Previous studies have revealed poor outcomes among patients with relapsed/refractory DLBCL,1,2,6 although there is no consensus regarding the optimal second-line treatment at this time.9–12, 17,19–21 To the best of our knowledge, this is the first study to compare RB and R-ICE as second-line treatments for relapsed/refractory DLBCL. The de-identified EHR-derived database was used to perform real-world analysis of patients who were treated outside of clinical trials, which revealed that the RB group had significantly longer TTNT and OS than the R-ICE group, despite patients in the RB group tending to be older and have poorer ECOG performance statuses. The multivariable analysis revealed that second-line RB treatment appeared to reduce the risk of relapse or death, regardless of age, rwPOD, ECOG performance status, stage at diagnosis, double-/triple-hit subtype, and number of extranodal sites.
The CORAL study and other studies of non-Hodgkin lymphoma revealed that early progression predicted poor OS, without any significant differences in the effects of the second-line regimens.9,22−24 In the present study, the median time from diagnosis to the start of second-line treatment (which we interpreted as rwPOD) was ≤12 months for the RB and R-ICE groups, which reflects the aggressive nature of relapsed/refractory DLBCL. As expected, patients in our study with rwPOD at ≤12 months had poorer outcomes than patients with rwPOD at >12 months, and patients with early relapse did not exhibit any treatment-specific differences in their TTNT and OS outcomes.
The treatment outcomes varied between the RB and R-ICE groups, as death was observed for 91 patients in the RB group (66%) and 103 patients in the R-ICE group (39%). Furthermore, ASCT was only performed for two patients in the RB group (1.5%), while ASCT was performed for 124 patients in the R-ICE group (46%). These differences reflect real-world practice, where younger and more fit patients tend to receive R-ICE treatment, while more frail patients tend to receive RB treatment. Nevertheless, >50% of the patients in the R-ICE group experienced second-line treatment failure and were not able to undergo ASCT, which highlights the difficulty in identifying patients who can ultimately undergo ASCT after intensive chemotherapy.
The multicenter phase III CORAL study established the utility of R-ICE treatment, although there have been no significant subsequent improvements in salvage therapies for relapsed/refractory DLBCL9. Only approximately 30–50% of these patients respond to intensive second-line chemotherapy and can undergo transplantation.10 Furthermore, the 3-year PFS rates were 37% in the CORAL study and 28% in the LY.12 study, while the 2-year PFS rate was 25% in the ORCHARRD Study.9–11
Ohmachi et al.’s multicenter phase II study revealed an overall response rate (ORR) of 63% to RB treatment, and >60% of those patients were ≥65 years old and 57/59 patients had previously received rituximab-containing regimens.17 Although the median PFS was relatively short, it is noteworthy that the patient population was also relatively frail. Merchionnea et al. performed a retrospective real-world analysis and reported an ORR of 50% and a median PFS of eight months among 28 patients who received RB for relapsed/refractory DLBCL.18 Another multicenter study revealed an ORR of 55% for RB treatment among 58 patients with relapsed/refractory DLBCL, and 60% of those patients had previously received treatment using R-ICE, R-ESHAP (etoposide, methylprednisolone, high-dose cytarabine, cisplatin), R-DHAP (dexamethasone, high-dose cytarabine, cisplatin), or R-GDP (gemcitabine, dexamethasone, cisplatin).25 These results highlight the need for better therapeutic and diagnostic strategies. Unfortunately, despite the majority of patients not responding to even intensive chemotherapies, our understanding of the biomolecular basis for chemoresistance in relapsed/refractory DLBCL remains limited. Furthermore, there are few prognostic biomarkers that can be used to guide the selection of patients who are likely to respond to intensive chemotherapy and undergo ASCT or patients who are more suitable for alternative or novel treatment options. For example, some early-phase studies have provided promising data regarding the use of targeted therapy in combination regimens for treating relapsed/refractory DLBCL.26–33 Nevertheless, long-term follow-up data are needed to evaluate the real-world outcomes of targeted therapy in this setting.
This study provided real-world results regarding second-line treatments for patients with relapsed/refractory DLBCL. However, the retrospective design is subject to various confounding factors, and it would be difficult to assess the potential contributions of these factors. In addition, we substituted TTNT for PFS (a more commonly used endpoint), as the EHRs did not contain sufficient data to calculate PFS. Nevertheless, TTNT may be a clinically meaningful endpoint and has become increasingly used in real-world practice.34–39 Lastly, this study included patients who were treated during a prolonged study period, and changes in treatment strategy may be a relevant factor, although we confirmed that the calendar years of diagnosis were fairly evenly distributed in both groups (Table 1).
In summary, we believe that this is the first real-world analysis to compare the effectiveness of second-line treatment using RB or R-ICE for relapsed/refractory DLBCL. The results suggest that second-line RB treatment is a potential alternative to R-ICE for select patients with DLBCL, such as younger patients with a fair ECOG performance status or POD at >12 months. However, further studies are needed to validate these findings.