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Brief Report

CLINICAL TRIALS AND OBSERVATIONS

A European collaborative study of cyclophosphamide, bortezomib, and

dexamethasone in upfront treatment of systemic AL amyloidosis
Giovanni Palladini,1 Sajitha Sachchithanantham,2 Paolo Milani,1 Julian Gillmore,2 Andrea Foli,1 Helen Lachmann,2
Marco Basset,1 Philip Hawkins,2 Giampaolo Merlini,1 and Ashutosh D. Wechalekar2
1
Amyloidosis Research and Treatment Center, Fondazione IRCCS Policlinico San Matteo, and Department of Molecular Medicine, University of Pavia,
Pavia, Italy; and 2National Amyloidosis Centre, University College London Medical School, Royal Free Hospital Campus, London, United Kingdom

The combination of cyclophosphamide/bortezomib/dexamethasone (CyBorD) showed

Key Points
early promise of high rates of hematologic responses tempered by studies showing the
• CyBorD achieves excellent inability to overcome poor prognosis of advanced cardiac amyloidosis. Large studies are
outcome in noncardiac needed to clarify its role in light chain (AL) amyloidosis. We report the outcome of 230
patients with AL amyloidosis patients treated frontline with CyBorD. Overall hematologic response rate was 60%, and
and can rescue subjects with in the 201 patients with measurable disease it was 62%, with 43% achieving at least very
good partial response (VGPR). Cardiac response was reached in 17% of patients and renal
reversible heart damage.
response in 25% of patients. Advanced cardiac stage III patients (amino-terminal pro-
• The outcome of high-risk
natriuretic peptide type B >8500 ng/L) had lower response rates (42%, ‡ VGPR 23%) and
patients remains poor, but poorer survival (median, 7 months). Nevertheless, hematologic response improved sur-
response to CyBorD can also vival in these subjects (67% at 2 years), showing the importance of striving for a good
improve survival in this group. response even in this group. (Blood. 2015;126(5):612-615)

Introduction
In amyloid light chain (AL) amyloidosis, clonal plasma cells use pro- Study design
teasomes to cope with misfolded light chain-induced proteotoxicity,
and the proteasome inhibitor bortezomib is a potential targeted therapy.1,2 Our prospectively maintained databases were searched for newly diagnosed
Early reports supported this expectation, showing high response rates, patients with AL amyloidosis treated with CyBorD. All 230 patients receiving
particularly upfront.3 A prospective trial showed that single-agent this regimen between August 2006 and March 2013 were included. At the
bortezomib is highly and rapidly effective.4 Combinations with alkylators National Amyloidosis Centre, CyBorD substituted CTD as standard frontline
are even more promising. Two studies, including 30 patients receiving therapy. In Italy, all patients not enrolled in clinical trials receive CyBorD or
BMDex; cyclophosphamide is preferred in patients younger than 65 years with
cyclophosphamide/bortezomib/dexamethasone (CyBorD) frontline,
potentially reversible contraindications to autologous stem cell transplantation.10
reported hematologic response in 90% of cases, with ;65% of patients Patients had biopsy-proven amyloidosis. The deposits were characterized as AL-
reaching complete response (CR).5,6 This led to CyBorD becoming one type by immunohistochemistry, immunoelectron microscopy,11 or proteomics,12
of the regimens most commonly prescribed in AL amyloidosis. How- and hereditary forms were excluded by DNA analysis.13 Patients gave written
ever, a subsequent study showed that in patients with advanced cardiac informed consent for use of their clinical data as approved by Ethics Committees.
involvement, CRs are rarer and survival remains poor.7 Additionally, The Mayo Cardiac Staging System was used for stratification.14 Further-
2 parallel matched case-control studies comparing CyBorD and more, stage III patients were divided into 2 groups based on whether amino-
bortezomib/melphalan/dexamethasone (BMDex) with standards terminal pronatriuretic peptide type-B (NT-proBNP) was below (stage IIIa) or
of care cyclophosphamide/thalidomide/dexamethasone (CTD) and above (stage IIIb) 8500 ng/L, which indicates very poor prognosis.15 Hema-
melphalan/dexamethasone (MDex), showed that the higher rates of tologic and cardiac response were assessed according to the International Society
good quality hematologic response obtained with bortezomib-based of Amyloidosis criteria.16 Measurable disease was defined as the difference
between involved and uninvolved free light chain .50 mg/L for hematologic
regimens did not improve overall survival.8,9 Thus, there is the need
response and NT-proBNP .650 ng/L for cardiac response. Two patients with
for large studies to identify patients who benefit most from these cardiac involvement and NT-proBNP ,650 ng/L were not included in the
combinations. We report the outcome of 230 newly diagnosed patients calculation of cardiac response. Renal response was evaluated according to
treated with CyBorD at the National Amyloidosis Centre (London, recent criteria.17 Treatment was discontinued in case of unsatisfactory response
United Kingdom) and the Amyloidosis Research and Treatment or toxicity. Statistical methods are reported in the supplemental Methods on the
Center (Pavia, Italy). Blood Web site.

Submitted January 2, 2015; accepted May 6, 2015. Prepublished online as The publication costs of this article were defrayed in part by page charge
Blood First Edition paper, May 18, 2015; DOI 10.1182/blood-2015-01-620302. payment. Therefore, and solely to indicate this fact, this article is hereby
marked “advertisement” in accordance with 18 USC section 1734.
The online version of this article contains a data supplement.
There is an Inside Blood Commentary on this article in this issue. © 2015 by The American Society of Hematology

612 BLOOD, 30 JULY 2015 x VOLUME 126, NUMBER 5

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BLOOD, 30 JULY 2015 x VOLUME 126, NUMBER 5 CyBorD IN AL AMYLOIDOSIS 613

Table 1. Hematologic response rate by intent-to-treat according to cardiac stage and bortezomib and dexamethasone dosages in 201
patients with measurable disease
Response category Stage I (30 patients) Stage II (67 patients) Stage IIIa (61 patients) Stage IIIb (43 patients)

Overall response 23 (77%) 43 (64%) 42 (69%) 18 (42%)*

CR 10 (33%) 12 (18%) 14 (23%) 6 (14%)
VGPR 7 (23%) 18 (27%) 16 (26%) 4 (9%)
PR 6 (20%) 13 (19%) 12 (20%) 8 (19%)
Response category Full bortezomib dose Intermediate bortezomib dose Low bortezomib dose
(35 patients) (82 patients) (79 patients)
Overall response 29 (83%) 57 (69%) 42 (53%)†
CR 12 (34%) 20 (24%) 11 (14%)†
VGPR 7 (20%) 21 (26%) 17 (21%)
PR 10 (29%) 16 (19%) 14 (18%)
Response category Full dexamethasone dose Intermediate dexamethasone dose Low dexamethasone dose
(58 patients) (102 patients) (41 patients)
Overall response 45 (78%) 62 (61%) 20 (49%)†
CR 15 (26%) 21 (21%) 6 (15%)†
VGPR 17 (29%) 23 (22%) 5 (12%)†
PR 12 (21%) 18 (18%) 9 (22%)

Measurable disease is defined as a baseline difference between involved (amyloidogenic) and uninvolved free light chains .50 mg/L. Forty subjects with measurable
disease died before evaluation of response and are considered nonresponders in the present intent-to-treat analysis. Data on bortezomib dosage were available in 196 of 201
patients with measurable disease. Cardiac staging is based on NT-proBNP (cutoff, 332 ng/L) and cTnT (cutoff, 0.035 ng/mL), or cTnI (cutoff, 0.1 ng/mL), with stage I, II, and III
patients having none, one, or two markers above the cutoff, respectively. Stage IIIa patients have NT-proBNP #8500 ng/L and stage IIIb patients have NT-proBNP .8500 ng/L.
Bortezomib dosage: full dose, 1.3 mg/m2 twice weekly or 1.6 mg/m2 once weekly; intermediate dose, 1.0 mg/m2 twice weekly or 1.3 mg/m2 once weekly; low dose,
,1.0 mg/m2 twice weekly or 1.3 mg/m2 once weekly. Dexamethasone dosage: full dose, at least 160 mg per cycle; intermediate dose, ,160 mg and $80 mg per cycle; low
dose, ,80 mg per cycle.
PR, partial response.
*P , .05 compared with stages I, II, and IIIa.
†P , .05 compared with full dose. Among the 15 patients who received 1.0 mg/m2 twice weekly, 2 achieved VGPR and 4 reached PR. Notably, in a multiple logistic
regression analysis, only cardiac stage IIIb (P 5 .008) and not low doses of bortezomib (P 5 .191) and dexamethasone (P 5 .353), was an independent predictor
of hematologic response, indicating that lower response rates in patients receiving lower doses of bortezomib or dexamethasone were likely explained by early deaths.
Response rate was not affected by twice or once weekly administration (67% vs 62%; P 5 .549), or by IV or subcutaneous bortezomib administration (63% vs 61%;
P 5 .862).

response significantly improved survival (Figure 1C-D). At multivariate

Results and discussion analysis, stage IIIb was the only independent prognostic factor at
baseline, whereas in the 3-month landmark analysis, hematologic re-
Patients’ characteristics and treatment schedules are reported in sup- sponse also independently predicted survival (supplemental Table 2).
plemental Table 1. Briefly, 73% of patients had cardiac involvement Twenty patients received second-line therapy with lenalidomide/
(stage IIIa, 29%; stage IIIb, 20%), and 68% had renal involvement dexamethasone: 14 (70%) responded, including 3 refractory to CyBorD,
with 2 CRs and 5 VGPRs. Seventeen patients, 7 of whom were refractory
(stage III, 8%). Cyclophosphamide was administered orally at
to CyBorD, underwent autologous stem cell transplantation: 11 (65%)
300 mg/m2 weekly in all patients. Sixteen percent of patients received
responded, with 8 CRs (47%) and 1 (6%) VGPR. Four of 9 patients
bortezomib 1.6 mg/m2 weekly or 1.3 mg/m2 twice weekly, the max-
with cardiac involvement achieved cardiac response before trans-
imum tolerated doses in the prospective trial of bortezomib in AL
plant. There was no transplant-related mortality. Eleven relapsing
amyloidosis,18 and 42% received 1.3 mg/m2 weekly or 1.0 mg/m2 twice
patients received second-line bortezomib-based treatment, and in 3
weekly. Most patients (184 or 80%) received at least 80 mg of patients VGPR was restored. An additional 8 patients had an immu-
dexamethasone per week. nomodulatory drug (thalidomide in 6 subjects and lenalidomide in 2)
Twenty-three patients experienced severe adverse events (detailed added to bortezomib/dexamethasone, and 7 responded (including 2
in “Treatment toxicity” in the supplemental Data), and 29 patients (11, CRs and 3 VGPRs).
stage IIIa; 18, stage IIIb) died within 3 months of diagnosis. With 230 patients enrolled, the current report is the largest study
By intent-to-treat, hematologic response was achieved in 138 of 230 of CyBorD in AL amyloidosis. As per most studies in this rare dis-
patients (60%), with CR in 54 cases (23%). Among 201 patients with ease, our report is limited by retrospective design. In this “real-word”
measurable disease, 125 (62%) responded (CR in 42, 21%; very good study of unselected subjects, overall response rates, particularly organ
partial response [VGPR] in 45, 22%). Response rates were lower in response, were lower than previously reported, and comparable to that
stage IIIb patients (Table 1). In a landmark analysis excluding patients observed with other regimens, such as MDex,8,19 CTD,9,20 and BMDex
dying within 3 months, 126 of 174 patients (72%) responded, with 42 in the interim analysis of the randomized trial vs MDex.21 This was
CRs (24%) and 45 VGPRs (26%). By intent-to-treat, after completing due to the inability of CyBorD to reduce early mortality in high-
a median of 4 cycles, 29 patients (17%) achieved cardiac response and risk (stage IIIb) patients. However, CyBorD proved highly effective
40 patients (25%) achieved renal response (response by stage is reported in patients without advanced cardiac involvement. We did not
in “Cardiac and renal response by stage” in the supplemental Data). Eight observe differences in survival between stage II and stage IIIa
patients (32%) had liver response. subjects, identifying an “intermediate-risk” group comprising the
Overall, 55% of patients were projected to survive 5 years, and me- “old” stage II and stage IIIa patients and indicating the impact of
dian time to second-line therapy or death was 13 months (Figure 1A). treatment regimens in redefining staging systems. Importantly,
Cardiac stage determined the outcome (Figure 1B), and hematologic CyBorD improved survival even in stage IIIb subjects who were
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614 PALLADINI et al BLOOD, 30 JULY 2015 x VOLUME 126, NUMBER 5

Figure 1. Survival of 230 patients with AL amyloidosis treated with CyBorD. After a median follow-up of living patients for 25 months, 94 patients (41%) died. (A)
Overall survival (cumulative proportion survival at 3 years, 55%) and time to second-line therapy or death (median, 13 months). (B) Survival according to cardiac stage.
Cardiac staging is based on NT-proBNP (cutoff, 332 ng/L) and cTnT (cutoff, 0.035 ng/mL), or cTnI (cutoff, 0.1 ng/mL), with stage I, II, and III patients having none, one, or
two markers above the cutoff, respectively. Stage IIIa patients have NT-proBNP #8500 ng/L and stage IIIb patients have NT-proBNP .8500 ng/L. Stage I, II, IIIa, and IIIb
patients were 41, 77, 67, and 45, respectively. There were no deaths among stage I patients. Cumulative proportion survival at 3 years was 52% in stage II, 55% in stage
IIIa, and 19% in stage IIIb. Survival of stage II and stage IIIa subjects was significantly shorter than that of stage I patients (P , .001). There was no difference in survival
of stage II and stage IIIa patients (P 5 .613). The median survival of stage IIIb patients was 7 months (P , .001 compared with stages I, II, and IIIa). (C) Survival of 118
cardiac stage II and IIIa patients according to hematologic response (3-month landmark). Cumulative proportion survival at 3 years was 84% in patients reaching at least
VGPR, 67% in subjects attaining PR (P 5 .042 compared with $ VGPR), and 10% in nonresponders (P , .001 compared with PR). The median survival of
nonresponders was 10 months. (D) Survival of 31 cardiac stage IIIb patients according to hematologic response (3-month landmark). Median survival was 26 months for
responders and 6 months for nonresponders (P , .001). The small number of patients did not allow discrimination between response categories. NR, no response; PR,
partial response.

able to receive enough treatment (ie, surviving at least 3 months subjects, in agreement with previous observations.23 In conclusion,
from diagnosis), supporting the case for hematologic response to for patients who cannot be enrolled into clinical trials, CyBorD is a
extend survival by preventing further worsening of cardiac damage. useful, highly effective upfront option. Results of an ongoing trial
Timing of cardiac responses in stage IIIb remains unclear (low in comparing BMDex and MDex are eagerly awaited to prospectively
our series at an early assessment time point) and may well be de- confirm the utility of bortezomib/alkylators/steroid combinations
layed in this advanced setting. This emphasizes the importance of in AL amyloidosis.
striving for a good and rapid response even in this poor-risk group.
In the present study, CyBorD appeared to be well tolerated. How-
ever, despite rigorous prospectively maintained databases, due to
the retrospective nature of this study, safety data need to be in-
terpreted with caution to avoid a serious risk of underestimating
toxicity. Indeed, in the prospective ALChemy series, grades 3 to 4 Acknowledgments
toxicity with CyBorD occurs in ;50% of patients.22 The present
study also allowed some observations on second-line therapy after The authors acknowledge the staff in histopathology, immunology,
CyBorD. Cardiac response to CyBorD may allow second-line transplant echocardiography, and genetics laboratories for their help with
in previously ineligible patients, and immunomodulatory drugs, confirmation of diagnosis, as well as clinical fellows, nurses, and
particularly lenalidomide, combined with dexamethasone alone or other staff for looking after the patients. The authors specially thank
added to bortezomib, appear to be good rescue agents in refractory the hematologists who treated the patients reported in this study.
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BLOOD, 30 JULY 2015 x VOLUME 126, NUMBER 5 CyBorD IN AL AMYLOIDOSIS 615

This study was supported in part by grants from the Associazione final approval; S.S., P.M., J.G., A.F., H.L., and M.B. evaluated patients,
Italiana per la Ricerca sul Cancro, Special Program Molecular Clin- collected data, analyzed data, critically reviewed the manuscript, and
ical Oncology 5 per mille n. 9965 and CARIPLO “Structure-function gave final approval; and P.H. critically reviewed the manuscript and
relation of amyloid: understanding the molecular bases of protein gave final approval.
misfolding diseases to design new treatments n. 2013-0964.” Conflict-of-interest disclosure: G.M. received honoraria from
Millennium-Takeda. G.P. and A.D.W. received honoraria from
Janssen-Cilag. The remaining authors declare no competing financial
Authorship interests.
Correspondence: Giampaolo Merlini, Amyloidosis Research and
Contribution: G.P., G.M., and A.D.W. designed the study, evaluated Treatment Center, Fondazione IRCCS Policlinico San Matteo, Viale
patients, collected data, analyzed data, wrote the manuscript, and gave Golgi, 19-27100 Pavia, Italy; e-mail: gmerlini@unipv.it.

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 From www.bloodjournal.org by guest on July 31, 2015. For personal use only.

2015 126: 612-615

doi:10.1182/blood-2015-01-620302 originally published
online May 18, 2015

A European collaborative study of cyclophosphamide, bortezomib, and

dexamethasone in upfront treatment of systemic AL amyloidosis
Giovanni Palladini, Sajitha Sachchithanantham, Paolo Milani, Julian Gillmore, Andrea Foli, Helen
Lachmann, Marco Basset, Philip Hawkins, Giampaolo Merlini and Ashutosh D. Wechalekar

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