continued at mg if patient is receiving 45 mg; 15 mg if patient is receiving 30 mg).
the re-escalated dose until loss of response or unacceptable toxicity. Discontinue ponatinib if patient is receiving 15 mg.
• AP-CML or BP-CML: The recommended initial dose is 45 mg once daily. • Pancreatitis (symptomatic), grade 3: Hold drug until serum lipase levels
Consider reducing the dose for patients with AP-CML who have achieved are ≤grade 1. Resume at lower dose after recovery (30 mg if patient
an MCyR. Consider discontinuing ponatinib if response has not occurred is receiving 45 mg; 15 mg if patient is receiving 30 mg). Discontinue
by 3 months. ponatinib if patient is receiving 15 mg. Grade 4: Discontinue ponatinib.
Dose Adjustments: Rare But Serious Toxicities
Hematologic Toxicities • Hemorrhage: Hemorrhagic events were reported in clinical trials. Cerebral
• ANC <1.0 x 109/L or platelets <50 x 109/L and GI hemorrhage were the most commonly reported serious bleeding
First occurrence: Hold ponatinib until ANC ≥1.5 x 109/L and platelets ≥75 events. Serious hemorrhage should be managed with dose interruption.
x 109/L and resume at initial dose of 45 mg. • Cardiac arrhythmias: Advise patients to report signs and symptoms
Second occurrence: Hold ponatinib until ANC ≥1.5 x 109/L and platelets suggestive of alterations in heart rate (fainting, dizziness, chest pain, or
≥75 x 109/L and resume at 30 mg. palpitations).
Third occurrence: Hold ponatinib until ANC ≥1.5 x 109/L and platelets ≥75 • Tumor lysis syndrome: Ensure adequate hydration and correct high
x 109/L and resume at 15 mg. uric acid levels prior to initiating therapy with ponatinib in patients with
• Growth factors can be used in combination with ponatinib for patients with advanced phase CML.
persistent neutropenia and thrombocytopenia. Specific Interventions
• Grade 3–4 anemia:2 Check reticulocyte count, ferritin, iron saturation, B12, • Fluid retention events (ie, edema, ascites, pleural and pericardial effusion)
folate, and correct nutritional deficiencies if present. Transfusion support are managed with dose interruption, dose reduction, or discontinuation of
should be used if patient is symptomatic. ponatinib as clinically indicated.
Non-Hematologic Toxicities • Hypertension: Monitor and manage blood pressure elevations.
• Liver transaminase >3 x IULN (grade ≥2): Monitor hepatic function. Hold • Rash: Topical or systemic steroids, dose reduction, dose interruption, or
drug until serum levels are <3 x IULN. Resume at lower dose after recovery dose discontinuation.
(30 mg if patient is receiving 45 mg; 15 mg if patient is receiving 30 mg).
Discontinue ponatinib if patient is receiving 15 mg.
• AST or ALT ≥3 x IULN concurrent with bilirubin >2 x IULN and alkaline
phosphatase <2 x IULN: Discontinue ponatinib.
1 Please refer to package insert for full prescribing information and monitoring of hematologic or biochemical abnormalities: https://www.accessdata.fda.gov/scripts/cder/daf/index.cfm.
2 Although erythropoietin is effective, guidelines from CMS and the FDA do not support the use of ESAs in myeloid malignancies.

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

Clinical Trials: NCCN believes that the best management of any patient with cancer is in a clinical trial. Participation in clinical trials is especially encouraged.
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DRUG INTERACTIONS OF TKIs1,5

Drug interactions of TKIs with the most commonly used medication and supplements are listed in the table below.
It is always important to take a detailed medication history (including herbal supplements) at every visit.
Drugs/ Change in TKI Level
Supplements Asciminib Bosutinib Dasatinib Imatinib Nilotinib Ponatinib
Proton Pump No major Decrease in Decrease in No major interaction Decrease in Minor decrease in
Inhibitors (PPIs) interaction exposure exposure exposure exposure
• Lansoprazole
• Rabeprazole
• Esomeprazole
• Omeprazole
• Pantoprazole
Histamine No major Decrease in Decrease in No major interaction Decrease in No major
2 Receptor interaction exposure; AVOID; If exposure; AVOID; If exposure; AVOID; If interaction
Antagonists absolutely necessary absolutely necessary absolutely necessary
(H2RAs) consider once-daily consider once-daily consider once-daily
• Famotidine H2RA ≥2 hours after H2RA ≥2 hours after H2RA ≥2 hours after
• Ranitidine taking bosutinib taking dasatinib or ≥10 hours before
• Nizatidine taking nilotinib
Antacids No major Decrease in Decrease in No major interaction Decrease in No major
interaction exposure if exposure if exposure if interaction
concomitant; Use concomitant; Use concomitant; Use
antacids at least 2 antacids at least 2 antacids at least 2
hours before or at hours before or at hours before or at
least 2 hours after least 2 hours after least 2 hours after
taking bosutinib taking dasatinib taking nilotinib
Antidepressants No major Minor increase Minor increase Minor increase AVOID if possible Minor increase
• Fluoxetine interaction in exposure; QTc in exposure; QTc in exposure; QTc due to cumulative in exposure; QTc
• Bupropion monitoring monitoring monitoring QTc prolongation risk monitoring
• Citalopram
Cardiovascular No major Increase in exposure Increase in exposure Increase in Increase in exposure Increase in
Medications interaction and arrhythmia risk; and arrhythmia risk; exposure; and arrhythmia risk; exposure;
• Amiodarone Strongly consider Strongly consider Strongly consider AVOID Strongly consider
• Diltiazem alternative cardiac alternative cardiac alternative cardiac alternative cardiac
• Verapamil medication or TKI medication or TKI medication or TKI medication or TKI
dose adjustment dose adjustment dose adjustment dose adjustment
Note: All recommendations are category 2A unless otherwise indicated.
Continued
Clinical Trials: NCCN believes that the best management of any patient with cancer is in a clinical trial. Participation in clinical trials is especially encouraged.
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Chronic Myeloid Leukemia Discussion

DRUG INTERACTIONS OF TKIs1,5

Drug interactions of TKIs with the most commonly used medication and supplements are listed in the table below.
It is always important to take a detailed medication history (including herbal supplements) at every visit.
Drugs/Supplements Change in TKI Level
Asciminib Bosutinib Dasatinib Imatinib Nilotinib Ponatinib
Anti-infectives Increase in Increase in Increase in Increase in Increase in Increase in
• Azole Antifungals exposure; exposure; exposure; exposure; exposure; exposure;
Fluconazole ≥200 mg Strongly consider Strongly consider Strongly consider Strongly consider Strongly consider Strongly consider
Voriconazole alternative anti- alternative anti- alternative anti- alternative anti- alternative anti- alternative anti-
Itraconazole infective or TKI infective or TKI infective or TKI infective or TKI infective or TKI infective or TKI
Posaconazole dose adjustment dose adjustment dose adjustment dose adjustment dose adjustment dose adjustment
Isavuconazole
• Clarithromycin
• Telithromycin
• Ritonavir
Anti-infectives No major QTc monitoring QTc monitoring No major Use with caution No major
• Fluoroquinolones interaction interaction interaction
Levofloxacin
Moxifloxacin
Ciprofloxacin
Herbal Supplements6,7 Increase in Increase in Increase in Increase in Increase in Increase in
• Curcumin (Turmeric) exposure; exposure; exposure; exposure; exposure; exposure;
• Ginkgo Biloba Strongly consider Strongly consider Strongly consider Strongly consider Strongly consider Strongly consider
• Green Tea Extract supplement supplement supplement supplement supplement supplement
discontinuation discontinuation discontinuation discontinuation discontinuation discontinuation
Herbal Supplements6,7 Decrease in Decrease in Decrease in Decrease in Decrease in Decrease in
• St. John’s Wort exposure; AVOID exposure; AVOID exposure; AVOID exposure; AVOID exposure; AVOID exposure; AVOID

1 Please refer to package insert for full prescribing information and drug interactions: https://www.accessdata.fda.gov/scripts/cder/daf/index.cfm.
5 van Leeuwen RW, van Gelder T, Mathijssen RH, et al. Drug-drug interactions with tyrosine-kinase inhibitors: a clinical perspective. Lancet Oncol 2014;15:e315-e326.
6 Zhang W, Lim LY. Effects of spice constituents on P-glycoprotein-mediated transport and CYP3A4-mediated metabolism in vitro. Drug Metab Dispos 2008;36:1283-1290.
7 Scott GN, Elmer GW. Update on natural product–drug interactions. Am J Health Syst Pharm 2002;59:339-347.

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

Clinical Trials: NCCN believes that the best management of any patient with cancer is in a clinical trial. Participation in clinical trials is especially encouraged.
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ABBREVIATIONS

1G first-generation DM Diabetes Mellitus MCyR major cytogenetic response

2G second-generation DLI donor lymphocyte infusion MMR major molecular response
3G third-generation DMR deep molecular response
PAH pulmonary arterial hypertension
ACAs additional chromosomal ECG electrocardiogram PAOD peripheral arterial occlusive
abnormalities ELTS EUTOS long-term survival disease
ALL acute lymphoblastic leukemia EMR early molecular response PCyR partial cytogenetic response
ALT alanine aminotransferase ESA erythropoiesis-stimulating agent Ph Philadelphia chromosome
AML acute myeloid leukemia EUTOS European Treatment and Outcome PPI proton pump inhibitor
ANC absolute neutrophil count Study
AOEs arterial occlusive events qPCR quantitative RT-PCR
AP-CML accelerated phase CML FISH fluorescence in situ hybridization QTc QT corrected for heart rate
AST aspartate aminotransferase
AUC area under the curve GI gastrointestinal RT-PCR reverse transcriptase polymerase
chain reaction
BP-CML blast phase CML H2RA histamine 2 receptor antagonist
TFR treatment-free remission
HCT hematopoietic cell transplant
CBC complete blood count TKI tyrosine kinase inhibitor
HLA human leukocyte antigen
CCyR complete cytogenetic response
CHR complete hematologic response VTE venous thromboembolism
IBMTR International Bone Marrow
CML chronic myeloid leukemia Transplant Registry
CMS Centers for Medicare & Medicaid ICC International Consensus WBC white blood cell
Services Classification
CNS central nervous system IS International Scale
CP-CML chronic phase CML IULN institutional upper limit of normal
CrCl creatinine clearance IVF in vitro fertilization
CTCAE common terminology criteria for
adverse events LVEF left ventricular ejection fraction

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NCCN Categories of Evidence and Consensus

Category 1 Based upon high-level evidence, there is uniform NCCN consensus that the intervention is appropriate.
Category 2A Based upon lower-level evidence, there is uniform NCCN consensus that the intervention is appropriate.
Category 2B Based upon lower-level evidence, there is NCCN consensus 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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Discussion This discussion corresponds to the NCCN Guidelines for Chronic Myeloid Leukemia. Last updated: April 13, 2023.

Table of Contents
Overview ..................................................................................................................................................................................................................MS-2

Guidelines Update Methodology ...............................................................................................................................................................................MS-2

Literature Search Criteria ..........................................................................................................................................................................................MS-2

Sensitive/Inclusive Language Usage ........................................................................................................................................................................MS-3

Diagnosis and Workup ..............................................................................................................................................................................................MS-3

Additional Evaluation ................................................................................................................................................................................................MS-5

Management of Chronic Phase CML ........................................................................................................................................................................MS-6

Management of Advanced Phase CML ...................................................................................................................................................................MS-21

Emerging Treatment Options ..................................................................................................................................................................................MS-23

Management of CML During Pregnancy and Breastfeeding ...................................................................................................................................MS-24

Specific Considerations for Children with CML .......................................................................................................................................................MS-26

Immunizations ........................................................................................................................................................................................................MS-26

References .............................................................................................................................................................................................................MS-42

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Overview years on average.5 Progression to AP-CML and BP-CML bridges a

Chronic myeloid leukemia (CML) accounts for 15% of adult leukemias. continuum of clinical features (ie, fever, bone pain, spleen size),
The median age of disease onset is 67 years; however, CML occurs in all cytogenetic changes, and blast count. Gene expression profiling has
age groups (SEER statistics). In 2023, an estimated 8,930 people will be shown a close correlation of gene expression between AP-CML and
diagnosed with CML in the United States, and 1,310 people will die from BP-CML indicating that the bulk of the genetic changes in progression
the disease.1 occur in the transition from CP-CML to AP-CML.6 The activation of
beta-catenin signaling pathway in CML granulocyte-macrophage
CML is defined by the presence of Philadelphia chromosome (Ph) in a progenitors (which enhances the self-renewal activity and leukemic
patient with a myeloproliferative neoplasm (MPN). Ph results from a potential of these cells) may be a key pathobiologic event in the evolution
reciprocal translocation between chromosomes 9 and 22 [t(9;22] that gives to BP-CML.7
rise to a BCR::ABL1 fusion gene.2 In the majority of patients, the
chromosomal break points are located in intron 13 or 14 of the BCR gene The NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®)
on chromosome 22 (major breakpoint cluster region; M-BCR); in the ABL1 Chronic Myeloid Leukemia discuss the clinical management of CML in all
gene they are located between the two alternative ABL1 exons Ib and Ia, three phases (chronic, accelerated, or blast phase). Evaluation for
or between ABL1 exons 1 and 2.3,4 Irrespective of the precise ABL1 diseases other than CML as outlined in the NCCN Guidelines® for
breakpoint, splicing almost invariably fuses ABL1 exon 2 with BCR exons Myeloproliferative Neoplasms is recommended for all patients with
13 or 14, resulting in e13a2 and e14a2 transcripts that code for a protein, BCR::ABL1–negative MPN.
p210, with deregulated tyrosine kinase activity, which causes CML.
Unusual BCR::ABL1 transcripts, e1a2 encoding for p190 (involving the Guidelines Update Methodology
minor breakpoint cluster region; m-BCR), or e19a2 encoding for p230 The complete details of the Development and Update of the NCCN
(involving the micro breakpoint cluster region; μ-BCR), are found Guidelines are available at www.NCCN.org.
infrequently.3,4 p190 is usually produced in the setting of Ph-positive acute
lymphoblastic leukemia (ALL), and p230 is associated with enhanced Literature Search Criteria
neutrophil differentiation. Atypical BCR::ABL1 transcripts (eg, e13a3, Prior to the update of this version of the NCCN Guidelines® for Chronic
e14a3, e6a2) have also been detected in about 1% to 2% of patients with Myeloid Leukemia, an electronic search of the PubMed database was
CML. The proportion of different BCR::ABL1 transcripts and the impact of performed to obtain key literature in Chronic Myeloid Leukemia since the
BCR::ABL1 transcript type on response to tyrosine kinase inhibitor (TKI) last guideline update using the following search terms: chronic myeloid
therapy are discussed on MS-4. leukemia or chronic myelogenous leukemia. The PubMed database was
chosen as it remains the most widely used resource for medical literature
CML occurs in three different phases (chronic, accelerated, and blast
and indexes peer-reviewed biomedical literature.8
phase) and is usually diagnosed in the chronic phase in the developed
world. Untreated chronic phase CML (CP-CML) will eventually progress to
accelerated phase CML (AP-CML) or blast phase CML (BP-CML) in 3 to 5

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The search results were narrowed by selecting studies in humans Diagnosis and Workup
published in English. Results were confined to the following article types:
Initial evaluation should consist of a history and physical exam, including
Randomized Controlled Trial; Clinical Trial, Phase II; Clinical Trial, Phase
palpation of spleen, complete blood count (CBC) with differential,
III; Guideline; Meta-Analysis; Systematic Reviews; and Validation Studies.
chemistry profile, and hepatitis B panel. Bone marrow aspirate and biopsy
The data from key PubMed articles selected by the panel for review during for morphologic and cytogenetic evaluation and quantitative reverse
the Guidelines update meeting as well as articles from additional sources transcriptase polymerase chain reaction (RT-PCR) to establish the
deemed as relevant to these Guidelines have been included in this version presence of quantifiable BCR::ABL1 mRNA transcripts at baseline are
of the Discussion section. Recommendations for which high-level recommended to confirm the diagnosis of CML (CML-1).
evidence is lacking are based on the panel’s review of lower-level
evidence and expert opinion. Bone marrow cytogenetics should be done at initial workup to detect
additional chromosomal abnormalities in Ph-positive cells (ACA/Ph+),
Sensitive/Inclusive Language Usage also known as clonal cytogenetic evolution.9 If bone marrow evaluation is
NCCN Guidelines strive to use language that advances the goals of not feasible, fluorescence in situ hybridization (FISH) on a peripheral
equity, inclusion, and representation. NCCN Guidelines endeavor to use blood specimen with dual probes for BCR and ABL1 genes is an
language that is person-first; not stigmatizing; anti-racist, anti-classist, acceptable method to confirm the diagnosis of CML. Interphase FISH is
anti-misogynist, anti-ageist, anti-ableist, and anti-fat-biased; and inclusive performed on peripheral blood but can be associated with a
of individuals of all sexual orientations and gender identities. NCCN false-positive rate of 1% to 5% depending on the specific probe used in
Guidelines incorporate non-gendered language, instead focusing on the assay.10 Hypermetaphase FISH is more sensitive and can analyze up
organ-specific recommendations. This language is both more accurate to 500 metaphases at a time, but it is applicable only to dividing cells in
and more inclusive and can help fully address the needs of individuals of the bone marrow.11 Double-fusion FISH is associated with low
all sexual orientations and gender identities. NCCN Guidelines will false-positive rates and can detect all variant translocations of the
continue to use the terms men, women, female, and male when citing Ph-chromosome.12
statistics, recommendations, or data from organizations or sources that do
Quantitative RT-PCR (qPCR) should be done at initial workup to establish
not use inclusive terms. Most studies do not report how sex and gender
the presence of quantifiable BCR::ABL1 mRNA transcripts. qPCR, usually
data are collected and use these terms interchangeably or inconsistently.
done on peripheral blood, is the most sensitive assay available for the
If sources do not differentiate gender from sex assigned at birth or organs
measurement of BCR::ABL1 mRNA and it can detect one CML cell in a
present, the information is presumed to predominantly represent cisgender
background of ≥100,000 normal cells. qPCR results can be expressed in
individuals. NCCN encourages researchers to collect more specific data in
various ways, for instance as the ratio of BCR::ABL1 transcript numbers
future studies and organizations to use more inclusive and accurate
to the number of control gene transcripts.13 An International Scale (IS)
language in their future analyses.
has been established to standardize molecular monitoring with qPCR
across different laboratories with the use of one of three control genes

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(BCR, ABL1, or GUSB) and a qPCR assay with a sensitivity of at least molecular response rates in patients with e13a2 as well as e14a2
4-log reduction from the standardized baseline.14 In recent years, IS has transcripts compared to imatinib 800 mg or dasatinib.21,27 The results of a
become the gold standard of expressing qPCR values. More details on more recent study indicate that the difference in the amplification
monitoring with qPCR using IS are provided on MS-9. Qualitative RT-PCR characteristics between the e13a2 and e14a2 transcripts can affect the
for the detection of atypical BCR::ABL1 transcripts should be considered if measurement of residual disease and thus emphasizing the need to
there is discordance between FISH and qPCR results. See the section on consider sequential measurement of minimal residual disease in addition
BCR::ABL1 Transcript Variants in CML below. to the achievement of response milestones at specific timepoints.28

BCR::ABL1 transcripts in the peripheral blood at very low levels (1–10 out The presence of e1a2 transcript (encoding for p190) is associated with
of 108 peripheral blood leukocytes) can be detected in approximately 30% higher risk of disease progression and inferior cytogenetic and molecular
of normal individuals, and the incidence of this increases with age. The responses to TKI therapy.29-33 In a multivariate analysis, e1a2 transcript
risk of developing CML for these individuals is extremely low, and neither was also identified as an independent predictor of inferior survival
continued monitoring nor therapy are indicated.15,16 outcomes.31 It is important to be aware that these data refer to the
presence of dominant e1a2 transcript, not to the presence of low-level
BCR::ABL1 Transcript Variants in CML e1a2 transcripts in patients with dominant e13a2 or e14a2 transcripts.
e13a2 and e14a2 transcripts (both encoding for p210) were the most The presence of e19a2 transcript (encoding for p230) is associated with
common BCR::ABL1 transcript variants identified in about 39% and 62% lower rates of cytogenetic and molecular response to TKIs and inferior
of patients, respectively; e13a2 was more frequent in males and the survival outcomes, despite previous reports of an indolent disease
proportion decreased with age in both sexes.17,18 Unusual or atypical course in the pre-TKI era.32-34 Referral to centers with expertise in the
transcripts were identified in about 2% of patients (e1a2, e19a2, e13a3, management of CML is recommended.
and e14a3 were the most frequently identified transcripts).17 The
Qualitative RT-PCR, nested RT-PCR, or Sanger sequencing are useful
incidence of these atypical transcripts was higher in females and the
for the identification of atypical BCR::ABL1 transcripts.35,36 qPCR using
proportion decreased with age in both genders. The presence of e14a2
log-reduction from standardized baseline can be used to monitor e1a2
at baseline was associated with higher molecular response rates to
transcripts, and monitoring e19a2 transcripts is usually performed using
imatinib.19-25 While some studies have demonstrated a trend towards
qualitative RT-PCR or nested RT-PCR. However, there are no
better survival outcomes with e14a2 transcript,21,22 in other studies the
standardized qPCR assays for monitoring molecular response to TKI
type of transcript did not have any significant impact on long-term
therapy in patients with atypical BCR::ABL1 transcripts.37,38 The utility of
survival outcomes.20,23,26
multiplex PCR assays and patient-specific genomic DNA
Limited available data from studies that have evaluated the impact of quantitative PCR assay for monitoring atypical BCR::ABL1 transcripts
BCR::ABL1 transcript variants on response to second-generation (2G) has been demonstrated in some reports.39-43
TKI therapy suggest that nilotinib may be associated with inferior

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Clonal Cytogenetic Evolution Additional Evaluation

The prognostic significance of ACA/Ph+ is related to the specific Chronic Phase CML (CML-1)
chromosomal abnormality and other features of accelerated phase.44-48 Sokal and Hasford (Euro) scoring systems have been used for the risk
The presence of “major route” ACA/Ph+ (trisomy 8, isochromosome 17q, stratification of patients into three risk groups (low, intermediate, and high)
second Ph, and trisomy 19) at diagnosis may have a negative prognostic in clinical trials evaluating TKIs (CML-A).70,71 The Sokal score is based on
impact on survival and disease progression to accelerated or blast the patient’s age, spleen size on clinical examination, platelet count, and
phase.49-52 However, in a more recent analysis that evaluated the percentage of blasts in the peripheral blood.70 The Euro score includes
outcomes of patients with CP-CML (with or without ACA) treated with TKI eosinophils and basophils in the peripheral blood in addition to the same
therapy in prospective studies, the presence of ACA/Ph+ at the time of clinical variables used in the Sokal score.71
diagnosis was not associated with worse prognosis.53 Survival outcomes
were not statistically significantly different among patients with ACA/Ph+ The European Treatment and Outcome Study long-term survival (ELTS)
based on TKI therapy (imatinib vs. 2G TKIs) or imatinib dose (400 mg vs. score is based on the same variables as the Sokol score and provides the
800 mg). It remains uncertain if 2G TKIs or high-dose imatinib would be most useful predictor of CML-related death in patients treated with first-line
more beneficial for patients with ACA/Ph+. Patients with ACA/Ph+ at imatinib.72 The ELTS score has been validated in a cohort of 1120 patients
diagnosis should be watched carefully for evidence of therapy failure. with CP-CML treated with imatinib in six clinical trials. Higher age, higher
peripheral blasts, bigger spleen, and low platelet counts were significantly
Clonal cytogenetic evolution in Ph-negative cells has also been reported in associated with increased probabilities of dying of CML. Patients in the
a small subset of patients treated with TKI therapy.54-65 The most common intermediate- and the high-risk group had significantly higher probabilities
abnormalities include trisomy 8 and loss of Y chromosome. Previous work of dying of CML than those in the low-risk group, and the probabilities
suggested that the overall prognosis of Ph-negative clonal evolution is were also significantly different between the intermediate- and high-risk
good and is dependent on response to imatinib therapy.58 Recently, groups. Unlike other scoring systems, the ELTS score is focused on
however, the presence of chromosome abnormalities other than loss of Y CML-specific overall survival (OS). This is important, as many patients
chromosome has been associated with decreased survival in patients with with CML die from non-CML causes, reflecting the efficacy of TKI therapy.
CP-CML treated with various TKIs, suggesting that closer follow-up is
indicated.66 Progression to myelodysplastic syndromes (MDS) and acute Determination of risk score using either the Sokal or Euro or ELTS scoring
myeloid leukemia (AML) have been reported in patients with monosomy 7 systems prior to initiation of TKI therapy is recommended for patients
(del 7q).67-69 diagnosed with CP-CML.70-72

Advanced Phase CML (CML-1)

The modified MD Anderson Cancer Center criteria for AP-CML (15% and
29% peripheral blood or bone marrow myeloblasts; ≥30% of peripheral
blood myeloblasts and promyelocytes; ≥20% of peripheral blood or bone
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NCCN Guidelines Version 1.2024

Chronic Myeloid Leukemia

marrow basophils; platelet count ≤100 x 109/L unrelated to therapy; and Flow cytometry to determine cell lineage, mutational analysis, and
clonal cytogenetic evolution in Ph+ cells) are used in many clinical trials human leukocyte antigen (HLA) testing, if considering allogeneic
that have evaluated the efficacy of TKIs (CML-B).73 AP-CML defined only hematopoietic cell transplant (HCT), are recommended for patients with
by clonal cytogenetic evolution on imatinib therapy is associated with a advanced phase CML.
better prognosis than AP-CML defined by clonal cytogenetic evolution and
additional features of progression.49,74 Management of Chronic Phase CML
Primary Treatment (CML-2)
The 2022 International Consensus Classification (ICC) includes a lower
threshold (10%–19%) of bone marrow or peripheral blasts and the Long-term efficacy data from randomized phase III studies for first-line
presence of ACA/Ph+ for the diagnosis of AP-CML whereas AP-CML is TKI therapy in patients with newly diagnosed CP-CML are summarized in
not included in the updated 2022 World Health Organization (WHO) Table 1.78-82 In summary, 1) all TKIs recommended are highly effective in
classification.75,76 The updated WHO classification emphasizes on the newly diagnosed CP-CML, with long-term OS expected to be similar to
high-risk features associated with the progression of CP-CML to that of aged-matched controls; 2) 2G TKIs, compared to imatinib,
BP-CML.76 generally result in faster cytogenetic and molecular responses, with less
progression to advanced phase CML; and 3) as of yet, in randomized
The International Bone Marrow Transplant Registry (IBMTR) criteria define clinical trials, there are no significant differences in OS in patients who
blast phase as the presence of ≥30% myeloblasts in the blood, bone initiate imatinib versus a 2G TKI (dasatinib, nilotinib, and bosutinib).
marrow, or both, or as the presence of extramedullary disease (CML-B).77
Any increase in lymphoblasts should be concerning for nascent lymphoid The selection of first-line TKI therapy (bosutinib, dasatinib, imatinib, or
blast phase disease. IBMTR criteria were used in most of the clinical trials nilotinib) in a given patient should be based on the risk score, toxicity
leading to the approval of TKIs and is best aligned with prognostication profile, patient’s age, ability to tolerate therapy, and the presence of
systems derived from these studies. The 2022 ICC and WHO comorbid conditions. Allogeneic HCT is no longer recommended as a
classification require the presence of 20% or more blast cells in the first-line treatment for patients with CP-CML.
peripheral blood or bone marrow, the presence of extramedullary blast
Clinical Considerations for the Selection of First-Line Therapy
proliferation, and the presence of increased lymphoblasts in peripheral
blood or bone marrow to confirm the diagnosis of BP-CML.75,76 Risk Stratification
Imatinib (400 mg daily) and 2G TKIs (bosutinib [400 mg daily], dasatinib
However, as clinical trials in the TKI era have almost uniformly utilized [100 mg once daily], and nilotinib [300 mg twice daily]) are all appropriate
modified MD Anderson Cancer Center or the IBMTR criteria, the use of options for first-line TKI therapy for patients with CP-CML across all risk
ICC or WHO criteria for the diagnosis of AP-CML and BP-CML is scores.78-82
disfavored.
Data from randomized phase III studies that have evaluated high-dose
imatinib as first-line therapy for CP-CML suggest that imatinib 800 mg

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NCCN Guidelines Version 1.2024

Chronic Myeloid Leukemia

was not associated with lower rates of disease progression than imatinib of lung disease or deemed to be at risk of developing pleural effusions.
400 mg, despite improved early responses (Table 2).83-85 Imatinib 800 Dasatinib or bosutinib may be preferred in patients with a history of
mg was also associated with higher rates of dose interruption, reduction, arrhythmias, cardiovascular disease, pancreatitis, or hyperglycemia.
or discontinuation due to grade 3 or 4 adverse events in all of the
studies. However, patients who were able to tolerate the higher dose of Adverse events of first-line TKI therapy in patients with CP-CML reported
imatinib achieved higher response rates than those receiving in phase III randomized studies are discussed below and are also
standard-dose imatinib.86 Imatinib 800 mg is not recommended as initial summarized in Table 4. See CML-F for the management of toxicities
therapy, given the recent data showing superior efficacy of 2G TKIs in associated with TKI therapy.
newly diagnosed CP-CML.
Bosutinib
Disease progression is more frequent in patients with intermediate- or In the BFORE study, diarrhea, increased alanine aminotransferase (ALT),
high-risk score, and prevention of disease progression to AP-CML or and aspartate aminotransferase (AST) were more common with bosutinib
BP-CML is the primary goal of TKI therapy in patients with CP-CML. 2G whereas muscle spasms and peripheral edema were more common with
TKIs are associated with lower risk of disease progression than imatinib imatinib.80,81 Grade 3/4 thrombocytopenia was higher with bosutinib and
and are therefore preferred for patients with an intermediate- or high-risk grade 3/4 neutropenia was higher with imatinib. Grade 3/4 anemia was
Sokal or Euro score. 2G TKIs also result in quicker molecular responses similar in both groups. Discontinuation of therapy due to drug-related
and higher rates of major molecular response (MMR; ≤0.1% BCR::ABL1 adverse events occurred in 14% of patients in the bosutinib group
IS) and DMR (MR4.0 [≤0.01% BCR::ABL1 IS] or MR4.5 [≤0.0032% compared to 11% in the imatinib group. Increased ALT (5%) and
BCR::ABL1 IS]) in patients with CP-CML across all risk scores (Table 3), increased AST (2%) were the most common adverse events leading to
which may facilitate subsequent discontinuation of TKI therapy in discontinuation of bosutinib. However, there were no hepatotoxicity-related
selected patients.79,80,82 fatalities during the study.

Therefore, 2G TKIs may be preferred over imatinib for younger patients, Dasatinib
particularly females since the achievement of a deep and rapid molecular In the DASISION study, the incidences of grade 3/4 hematologic
response may allow for eventual safe interruption of TKI therapy for toxicities (anemia, neutropenia, and thrombocytopenia) were higher for
fertility purposes. Imatinib may be preferred for older patients with dasatinib than imatinib.79 Nonhematologic adverse events such as
comorbidities, especially cardiovascular comorbidities. muscle spasms, peripheral edema, and hypophosphatemia were more
frequent with imatinib. Discontinuation of therapy because of
Toxicity Profile
drug-related adverse events occurred in 16% and 7% of patients in the
All the TKIs are generally well tolerated. Since bosutinib, dasatinib, and
dasatinib and imatinib arms, respectively. Dasatinib is associated with
nilotinib have very good efficacy in the upfront setting, differences in their
significant but reversible inhibition of platelet aggregation that may
potential toxicity profiles may inform the selection of a specific TKI as initial
therapy. Nilotinib or bosutinib may be preferred for patients with a history

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NCCN Guidelines Version 1.2024

Chronic Myeloid Leukemia

contribute to bleeding in some patients, especially if accompanied by Nilotinib

thrombocytopenia.87 In the ENESTnd study, rates of nonhematologic adverse events such as
nausea, diarrhea, vomiting, muscle spasm, and peripheral edema of any
Pleural effusion was also more common with dasatinib (28% in the
grade were higher for patients receiving imatinib. Conversely, rash and
DASISION study compared to <1% with imatinib and 33% in a dose
headache were more common with nilotinib.82 Grade 3 or 4 neutropenia
optimization study) and age has been identified as a significant risk factor
was more frequently observed in the imatinib group, whereas
for the development of pleural effusion.88 The occurrence of pleural
thrombocytopenia and anemia were similar in both groups. Electrolyte
effusion is significantly reduced with dasatinib 100 mg once daily
abnormalities and elevations in lipase, glucose, and bilirubin were more
compared with 70 mg twice daily. Patients with prior cardiac history, with
frequent with nilotinib than with imatinib. Patients with a previous history of
hypertension, and receiving dasatinib 70 mg twice daily are at increased
pancreatitis may be at greater risk of elevated serum lipase. The overall
risk of developing pleural effusions.89 Close monitoring and timely
incidences of adverse events leading to discontinuation of therapy were
intervention are necessary for patients at risk of developing pleural
comparable in the nilotinib 300 mg twice-daily and imatinib arms (12% and
effusions.
14%, respectively) and slightly higher in the nilotinib 400 mg twice-daily
Largely reversible pulmonary arterial hypertension has been reported as a arm (20%).
rare but serious side effect of dasatinib.90-92 In the DASISION study,
Nilotinib labeling contains a black box warning regarding the risk of QT
pulmonary hypertension was reported in 5% of patients treated with
interval prolongation, and sudden cardiac death has been reported in
dasatinib compared to less than 1% of patients treated with imatinib.79
patients receiving nilotinib.92 QT interval prolongation could be managed
Evaluation for signs and symptoms of underlying cardiopulmonary disease
with dose reduction. Electrolyte abnormalities should be corrected prior to
prior to initiating and during treatment with dasatinib is recommended. If
initiation of treatment with nilotinib and electrolytes should be monitored
pulmonary arterial hypertension is confirmed, dasatinib must be
periodically. Drugs that prolong QT interval should be avoided.
permanently discontinued.
Electrocardiogram (ECG) should be obtained to monitor the QT interval at
Imatinib baseline, 7 days after initiation of nilotinib, and periodically thereafter, as
well as following any dose adjustments.
Chronic fatigue (often correlated with musculoskeletal pain and muscular
cramps) is a major factor reducing quality of life.93 Hypophosphatemia and Nilotinib is associated with an increased risk of ischemic heart disease,
decrease in bone mineral density have been noted in a small group of ischemic cerebrovascular disease and peripheral arterial occlusive
patients, suggesting that monitoring bone health should be considered for disease (PAOD).82 The 10-year follow-up data from ENESTnd study
patients taking imatinib.94,95 Skin hypopigmentation has also been reported showed a higher rate cardiovascular events with nilotinib (17% and 24%,
as a side effect of imatinib and is reversible upon discontinuation or dose respectively for nilotinib 300 mg twice daily and nilotinib 400 mg twice
reduction.96,97 Reversible renal dysfunction with prolonged use of imatinib daily) versus imatinib (4%).82 Evaluation for pre-existing cardiovascular
has also been reported.98 risk factors prior to initiating treatment with nilotinib and close monitoring

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NCCN Guidelines Version 1.2024

Chronic Myeloid Leukemia

for any cardiovascular events during treatment with nilotinib is analyses have been based on conventional bone marrow cytogenetics.
recommended for all patients. Patients with cardiovascular risk factors With the advent of qPCR, bone marrow cytogenetic analyses to assess
should be referred to a cardiologist. response are rarely performed. If conventional bone marrow cytogenetics
yield no analyzable metaphases, cytogenetic response can be evaluated
Management of Hematologic Toxicities of TKI Therapy
by FISH, preferably with a dual color probe to minimize false-positive
Cytopenias (anemia, neutropenia, and thrombocytopenia) should be rates. FISH and cytogenetic results are correlated, but are not
managed with transient interruptions of TKI therapy and dose superimposable.102-104 Although some investigators have reported that
modifications. Please see the package insert for full prescribing interphase FISH can be used to monitor complete cytogenetic response
information, available at www.accessdata.fda.gov, for the recommended (CCyR), endpoints for TKI failure have not been defined on the basis of
dose modifications of specific TKI therapy. FISH analysis.105,106 The panel feels that FISH has been inadequately
studied for monitoring response to TKI therapy and is not generally
Assessment of reticulocyte count, ferritin, iron saturation, vitamin B12,
recommended for monitoring response if conventional cytogenetics or
and folate and correction of nutritional deficiencies if present is
qPCR are available.
recommended for patients with grade 3–4 anemia. Red blood cell
transfusions are indicated in symptomatic patients. Myeloid growth factor qPCR is the only tool capable of monitoring responses after the patient
support can be used in combination with TKI therapy for the has achieved CCyR, since BCR::ABL1 transcripts typically remain
management of neutropenia.99,100 The use of erythropoiesis-stimulating detectable after CCyR is achieved. A major advantage of qPCR is the
agents (ESAs) did not impact survival or cytogenetic response rate, but strong correlation between the results obtained from the peripheral blood
was associated with a higher thrombosis rate in patients with CP-CML.101 and the bone marrow, allowing for molecular monitoring without bone
Recent guidelines from the U.S. Centers for Medicare & Medicaid marrow aspirations.107,108
Services (CMS) and the U.S. Food and Drug Administration (FDA) do not
support the use of ESAs in patients with myeloid malignancies. Standardization of Molecular Monitoring Using the International Scale
In the IS, the standardized baseline (defined as the average expression of
Monitoring Response to TKI Therapy BCR::ABL1 transcripts in 30 patients with untreated CML enrolled in the
Response to TKI therapy is determined by the measurement of IRIS trial) is set to 100%. Molecular response is expressed as
hematologic (normalization of peripheral blood counts), cytogenetic log-reduction from 100%. For example, a 2-log reduction or greater (≤1%
(decrease in the number of Ph-positive metaphases using bone marrow BCR::ABL1 IS; MR2.0) generally correlates with CCyR and a ≥3-log
cytogenetics), and molecular assessments (decrease in the amount of reduction (≤0.1% BCR::ABL1 IS) is referred to as MMR or MR3.0.14,109,110
BCR::ABL1 chimeric mRNA using qPCR). The criteria for hematologic,
DMR is defined by the assay's level of sensitivity [≤0.01% BCR::ABL1 (IS),
cytogenetic, and molecular response are summarized in CML-D.
MR4.0; ≤0.0032% BCR::ABL1 (IS), MR4.5].111 The sensitivity of a qPCR
Conventional bone marrow cytogenetics is the standard method for assay depends not only on the performance of the assay, but also on the
monitoring cytogenetic responses, and many clinical trial response quality of a given sample.

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As such, the term “complete molecular response” to denote undetectable frequency of molecular monitoring can be reduced, though the optimal
BCR::ABL1 transcripts (a negative qPCR test) should be abandoned, as frequency is unknown. Molecular monitoring of response to TKI therapy
it may refer to very different levels of response, dependent on the quality more frequently than every 3 months is not presently recommended.
of the sample and sensitivity of the test. Laboratories can use their
individual assays, but the BCR::ABL1 transcripts obtained in a given Prognostic Significance of Cytogenetic and Molecular Response
laboratory should be converted to the IS by applying a laboratory-specific Early molecular response (EMR; ≤10% BCR::ABL1 IS at 3 and 6
conversion factor (CF).14,112 months) after first-line TKI therapy has emerged as an effective
prognosticator of favorable long-term PFS and OS (Table 5).79,82,85,114
Recommendations for Monitoring Response to TKI Therapy
Some reports suggest that EMR at 3 months has a superior prognostic
qPCR (IS) is the preferred method to monitor response to TKI therapy.
value and supports the use of early intervention strategies based on the
qPCR assays with a sensitivity of ≥4.5-log reduction from the standardized
BCR::ABL1 transcript level at 3 months.115,116 However, other studies
baseline are recommended for the measurement of BCR::ABL1 transcripts
yielded partially conflicting results regarding the predictive value of
(CML-C). In patients with prolonged myelosuppression who may not be in
BCR::ABL1 transcripts at 3 months.117 From a practical perspective, it is
complete hematologic response (CHR) due to persistent cytopenias or
important to consider these data points within the clinical context. For
unexplained drop in blood counts during therapy, bone marrow
instance, if BCR::ABL1 transcript level is minimally above the 10% cutoff
cytogenetics is indicated to confirm response to TKI therapy and exclude
(eg, 11%–15% at 3 months), it is reasonable to reassess at 6 months
other pathology, such as MDS or the presence of chromosomal
before considering major changes to the treatment strategy.
abnormalities other than Ph.
Quite recently, studies have suggested that the rate of decline in
Monitoring with qPCR (IS) every 3 months is recommended for all patients BCR::ABL1 transcripts correlates with longer-term response.118-120
after initiating TKI therapy, including those who meet response milestones Among patients with >10% BCR::ABL1 IS after 3 months of treatment
at 3, 6, and 12 months (≤10% BCR::ABL1 IS at 3 and 6 months, ≤1% with imatinib, those with a faster decline in BCR::ABL1 (BCR::ABL1
BCR::ABL1 IS at 12 months, and ≤0.1% BCR::ABL1 IS at >12 months). halving time <76 days) had a superior outcome compared to those with a
After CCyR (≤1% BCR::ABL1 IS) has been achieved, molecular slower decline (4-year PFS rate was 92% vs. 63%, respectively).118 In
monitoring is recommended every 3 months for 2 years and every 3 to 6 the German CML IV study, lack of a half-log reduction of BCR::ABL1
months thereafter. transcripts at 3 months was associated with a higher risk of disease
progression on imatinib therapy.119 The results of the D-First study also
Frequent molecular monitoring with qPCR (IS) can help to identify
showed that in patients treated with dasatinib, BCR::ABL1 halving time of
non-adherence to TKI therapy early in the treatment course.113 Since
14 days or less was a significant predictor of MMR by 12 months and
adherence to TKI therapy is associated with better clinical outcomes,
DMR (MR4.0; ≤0.01% BCR::ABL1 IS) by 18 months.120
frequent molecular monitoring is essential if there are concerns about the
patient's adherence to TKI therapy. In patients with deeper molecular Achievement of CCyR or ≤1% BCR::ABL1 IS within 12 months after
responses (MMR and better) and who are compliant with TKI therapy, the first-line TKI therapy is an established prognostic indicator of long-term

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NCCN Guidelines Version 1.2024

Chronic Myeloid Leukemia

survival.121,122 In the IRIS study, the estimated 6-year PFS rate was 97% BCR::ABL1 IS), which may facilitate discontinuation of TKI therapy.38,129
for patients achieving a CCyR at 6 months compared to 80% for patients In view of the ongoing evolution of treatment goals (OS vs.
with no cytogenetic response at 6 months.121 In an analysis of patients treatment-free remission [TFR]), expert panels have emphasized the
with newly diagnosed CP-CML treated with imatinib or 2G TKIs, the importance of joint decision-making between patient and provider,
3-year event-free survival (EFS) and OS rates were 98% and 99% for particularly in ambiguous situations.132
patients who achieved CCyR at 12 months compared to 67% and 94% in
patients who did not achieve a CCyR.122 Response Milestones After First-Line TKI Therapy (CML-3)

MMR (≤0.1% BCR::ABL1 IS) as a predictor of PFS and OS has also The most important goals of TKI therapy are to prevent disease
been evaluated in several studies.107,123-129 In all of these studies, the progression to AP-CML or BP-CML and to achieve either MR2.0 (≤1%
analyses were done for different outcomes measures at multiple time BCR::ABL1 IS, which corresponds to CCyR) or MMR (≤0.1% BCR::ABL1
points, but failed to adjust for multiple comparisons, thereby reducing the IS) within 12 months after first-line TKI therapy. The guidelines emphasize
validity of the conclusions. The general conclusion from these studies is that achievement of response milestones must be interpreted within the
that the achievement of MMR is associated with durable long-term clinical context, before making drastic changes to the treatment strategy,
cytogenetic remission and lower rate of disease progression, but MMR is especially in ambiguous situations.
not a significant predictor of superior OS in patients who are in stable
The panel has included ≤10% BCR::ABL1 IS at 3 and 6 months after
CCyR. Importantly, with longer follow-up, CCyR becomes an
initiation of first-line TKI therapy as a response milestone, since the
ever-stronger indicator of MMR, reducing the added prognostic value of
achievement of EMR after first-line TKI therapy is an effective
MMR. Although the CML IV study showed that MR4.5 (≤0.0032%
prognosticator of favorable long-term PFS. Achievement of >0.1%–1%
BCR::ABL1 IS) at 4 years was associated with a significantly higher OS
BCR::ABL1 IS (≤1% BCR::ABL1 IS, which correlates with CCyR) is
(independent of therapy) than MR2.0 (≤1% BCR::ABL1 IS, which
considered the optimal response milestone at 12 months if the goal of
corresponds to CCyR), this study demonstrated no significant differences
therapy in an individual patient is long-term survival, whereas the
in OS in patients who achieved MMR (≤0.1% BCR::ABL1 IS) and those
achievement of MMR (≤0.1% BCR::ABL1 IS) at 12 months should be
who achieved MR2.0 (≤1% BCR::ABL1 IS).128
considered as the optimal response milestone if the treatment goal in an
The absence of MMR in the presence of a CCyR is therefore not individual patient is TFR. Patients who achieve these response milestones
considered a treatment failure. While some investigators have reported are considered to have TKI-sensitive disease, and continuation of the
that dose escalation of imatinib might benefit patients in CCyR with no same dose of TKI and assessment of BCR::ABL1 transcripts with qPCR
MMR,130 there are no randomized studies to show that a change of (IS) every 3 months is recommended for this group of patients.
therapy would improve survival, PFS, or EFS in this group of patients.131
In patients with a >10% BCR::ABL1 IS at 3 months and >1% BCR::ABL1
However, the achievement of MMR (≤0.1% BCR::ABL1 IS) at 12 months
IS at 12 months, clinical judgment should be used, considering problems
is associated with a very low probability of subsequent loss of response
with adherence (which can be common given drug toxicity at initiation of
and a high likelihood of achieving a subsequent DMR (MR4.0; ≤0.01%

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therapy), rate of decline in BCR::ABL1 (the faster, the better), and how far for cytogenetic relapse in patients who had achieved cytogenetic response
from the cutoff the BCR::ABL1 value falls. Failure to achieve ≤10% with imatinib 400 mg daily, although the duration of responses has
BCR::ABL1 IS at 3 months or ≤1% BCR::ABL1 IS at 12 months is typically been short.133-136 However, it is unlikely to benefit patients with
associated with a higher risk for disease progression. Patients with >10% hematologic failure or those who never had a cytogenetic response with
BCR::ABL1 at 3 months or >1% BCR::ABL1 at 12 months can continue imatinib 400 mg daily. In patients with >10% BCR::ABL1 IS at 3 months
the same dose of dasatinib, nilotinib, or bosutinib for another 3 months. after imatinib 400 mg, switching to nilotinib or dasatinib has been shown to
BCR::ABL1 mutational analysis and evaluation for allogeneic HCT should result in higher rates of MMR at 12 months than dose escalation of
be considered. Bone marrow cytogenetics should be considered to assess imatinib.137-139 Although dose escalation of imatinib has been shown to be
for major cytogenetic response (MCyR) at 3 months or CCyR at 12 beneficial for patients in CCyR without MMR, no randomized studies have
months. shown that a change of therapy would improve PFS or EFS in this group
of patients.130,131
In patients with >0.1%–1% BCR::ABL1 IS at 12 months, shared
decision-making is recommended depending on the goal of therapy in Dasatinib, nilotinib, and bosutinib, which are more potent than imatinib in
individual patients (longer-term survival vs. TFR). As discussed before, vitro and retain activity against many of the imatinib-resistant BCR::ABL1
although not associated with increased OS, MMR at 12 months is kinase domain mutants except T315I, are effective treatment options for
associated with lower rate of disease progression and a higher likelihood patients with CP-CML intolerant or resistant to imatinib.140-142 Bosutinib
of achieving DMR, which is a prerequisite for TFR. Switching to a 2G TKI also has demonstrated activity in patients with CP-CML resistant to
from imatinib might be considered to increase the probability of achieving multiple TKIs (imatinib, dasatinib, and nilotinib).143,144 Ponatinib and
MMR (≤0.1% BCR::ABL1 IS) at 12 months. However, there is a possibility asciminib (specifically targeting the ABL myristoyl pocket [STAMP]
that a switch will be associated with increased toxicity. Referral to inhibitor) are active against most of the resistant BCR::ABL1 kinase
specialized CML centers and/or enrollment in a clinical trial should be domain mutants including T315I.145-149
considered.
Long-term efficacy data from clinical trials on second-line and subsequent
Patients with >10% BCR::ABL1 IS at 6 and 12 months are considered to TKI therapy for CP-CML are summarized in Table 6.
have TKI-resistant disease. Evaluation for allogeneic HCT (that is, a
discussion with a transplant specialist, which might include HLA testing) is Ponatinib was initially approved as a treatment option for patients with a
recommended. Alternate treatment options should be considered as T315I mutation and/or for patients for whom no other TKI is indicated
described below. based on the results of the PACE trial (Table 6).145 The recommended
initial dose of ponatinib was 45 mg once daily. The high-dose intensity of
Second-Line Therapy ponatinib was associated with increased risk of arterial occlusive events
(AOE) and the incidence of cardiovascular adverse events was highest
Dose escalation of imatinib up to 800 mg daily has been shown to
among patients with preexisting cardiovascular risk factors.145,150-152 In
overcome some cases of primary resistance and is particularly effective
the PACE trial, serious AOE (cardiovascular, cerebrovascular, and

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NCCN Guidelines Version 1.2024

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peripheral vascular) and venous thromboembolic events occurred in 31% T315I mutation and/or CP-CML with resistance or intolerance to at least
and 6% of patients, respectively.145 Cardiovascular, cerebrovascular, and two prior TKIs.
peripheral AOEs were reported in 16%, 13%, and 14% of patients,
respectively. In the phase III randomized study (ASCEMBL), asciminib 40 mg twice
daily achieved higher molecular response rates (MMR, MR4.0, and
In the OPTIC trial that evaluated the safety and efficacy of MR4.5) than bosutinib 500 mg once daily in patients with CP-CML
response-adjusted dosing regimen, patients were randomized to ponatinib previously treated with ≥2 prior TKIs, and the incidence of adverse events
starting doses of 45 mg, 30 mg, and 15 mg, with dose reduction to 15 mg leading to treatment discontinuation was also lower with asciminib (6% vs.
with achievement of ≤1% BCR::ABL1 (IS) in the 45 mg and 30 mg 21%) (Table 6).148,149 Gastrointestinal toxicities (diarrhea, nausea, and
cohorts.146 Ponatinib was effective at all 3 dose levels (45 mg, 30 mg, and vomiting) and biochemical abnormalities (increased ALT and AST levels)
15 mg) and with the maximum benefit was observed with 45 mg (Table 6). were notably higher with bosutinib. AOEs were reported in 3% and 1% of
After a median follow-up of 32 months, BCR::ABL1 (IS) ≤1% at 12 months patients treated with asciminib and bosutinib, respectively. Patients with a
was achieved in 44% of patients in the 45 mg cohort compared to 29% history of cardiovascular risk factors for cardiovascular signs and
and 23% in the 30 mg and 15 mg cohorts, respectively. After symptoms should be carefully monitored and appropriate treatment should
response-based dose reduction to 15 mg, responses were maintained in be initiated as clinically indicated. The recommended initial dose of
73% and 79% of patients in 45 mg and 30 mg cohorts, respectively. The asciminib is 80 mg once daily or 40 mg twice daily in patients without a
rate of any AOE reported in the OPTIC trial (10% in the 45 mg cohort; 5% T315I mutation and 200 mg twice daily for patients with a T315I mutation.
and 3% in the 30 mg and 15 mg cohorts, respectively) was lower than that In the phase I study, the majority of patients with a T315I mutation
reported for ponatinib 45 mg in the PACE trial. Based on the results of the achieving CCyR and MMR had received >150 mg twice-daily asciminib.147
OPTIC trial, the FDA has approved a response-adjusted dosing regimen
for ponatinib [starting dose of 45 mg once daily with a reduction to 15 mg Omacetaxine is a treatment option for patients with CP-CML resistant or
upon achievement of BCR::ABL1 (IS) ≤1%] for patients with CP-CML with intolerant to ≥2 TKIs including those with a T315I mutation.154,155
resistance or intolerance to at least two prior kinase inhibitors. Omacetaxine resulted in MCyR, CCyR, and MMR rates of 23%, 16%, and
17%, respectively, in the cohort of patients with CP-CML resistant to prior
Cardiovascular risk factors (eg, diabetes mellitus, hypertension, TKI therapy and T315I mutation (CML 202 study; n = 62) and the T315I
hyperlipidemia, smoking, estrogen use) should be identified and controlled clone declined to below detection limits in 61% of patients.154 The median
before starting ponatinib. Patients should be monitored for high blood PFS was 8 months and the median OS had not yet been reached. In the
pressure, evidence of arterial occlusive or thromboembolic events, and cohort of patients with CP-CML resistant or intolerant to ≥2 TKIs (CML 203
reduced cardiac function.153 Ponatinib should be interrupted or stopped study; n = 46), the MCyR and CCyR rates were 22% and 4%, respectively.
immediately for vascular occlusion and for new or worsening heart failure. The median PFS and OS were 7 months and 30 months, respectively.155
Patients with cardiovascular risk factors should be referred to a The response rates and survival outcomes, however, were substantially
cardiologist. Asciminib is approved for patients with CP-CML having the lower than that observed with ponatinib in the PACE trial. Omacetaxine

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had an acceptable toxicity profile, and the most common grade 3/4 concentration of TKIs, whereas CYP3A4 inhibitors and drugs that are
adverse events were thrombocytopenia (67%), neutropenia (47%), and metabolized by the CYP3A4 or CYP3A5 enzyme might result in increased
anemia (37%). plasma levels of TKIs. In addition, imatinib is also a weak inhibitor of the
CYP2D6 and CYP2C9 isoenzymes and nilotinib is a competitive inhibitor
Clinical Considerations for the Selection of Second-Line TKI of CYP2C8, CYP2C9, CYP2D6, and UGT1A1, potentially increasing the
Therapy plasma concentrations of drugs eliminated by these enzymes. Asciminib is
Switching to a 2G TKI is recommended for patients with disease that is also a CYP2C9 inhibitor and concomitant use of asciminib increases the
resistant to imatinib 400 mg daily. Patients with disease that is resistant plasma concentration of other drugs that are CYP2C9 substrates.
to bosutinib, dasatinib, or nilotinib could be switched to an alternate TKI
Drug interactions between TKIs and some of the most commonly used
(other than imatinib). However, there is no clear evidence to support that
drugs and supplements are summarized in CML-F. Concomitant use of
switching to alternate TKI therapy would improve long-term clinical
drugs that are metabolized by these enzymes requires caution, and
outcome for this group of patients. Evaluation of allogeneic HCT should
appropriate alternatives should be explored to optimize treatment
be considered for this group of patients. The use of an alternate 2G TKI
outcome. If coadministration cannot be avoided, dose modification should
after treatment failure with two prior TKIs, is not associated with durable
be considered.
responses except in occasional patients with CP-CML.156 Treatment with
ponatinib, asciminib or enrollment in a clinical trial should be considered. Adherence to Therapy
Treatment interruptions and non-adherence to therapy may lead to
EMR (≤10% BCR::ABL1 IS at 3 and 6 months) after second-line TKI
undesirable clinical outcomes.159-161 In the ADAGIO study, non-adherence
therapy with dasatinib or nilotinib has also been reported to be a
to imatinib was associated with poorer response. Patients with suboptimal
prognosticator of OS and PFS (Table 7). Patients who do not achieve
response missed significantly more imatinib doses (23%) than did those
cytogenetic or molecular responses at 3, 6, or 12 months after
with optimal response (7%).159 Adherence to imatinib therapy has been
second-line and subsequent TKI therapy should be considered for
identified as the only independent predictor for achieving complete
alternative therapies or allogeneic HCT if deemed eligible.
molecular response (CMR) on standard-dose imatinib.160 The 6-year
BCR::ABL1 kinase domain mutation analysis (see below), evaluation of probability of achieving CMR was significantly higher for patients with
drug interactions, and compliance to therapy are recommended prior to >90% adherence rate (44% compared to 0% for patients with ≤90%
the initiation of second-line TKI therapy. adherence rate; P = .002).160 Poor adherence to imatinib therapy has also
been identified as the most important factor contributing to cytogenetic
Drug Interactions relapse and imatinib failure.161 Patients with adherence of 85% or less had
All TKIs are metabolized in the liver by cytochrome P450 (CYP) enzymes, a higher probability of losing CCyR at 2 years than those with adherence
and concomitant use of drugs that induce or inhibit CYP3A4 or CYP3A5 of greater than 85% (27% and 2%, respectively). Poor adherence to
enzymes may alter the therapeutic effect of TKIs.157,158 Drugs that are
CYP3A4 or CYP3A5 inducers may decrease the therapeutic plasma
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therapy has also been reported in patients receiving dasatinib and nilotinib outcomes, and assays that measure plasma levels of imatinib are not
following imatinib failure.162,163 widely available.

Patient education on adherence to therapy and close monitoring of BCR::ABL1 Kinase Domain Mutation Analysis
patient’s adherence is critical to achieving optimal responses. In a Point mutations in the BCR::ABL1 kinase domain are a frequent
significant proportion of patients with TKI-induced toxicities, responses mechanism of secondary resistance to TKI therapy and are associated
have been observed with doses well below their determined maximum with poor prognosis and higher risk of disease progression.179-184 E255K/V,
tolerated doses.164 Short interruptions or dose reductions, when medically F359C/V, Y253H, and T315I mutants are most commonly associated with
necessary, may not have a negative impact on disease control or other disease progression and relapse.185,186 Among the BCR::ABL1 kinase
outcomes. Adequate and appropriate management of side effects and domain mutations, T315I confers complete resistance to imatinib,
scheduling appropriate follow-up visits to review side effects may be dasatinib, nilotinib, and bosutinib.187,188 The T315A, F317L/I/V/C, and
helpful to improve patient adherence to therapy.165 Switching to an V299L mutants are resistant to dasatinib and E255K/V, F359V/C, and
alternate TKI because of intolerance might be beneficial for selected Y253H mutants are resistant to nilotinib.185,189-191 G250E, and V299L
patients with acute grade 3/4 non-hematologic toxicities or in those with mutants are resistant to bosutinib.143
chronic, low-grade nonhematologic toxicities that are not manageable with
adequate supportive care measures.166,167 Bosutinib and dasatinib have demonstrated activity in patients with
BCR::ABL1 mutants resistant to nilotinib (Y253H, E255K/V, and
Resistance to TKI Therapy F359C/I/V).143,191 Bosutinib has minimal activity against F317L mutation
Aberrant expressions of drug transporters168-170 and plasma protein (which is resistant to dasatinib) and nilotinib may be preferred over
binding of TKI171-173 could contribute to primary resistance by altering the bosutinib in patients with F317L mutation.185,190,192 Ponatinib is active
intracellular and plasma concentration of TKI. against BCR::ABL1 mutants resistant to dasatinib or nilotinib, including
E255V, Y253H, and F359V, in addition to T315I.145 There are not enough
Pretreatment levels of organic cation transporter 1 (OCT1) have been data available regarding the impact of mutations on the efficacy of
reported as the most powerful predictor of response to imatinib.174 On the asciminib because of the heterogeneity of reported mutations and low
other hand, cellular uptake of dasatinib or nilotinib seems to be patient numbers in the ASCEMBL trial.148 Patients with detectable
independent of OCT1 expression, suggesting that patients with low bosutinib-resistant BCR::ABL1 mutations (T315I or V299L) were ineligible
OCT1 expression might have better outcomes with dasatinib or nilotinib to participate in this trial.148 Although new myristoyl-pocket mutations have
than with imatinib.175-178 been detected during asciminib treatment, there is insufficient data as yet
to determine their significance.
Monitoring imatinib plasma levels may be useful in determining patient
adherence to therapy. However, there are no data to support that change Response rates to TKI therapy based on BCR-ABL mutation status are
of therapy based on plasma imatinib levels will affect treatment listed in Table 8.

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NCCN Guidelines Version 1.2024

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BCR::ABL1 compound mutations (variants containing ≥2 mutations within IKZF1 exon deletions and mutations in ASXL1, RUNX1, and BCOR genes
the same BCR::ABL1 allele that presumably arise sequentially) confer were the most frequently described secondary alterations in advanced
different levels of resistance to TKI therapy, and T315I-inclusive phase CML, while IDH1/2 mutations were detected at a markedly lower
compound mutants confer the highest level of resistance to all TKIs, frequency.198,203,206,208,209 IKZF1, RUNX1 and DNMT3A alterations were
including ponatinib.193,194 In a more recent study that used NGS to detect identified as important markers of disease progression to advanced phase
low-level and BCR::ABL1 compound mutations in 267 patients with heavily CML and risk of relapse after discontinuation of TKI.197,199,203,212 Mutations
pretreated CP-CML from the PACE trial, no compound mutation was in ASXL1 gene are most commonly described secondary alterations in
identified that consistently conferred resistance to ponatinib, suggesting patients with CP-CML and have been identified as an independent
that such compound mutations are uncommon following treatment with predictor of inferior EFS rates.210
bosutinib, dasatinib, or nilotinib for CP-CML.195
The presence of epigenetic gene mutations at diagnosis has also been
BCR::ABL1 kinase domain mutational analysis is helpful in the selection of associated with lower rates of molecular/cytogenetic responses and lower
subsequent TKI therapy for patients with inadequate initial response to rates of PFS/EFS.200,201,205,211 However, in a study of 124 patients with
first-line or second-line TKI therapy.196 The guidelines recommend newly diagnosed CP-CML, these mutations were predictive of response
BCR::ABL1 kinase domain mutational analysis for patients who do not rates only in patients treated with imatinib and did not have any impact on
achieve response milestones, for those with any sign of loss of response the outcomes in patients treated with 2G TKIs.205
(hematologic or cytogenetic relapse), and if there is a 1-log increase in
BCR::ABL1 level with loss of MMR. Treatment options based on BCR::ABL1-independent gene mutations have also been frequently
BCR::ABL1 kinase domain mutation status are outlined on CML-5. described in Ph-negative clones and the impact of mutations is also
variable depending on whether they occur in Ph-positive or Ph-negative
BCR::ABL1 kinase domain mutational analysis provides additional clones.213
guidance in the selection of subsequent TKI therapy only in patients with
identifiable mutations. In patients with no identifiable mutations, the Next generation sequencing (NGS) allows for the detection of low-level
selection of subsequent TKI therapy should be based on the patient’s BCR::ABL1 kinase domain mutations as well as resistance mutations in
age, ability to tolerate therapy, presence of comorbid conditions and genes other than BCR::ABL1 that may confer resistance to TKIs or
toxicity profile of the TKI. Adverse events of second-line and subsequent portend disease progression.214,215 In a recent, prospective, multicenter
TKI therapy in patients with CP-CML are summarized in Table 9. study (NEXT-in-CML) that assessed the feasibility of NGS in detection of
low-level mutations in 236 consecutive patients with CML and
BCR::ABL1–independent Mutations inadequate response to TKI therapy, NGS was more effective than
Mutations in epigenetic modifier genes (eg, ASXL1, IKZF1, BCOR, conventional Sanger sequencing in the detection of low-level
TET1/2, IDH1/2, DNMT3A/3B, EZH2) have been described in patients with mutations.215 Prospective monitoring of mutation kinetics demonstrated
CML.197-211 that TKI-resistant low-level mutations are invariably selected if the

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NCCN Guidelines Version 1.2024

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patients are not switched to another TKI or if they are switched to an different from a 5-fold increase in BCR::ABL1 transcripts after achieving
inappropriate TKI or TKI dose.215 MMR.

Testing for BCR::ABL1–independent mutations may be useful for Currently there are no specific guidelines for changing therapy only based
patients who do not achieve optimal response milestones due to the on rising BCR::ABL1 levels as detected by qPCR, and it should be done
presence of cytopenias and for those with TKI-resistant disease.204,207 only in the context of a clinical trial.
NGS with myeloid mutation panel should be considered for patients with
no identifiable BCR::ABL1 mutations. Discontinuation of TKI Therapy
The feasibility of discontinuation of TKI therapy (with close monitoring) in
Rising BCR::ABL1 Transcripts
carefully selected patients who have achieved and maintained DMR
Rising BCR::ABL1 transcripts are associated with an increased likelihood
(≥MR4.0; ≤0.01% BCR::ABL1 IS) for 2 or more years has been evaluated
of detecting BCR::ABL1 kinase domain mutations and cytogenetic
in several clinical studies. Limited longer-term follow-up data from the TKI
relapse.216-220 In patients who had achieved very low levels of BCR::ABL1
discontinuation trials are summarized in Table 10.
transcripts, emergence of BCR::ABL1 kinase domain mutations was more
frequent in those who had a >2-fold increase in BCR::ABL1 transcripts The possibility of TFR after discontinuation of imatinib was first evaluated
compared to those with stable or decreasing BCR::ABL1 transcripts.216 A in the Stop Imatinib (STIM1) study in 100 patients with undetectable
serial rise has been reported to be more reliable than a single ≥2-fold BCR::ABL1 transcripts for at least 2 years (5-log reduction in BCR::ABL1
increase in BCR::ABL1 transcripts.217,218 Among patients in CCyR with a transcripts and undetectable minimal residual disease on qPCR with a
≥0.5-log increase in BCR::ABL1 transcripts on at least two occasions, the sensitivity of ≥4.5-log reduction from the standardized baseline).221,222
highest risk of disease progression was associated with loss of MMR and With a median follow-up of 77 months after discontinuation of imatinib,
>1-log increase in BCR::ABL1 transcripts.218 the molecular recurrence-free survival was 43% at 6 months and 38% at
60 months.222 Other subsequent studies that have evaluated the
Rising transcript levels should prompt investigation of treatment
discontinuation of imatinib have also reported similar findings.223-227
adherence and reassessment of coadministered medications. The precise
increase in BCR::ABL1 transcripts that warrants a mutation analysis More recent studies have also confirmed the feasibility of TFR after
depends on the performance characteristics of the qPCR assay.220 Some discontinuation of dasatinib or nilotinib in patients with CP-CML who
labs have advocated a 2- to 3-fold range,126,219,220 while others have taken have achieved and maintained MR4.5 for 12 months after ≥2 years of
a more conservative approach (5- to 10-fold).218 Obviously, some common TKI therapy in the first-line or second-line setting (TFR rates ranging
sense must prevail, since the amount of change in absolute terms from 44% to 54%).228-235
depends on the level of molecular response. For example, a finding of any
BCR::ABL1 after achieving a DMR (MR4.5; ≤0.0032% BCR::ABL1 IS) is The feasibility of TFR following discontinuation of TKIs other than
an infinite increase in BCR::ABL1 transcripts. However, a change in dasatinib, imatinib, or nilotinib has not yet been evaluated in clinical
BCR::ABL1 transcripts from a barely detectable level to MR4.5 is clearly studies. In the EURO-SKI study that evaluated TFR after discontinuation

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of any first-line TKI therapy (imatinib, dasatinib, or nilotinib) in eligible In the EURO-SKI study, duration of treatment with imatinib (≥6 years)
patients, the type of first-line TKI therapy did not significantly affect and duration of DMR (MR4.0 for 3 years) were significantly associated
molecular relapse-free survival.230 Therefore, it is reasonable to assume with MMR maintenance at 6 months after discontinuation of imatinib and
that the likelihood of TFR following discontinuation would be similar lack of MR4.0 at 36 months after discontinuation of TKI therapy was
irrespective of TKI in patients who have achieved and maintained DMR highly predictive of subsequent loss of MMR.230,237 A rapid initial decline
(MR4.0; ≤0.01% BCR::ABL1 IS) for 2 or more years. in BCR::ABL1 transcripts after initiation of first-line TKI therapy has also
been shown to be an independent predictor of TFR eligibility and
The results of the RE-STIM study demonstrated the safety of a second sustained TFR.238
TKI discontinuation after a first unsuccessful attempt.236 The rate of
molecular relapse after the first TKI discontinuation attempt was the only Resumption of TKI therapy immediately after recurrence results in the
factor significantly associated with outcome. The TFR rate at 24 months achievement of DMR in almost all patients. In the STIM study, molecular
after second TKI discontinuation was higher for patients who remained in relapse (trigger to resume TKI therapy) was defined as positivity for
DMR within the first 3 months after the first TKI discontinuation (72% vs. BCR::ABL1 transcripts by qPCR confirmed by a 1-log increase in
32% for other patients). BCR::ABL1 transcripts between two successive assessments or loss of
MMR at one point.221,222 The results of the A-STIM study showed that loss
TKI withdrawal syndrome (aggravation or new development of of MMR (≤0.1% BCR::ABL1 IS) could be used as a practical criterion for
musculoskeletal pain and/or pruritus after discontinuation of TKI therapy) restarting TKI therapy. The estimated probability of MMR loss was 35% at
has been reported during the TFR period in some TKI discontinuation 12 months and 36% at 24 months after discontinuation of imatinib.224
studies,226,231,233,234 and the occurrence of imatinib withdrawal syndrome
was associated with a lower rate of molecular relapse in the KID study.226 Clinical studies that have evaluated the safety and efficacy of
discontinuation of TKI have used strict eligibility criteria and have
Approximately 40% to 60% of patients who discontinue TKI therapy after mandated more frequent molecular monitoring than typically
achieving DMR experience recurrence within 12 months of treatment recommended for patients on TKI therapy. Access to a reliable qPCR (IS)
cessation, in some cases as early as one month after discontinuation of with a sensitivity of detection of at least MR4.5 (BCR::ABL1 ≤0.0032% IS)
TKI therapy. Several factors may help predict the risk of recurrence after and the availability of test results within 2 weeks is one of the key
discontinuation of TKI therapy (a higher Sokal risk score, female gender, requirements to monitor patients after discontinuation of TKI therapy and
lower natural killer cell counts, suboptimal response or resistance to ascertain their safety.
imatinib, duration of TKI therapy, and DMR prior to TKI discontinuation).
However, only the duration of TKI therapy and DMR prior to Based on available evidence from clinical studies that have evaluated the
discontinuation of TKI therapy have been associated with TFR with a feasibility of TFR, the panel members feel that discontinuation of TKI
high level of consistency.221,226,230,231 therapy (with close monitoring) is feasible in carefully selected, consenting
patients (in early CP-CML) who have achieved and maintained a DMR
(≥MR4.0) for 2 or more years. The criteria for the selection of patients

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NCCN Guidelines Version 1.2024

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suitable for discontinuation of TKI therapy are outlined on CML-E. The daily dose that was used in the initial randomized phase III trial) and 500
guidelines emphasize that discontinuation of TKI therapy outside of a mg once daily for intolerant or resistant CP-CML.
clinical trial should be considered only if ALL the criteria included on the
list are met. In patients with newly diagnosed CP-CML, recommendations from an
expert panel suggest initiating bosutinib at 200 to 300 mg once daily (with
The panel acknowledges that more frequent molecular monitoring is dose escalation as clinically indicated) in most patients and initiation at
essential following discontinuation of TKI therapy for the early identification 400 mg daily is recommended only for patients with high-risk disease.239
of loss of MMR. Frequency of molecular monitoring has varied The results of a retrospective analysis suggest that dose reduction of
substantially among different studies, and the optimal frequency of bosutinib to 300 mg or 400 mg results in better tolerability and improved
molecular monitoring in patients with a loss of MMR after discontinuation efficacy in patients with CP-CML resistant imatinib, dasatinib and/or
of TKI therapy has not been established. The panel recommendations for nilotinib.240
molecular monitoring in TFR phase are outlined on CML-E.
Dasatinib
Dose Modifications of TKI Therapy The recommended starting dose of dasatinib is 100 mg once daily for
Limited available evidence (mostly from non-randomized studies and patients with CP-CML.
retrospective analysis) suggests that initiation of TKIs (bosutinib,
Long-term follow-up of a single-arm study (81 evaluable patients) suggest
dasatinib, nilotinib) at lower doses and/or de-escalation for all TKIs (with
that dasatinib 50 mg once daily may have similar efficacy in patients with
close monitoring) in patients who achieve optimal responses are
low- or intermediate-risk CP-CML.241,242 Dasatinib 20 mg once daily has
appropriate strategies for the prevention and management of
also been shown to be an appropriate starting dose for patients 65 years
treatment-related adverse events and to avoid long-term toxicities.
and over with newly diagnosed CP-CML.243,244 Intermittent dosing (on/of
However, with the exception of ponatinib (OPTIC trial), the minimum
treatment with a drug holiday) or dose reduction to 50 mg once daily has
effective dose or optimal de-escalation of TKI has not yet been
also been shown to be effective as second-line and subsequent therapy in
established in prospective phase III randomized clinical trials.
patients with CP-CML resistant/intolerant to imatinib.245-248
Initiation of TKIs at Lower Dose
Dasatinib at 50 mg (20 mg with careful monitoring in selected patients)
Low dose TKIs for first-line or dose modifications for intolerance or
should be considered for patients with clinically significant intolerance to
resistance has been evaluated mostly in non-randomized studies and
dasatinib 100 mg once daily to avoid serious adverse events (eg, pleural
retrospective analyses. Data from selected studies are outlined in Table
effusion, myelosuppression), necessitating the discontinuation of
11 and Table 12.
dasatinib.
Bosutinib
The recommended starting dose of bosutinib is 400 mg daily for patients
with newly diagnosed CP-CML (which is better tolerated than the 500 mg

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NCCN Guidelines Version 1.2024

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Imatinib at 45 mg for patients with the T315I mutation followed by dose reduction to
The recommended starting dose of imatinib is 400 mg once daily for 15 mg upon achievement of BCR::ABL1 (IS) ≤1%.146 The results of a
patients with CP-CML. retrospective analysis showed that ponatinib 15 mg day was associated
with a lower incidence of drug related adverse events (AEs) with no impact
In a phase II study that evaluated imatinib 400 mg in 481 patients with on efficacy.252
newly diagnosed CML, dose reduction was required in 46% of patients
due to intolerance and excessive dose reductions to less than 300 mg was De-escalation or Intermittent Dosing of TKI
associated with inferior response rates and survival outcomes.249 TKI de-escalation has been shown to be feasible in patients, primarily
those without prior TKI resistance, who had received TKI therapy for 2 or
Nilotinib more years with durable MMR or DMR for 12 or more months.253-260 Data
The recommended starting dose of nilotinib is 300 mg twice daily for from selected clinical trials that have evaluated this approach are
patients with newly diagnosed CP-CML and 400 mg twice daily for summarized in (Table 13).
resistant or intolerant CP-CML. The phase II INTERIM study first established that intermittent dosing of
imatinib is feasible in patients 65 years and over in stable MMR or MR4,
In a retrospective analysis of 70 patients with newly diagnosed CP-CML,
after 2 or more years of treatment.253 The interim analysis of phase III
early dose reduction of nilotinib to less than 600 mg/day resulted in lower
OPTkIMA study demonstrated that this approach is also feasible for
rate of adverse events and better therapeutic efficacy.250 One-year MMR
patients treated with dasatinib or nilotinib.260 OPTkIMA is an ongoing
and overall MR4.5 rates were 90% and 60%, respectively for the 10
study that is evaluating the progressing de-escalation of all TKIs after
patients treated with 600 mg/day of nilotinib throughout the study, with no
achieving a stable DMR.
disease progression to advanced phase.
The DESTINY trial showed the feasibility de-escalation of TKI (imatinib,
The ENESTswift study showed that switching to nilotinib 300 mg twice
dasatinib or nilotinib) to half the standard dose for 12 months (imatinib
daily (which is lower than the recommended dose of 400 mg daily in the
200 mg once daily; dasatinib 50 mg once daily, or nilotinib 200 mg twice
second-line setting) was effective and well-tolerated in most patients with
daily) in patients achieving MMR or MR4 followed by discontinuation for
CP-CML with intolerance to imatinib or dasatinib in the first-line setting.251
24 months (with frequent monitoring).256,257
Ponatinib
NILO-RED study (published only an abstract) demonstrated the
The recommended initial dose of ponatinib is 45 mg once daily. feasibility of maintenance therapy with reduced dose nilotinib (once daily)
in patients achieving MMR on standard-dose nilotinib (twice daily).
In the OPTIC trial, the optimal benefit was observed with 45 mg for all
patients including those with T315I mutation. Ponatinib at lower dose
levels (30 mg and 15 mg dose levels) resulted in clinical benefit in patients
without T315I mutation (Table 6). These data support initiation of ponatinib

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Management of Advanced Phase CML with confirmed T315I mutation at baseline. The median PFS and OS were
Imatinib has induced favorable hematologic and cytogenetic response 5 months and 18 months, respectively. As with CP-CML, the response
rates in patients with AP-CML or BP-CML.261-265 Dasatinib,266-268 rates and survival outcomes were lower than that observed with ponatinib
nilotinib,269,270 bosutinib,271 and ponatinib145 have demonstrated activity in in the PACE trial for patients with AP-CML. The most common grade 3/4
imatinib-resistant or imatinib-intolerant AP-CML and/or BP-CML. Ponatinib hematologic adverse events were thrombocytopenia (51%), anemia
is a treatment option for patients with a T315I mutation or patients for (39%), neutropenia (20%), and febrile neutropenia (14%).
whom no other TKI is indicated.
Treatment Considerations (CML-4)
Long-term follow-up data from phase II/III studies of TKI therapy for Disease progression to AP-CML or BP-CML while on TKI therapy has a
disease progression to AP-CML and BP-CML are summarized in Table 14 worse prognosis than de novo AP-CML or BP-CML. Participation in clinical
and Table 15, respectively. trials and evaluation for allogeneic HCT is recommended for all patients
with AP-CML and BP-CML. In patients with disease progression to
The efficacy of imatinib in combination with decitabine or AP-CML or BP-CML, the selection of TKI therapy is based on prior therapy
cytarabine-based chemotherapy in AP-CML and myeloid BP-CML has and/or BCR::ABL1 kinase domain mutational analysis.
been demonstrated in several small studies.272-275 Hyper-CVAD in
combination with imatinib or dasatinib is also effective for patients with De novo AP-CML can often be initially managed like CP-CML with
lymphoid BP-CML, particularly when followed by allogeneic HCT.276,277 single-agent TKI followed by evaluation for allogeneic HCT.281,282
Treatment with TKI in combination with intensive chemotherapy resulted However, patients with disease progression from CP-CML to AP-CML
in better outcomes (higher response rates, lower risk of relapse and while on a TKI therapy have a high rate of progression to BP-CML, with
improved OS and EFS rates) compared to treatment with TKI alone in predictably poor survival. These patients should be considered for a
patients with myeloid BP-CML.278 clinical trial and/or allogeneic HCT. Treatment with a course of alternate
2G or third-generation (3G) TKI (not received before) can be beneficial as
A significant proportion of patients with AP-CML or BP-CML treated with a “bridge” to allogeneic HCT in patients with disease progression to
TKI therapy achieve a MCyR but not a concomitant CHR because of AP-CML. There is a lack of evidence for the definition of optimal response
persistent cytopenias, which in turn is associated with an inferior milestones on TKI therapy. Evaluation for allogeneic HCT should be
outcome.279 Omacetaxine has shown efficacy in patients with AP-CML that considered if response milestones (recommended for CP-CML) are not
is resistant to multiple TKIs as well as in patients with a T315I mutation.280 achieved at 3, 6, and 12 months. Imatinib or omacetaxine are included as
Among the 51 patients with AP-CML, after a median follow-up of 16 options for patients with disease progression to AP-CML on TKI therapy
months, major hematologic response (MaHR), CHR, and minor with a contraindication to 2G or 3G TKI.280
cytogenetic response were achieved or maintained in 37%, 29%, and 11%
of patients, respectively.280 The MaHR rates were 55% and 58%, TKI in combination with induction chemotherapy (ALL-type chemotherapy
respectively, for patients with a history of a T315I mutation and for those for lymphoid BP-CML and AML-type chemotherapy for myeloid BP-CML)

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followed by allogeneic HCT is the preferred treatment option for de novo Disease phase, HLA matching, age and sex of the donor and recipient,
BP-CML and disease progression to BP-CML.278,283 For patients who are and time from diagnosis to transplant have been identified as
not candidates for induction chemotherapy, TKI + steroids is an option for pretransplant risk factors.307 A low HCT comorbidity index is a prognostic
patients with lymphoid BP-CML and TKI alone is an option for those with indicator of lower non-relapse mortality and improved survival.308 The
myeloid BP-CML. Since TKI (alone or in combination with minimal disease phase at the time of transplant remains an important prognostic
chemotherapy or steroids) is less effective in BP-CML compared to factor, and the survival outcomes following transplant are clearly better for
Ph-positive ALL, interphase FISH for the detection of BCR::ABL1 patients in second chronic CP-CML compared to patients with AP-CML or
transcript on blood granulocytes is recommended to differentiate between BP-CML.309-314 Therefore, the potential use of allogeneic HCT must be tied
de novo BP-CML and de novo Ph-positive ALL. Central nervous system to faithful monitoring of disease, since the major potential pitfall in delaying
(CNS) involvement has been described in case reports of BP-CML.284-287 transplantation is “missing” the chronic phase interval.
Lumbar puncture and CNS prophylaxis is recommended for lymphoid
Monitoring Response After Allogeneic HCT (CML-6)
BP-CML. Documented CNS involvement in patients with lymphoid
BP-CML should be managed according to the standard of care for AML or BCR::ABL1 transcripts may persist for many years in patients after
ALL. Dasatinib has been reported to cross the blood brain barrier and may allogeneic HCT. The prognostic significance of BCR::ABL1 positivity is
represent the best TKI option for patients with CNS disease.288 TKI influenced by the time of testing after allogeneic HCT. A positive qPCR
therapy has not been optimized for patients with CNS involvement. assay for BCR::ABL1 at 18 months or more after allogeneic HCT is
associated with a lower risk of relapse than a positive qPCR assay for
Allogeneic Hematopoietic Cell Transplant BCR::ABL1 at 6 to 12 months after allogeneic HCT.315-322 Early detection
of BCR::ABL1 transcripts after allogeneic HCT may be useful to identify
Allogeneic HCT is a potentially curative treatment for patients with CML.
patients who may be in need of alternative therapies before overt relapse
Ongoing advances in alternative donor sources (such as unrelated donors
occurs.
and cord blood), more accurate HLA testing for a stringent selection of
unrelated matched donors, and the use of reduced-intensity conditioning Management of Post-transplant Relapse (CML-6)
regimens have improved outcomes following allogeneic HCT.289-295 Donor lymphocyte infusion (DLI) is effective in inducing durable molecular
remissions in the majority of patients with relapsed CML following
Allogeneic HCT is an appropriate treatment option for the very rare
allogeneic HCT, although it is more effective in patients with chronic phase
patients presenting with BP-CML at diagnosis, patients with disease that is
relapse than advanced phase relapse.323-329 However, DLI is associated
resistant to TKIs, patients with progression to AP-CML or BP-CML while
with complications such as graft-versus-host disease (GVHD),
on TKI therapy, and patients with CML that is resistant and/or intolerant to
susceptibility to infections, and immunosuppression.323 Improvements in
all TKIs.296-299 Several studies have confirmed that prior TKI therapy does
the methods of detecting BCR::ABL1 transcripts to predict relapse, the
not compromise the outcome following allogeneic HCT or increase
development of reduced-intensity conditioning regimens, modified delivery
transplant-related toxicity.300-306
of lymphocytes with the depletion of CD8+ cells, and the use of escalating

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Chronic Myeloid Leukemia

cell dosage regimens have reduced the incidence of GVHD associated In patients with CML that have previously failed imatinib, there are no data
with DLI.330-334 to support the use of post-transplant imatinib, and dasatinib, nilotinib,
bosutinib, ponatinib, or omacetaxine may be more appropriate options.
Imatinib induces durable cytogenetic and molecular responses in the However, there are no data to support the use of post-transplant bosutinib,
majority of patients relapsing with chronic and advanced phase CML ponatinib, or omacetaxine. CNS relapse of CML following allogeneic HCT
following allogeneic HCT, and the response rates are higher in patients has been described in few case reports.354,355 Participation in a clinical trial
with chronic phase relapse than advanced phase relapse.335-342 Very is highly desirable. Dasatinib may also be an effective treatment for
limited data are available on the use of dasatinib and nilotinib in patients extramedullary relapse following allogeneic HCT.288,356,357
with post-transplant relapse.343-346 There are also data suggesting that the
use of DLI in combination with imatinib may be more effective at inducing Emerging Treatment Options
rapid molecular remissions than either modality alone.347 Recent Novel BCR::ABL1 inhibitors and small molecule inhibitors targeting
retrospective studies have shown that TKIs are superior to DLI alone or in several BCR::ABL1–independent pathways have demonstrated efficacy
combination with TKI for post-transplant relapse.348,349 However, these in preliminary clinical trials.358,359 These novel agents (either as
observations are yet to be confirmed in randomized trials. Post-transplant monotherapy or in combination with currently approved TKIs) are being
TKI therapy is also effective to prevent relapse following allogeneic HCT evaluated in ongoing clinical trials in all three phases of CML. Results
in high-risk patients.350-352 from selected published phase II/III studies are outlined in Table 16.
Patients who are in CCyR (qPCR-negative) should undergo regular The use of low-dose interferon in combination with TKI for a limited
qPCR monitoring (every 3 months for 2 years, then every 3–6 months period prior to discontinuation of TKI, and gradual de-escalation of TKI
thereafter). Given the high risk for hematologic relapse in patients with prior to discontinuation of TKI therapy in patients with DMR are also
prior accelerated or blast phase, post-transplant TKI therapy should be being explored in ongoing clinical trials as potential strategies to improve
considered for at least one year in this cohort of patients who are in TFR outcome.257,359 Pegylated interferon in combination with TKIs has
remission following allogeneic HCT.350-352 demonstrated promising results, and ongoing clinical trials are evaluating
the combination of 2G TKIs with various pegylated interferons.360
TKI with or without DLI or omacetaxine can be considered for patients who
are not in remission or in cytogenetic relapse or those with an increasing Immunologic approaches such as the use of BCR::ABL1 immune
level of molecular relapse. The selection of TKI depends on prior TKI, the peptides, immune checkpoint blockade, leukemia-associated antigens,
side effect profile of the TKI under consideration, the presence of and dendritic cell vaccines are also being evaluated to improve
comorbidities, and BCR::ABL1 mutation status. Pre-existing mutations in molecular response.358
the BCR::ABL1 kinase domain, frequently associated with resistance to
TKIs, are detectable in the majority of patients who relapse after
allogeneic HCT.353 BCR::ABL1 mutational analysis is therefore essential
prior to the selection of TKI for the treatment of post-transplant relapse.

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Management of CML During Pregnancy and were reported in 7 cases. Among 33 patients who conceived with
Breastfeeding dasatinib-treated males, 30 (91%) delivered infants who were normal at
The median age of disease onset is 65 years, but CML occurs in all age birth. A recent report of 16 pregnancy cases among patients assigned
groups. The EUTOS population-based registry has reported that female at birth treated with bosutinib noted six live births, four abortions,
approximately 37% of patients at the time of diagnosis are of and six unknown outcomes.373 Although there is paucity of data
reproductive age.361 Clinical care teams should be prepared to address regarding the outcome of pregnancy in patients receiving bosutinib or
issues relating to fertility and pregnancy as well as counsel these ponatinib or asciminib at the time of conception, these TKIs also must be
patients about the potential risks and benefits of treatment considered unsafe for use during pregnancy.
discontinuation and possible resumption of TKI therapy should CML
Discontinuation of TKI therapy because of pregnancy in patients
recur during pregnancy.
assigned female at birth who were not in DMR (≥MR4.0; ≤0.01%
TKI Therapy and Conception BCR::ABL1 IS) has only been reported in a small series of patients.374-377
In one series, among 10 patients who stopped imatinib because of
TKI therapy appears to affect some male hormones at least transiently,
pregnancy after a median of 8 months of therapy, five of the nine
but does not appear to have a deleterious effect on male fertility.
patients who had achieved a CHR lost the response after stopping
Furthermore, the miscarriage or fetal abnormality rate is not elevated in
therapy, and six had an increase in Ph-positive metaphases.374 At 18
female partners of males on TKI therapy.362-366
months after resuming therapy, all nine patients had achieved a CHR but
The situation is more complex for patients assigned female at birth, as only three females achieved a CCyR and none had achieved an MMR. In
TKI therapy during pregnancy has been associated with both a higher another series that reported the outcomes of seven patients who were
rate of miscarriage and fetal abnormalities. Limited evidence from case not in DMR at the time imatinib was stopped because of pregnancy,
reports indicates the need for close monitoring, a prolonged washout three were in an MMR.375 All seven patients had disease relapse. The
period prior to pregnancy, and prompt consideration of holding TKI three who had an MMR at the time imatinib was stopped were able to
therapy if pregnancy occurs while on imatinib, nilotinib, or dasatinib.367-372 regain the same response once the drug was restarted, whereas the
In one report on the outcome of pregnancies in 180 patients exposed to remaining four patients were not.
imatinib during pregnancy, 50% of pregnancies with known outcome
Depending on other factors such as age, a natural pregnancy may occur
were normal and 10% of pregnancies with known outcome had fetal
months after stopping TKI therapy. Assuming the earliest time a patient
abnormalities.367 Eighteen pregnancies ended in spontaneous abortion.
assigned female at birth could conceive and give birth naturally (without
In another report on the outcomes of pregnancy and conception during
any washout period), is 10 months after stopping TKI, the likelihood is
treatment with dasatinib, among 46 patients treated with dasatinib, 15
about 60% that her PCR will become positive if the patient was in DMR
patients (33%) delivered a normal infant.368 Elective or spontaneous
at the time of getting pregnant.374,375
abortions were reported in 18 (39%) and 8 patients (17%), respectively,
and 5 patients (11%) had an abnormal pregnancy. Fetal abnormalities

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Chronic Myeloid Leukemia

Conception while on active TKI therapy is strongly discouraged due to appointments. It is also important to note that not all states allow
the risk of fetal abnormalities. Prior to attempting pregnancy, patients surrogacy.
and their partners should be counseled that no guidelines exist regarding
how best to monitor CML during pregnancy, nor how best to manage Treatment During Pregnancy
progressive disease should it occur during pregnancy. Fertility Most of the literature regarding treatment during pregnancy consists of
preservation should be discussed with all patients of childbearing age case reports. The use of TKI therapy, particularly during the first
prior to the initiation of TKI therapy. Referral to a CML specialty center trimester, should be avoided. If TKI therapy should be considered during
and consultation with a high-risk obstetrician is recommended. pregnancy, the potential benefit for the mother and the potential risk to
the fetus of continuing TKI therapy versus the risk of treatment
Planning a Pregnancy
interruption leading to the loss of optimal disease response must be
In patients assigned male at birth, the general recommendation is that carefully evaluated on an individual basis prior to initiation of TKI
TKI therapy need not be discontinued if a pregnancy is planned. therapy.
However, experience is limited. Sperm banking can also be performed
prior to starting TKI therapy, although there are no data regarding quality Interferon alfa-2a or peginterferon alfa-2a have been used during
of sperm in males with untreated CML. pregnancy and most of the data using interferons during pregnancy have
been reported in patients with essential thrombocythemia.378-383 If
In patients assigned female at birth, due to the risk of miscarriage and treatment is needed during pregnancy, it is preferable to initiate
fetal abnormalities during pregnancy, TKI therapy should be stopped treatment with interferons and if introduced earlier, interferons can
prior to natural conception and the patient should remain off therapy preserve molecular remission after discontinuation of TKI.384,385 The
during pregnancy.367-369 Referral to an in vitro fertilization (IVF) center is panel recommends against the use of hydroxyurea during pregnancy,
recommended in coordination with the patient’s obstetrician. TKI should especially in the first trimester, if possible.386-388
be stopped prior to attempting a natural pregnancy or oocyte retrieval,
Leukapheresis can be used for a rising white blood cell (WBC) count,
but the optimal timing of discontinuation is unknown. Compounding the
although there are no data that recommend at what level of WBC count
high incidence of disease recurrence off TKI therapy are the significant
leukapheresis should be initiated.389-392 Low-dose aspirin or
obstacles that exist for those choosing one of the above forms of IVF,
low-molecular-weight heparin can be considered for patients with
(eg, lack of access to centers that perform the procedure, high costs
thrombocytosis.393,394
associated with drugs and surgical procedures that may not be covered
by insurance, costs of embryo/oocyte storage, and access to surrogate Breastfeeding
programs). Some patients may require more than one IVF cycle to obtain
TKI therapy can be restarted after delivery. However, patients on TKI
enough potentially viable embryos for implantation. In addition, patients
therapy should be advised not to breastfeed, as TKIs pass into human
may need to take family medical leave from work to attend IVF
breast milk.395-398 Breastfeeding without TKI therapy may be safe with

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molecular monitoring, preferably in those patients with CML who have Monitoring for Long-Term Side Effects
durable DMR. It may be acceptable to avoid TKIs for the short period of
Children have a much longer life expectancy than adults and TKI therapy
the first 2 to 5 days after labor to give the child colostrum.398,399
may be needed for many decades; therefore, there are potential long-term
Close molecular monitoring is recommended for females who extend the side effects (such as delayed growth, changes in bone metabolism, thyroid
treatment-free period for breastfeeding. If the loss of MMR after abnormalities, and effects on puberty and fertility) that may not be seen in
treatment cessation is confirmed, breastfeeding needs to be terminated adults.410
and TKI should be restarted.398
A number of studies have reported impaired longitudinal growth in children
Specific Considerations for Children with CML with CML treated with TKI therapy, and the effect is more significant when
CML accounts for less than 3% of all pediatric leukemias. In general, treatment was initiated during prepubertal age.411-417 Growth should be
children are diagnosed at a median age of 11 to 12 years, with monitored closely and a bone age x-ray should be obtained if longitudinal
approximately 10% presenting in advanced phase. Due to its rarity, there growth is delayed. A dual-energy x-ray absorptiometry (DEXA) scan
are no evidence-based recommendations for the management of CML in should be obtained if bone mineral density is decreased on plain
the pediatric population. Many pediatric oncologists follow treatment radiograph or if there is unprovoked fracture. Further evaluation and
guidelines that are designed for adult patients. However, clinical referral to an endocrinologist is also warranted.
presentations and host factors are different between children and adults,
The feasibility of discontinuation of imatinib in children in sustained DMR
and several factors should be considered when treating pediatric patients
for ≥2 years has been demonstrated in two small studies.418,419 Further
with CML.400
studies in a larger cohort of patients are needed to identify the criteria for
Selection of TKI discontinuation of TKI therapy in children. Therefore, discontinuation of
TKI therapy in children is not recommended outside the context of a
Imatinib, dasatinib, and nilotinib are currently approved for treatment of clinical trial.
CML in children.401-403 Higher dose imatinib (340 mg/m²) has also been
shown to be effective and well tolerated in children.404-406 There are very Immunizations
little data on the safety and efficacy of bosutinib and ponatinib in There are little data regarding the long-term impact of TKIs on the immune
children.407 function of patients with CML receiving TKI therapy. Available evidence
suggests that TKI therapy could potentially hinder routine immunization
The validity of prognostic scores (eg, Sokal, Euro) for risk assessment or
with some vaccines in adults and children with CML.420-422 A study that
to make treatment decisions has not been established in the pediatric
evaluated the safety and efficacy of H1N1 influenza vaccine in patients
population.408 The ELTS score has demonstrated better differentiation of
with hematologic malignancies showed a higher seroconversion rate in
PFS than Sokal and Euro scores in children treated with imatinib.409
adult patients with CML compared to patients with B-cell malignancies or
HCT recipients.420 The findings from another study that evaluated the

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Chronic Myeloid Leukemia

impact of TKI therapy on B-cell responses to vaccination in patients with updated general information. The Centers for Disease Control and
CML suggest that TKI therapy with dasatinib, imatinib, or nilotinib is Prevention (CDC) recommends COVID-19 vaccination for adolescents 12
associated with impaired B-cell response to polysaccharide pneumococcal years and over and children aged 5 through 11 years. See the CDC’s
(PPS) vaccine due to the off-target inhibition of kinases involved in B-cell COVID-19 Vaccines for Children and Teens for dosage and administration
signaling pathway.421 of vaccines in children and teens.

In general, the use of inactivated killed vaccines for children on TKI

therapy is safe, although it is unknown whether responses are comparable
to those seen in healthy children. Administration of live vaccines during
TKI therapy is not recommended in general, although preliminary findings
from a few recent case reports have shown that MMR and varicella
vaccine could be safely given to some children with immune
deficiency.422,423 Live attenuated annual influenza vaccine (nasal spray)
should be avoided, and the inactivated killed vaccine (flu shot) should be
used for children receiving TKI therapy. Live vaccines could be considered
after stopping TKI therapy for several weeks in patients with a DMR.424 In
the United States, all required live vaccines are completed by age 4 to 6
years (http://www.cdc.gov/vaccines/). As CML is rarely seen in children
younger than this age, few patients face this issue.

The mRNA-based vaccines have shown safety and efficacy against the
SARS-CoV-2 infection (COVID-19) among immunocompetent
individuals.425 Studies that have evaluated the efficacy of these vaccines in
patients with hematologic malignancies have reported higher
seroconversion rate and robust memory T-cell responses in patients with
CML in contrast to patients with solid tumors or other hematologic
malignancies.426-429 The mRNA-based vaccines are considered inactivated
vaccines. The FDA has given full approval for their use in individuals ≥16
years and emergency use authorization (EUA) for use in children aged 5
to 15 years. The NCCN COVID-19 Vaccination Advisory Committee
recommends that COVID-19 vaccines should be given to all adult patients
with cancer. See NCCN: Cancer and COVID-19 Vaccination for additional

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Table 1: First-Line TKI Therapy for CP-CML: Long-Term Follow-up Data from Phase III Studies
Disease
No. of Median
Trial Study Arms CCyRa MMRb Progression PFSc OS
Patients Follow-up
n (%)

Imatinib (400 mg once daily) 553 83% — 38 (7%) 92% 83%

78,d
IRIS 11 years
Interferon alpha plus — —
553 71 (13%) — 79%e
low-dose cytarabine
76%
Dasatinib (100 mg once daily) 259 — 12 (5%) 85% 91%
(P = .002)
DASISION79 5 years
Imatinib (400 mg once daily) 260 — 64% 19 (7%) 86% 90%
78%
Nilotinib (300 mg twice daily) 282 — 11 (4%) 86% 88%
82
(P < .0001)
ENESTnd 10 years
Imatinib (400 mg once daily) 283 — 63% 24 (8.5%) 87% 88%

Bosutinib (400 mg once daily) 268 83% 74% 6 (2%) — 95%

BFORE81,f 60 months
Imatinib (400 mg once daily) 268 77% 65% 7 (3%) — 95%

CCyR, complete cytogenetic response; MMR, major molecular response (≤0.1% BCR::ABL1 IS); OS, overall survival; PFS, progression-free survival

a. Confirmed CCyR rate at 12 months was the primary endpoint of DASISION study.
b. MMR (≤0.1% BCR::ABL1 IS) rate at 12 months was the primary endpoint of ENESTnd and BFORE studies.
c. Primary endpoint of IRIS trial in the imatinib group.
d. Due to the high rate of crossover to imatinib (66%) and the short duration of therapy (<1 year) before crossover among patients who had been randomly assigned to
interferon alfa plus cytarabine, the long-term follow-up data focused on patients who had been randomly assigned to receive imatinib.
e. Data include survival among the 363 patients who crossed over to imatinib.
f. There were no differences in survival rates between the two treatment arms after a minimum follow-up of 12 months; long-term follow-up is ongoing.

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Table 2: High-Dose Imatinib as First-Line Therapy for CP-CML: Long-Term Follow-up Data from Phase III Studies

No. of Median
Trial Study Arms MMR MR4.5 PFS OS
Patients Follow-up
96% 93%
Imatinib (800 mg once daily) 319 79% —
at 48 months at 48 months
TOPS study83,a 42 months
94% 94%
Imatinib (400 mg once daily) 157 76% —
at 48 months at 48 months
Imatinib (800 mg once daily) 420 89% 71% 77% 79%
CML IV study85,b 10 years
Imatinib (400 mg once daily) 400 92% 67% 80% 80%
92% 95%
Imatinib (800 mg once daily) 73 53% 19%
(4-year PFS) (4-year OS)
SWOG study84,c 12 months
80% 90%
Imatinib (400 mg once daily) 72 36% 9%
(4-year PFS) (4-year OS)

MMR, major molecular response (≤0.1% BCR::ABL1 IS); MR, molecular response; MR4.5: ≥4.5-log reduction in BCR::ABL1 transcripts from baseline; OS, overall
survival; PFS, progression-free survival

a. Primary endpoint: MMR rate at 12 months (≤0.1% BCR::ABL1), which corresponds to a 3-log reduction in BCR::ABL1 transcripts compared with the standardized
baseline established in IRIS study.
b. Primary endpoint: The impact of MMR on survival at 12 months. This study had 5 treatment arms (imatinib 400 mg once daily alone; imatinib 800 mg twice daily;
imatinib 400 mg once daily with interferon or cytarabine; and imatinib after interferon failure). Only the data for imatinib 400 mg once daily alone vs. imatinib 800 mg
twice daily are included in this table.
c. Primary endpoint: MR4.0 (≥4-log reduction in BCR::ABL1 transcripts from baseline) at 12 months. Results from the first part of SWOG S0325 study; follow-up after 12
months was not required for this study.

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Table 3: First-Line TKI Therapy for CP-CML: Outcomes According to Risk Score

Low-Risk Intermediate-Risk High-Risk

Trial Study Arms
MMR MR4.5 PFS/OSa MMR MR4.5 PFS/OSa MMR MR4.5 PFS/OSa
90% 43% —
Dasatinib (100 mg once daily) 55% — 71% 67% 31%
DASISION79
(Euro risk score) —
Imatinib (400 mg once daily) 69% 44% — 65% 28% 54% 30%

ENESTnd82 Nilotinib (300 mg twice daily) — 51% 94%/95% — 55% 87%/88% — 40% 74%/77%
(Sokal risk score)
Imatinib (400 mg once daily) — 39% 98%/99% — 30% 84%/84% — 23% 78%/79%
— — —
Bosutinib (400 mg once daily) 58% 45% 34%
BFORE80
(Sokal risk score) — — —
Imatinib (400 mg once daily) 46% 39% 17%

a. 10-year outcomes according to Sokal risk score;

MMR, major molecular response (≤0.1% BCR::ABL1 IS); MR, molecular response; MR4.5: 4.5-log reduction in BCR::ABL1 transcripts from baseline;
OS, overall survival; PFS, progression-free survival

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Table 4. Adverse Events of First-Line TKI Therapy in CP-CML

DASISION79 ENESTnd82 BFORE80
Toxicity
Dasatinib 100 mg QD Imatinib 400 mg QD Nilotinib 300 mg BID Imatinib 400 mg QD Bosutinib 400 mg QD Imatinib 400 mg QD
Hematologic toxicities (Grade 3/4)

Anemia 13% 9% 6% 7% 3% 5%

Neutropenia 29% 24% 12% 15% 7% 12%

Thrombocytopenia 22% 14% 10% 9% 14% 6%

Biochemical abnormalities (Grade 3/4)

Increased lipase NR NR 10% 4% 13% 6%

Increased glucose NR NR 9% <1% 2% 2%

Decreased phosphate 7% 28% 9% 13% 5% 17%

Increased ALT NR NR 4% 3% 23% 3%

Increased AST NR NR NR NR 12% 3%

Nonhematologic toxicities (any grade) *

Rash 13% 18% 39% 21% 20% 13%

Headache 13% 11% 34% 25% 19% 13%

Fatigue 9% 11% 25% 20% 19% 18%

Muscle spasms 23% 41% 14% 35% 2% 26%

Peripheral edema 13% 37% 12% 23% 4% 14%

Pleural effusion 28% <1% NR NR NR NR

Hypertension NR NR 16% 6% NR NR

Pulmonary hypertension 5% <1% NR NR NR NR

Diarrhea 21% 22% 21% 48% 70% 34%

Constipation NR NR 23% 9% NR NR

Nausea 10% 24% 22% 42% 35% 39%

Vomiting 5% 11% 17% 28% 18% 16%

ALT, alanine aminotransferase; AST, aspartate aminotransferase; BID, twice daily; QD, once daily. * Non-hematologic toxicities from the DASISION study (except pleural effusion) are from the
3-year follow-up. No new adverse events were observed with 5-year follow-up.

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Table 5. Early Molecular Response (≤10% BCR::ABL1 IS at 3 months) After First-Line TKI Therapy and Survival Outcomes

5-Year PFS 5-Year OS

Trial Study Arms
BCR::ABL1 ≤10% BCR::ABL1 >10% BCR::ABL1 ≤10% BCR::ABL1 >10%
Dasatinib (100 mg once daily) 89% 72% 94% 81%
DASISION79
Imatinib (400 mg once daily) 93% 72% 95% 81%

Nilotinib (300 mg twice daily) 95% 78% 98% 82%

ENESTnd430 Nilotinib (400 mg twice daily) 96% 89% 96% 93%

Imatinib (400 mg once daily) 98% 79% 99% 79%

CML IV Study114 Imatinib (400 mg once daily) 92% 87% 94% 87%

OS, overall survival; PFS, progression-free survival

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Table 6. Second-Line and Subsequent TKI Therapy for CP-CML: Long-Term Follow-up Data from Phase II/III Studies

Median
TKI/Trial Study Arms (No. of patients) MCyR CCyR MMR PFS OS
Follow-up
Imatinib-R (n = 124) — — 43% 39% 63%
Dasatinib140,a
7 years
(100 mg once daily) Imatinib-I (n = 43) — — 55% 51% 70%

Nilotinib141,b Imatinib-R (n = 226)

4 years 59% 45% — 57% 78%
(400 mg twice daily) Imatinib-I (n = 95)

Imatinib and dasatinib-R (n = 38) 39% 22% — — 67%

143,b
Bosutinib — —
Imatinib and dasatinib-I (n = 50) 4 years 42% 40% 80%
(500 mg once daily)
Imatinib and nilotinib-R (n = 26) 38% 31% — — 87%

Dasatinib or nilotinib-R or I (n = 203) 52% 76%

56% 49% 35%
Ponatinib (PACE)145,c at 5 years at 5 years
57 months
(45 mg once daily) 50% 66%
T315I mutation (n = 64) 72% 70% 58%
at 5 years at 5 years
45 mg (n = 93) 73% 89%
51% 44% 34%
at 3 years at 3 years
30 mg (n = 93) 66% 89%
Ponatinib (OPTIC)146 32 months 33% 29% 25%
at 3 years at 3 years
15 mg (n =91) 70% 92%
44% 23% 23%
at 3 years at 3 years
Asciminib (40 mg twice daily; n = 157) 40%e 38%
— 94% 97%
Asciminib (ASCEMBL) at 96 weeks at 96 weeks
2 years
(40 mg twice daily)149,d Bosutinib (500 mg once daily; n = 76) 16%e 16%
— 91% 99%
at 96 weeks at 96 weeks

CCyR, complete cytogenetic response; I, Intolerant; PFS, progression-free survival; R, Resistant; MCyR, major cytogenetic response; MMR, major molecular response
(≤0.1% BCR::ABL1 IS); OS, overall survival;

a. Primary endpoint: MCyR rate at 6 months when administered 100 mg once daily versus 70 mg twice daily.
b. Primary endpoint: MCyR rate in patients with imatinib intolerance or imatinib-resistant disease.
c. Primary endpoint: MCyR at any time within the first 12 months.
d. Primary endpoint: MMR rate at 24 weeks; Secondary endpoint: MMR rate at 96 weeks.
e. CCyR rate in patients who were not in CCyR at baseline.

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Table 7. Early Molecular Response (≤10% BCR::ABL1 IS) After Second-Line TKI Therapy and Survival Outcomes

Progression-Free Survival (PFS) Overall Survival (OS)

Median
TKI BCR::ABL1 ≤10% BCR::ABL1 >10% BCR::ABL1 ≤10% BCR::ABL1 >10%
Follow-up
3 months 6 months 3 months 6 months 3 months 6 months 3 months 6 months

Dasatinib140
7 years 56% 57% 21% 4% 72% 74% 56% 50%
(100 mg once daily)
Nilotinib141
4 years 67% 58% 42% 39% 81% 82% 71% 73%
(400 mg twice daily)

Table 8. Responses to TKI Therapy Based on BCR::ABL1 Mutation Statusa

Bosutinib143 Dasatinib191 Nilotinib185 Ponatinib195

BCR::ABL1 Mutations
MCyR CCyR MCyR CCyR MCyR MCyR
Contraindicated to
G250E 0/5 (0%) 20/60 (33%) 29/60 (48%) 3/5 (60%) 3/5 (60%) 8/12 (67%)
bosutinib

Contraindicated to F317Lb 1/7 (14%) 1/14 (7%) 2/14 (14%) — — 13/29 (45%)
bosutinib and dasatinib V299L — — — 3/8 (38%)
0/2 (0%) —
E255K — 6/16 (38%) 9/16 (56%) 8/13 (62%)
0/7 (0%) 3/7 (43%)
E255V — 4/11 (36%) 4/11 (36%) 1/4 (25%)

Contraindicated to F359C 1/2 (50%) 3/5 (60%) 3/5 (60%) 1/7 (14%)
0/11 (0%) 1/11 (9%)
nilotinib F359V 2/3 (67%) 14/27 (52%) 17/27 (63%) 11/20 (55%)

F359I 2/2 (100%) 7/12 (58%) 10/12 (83%) — — 3/4 (75%)

Y253H 5/6 (83%) 14/23 (61%) 15/23 (65%) 0/8 (0%) 1/8 (13%) 1/2 (50%)
a. Mutations contraindicated for imatinib are too numerous to include. There are compound mutations that can cause resistance to ponatinib, but those are
uncommon following treatment with bosutinib, dasatinib, or nilotinib.
b. Bosutinib has minimal activity against F317L mutation. Nilotinib may be preferred over bosutinib in patients with an F317L mutation.

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Table 9. Adverse Events of Second-Line and Subsequent TKI Therapy in CP-CML

Dasatinib140 Nilotinib141 Bosutinib143 Ponatinib145 Asciminib
Toxicity (any grade)
(100 mg once daily) (400 mg twice daily) (500 mg once daily) (45 mg once daily) (40 mg twice daily)148
Rash 33% 31% 28% 47% 7%
Headache — 18% 27% 43% 16%
Fatigue 37% 21% 24% 30% 10%
Myalgias/Arthralgias 38% 11% 18% 24%/33% 9%

Pleural effusion 28% — 17% — —

Hypertension — — 8% 37% 12%

Hemorrhage 26% — — — —

Diarrhea 42% 12% 83% 20% 12%

Constipation — 13% 13% 41% —

Nausea 25% 48% 29% 12%

27%
Vomiting 13% 38% 19% 7%

Increased blood creatinine — — 13% — —

Increased lipase — — — 27%

Increased ALT/AST — — 15% — 4%

ALT, alanine aminotransferase; AST, aspartate aminotransferase; BID, twice daily; QD, once daily

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Table 10. Summary of Limited Longer-Term Follow-up Data from the TKI Discontinuation Trials
Depth and Duration of MR Trigger to
Treatment Prior to No. of Median Treatment-free
Trial Required for Resume TKI
Discontinuation Patients Follow-up Remission (TFR) Rate
Discontinuation Therapy
STIM1222 Imatinib ± interferon 100 MR5.0 for at least 2 years Loss of MR5.0 77 months 38% at 60 months

45%
TWISTER227 Imatinib ± interferon 40 MR4.5 for at least 2 years Loss of MR5.0 103 months (molecular relapse-free
survival 45% at 8 years)

HOVON223 Imatinib + cytarabine 15 MR4.5 for at least 2 years Loss of MR4.5 36 months 33% at 24 months

A-STIM224 Imatinib ± interferon 80 MR5.0 for at least 2 years Loss of MMR 31 months 61% at 36 months

Imatinib (after failure of

ISAV study225 108 CMR for at least 18 months Loss of MMR 36 months 52% at 36 months
interferon or hydroxyurea)

KID study226 Imatinib ± interferon 90 MR4.5 for at least 2 years Loss of MMR 27 months 59% at 24 months

Dasatinib/Nilotinib
Stop 2G-TKI228 60 MR4.5 for at least 24 months Loss of MMR 47 months 54% at 48 months
(first- or second-line)
Dasatinib
DASFREE231 84 MR4.5 for 12 months Loss of MMR 2 years 46% at 24 months
(first- or second-line)

ENESTFreedom233 Nilotinib (first-line) 190 MR4.5 for 12 months Loss of MMR 5 years 43% at 5 years

ENESTop study234 Nilotinib (second-line) 126 MR4.5 for 12 months Loss of MMR 5 years 43% at 5 years

DADI232 Dasatinib (first-line) 68 MR4.5 for at least 24 months Loss of MMR 23 months 55% at 6 months

DADI229 Dasatinib (second-line) 63 MR4.0 for at least 12 months Loss of MR4.0 44 months 44% at 36 months

EURO-SKI230 Any TKI 758 MR4.0 for at least 1 year Loss of MMR 27 months 50% at 24 months

CMR, complete molecular response (undetectable BCR::ABL1 by qPCR as determined by local laboratories); MMR, major molecular response (≤0.1% BCR::ABL1 IS); MR,
molecular response; MR4.0, ≤0.01% BCR::ABL1 IS; MR4.5, ≤0.0032% BCR::ABL1 IS or >4.5-log reduction of BCR::ABL1 and undetectable minimal residual disease on
qPCR with a sensitivity of ≥4.5-log reduction; MR5.0, 5-log reduction in BCR ABL1 levels and undetectable minimal residual disease on qPCR with a sensitivity of ≥4.5-log
reduction

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Table 11. Initiating Lower Dose First-line TKI Therapy

TKI Study Patient Characteristics TKI Dose Study Findings

81 evaluable patients (majority of
patients had low-risk (n = 55; 66%) or The cumulative rates for MMR, MR4, and MR4.5 at 12
Single center
intermediate-risk (n = 21; 25%) 50 mg/day months were achieved in 81%, 55%, and 49% of patients
Pilot Study241
disease by Sokol score respectively.
Dasatinib Minimum follow up: 12 months

DAVLEC 52 patients; aged >70 years; Median

20 mg/day MMR at 12 months was achieved in 60% of patients.
(Phase II study)244 follow-up of 366 days

Table 12. Dose Modifications for Intolerance or Resistance

TKI Study Patient Characteristics TKI Dose Study Findings

Newly diagnosed CP-CML; Dose reduction due to intolerance in MR4.5 rates were comparable for the
NordCML006
dasatinib (n = 22) vs. 27% of patients (50 mg/day; mean dose-reduced group and the standard dose
(Phase II study)247
imatinib (n = 24) dose was 50 mg at 36 months). group (100 mg once daily).
Dasatinib
5 patients attained MMR by 12 months and 3
Japanese LD-CML CP-CML resistant to imatinib
Starting dose 50 mg/day patients achieved a deep molecular
study248 ≤200 mg/day (n = 9)
response (DMR) by 18 months.

Dose reduction due to intolerance. Response rates and survival were

JALSG CML202 481 patients with newly
Imatinib (n = 90; 300 mg group); significantly inferior in the 200 mg group
(Phase II study)249 diagnosed CP-CML
(n = 67; 200 mg group) compared to 300 mg group.
CP-CML intolerant to
ENESTswift MR4.5 at any time point (up to 24 months)
Nilotinib imatinib (n = 16) or Starting dose 300 mg BID
(Phase IIIb Study)251 was achieved in 10 of 20 patients (50%).
dasatinib (n = 4)

271 patients randomized to 45 mg,

OPTIC CP-CML resistant to or 30 mg and 15 mg; Dose reduction to Results demonstrated the safety and efficacy
Ponatinib (Phase II Dose intolerant of at least 2 prior 15 mg in the 45 mg and 30 mg of response-adjusted dosing regimen for
ranging study)146 TKIs or with T315I mutation. cohorts after achievement of ponatinib (Table 6).
BCR::ABL1 (IS) ≤1%.

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Table 13. De-escalation or Intermittent Dosing of TKI

TKI Study Patient Characteristics TKI Dose Study Findings

76 patients (≥ 65 years) on imatinib 21% of patients lost CCyR and MMR; All patients
INTERIM253 Intermittent imatinib
Imatinib for ≥2 years with a stable CCyR and regained CCyR and MMR after resumption of
(1 month ON/OFF)
MMR; Minimum follow-up: 6 years imatinib.

During the dose reduction phase, loss of

De-escalation to half the molecular response occurred in 3 (2%) patients
174 patients with CP-CML on TKI
standard dose for 12 months with MR4 and 9 (19%) of patients with MMR.
DESTINY256,257 therapy for a median of 7 years
after achieving MMR (n = 49) or At 36 months, the RFS rates were 72% and 36%
(imatinib, n = 148; dasatinib, n = 10;
MR4 (n = 125), then stop for a for patients with MR4 and MMR group,
nilotinib = 16)
further 24 months respectively. All recurrences regained MMR within
Imatinib, 5 months of resumption of TKI therapy.
Dasatinib
or Nilotinib Patients with CP-CML (≥60 years) in Intermittent dosing of TKI;
stable MMR or MR4.0 after ≥2 years “fixed” (1 month ON/OFF) vs “Fixed” intermittent dosing of any TKI (1 month
of TKI therapy (imatinib, dasatinib, “progressive” (1 month ON/OFF ON/OFF) maintained MMR /MR4.0 in 81% of the
OPTkIMA
nilotinib) randomized to receive for the 1st year; 1 month ON/2 patients during the first 12–24 months. All 24% of
(Phase III study)260
“fixed” (n = 99) or “progressive” (n = months OFF for the 2nd year; patients who lost MMR regained after resumption
86) intermittent dosing of TKI until 1 month ON/3 months OFF of TKI therapy.
loss of MMR. for the 3rd year)

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Table 14. TKI Therapy for Disease Progression to AP-CML: Long-Term Follow-up Data from Phase II/III Studies

Median
TKI No. of Patients MCyR CCyR OS PFS
Follow-up

Dasatinib266,a Imatinib-R (n = 117) 36% 29%

24 months 63% 51%
(140 mg once daily) Imatinib-I (n = 41) 46% 41%

Nilotinib269,b Imatinib-R (n = 109) 30% 19%

24 months 70% 33%
(400 mg twice daily) Imatinib-I (n = 27) 41% 30%

Prior imatinib only (n = 49) 48% 35% 66% —

Bosutinib271,c
48 months
(500 mg once daily)
Imatinib followed by dasatinib or nilotinib (n = 30) 27% 23% 45% —

Dasatinib or nilotinib-R or I (n = 65) 48% 19%

45% 28%
Ponatinib145,d at 5 years at 5 years
32 months
(45 mg once daily) 52% 29%
T315I mutation (n = 18) 67% 44%
at 5 years at 5 years

I, Intolerant; R, Resistant; CCyR, Complete cytogenetic response; MCyR, major cytogenetic response; OS, overall survival;
PFS, progression-free survival

a. Primary endpoint: Major hematologic response (MaHR). The rate of MaHR at 5 years was 67% for 140 mg once daily and 69% for 70 mg twice daily (Ottmann O,
et al. Blood Cancer J 2018;8:88).
b. Primary endpoint: Confirmed complete hematologic response rate, achieved in 30% of patients with imatinib-resistant disease and 37% of imatinib-intolerant
patients.
c. Primary endpoint: Confirmed overall hematologic response by 48 weeks.
d. Primary endpoint: MaHR at any time within the first 6 months.

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Table 15. TKI Therapy for Disease Progression to BP-CML: Long-Term Follow-up Data from Phase II/III Studies

Median
TKI No. of Patients MCyR CCyR OS
Follow-up

Dasatinib268,a Lymphoid blast phase (n = 33) 50% 38% 21%

(140 mg once daily) 24 months
Myeloid blast phase (n = 75) 25% 14% 24%

Nilotinib270,b Lymphoid blast phase (n = 31) 52% 32% 10%

(400 mg twice daily) 24 months
Myeloid blast phase (n = 105) 38% 30% 32%

Bosutinib271,c Prior imatinib only (n = 36) 50% 37% 28%

(500 mg once daily) 48 months
Imatinib followed by dasatinib or nilotinib (n = 28) 21% 17% 17%

Dasatinib or nilotinib-R or -I (n = 38) 18% 16%

Ponatinib145,d 9%
6 months
(45 mg once daily) T315I mutation (n = 24) at 3 years
29% 21%

I, Intolerant; R, Resistant; CCyR, complete cytogenetic response; MCyR, major cytogenetic response; OS, overall survival

a. Primary endpoint: Major hematologic response (MaHR).

b. Endpoints: Duration of MaHR, MCyR, and OS.
c. Primary endpoint: Confirmed overall hematologic response by 48 weeks.
d. MaHR at any time within the first 6 months.

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Table 16: Results from Selected Published Clinical Trials Evaluating Novel Treatment Options
Median
Drug Class Clinical Trial TKI No. of Patients Response Rates
Follow-up
Radotinib (300 mg twice daily) n = 79 MMR: 85%; MR4.5: 58%
431
Phase III (REPRISE study)
Radotinib (400 mg twice daily) n = 81 ≥48 months MMR: 83%; MR4.5: 56%
Newly diagnosed CP-CML
Imatinib (400 mg once daily) n = 81 MMR: 75%; MR4.5: 49%
EMR: 82%;
BCR::ABL1 Flumatinib (600 mg once daily) n = 196
Phase III (FESTnd study) 432 MMR at 12 months: 53%
inhibitors Newly diagnosed CP-CML EMR: 53%;
Imatinib (400 mg once daily) n = 198
MMR at 12 months: 40%

Phase II433
CP-CML or AP-CML with MCyR: 65%; CCyR: 47%;
Radotinib (400 mg twice daily) n = 77 23 months
resistance or intolerance to MMR:14%
imatinib
CHR: 7%; MCyR: 13%;
Tozasertib (5-day continuous IV CP-CML (n = 15)
Aurora Phase II434 CCyR: 13%
infusion every 14 days at 40
Kinase CP-CML, AP/BP-CML with AP-CML (n = 14) MCyR: 7%; CCyR: 7%
mg/m2/h, 32 mg/m2/h, or 24
inhibitors T315I mutation
mg/m2/h)
BP-CML (n = 11) MCyR: 9%

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11. Seong DC, Kantarjian HM, Ro JY, et al. Hypermetaphase fluorescence

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Chronic Myeloid Leukemia

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NCCN Guidelines Version 1.2024

Chronic Myeloid Leukemia

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NCCN Guidelines Version 1.2024

Chronic Myeloid Leukemia

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NCCN Guidelines Version 1.2024

Chronic Myeloid Leukemia

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Chronic Myeloid Leukemia

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Chronic Myeloid Leukemia

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Chronic Myeloid Leukemia

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Chronic Myeloid Leukemia

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Chronic Myeloid Leukemia

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Chronic Myeloid Leukemia

287. Aftimos P, Nasr F. Isolated CNS lymphoid blast crisis in a patient with conditioning for patients with chronic myeloid leukemia. Blood
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Chronic Myeloid Leukemia

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Chronic Myeloid Leukemia

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Chronic Myeloid Leukemia

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Chronic Myeloid Leukemia

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