Double hit lymphoma: do we need a ‘double hit’ of intensive therapy?

In this issue of Leukemia and Lymphoma, Chen and colleagues describe their single-centre experience treating patients with high-grade B-cell lymphoma with MYC and/or BCL2/BCL6 rearrangements, commonly known as double hit lymphoma (DHL), with six cycles of DA-EPOCH-R followed by consolidative highdose chemotherapy and autologous stem cell transplantation (ASCT) in fit, responding patients [1]. At this centre, testing for MYC and BCL2 rearrangements has been routinely performed on all diffuse large B-cell lymphoma biopsies since 2010, suggesting that consecutive patients would have been identified and considered for this treatment algorithm. In the final study cohort of 36 patients treated with DA-EPOCH-R, about one in four patients exhibited primary refractory disease and experienced poor outcomes. On the other hand, three in four patients achieved an excellent response to chemotherapy as assessed by positron emission tomography (PET), and this subgroup had excellent 3-year progression-free (PFS) and overall survival (OS). The most interesting study finding is that among patients within this subgroup of chemo-sensitive disease, proceeding to ASCT was not associated with a further improvement in outcome. However, this particular analysis was restricted to 28/56 (50%) of the initial potentially eligible study cohort. In line with most studies of stem cell transplantation, the patients included in this series were highly selected in the sense that they had to achieve a sustained response to induction therapy, remain in good physical condition, and meet other standard requirements (i.e. successful stem cell collection, adequate organ function) to be considered for ASCT. While the 3-year PFS and OS estimates were numerically higher for the 17/28 patients undergoing ASCT (Table 1), there is a major overlap between the wide 95% confidence intervals, largely due to the small sample size. On the other hand, since the decision to proceed to ASCT consolidation was not randomized, and was largely influenced by patient characteristics, one would expect to observe worse outcomes in the 11/28 non-ASCT patients due to the reasons that prohibited transplantation (six comorbidities, two advanced age, three refusal/insurance denial). Therefore, based on this study design and limited power, it is difficult to draw definitive conclusions regarding the merits of ASCT in this setting. Despite these limitations, it is reassuring that the findings reported by Chen et al. are consistent with other published studies evaluating the role of ASCT in DHL patients responding to front-line chemoimmunotherapy, as shown in Table 1 [1–5]. Overall, there is no strong signal within the current body of evidence in favor of consolidative ASCT in patients responding to intensive rituximab-containing regimens for DHL. However, presently the evidence is based on small retrospective studies with inherent selection biases, and therefore the overall role of consolidative ASCT remains undetermined. Almost all of the patients in the studies in Table 1 achieved a complete response (CR) after rituximab-containing induction regimens, and therefore one would have anticipated improved outcomes compared to historical DHL cohorts treated without ASCT [6,7]. Achieving a CR to induction chemoimmunotherapy without ASCT has been shown to be strongly associated with improved PFS and OS in patients with DHL and aggressive B-cell lymphomas with single MYC rearrangements [6]. This biases all of these cohorts towards good outcomes, and makes it impossible to tease out the actual contribution from the ASCT. As an additional layer, in the study by Chen et al., the excellent outcomes observed in the subgroup of patients achieving a CR may reflect improved response assessment with the