Bone Marrow Transplantation (2015) 50, 134–136 © 2015 Macmillan Publishers Limited All rights reserved 0268-3369/15 www.nature.com/bmt
LETTER TO THE EDITOR
Retrospective comparison of allogeneic vs autologous transplantation for diffuse large B-cell lymphoma with early relapse or primary induction failure Bone Marrow Transplantation (2015) 50, 134–136; doi:10.1038/ bmt.2014.198; published online 22 September 2014
Diffuse large B cell lymphoma (DLBCL) is the most common subtype of non-Hodgkin lymphoma (NHL), comprising approximately one-third of all cases of NHL.1 Although the addition of rituximab to conventional chemotherapy has improved the outcomes for patients with DLBCL, a significant number still relapse and eventually die from lymphoma.2 For patients with chemosensitive relapsed DLBCL autologous stem cell transplantation (auto-SCT) provides better outcomes than chemotherapy alone, with ~ 50% of patients able to achieve long-term diseasefree survival.3,4 However, the outcomes are worse for patients with chemoresistant or high-risk disease. This includes patients with early relapse, defined as relapse less than 1 year after the date of diagnosis, primary induction failure (PIF), defined as less than complete response to first-line chemotherapy, and/or relapse after rituximab. High-risk patients may benefit from allogeneic SCT (allo-SCT) as it provides a tumor-free source of stem cells and the potential benefit of a graft versus lymphoma (GVL) effect. Two larger retrospective studies comparing allo-SCT and auto-SCT for relapsed DLBCL showed higher non-relapse mortality (NRM) and similar OS and disease-free survival (DFS) in allo-SCT recipients, but these studies did not focus on patients with refractory disease and early relapses.5,6 Here, for the first time we compare the clinical outcomes of patients with early relapsed and PIF DLBCL undergoing allo-SCT vs auto-SCT. The Washington University School of Medicine transplant database was searched to identify patients with DLBCL who had undergone auto-SCT or allo-SCT for early relapse or primary induction failure between 1 January 1997 and 30 December 2010. The final study cohort was 121 patients (42 allo-SCT, 79 auto-SCT). Patient, disease and transplant characteristics are summarized in Table 1. The allo-SCT group was younger, more likely to have a transplant before 2003, included a higher proportion of patients with PIF and chemoresistant disease at the time of transplant, and received more chemotherapy regimens before transplant. Notably, there were no differences in stage at diagnosis, B symptoms, co-morbidity index, rituximab exposure or time from diagnosis to transplant. The maximal response to SCT was not significantly different between auto- (63% CR, 6% PR, 4% stable disease, 17% progressive disease, 10% unknown) and allo-SCT (52% CR, 3% PR, 7% stable disease, 24% progressive disease, 14% unknown) (P = 0.53). OS at 1, 3 and 5 years after transplant was 40%, 26% and 23%, respectively, after allo-SCT and 67%, 54% and 50%, respectively, after auto-SCT (P = 0.002). In multivariate analysis, allo-SCT, age 450 years and chemoresistance at the time of transplant were associated with lower survival (Table 2). PFS at 1, 3 and 5 years after transplant was 36%, 23% and 20%, respectively, in allo-SCT and 62%, 53% and 49%, respectively, after auto-SCT (P = 0.02). In multivariate analysis, PFS was adversely influenced by
allo-SCT, age 450 years and three or more prior chemotherapy regimens (Table 2). The cumulative incidence of relapse/progression was not different in the allo-SCT group compared with the auto-SCT group. At 1, 3 and 5 years after transplant, the cumulative incidence of relapse/progression was 37%, 41% and 41%, respectively, in the allo-SCT group, and 33%, 37% and 39%, respectively, in the auto-SCT group (P = 0.59). In multivariate analysis only refractory disease at transplant and longer interval between the dates of diagnosis and transplant were associated with greater risk of relapse/progression (Table 2). The cumulative incidence of NRM at 1, 3 and 5 years after transplant was 40%, 56% and 60%, respectively, in allo-SCT and 9%, 17% and 20%, respectively, in auto-SCT (P = 0.0002). In multivariate analysis, only type of transplant independently predicted NRM (Table 2). Multiple studies have found that early relapse predicts worse outcomes for DLBCL.3,7,8 In the phase III CORAL trial, patients with early relapsed DLBCL had half the response rate to salvage chemotherapy, were much less likely to proceed to auto-SCT, and had lower PFS than those who relapsed more than 12 months after the date of diagnosis.3 For patients who do undergo autoSCT, early relapse is a negative predictor of both OS and PFS.3,9 Allogeneic SCT for early relapse is largely understudied, but it is associated with a high risk of relapse post transplant for patients with NHL.10 Our study is the first to focus on auto- and allo-SCT for early relapsed/PIF DLBCL. Overall, our study shows that for a combined group of DLBCL patients who do not achieve CR with first-line chemotherapy and patients who relapse early after achieving CR, auto-SCT compared to allo-SCT is associated with better OS, PFS and NRM and a similar relapse rate. These results are similar to the retrospective registry study performed by Lazarus et al.6 despite variation in the two study populations. Compared to our study, the Lazarus study included patients with late relapses, had a lower percentage of patients with PIF and fewer patients with progressive disease during first-line chemotherapy. Despite greater chemoresistance among patients receiving allo-SCT (15% auto vs 33% allo), the incidence of relapse/progression was not different and the auto-SCT group was more likely to die of lymphoma (61% vs 35%). While this difference might be reflective of a GVL effect, it is offset by significantly higher NRM in the early post-transplant period. Of note, nearly all of the allo-SCT patients in our study were treated with myeloablative conditioning regimens. Reduced intensity conditioning (RIC) or non-myeloablative conditioning regimens have been shown to reduce NRM, but at a greater risk of relapse. Comparison of RIC allo-SCT and auto-SCT for DLBCL with PIF or early relapse is best addressed by a prospective randomized trial. In summary, our study suggests that while allo-SCT could be considered in patients with DLBCL with early relapse or refractory disease, auto-SCT is associated with better survival and is generally preferable. It is possible that some subsets of early-relapse patients benefit from the allo-SCT. A comparison of auto- and allo-SCT for early relapsed chemosensitive DLBCL with particular attention to various patient and disease characteristics deserves further analysis in a randomized clinical trial.
Letter to the Editor
135 Table 1.
Patients, disease and transplant-related characteristics
Variables Patient related Age, median (range), years Male sex HCT-CI Low Intermediate High Disease related Stage at diagnosis I II III IV B symptoms at diagnosis Number of prior chemotherapy regimens 1 2 ⩾3 Rituximab exposure prior to SCT Best response to first line of chemotherapy CR PR SD PD Interval from diagnosis to relapse in the early relapse group, median (range), days Chemosensitivity at transplanta Sensitive Resistant Disease status at transplant PIF-S PIF-R PIF-unknown REL-S REL-R Interval from diagnosis to SCT, median (range), days
Allogeneic, N = 42 (%)
P value
57 (22–76)
42 (21–60)
o 0.0001
50 (63)
20 (48)
12 (15) 17 (22) 50 (63)
5 (12) 11 (26) 26 (62)
7 19 17 36 26
6 9 7 20 14
Autologous, N = 79 (%)
0.10 0.79
0.76 (9) (24) (21) (46) (33)
(14) (21) (17) (48) (33)
0.96 0.04
2 61 16 66
37 18 6 18 271
(3) (77) (20) (84)
(47) (23) (7) (23) (114–353)
0 25 17 30
12 13 4 13 240
(0) (60) (40) (70)
(29) (31) (9) (31) (134–356)
OS Type of transplant, auto-SCT vs allo-SCT Age at transplant, years, 450 vs ⩽ 50 Disease sensitivity, resistant vs sensitive PFS Type of transplant, auto-SCT vs allo-SCT Age at transplant, years, 450 vs ⩽ 50 Number of prior chemo regimens 1 2 ⩾3
0.28
CIR Type of transplant, auto-SCT vs allo-SCT Months from diagnosis to SCT Disease sensitivity, resistant vs sensitive
0.52
NRM Type of transplant, auto-SCT vs allo-SCT
0.08
0.02 66 (85) 12 (15)
Table 2. Cox multivariate analyses of patient and disease-related factors affecting OS, PFS, CIR and NRM
28 (67) 14 (33)
P-value
Hazard ratio (95% CI)
o0.0001
0.36 (0.22, 0.59)
0.0007
2.50 (1.47, 4.26)
0.006
2.14 (1.24, 3.68)
0.001
0.48 (0.27, 0.72)
0.001
2.36 (1.41, 3.93)
0.026 1.0 2.09 (0.28, 15.78) 4.11 (0.53, 31.75) 0.5945
0.83 (0.42, 1.64)
0.0062 0.0109
1.05 (1.01, 1.08) 2.56 (1.24, 5.29)
0.0004
0.30 (0.16, 0.59)
Abbreviations: CIR = cumulative incidence of relapse/progression; NRM = non-relapse mortality; PFS = progression-free survival. Reference groups are allo-SCT, age ⩽ 50 years, sensitive disease and one prior chemoregimen.
0.02 34 7 1 32 5 371
(43) (9) (1) (41) (6) (183–2138)
Transplant related Donor type MRD MUD Year of transplant 1997–2003 30 (38) 2004–2010 49 (62) Conditioning regimen for allo-SCT TBI/CY BU/CY Others Conditioning regimen for auto-SCT BEAM 53 (67) BEAC 7 (9) TBI/VP/CY 7 (9) Others 12 (15)
17 13 0 11 1 351
(41) (31) (0) ((26) (2) (115–793)
CONFLICT OF INTEREST The authors declare no conflict of interest.
0.50
30 (71) 12 (29) 0.003 28 (67) 14 (33) 29 (69) 8 (19) 5 (12)
Abbreviations: BEAC = carmustine+etoposide+cytarabin+cylophosphamide; HCT-CI = comorbidity index; MRD = matched related donor; MUD = matched unrelated donor; PD = progressive disease; PIF-S/R = primary induction failure with sensitive/resistant disease at transplant; REL-S/R = early relapse with sensitive/resistant disease at transplant; SD = stable disease; VP = etoposide. a1 missing data in the autologous group.
© 2015 Macmillan Publishers Limited
A Ghobadi1,4, E Nolley2,4, J Liu3, A McBride1, K Stockerl-Goldstein1 and A Cashen1 1 Division of Medical Oncology, Washington University School of Medicine, St Louis, MO, USA; 2 Department of Internal Medicine, Washington University School of Medicine, St Louis, MO, USA and 3 Division of Biostatistics, Washington University School of Medicine, St Louis, MO, USA E-mail:
[email protected] 4 These authors contributed equally to this work.
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Letter to the Editor
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