A Keynote Debate Session on how to treat patients with relapsed or refractory diffuse large B-cell lymphoma (R/R DLBCL) took place on Tuesday 26 March 2019, during the 45th Annual Meeting of the European Society of Blood and Marrow Transplantation (EBMT), Frankfurt, DE.
During this Lymphoma Working Party (LWP) session (LWP-7), arguments in favour of the use of autologous stem cell transplantation (ASCT), allogeneic stem cell transplantation (allo-SCT) or chimeric antigen receptor T cell (CAR-T) therapy for the treatment of R/R DLBCL, were presented by the following experts, respectively:
- Prof Christian Gisselbrecht from Hospital Saint Louis, Paris Diderot VII University, Paris, FR
- Presented evidence in favour of ASCT
- Dr Stephen Robinson from University Hospitals Bristol NHS Foundation Trust, Bristol, UK
- Presented evidence in favour of allo-SCT
- Prof Marie José Kersten from the University of Amsterdam, Amsterdam, NL
- Presented evidence in favour or CAR-T therapy
All the experts clarified that with the lack of prospective trials comparing each of these three regimens with one another, it is not possible to accurately compare these treatments. Nevertheless, they sought to present results from phase II and III trials that have provided favourable evidence for each treatment strategy.
In the first part of the debate session, Prof Gisselbrecht started his presentation by stating that “ASCT is still the standard of care for R/R DLBCL”. He then continued on exploring key trials that substantiated the use of ASCT in this patient population, prior to and during the rituximab era.
Before the rituximab era
Prof Gisselbrecht presented evidence in favour of using ASCT to treat R/R DLBCL. He began by mentioning the very early results of the PARMA trial, which solidified ASCT together with high-dose chemotherapy as the standard of care in R/R DLBCL. Time-to-relapse and the International Prognostic Index (IPI) were identified as key prognostic factors of ASCT and high-dose chemotherapy success. Despite the long-term effect of ASCT observed in the PARMA trial (> 5 years), Prof Gisselbrecht mentioned a few caveats of the study. Namely, only ~50% of the enrolled patients were successfully transplanted, histology was not reviewed prior to the trial and the patients had not received rituximab prior to ASCT, as this trial was not conducted in the rituximab era.
During the rituximab era
Prof Gisselbrecht moved on to discuss the CORAL study (NCT00137995) that took place in the rituximab era in patients with R/R DLBCL. Two different rituximab-based chemotherapies (R-ICE versus R-DHAP) were explored followed by ASCT consolidation in responders, and then a second randomisation to rituximab or observation post-ASCT. The CORAL study showed no difference between R-ICE and R-DHAP and no benefit for rituximab maintenance after ASCT.
Among the patients who responded to first-line salvage chemotherapy and thus received ASCT, the age-adjusted IPI (aaIPI) was one of the best prognostic factors of response to ASCT. Indeed, > 50−60% of patients with a low aaIPI of 0−1 before and after ASCT, could be cured at 5 years.
Another important prognostic factor for R/R DLBCL patient outcomes that has been identified is fluorodeoxyglucose-positron emission tomography (FDG-PET). Prof Gisselbrecht mentioned the proven prognostic value of FDG-PET before ASCT and stated that ASCT is the best treatment option for the R/R DLBCL patient population who respond to first-line chemotherapy, have a low IPI and negative FGD-PET before and after ASCT, resulting in the cure of > 50% of these patients.
Moreover, he mentioned that the long-term follow-up of these studies together with the identification of important prognostic factors (aaIPI, FDG-PET etc.) are missing currently in the CAR-T field and thus, provide a great advantage for ASCT versus CAR-T at the current time.
Nevertheless, all these positive response rates and outcomes refer to the patient population in the CORAL study that responded to first-line salvage chemotherapy. Approximately, 50% of patients failed to respond to salvage chemotherapy and thus did not receive ASCT.
Prof Gisselbrecht ended his talk by stating that although patients need to respond to chemotherapy in order to proceed to transplantation (ASCT or allo-SCT) ─ something that is not required in the case of CAR-T cells ─ ASCT is still the only regimen with long follow-up that provides a cure for patients with R/R DLBCL (especially to those with a low aaIPI and first-line chemotherapy responders). He also added that the ultimate comparison between CAR-T and ASCT will become clear from the results of the ongoing ZUMA-7 (NCT03391466), phase III, prospective trial where CAR-T therapy is directly compared with the current standard of care (SOC; salvage chemotherapy followed by ASCT) in patients with R/R DLBCL.
Summary of all three sessions
For the summaries of the allo-SCT and CAR-T debate sessions follow these links respectively: https://lymphomahub.com/medical-information/ebmt-debate-session-how-to-treat-r-r-dlbcl-in-2019-part-2-allo-sct and https://lymphomahub.com/medical-information/ebmt-debate-session-how-to-treat-r-r-dlbcl-in-2019-part-3-car-t
All three experts agreed that more long-term data are needed regarding CAR-T cells and large prospective comparative trials like ZUMA-7 to validate the potential superiority of ASCT, allo-SCT or CAR-T in R/R DLBCL. A summary of some of the above-mentioned advantages and drawbacks of ASCT, allo-SCT and CAR-T are shown in Table 1 below.