Outcomes of Diffuse Large B-Cell Lymphoma Patients Relapsing After Autologous Stem Cell Transplantation: an Analysis of Patients Included in the CORAL Study

ORIGINAL ARTICLE Outcomes of diffuse large B-cell lymphoma patients relapsing after autologous stem cell transplantation: an analysis of patients included in the CORAL study

E Van Den Neste1, N Schmitz2, N Mounier3, D Gill4, D Linch5, M Trneny6, R Bouadballah7, J Radford8, M Bargetzi9, V Ribrag10, U Dührsen11,DMa12, J Briere13, C Thieblemont13, E Bachy14, CH Moskowitz15, B Glass2 and C Gisselbrecht13

In the CORAL study, 255 chemosensitive relapses with diffuse large B-cell lymphoma (DLBCL) were consolidated with autologous stem cell transplantation (ASCT), and 75 of them relapsed thereafter. The median time between ASCT and progression was 7.1 months. The median age was 56.1 years; tertiary International Prognosis Index (tIPI) observed at relapse was 0–2 in 71.6% of the patients and 42 in 28.4%. The overall response rate to third-line chemotherapy was 44%. The median overall survival (OS) was 10.0 months (median follow-up: 32.8 months). Thirteen patients received an allogeneic SCT, and three a second ASCT. The median OS was shorter among patients who relapsed o6 months (5.7 months) compared with those relapsing ⩾ 12 months after ASCT (12.6 months, P = 0.0221). The median OS in patients achieving CR, PR or no response after the third-line regimen was 37.7 (Po0.0001), 10.0 (P = 0.03) and 6.3 months, respectively. The median OS varied according to tIPI: 0–2: 12.6 months and 42: 5.3 months (P =0.0007). In multivariate analysis, tIPI 42, achievement of response and remission lasting o6 months predicted the OS. This report identiﬁes the prognostic factors for DLBCL relapsing after ASCT and thus helps to select patients for experimental therapy.

Bone Marrow Transplantation (2017) 52, 216–221; doi:10.1038/bmt.2016.213; published online 19 September 2016

INTRODUCTION outcome was dismal, and innovative strategies are awaited. There Salvage second-line chemotherapy followed by high-dose therapy are few registry data in the rituximab era for relapse post ASCT, and autologous stem cell transplantation (ASCT) is the standard of with a reported median overall survival (OS) of 9.9 months in 4 care for relapsed/refractory diffuse large B-cell lymphoma (DLBCL). rituximab-pretreated patients. The CORAL study provided In the CORAL study, two salvage regimens (R-DHAP (rituximab, a unique opportunity to look at 75 patients who relapsed after dexamethasone, cytarabine, cisplatinum) or R-ICE (rituximab, BEAM/ASCT and to shed more light on the outcome and ifosfamide, carboplatinum, etoposide)) were compared in 477 prognostic factors in this population who had an initial response fi patients, and no difference was found. Only 50% of the patients to rst salvage treatment. could proceed to per protocol ASCT, afterwards they were randomly assigned to rituximab or observation. The 4-year PATIENTS AND METHODS event-free survival post ASCT was 52% and 53% for the rituximab and observation groups, respectively (P = 0.7). International Prog- Study design and patient selection nosis Index (IPI) at relapse, that is, secondary IPI (sIPI), The CORAL study was a phase III, multicentre, randomised trial that compared the efficacy of three R-ICE or R-DHAP cycles, followed by ASCT independently predicted event-free survival, PFS and OS. Patients – o with or without rituximab maintenance in patients aged 18 65 years with with DLBCL relapsing 12 months after rituximab-containing relapsed DLBCL. Details of the inclusion criteria, treatment, assessment of first-line therapy were also identified as a subgroup with dismal response and monitoring have been reported previously.1,2 In total, 1,2 outcome. between July 2003 and June 2008, 477 patients were randomly assigned to In DLBCL patients who fail second-line therapies, third-line R-ICE (n = 243) or R-DHAP (n = 234). A total of 255 patients who achieved strategies are not well established. The CORAL investigators CR, PR or stable disease after the third cycle of salvage treatment with reported on the outcome of patients who could not proceed to adequate stem cell collection received consolidation with BEAM CORAL-scheduled ASCT, mainly because of treatment failure.3 (carmustine, etoposide, cytarabine and melphalan), followed by ASCT. Among them, 244 patients were further randomised between rituximab The results indicated that in ~ 30% of these patients, particularly maintenance (n = 122) or observation (n = 120). The present report focuses those with a lower tertiary IPI (tIPI), response to third-line on the 75 patients included in the CORAL study who relapsed after ASCT therapy and the possibility to consolidate with ASCT, long-term either before (n = 4) or after randomisation between rituximab (n = 37) and disease control could be achieved. In the remaining patients, the observation (n = 34; Figure 1). The CORAL study was registered under

1Cliniques Universitaires UCL Saint-Luc, Brussels, Belgium; 2AsklepiosKlinik St Georg, AbteilungHämatologie und Stammzelltransplantation, Hamburg, Germany; 3CHU de l'Archet, route de St Antoine-Ginestiere, Nice, France; 4Princess Alexandra Hospital, Woodville, South Australia, Australia; 5University College London, Cancer Institute, London, UK; 6Charles University and General Hospital, Praha, Czech Republic; 7Institut Paoli Calmette Département d’Onco-Hématologie, Institut Paoli-Calmettes, Marseille, France; 8University of Manchester and the Christie NHS Foundation Trust, Manchester Academic Health Science Centre, Manchester, UK; 9Hämatologie, Kantonsspital Aarau, Aarau, Switzerland; 10Institut Gustave Roussy, Villejuif, France; 11Universitätsklinikum Essen, KlinikfürHämatologie–Hufelandstraße, Essen, Germany; 12St Vincent’s Hospital Sydney, Darlinghurst, NSW, Australia; 13Hopital Saint Louis Paris, Paris, France; 14Hospices Civils de Lyon, Université de Lyon, Pierre Benite, France and 15Memorial Sloan Kettering Cancer Center, New York, NY, USA. Correspondence: Professor C Gisselbrecht, Hôpital Saint Louis, 1, avenue Claude Vellefaux, Paris 75010, France. E-mail: [email protected] Received 18 April 2016; revised 16 June 2016; accepted 5 July 2016; published online 19 September 2016 Outcome after third-line DLBCL E Van Den Neste et al 217

Randomly assigned in CORAL study (n = 481) CRF not recovered (n = 4)

R-ICE R-DHAP (n =243) (n = 243)

Completed iniduction phase Failed to proceed to BEAM and received BEAM+ASCT +ASCT (n = 255) (N = 222)1

CRF not recovered (n = 9)

Relapse2 (n=4)

Randomly assigned Randomly assigned in maintenance in observation (n = 122) (n = 120)

Relapse2 Relapse2 (n = 37) (n = 34)

Figure 1. Complete diagram of the patient distribution. CRF = case report form; FU = follow-up. 1The outcome of these patients was reported in reference 3; 2Population of patients retained for the current analysis (n = 75).

EudraCT (no. 2004-002103-32) and ClinicalTrials.gov (no. NCT 00137995). and relapse was 7.1 months (range 3.2–61.9), with 32.9% of The Lymphoma Academic Research Organization (LYSARC) monitored the patients relapsing ⩾ 12 months. The median age at relapse was data centrally. All patients had given written informed consent both to 56.1 years (range 20.9–67.7), and the sex ratio was 51 males/24 participate and to provide tissue material for biologic studies. females. For the patients in the second relapse, tIPI could be determined and was 0–2 in 71.6% and 42 in 28.4%. Of these Methods patients, 49.3% were in the rituximab arm, and 45.3% were in the The investigators were asked to update their patients’ status. The patient observation arm of the CORAL study; 5.3% relapsed before the characteristics at relapse, time between ASCT and failure, type of third-line second randomisation (Figure 1). All patients had previously regimen, response to third-line treatment, response by the CORAL received rituximab. Third-line therapy consisted of ICE-type maintenance arm (rituximab or observation) and OS were retrospectively (17.3%), DHAP-type (24%), gemcitabine-containing (28%), collected after an amendment. IPI was calculated based on the CHOP-like (13.3%) and miscellaneous regimens (17.3%). characteristics at relapse post ASCT (tIPI). Third-line treatments were grouped into major categories (see Van Den Neste et al.3 for a full description). All patients had been previously exposed to rituximab Tumour biology in the first- and/or second-line treatment and data on use of rituximab in The immunohistochemical expression of BCL2 and c-MYC in the third-line was not recorded. tumour cells was observed in 9/46 (19.6%) and 2/15 (13.3%) of the evaluable patients, respectively. Among the tumour samples Evaluations and analyses displaying interpretable fluorescent in situ hybridisation signals, Patients’ response was assessed by the investigators using conventional BCL2/18q21 and c-MYC/8q24 gene rearrangements were found in methods that included CT scans according to the International Working 11/26 (42.3%) and 3/27 (11.1%), respectively, with only one double Group criteria.5 PFS and event-free survival after the third-line treatment hit. Using the algorithm of Hans,7 36.4% (16/44) of the patients were not considered because it was anticipated that these results would were classified as germinal centre B (GCB)-cell like, and 63.6% be less reliable; indeed, the initial CORAL report showed that over 90% of (28/44) were classified as non-germinal centre B (not shown). deaths were lymphoma related.1 Thus, only the OS is given, defined as the time from the date of relapse after ASCT until death. The median follow-up was 32.8 months (range 24.3–45.8 months). Response to third-line chemotherapy Material for histology was only available in a subset of patients to The overall response rate to third-line chemotherapy, based on assess tumour biology. Immunohistochemistry and fluorescent in situ local investigator assessment, was 44%, with 32% CR/CR hybridisation were performed as previously reported and were centrally unconfirmed (CRu) and 12% PR. No significant difference among reviewed.6 The cell of origin was defined according to the algorithm published by Hans et al.7 the various salvage regimens was observed. For patients The Kaplan–Meier method was used to estimate the OS. The Wilcoxon's previously treated into the R-ICE arm of the CORAL study, the signed-rank test or χ2-test was used to compare the patient characteristics. following chemotherapies (+/ − rituximab) were used as the third- Cox regression analysis was used to calculate the hazard ratio (HR) line: ICE (n = 2), DHAP (n = 18), gemcitabine-containing (n = 9), between different patient categories. All reported P-values are two-sided, CHOP-like (n = 6) and other (n = 9). For patients treated in the and P-values o0.05 were considered significant. All statistical analyses R-DHAP arm of the CORAL study, regimens (+/ − rituximab) used were carried out using the SAS 9.2 software (SAS Institute, Cary, NC, USA). as the third-line were: ICE (n = 11), gemcitabine-containing (n = 12), CHOP-like (n = 4) and other (n = 4). Chemotherapy switch- RESULTS ing from ICE to DHAP, and oppositely from DHAP to ICE-yielded CR/PR rates of 35.3%/17.6% and 36.4%/18.2%, respectively. Patients’ characteristics Among the 75 patients, 16 (21.6%) could eventually be In total, 75 patients relapsed after CORAL-scheduled ASCT transplanted again, three patients received an autologous SCT (Table 1). The median time between ASCT scheduled in CORAL and 13 an allogeneic SCT, with various conditioning regimens,

© 2017 Macmillan Publishers Limited, part of Springer Nature. Bone Marrow Transplantation (2017) 216 – 221 Outcome after third-line DLBCL E Van Den Neste et al 218 1.0 Table 1. Patients’ characteristics and response to salvage treatment + Censored 95% Confidence limits

Parameter N =75 0.8

Age, years Median 56.1 0.6 Min–max 20.9–67.7 Sex M/F (n) 51/24 0.4

CORAL maintenance arm, n (%) Survival probability Rituximab 37 (49.3) 0.2 Observation 34 (45.3) NAa 4 (5.3) 0.0 73 48 26 20 17 14 7 4 2 1 0 Time between ASCT and relapse 0 6 12 18 24 30 36 42 48 54 60 Median (months) 7.15 Range (months) 3.2–61.9 Figure 2. OS (months) of 73 patients from the time of relapse post o6 months, n (%) 28 (38.4) ASCT to death from any cause. A full color version of this ﬁgure is 6–12 months, n (%) 21 (28.8) available at the Bone Marrow Transplantation journal online. 412 months, n (%) 24 (32.9)

b IPI, n (%) 1.0 0-2 + Censored 0–2 48 (71.6) >2 logrank p=0.0007 42 19 (28.4) 0.8 Type of salvage, n (%) ICE-like 13 (17.3) 0.6 DHAP-like 18 (24.0) Gemcitabine-containing 21 (28.0) 0.4 CHOP-like 10 (13.3) Miscellaneous 13 (17.3)

Survival probability 0.2 Response to salvage, n (%) CR/CRu 24 (32.0) 0.0 PR 9 (12.0) 0-2 46 37 22 17 14 13 63210 s.d./PD 34 (45.3) >2 19 9 3 2 2 0 NE/NA 8 (10.7) 0 6 12 18 24 30 36 42 48 54 60 Figure 3. OS (months) of 65 patients from the time of relapse post Second transplantation, n (%) ASCT to death from any cause according to tIPI. A full color version ASCT 3 (4.0) of this ﬁgure is available at the Bone Marrow Transplantation journal Allo-SCT 13 (17.6) online. No transplantation 58 (78.4)

Conditioning regimens was significantly different according to IPI at CORAL failure: tIPI 0– Fludarabine-containingc 10 (62.5) 2: 12.6 months (1-year OS 51.3%) compared with tIPI 42: Bu-Cy 1 (6.2) 5.3 months (1-year OS 21.1%, hazard ratio (HR) 2.805, 95% TBI-Cy 1 (6.2) confidence interval (CI) 1.510–5.210, P = 0.0007; Figure 3). HD-Mel 1 (6.2) The median OS was particularly dismal among patients who Ibritumomab tiuxetan 1 (6.2) relapsed o6 months after CORAL-scheduled ASCT (5.7 months, BEAM 1 (6.2) ⩾ o Other 1 (6.2) n = 28) compared with those relapsing either 6or 12 months (median OS: 11.3 months, n = 21, HR 0.407, 95% CI 0.206–0.806, Abbreviations: Allo-SCT = allogeneic SCT; ASCT = autologous stem cell P = 0.0099) or ⩾ 12 months after ASCT (median OS: 12.6 months, transplantation; Bu = busulfan; CRu = CR undetermined; Cy = cyclopho- n = 24, HR 0.467, 95% CI 0.244–0.896, P = 0.0221; Figure 4). sphamide; F = female; HD = high dose; IPI = International Prognostic Index; The median OS in patients achieving CR/CRu or PR after M = male; Mel = Melphalan; NA = not applicable; s.d./PD = stable disease/ – a third-line regimen was 37.7 months (HR 0.132, 95% CI 0.059 0.294, progressive disease. NA for patients who relapsed before arm assignment. o – bTertiary IPI (IPI at second relapse). cFludarabine (Flu)-containing P 0.0001) or 10.0 months (HR 0.375, 95% CI 0.152 0.929, regimens before allo-SCT included Flu-busulfan, Flu-cyclophosphamide, P = 0.034), respectively, compared with 6.3 months in those with Flu-melphalan, Flu-cyclophosphamide-TBI and Flu-TBI. no response (Figure 5). When patients were analysed separately according to the type of third-line salvage regimen, no significant difference was found (not shown). The median OS of patients who could eventually be which are detailed in Table 1. The intensity of conditioning transplanted (after a median follow-up of 32.7 months, range: regimens for allogeneic SCT was reduced in in nine patients and 24.3–55.2 months) was 17.4 months (1-year OS 68.2%) compared myeloabative in four of them. Among the transplanted patients, with a median OS of 8.0 months in those who were not 10 were in CR/CRu, one was in PR and 4 were in stable or transplanted (1-year OS 31.2%), with a HR of 0.575, but this progressive disease at the time of transplantation; the remaining difference was not statistically significant (P = 0.1106; Figure 6). patient was not evaluable. There was no difference (HR 1.035, P = 0.9654) according to the type of transplantation performed (ASCT or allogeneic SCT, not shown). Importantly, the characteristics of patients who could or Survival could not be transplanted were compared. The only difference The median OS was 10.0 months for the entire population with was the response to third-line regimen with 21/58 (36.2%) an estimated 1-year OS of 39.1% (Figure 2). The median OS non-transplanted patients in CR/CRu/PR compared with 11/16

1.0 1: <6 months 1.0 No + Censored 2: >=12 months Yes logrank p=0.1106 3: [6 - 12[ months 0.8 0.8

0.6 0.6

0.4 0.4

0.2 Survival probability Survival probability 0.2

0.0 1 28 12644321110 0.0 2 22 18 10 7 5 5 2 2 0 No 57 34 16 13 10 10 5 2 1 0 3 211798763110 Yes 16 14 10 7 7 4 2 2 1 1 0 0 6 12 18 24 30 36 42 48 54 60 0 6 12 18 24 30 36 42 48 54 60 Figure 4. OS (months) of DLBCL patients relapsing after CORAL- Figure 6. OS (months) after CORAL-scheduled ASCT according to the scheduled ASCT according to the interval between ASCT and relapse transplantation performed (No, n = 57 patients; Yes, n = 16 patients). o – ⩾ ( 6 months, 6 12 months and 12 months). A full color version of A full color version of this ﬁgure is available at the Bone Marrow ﬁ this gure is available at the Bone Marrow Transplantation journal Transplantation journal online. online. relapse and uniformly treated with DHAP or ICE combined with rituximab. Patients who could not proceed to CORAL-planned

1.0 CR/CRu ASCT were excluded; these patients have been previously PR 3 SD/PD reported. The present analysis thus focuses on the 75 patients 0.8 who were in CR/PR with adequate stem cell collection after R-DHAP/ICE, underwent ASCT and eventually relapsed. The 0.6 objective was to define the efficacy of the third-line regimen and prognostic factors for a better outcome in this population, for 0.4 which a standard strategy is lacking and the prognosis is notoriously dismal. One of the goals was to set an historical Survival probability 0.2 standard comparator for the development of new approaches. The ORR to third-line salvage was 44%, including 32% CRs. We 0.0 previously reported an ORR of 38% (CR 24%) in CORAL-included CR/CRu 22 22 19 15 13 11 5 3 2 1 0 patients who could not proceed to the transplantation because of PR 964322110 SD/PD 34 18 3 2 2 1 1 0 refractoriness to the first salvage chemotherapy. We showed that 0 6 12 18 24 30 36 42 48 54 60 this ORR could be achieved, at least partially, by shifting from DHAP-type to ICE-type and vice versa and similar results were Figure 5. OS (months) from the time of relapse post ASCT to death 3 from any cause according to the response to the third-line regimen. observed here. The nature of our study does enable a true A full color version of this figure is available at the Bone Marrow comparison between different salvage regimens. However, our Transplantation journal online. results show that even if this proportion is reduced, a significant proportion of patients with DLBCL in second relapse after ASCT remain chemosensitive. (68.7, P = 0.024) in the transplanted group. Other characteristics The OS of the entire population was 10 months, similar to that (age, sex, arm of second randomisation, disease-free survival from reported by Nagle et al.4 (9.9 months) in a retrospective analysis of ASCT, tIPI and type of salvage) were similar in both groups. 56 patients with disease progression after ASCT. Although limited, this OS appears to be better than initially reported in the pre- Prognostic factors rituximab era (3 months).8 This observation matches the recent The OS according to prognostic factors is depicted in Table 2. Of finding that for patients who respond to salvage chemotherapy note, the tumour biology was included in neither the univariate and manage to proceed to ASCT after a failure of first-line nor multivariate analysis because of missing data. There was one immunochemotherapy, ASCT is at least as effective as in patients double hit Bcl2 Myc rearrangement and two double expressors. who had failed chemotherapy in the preceding decade.9,10 A Transplantation was not included in the model because of the subgroup analysis indicated three independent factors that were small number of patients and closely related to CR/PR. It was predictive of a significantly improved outcome: low or low- moreover not significantly different. In multivariate Cox analysis intermediate tIPI at relapse, progression occurring ⩾ 6 months (for age, sex, tIPI, response to third-line regimen and time between after ASCT and chemosensitivity to third-line salvage. Patients who CORAL ASCT and relapse), tIPI 42 (HR 2.464, P = 0.0139), relapsedo6 months after CORAL transplantation had a median achievement of CR/CRu (HR 0.104, Po0.0001) or PR (HR 0.242, outcome (OS 5.7 months) in the range of those refractory to P = 0.0186), and post-ASCT disease-free interval (DFI) lasting CORAL salvage (OS 3.6 months), and should thus be considered o6 months (HR 2.270, P = 0.0497) independently predicted for similarly to the latter. The time to progression following ASCT has OS. This analysis was performed on 57 patients for whom all data been identified as a factor impacting OS in previous reports in were available. similar patients.4,11 Our results thus indicate that in selected DLBCL patients relapsing after ASCT, potentially on the basis of these latter characteristics, implementing a classical strategy with DISCUSSION third-line salvage chemotherapy and attempting to achieve a In this report, we retrospectively analysed the outcome of DLBCL response could remain a valid option, especially when an immune patients in the second relapse after ASCT. All patients had been consolidation with allogeneic transplantation is possible. prospectively included in the CORAL study at the time of their first Conversely, patients with post-ASCT relapse bearing high/

Table 2. Overall survival according to prognostic factors

Parameter n Median OS (months) Range 1-Year OS (%) 95% CI (lower–upper) P-value

Total population 75 10.0 0.9–55.2 39.1 6.6–12.6

Tertiary IPI at second relapse 0–2 46 12.6 0.9–55.2 51.3 8.8–30.8 0.0007 42 19 5.3 1.2–27.3 21.1 2.3–10.4

DFI after ASCTa o6 months 28 5.7 1.1–55.2 21.4 3.4–7.3 0.0132b ⩾ 6, o12 months 21 11.3 0.9–49.2 47.6 6.6-NA ⩾ 12 months 22 12.6 1.3–46.2 52.5 7.5–30.8

Response to third-line therapy CR/CRu 22 37.7 7.3–55.2 90.5 17.4–NA o0.0001b PR 9 10.0 2.3–45.8 44.4 2.3–NA s.d./PD 34 6.3 1.2–36.8 13.4 5.3–9.5

Transplantation Yes 16 17.4 0.9–49.2 68.2 7.3–NA 0.1106 No 57 8.0 4.8–55.2 31.2 5.8–10.6 Abbreviations: ASCT = autologous stem cell transplantation; CI = conﬁdence interval; CRu = CR undetermined; DFI = disease-free interval; IPI = International Prognosis Index; NA = not available; OS = overall survival; s.d./PD = stable disease/progressive disease. aInterval between CORAL-scheduled ASCT and relapse. bGlobal P-value.

intermediate–high tIPI and/or short post-ASCT DFI could be combining DHAP with ibrutinib in relapsed/refractory DLBCL is eligible for experimental strategies. illustrating this strategy. In our study, the actual role of consolidative allogeneic SCT is In conclusion, we analysed the outcome of DLBCL patients who difficult to define because most (69%) of the transplanted patients relapsed after ASCT. All of the patients had been prospectively were in CR/CRu/PR at transplantation. The disease status has included in the CORAL study at the second relapse and uniformly indeed been reported to be a major parameter affecting the treated prior to ASCT. All patients had received prior rituximab. 11–13 outcome at the time of allogeneic SCT as second transplant. We identified two prognostic factors (post-ASCT disease-free Overall, allogeneic SCT in DLBCL has been shown to be associated interval and tIPI) that could help clinicians to select an adequate with durable disease control and graft-versus-lymphoma effect, strategy. We also confirm the importance of achieving a response as demonstrated by the role of immunotherapeutic intervention 14–16 before proceeding to further treatment including transplantation. post allo-SCT. Although prior ASCT may adversely affect Future progress will hopefully come from a better understanding PFS, encouraging OS has been reported for allogeneic SCT as of the molecular characteristics of relapsing patients, This series second transplant procedure in DLBCL after various conditioning – could be used as a comparator to evaluate more active salvage regimens with various donor types.12,17 19 Recently, the CIBMTR and consolidation modalities. reviewed 503 patients with allogeneic SCT (25% myeloablative conditioning) after experiencing disease progression or relapse following prior ASCT. A prognostic model using 3 factors was CONFLICT OF INTEREST proposed: (i) Karnofsky score o80 (2 points), (ii) interval o EVDN: Roche: Travel accommodation. CG: Roche: Research funding. MT: Roche: between ASCT and allogeneic SCT 1 year (1 point), and Honoraria, research funding. JR: Roche: Consultancy. UD: Roche Pharma: Honoraria, (iii) chemoresistant disease at allogeneic SCT (2 points). Only research funding. CHM: Genentech: Consultancy, research funding. BG: Roche: fi patients with low risk (0-1 point) bene tted from acceptable PFS Honoraria, research funding. and OS (38% and 43% at 3 years, respectively).20 In the present report, we observed long-term disease control and a potential plateau in ~ 30% of patients who could receive allogeneic SCT, ACKNOWLEDGEMENTS similar to what was observed in registry data (9,11). There was We thank the LYSARC for coordinating the study; Fabienne Morand, Sami Boussetta, no specific recommendation in the CORAL protocol for the Marion Fournier, Laurence Girard, Clemence Capron and the project leaders from the management of failures, and the decision to perform allogeneic different countries; the patients and their families; AJE for reviewing the English SCT was thus left to the investigators‘ choice. language manuscript; Catherine Druon for preparing the manuscript; and all When analysed critically, our data show that the majority investigators and pathologists. Preliminary results presented at the 57th ASH 2015 (~60%) of patients with DLBCL relapsing after ASCT will not annual meeting (abstract #731). Written on behalf of CORAL (Collaborative trial in respond to salvage therapy, thus profoundly jeopardising survival Relapsed Aggressive Lymphoma). and emphasising the need for better salvage strategies. It is unlikely that improvement may come from chemotherapy-only REFERENCES strategies, even by switching to drugs with non-overlapping resistance mechanisms. Hopefully, novel strategies, including 1 Gisselbrecht C, Glass B, Mounier N, Singh Gill D, Linch DC, Trneny M et al. Salvage agents targeting oncogenic drivers in DLBCL or chimeric T cells, regimens with autologous transplantation for relapsed large B-cell lymphoma in the rituximab era. J Clin Oncol 2010; 28: 4184–4190. will allow more tailored and effective strategies (as reviewed in – 2 Gisselbrecht C, Schmitz N, Mounier N, Singh Gill D, Linch DC, Trneny M et al. references 21 23). In our study, when analysed for 44/75 patients, Rituximab maintenance therapy after autologous stem-cell transplantation in we found a majority of non-GC subtypes, which suggests that the patients with relapsed CD20(+) diffuse large B-cell lymphoma: final analysis of the pharmacological inhibition of BCR signalling might be a promising collaborative trial in relapsed aggressive lymphoma. J Clin Oncol 2012; 30: therapeutic option. The ongoing LYSA trial (NCT02055924) 4462–4469.

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