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.
During the second part of the debate, Dr Robinson discussed the current issues with ASCT and CAR-T therapies and highlighted the benefits of allo-SCT for R/R DLBCL.
He started off by underlying the lack of prospective trials comparing the three treatments to one another (ASCT, allo-SCT, CAR-T) and stated that ”we still do not know if one of these treatments is superior in the context of a prospective comparative trial”.
Dr Robinson went on to list the problems seen with the current standard of care (SOC) for R/R DLBCL (ASCT + salvage chemotherapy) and highlighted how inadequate it is for many patients. He began by stating that ~50−60% of patients with R/R DLBCL will respond to induction salvage chemotherapy, as seen in the CORAL study and others. From those, ~50% of patients will relapse after ASCT, with a higher risk in patient populations with high IPI, early relapse or avid FDG in PET scans prior to ASCT. Moreover, he added that in ~5−10% of patients who are meant to receive ASCT, their stem cells will not be able to be harvested despite the use of the peripheral blood stem cell mobiliser, plerixafor. Dr Robinson, highlighted two more problems associated with ASCT: a) the re-infusion of malignant cells during ASCT and b) the risk of late myelodysplastic (MDS)/acute myeloid leukemia (AML), which occurs in 5−10% of patients with longer follow-up (10 years).
He went on exploring the benefits of allo-SCT versus ASCT and providing evidence from various trials on the superiority of allo-SCT. The first study that was mentioned showed that relapse rates after ASCT in patients with R/R DLBCL where significantly higher (55%) than after syngeneic transplantation (29%). Dr Robinson stated that this difference in relapse rates was purely due to the contamination of the graft by malignant cells in the case of ASCT, pinpointing a benefit of allo-SCT. Furthermore, he mentioned that there is strong indirect evidence from multiple trials of the existence of an active graft-versus-lymphoma (GVL) effect in R/R DLBCL, with his own recent study showing that 41% of patients responded to donor lymphocyte infusion monotherapy.
In summary the benefits of allo-SCT that Dr Robinson presented, were:
- Uncontaminated graft (from malignant cells)
- Allogeneic GVL effect
- Minimal risk of late MDS/AML
- Donor cells can be harvested for every patient
Dr Robinson then mentioned that reduced-intensity allo-SCT has been shown to salvage patients with DLBCL, who have relapsed after ASCT in a retrospective analysis. Moreover, he briefly touched upon a few phase II trials that provided promising data in favour of allo-SCT in the aggressive R/R DLBCL context, with the DSHNHL R3 study being the main reference. In this study, patients with aggressive R/R DLBCL were treated with lymphoma-directed myeloablative conditioning and allo-SCT with or without rituximab. Rituximab had no effect on overall survival. In the primary analysis of this study, conditioning and allo-SCT led to a progression-free survival (PFS) of 39.7% at three years. However, when PFS was stratified by donor match and use of anti-thymocyte globulin (ATG), the PFS of patients with match-related donor (MRD) or match-unrelated donor (MUD) and ATG was calculated at 64.7%.
Dr Robinson briefly mentioned results from his own retrospective analysis of patients in the British Society of Blood and Marrow Transplantation (BSBMT) registry, who had undergone allo-SCT after BEAM-CAMPATH conditioning for aggressive non-Hodgkin lymphoma (NHL). He mentioned that the three-year non-relapse mortality (NRM) rate in patients receiving sibling allo-SCT was only 3%. He then presented a single-center study performed in John Hopkins University ─ as an example of many other studies with similar results ─ which concluded that allo-SCT results in superior outcomes when compared to ASCT, in patients with R/R DLBCL.
He concluded his talk by questioning the applicability of CAR-T therapy in the wider population, since that in the JULIET trial only approximately half of the screened patients received a CAR-T infusion. Furthermore, he touched upon the lack of long-term data and the fact CAR-T trials are mainly reporting their per-protocol analysis response rates and not the results from the intention-to-treat analysis, which will realistically be lower.
In summary, the main drawbacks of CAR-T therapy presented by Dr Robinson, were:
- Intention-to-treat analysis not reported
- Relatively short follow-up
- Durable responses only seen in those achieving a complete response
- Considerable toxicity
- Tailored patient therapy giving rise to scalability issues due to considerable costs, extensive logistics and regulatory requirements
Dr Robinson’s last remarks focused on the great need for prospective, comparative data not only between allo-SCT and CAR-T or ASCT, but also between allo-SCT and other promising regimens.
Summary of all three sessions
For the summaries of the ASCT 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-1-asct 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.