In this issue of Blood, Matasar and colleagues report the results of salvage treatments with anti-CD20 ofatumumab in combination with ifosfamide, carboplatinum, etoposide (ICE) or dexamethasone, high-dose cytarabine, cisplatin (DHAP) in relapsed refractory diffuse large B-cell lymphoma (DLBCL) before transplantation. They conclude that replacing rituximab with ofatumumab in second-line therapy is a promising approach.1
The development of rituximab, a chimeric anti-CD20 antibody, represented a revolutionary advance in the therapy of lymphomas. Despite these major advances, salvage treatments remain a challenge as we are now observing patients more refractory to any available treatment. Salvage therapy using autologous stem transplantation (ASCT) is still the standard of care, and requires efficient re-induction treatment. In 2 prospective randomized studies, CORAL2 or the Canadian Study LY12,3 only half of the patients underwent ASCT due to an insufficient response rate to R-ICE (rituximab and ICE), R-DHAP (rituximab and DHAP), or R-GDP (rituximab and gemcitabine, dexamethasone, platinum). Moreover, it did not seem that 1 regimen was clearly superior to the other.
In the CORAL study, the factors that significantly affected the response (P < .0001) after 3 cycles of R-ICE or R-DHAP were: refractory/relapse <12 months after initial treatment, second-line adjusted International Prognostic Index (saaIPI) >1, and prior exposure to rituximab. For patients experiencing an early relapse and having received chemoimmunotherapy, the overall response rate (ORR) was 46% with only 22% complete remission (CR). These parameters comprise a poor-prognosis group of patients where any progress in salvage therapy should be readily detected.
Large phase 3 studies with the introduction of new drug combinations require a major investment and will be problematic given the lack of progress in ORR reported in novel phase 2 study.
Ofatumumab, a human anti-CD20 monoclonal antibody that targets a different epitope than rituximab, demonstrated activity in rituximab-refractory indolent lymphomas.4 In this issue, Matasar et al1 report on a prospective phase 2 study of ofatumumab combined with salvage regimens ICE (O-ICE; 35 patients) or DHAP (O-DHAP; 26 patients). The 61 relapsed DLBCL or transformed follicular lymphoma patients treated with rituximab chemotherapy in the study had poor-prognosis features: 48% had a saaIPI index of 2 or 3, 48% had primary refractory disease, and 33% had duration of response <12 months.
The 61% ORR achieved was similar to the 63% ORR of the CORAL study. However, because all patients have been previously exposed to rituximab, the achieved ORR is more impressive. They achieved their experimental goal (ORR of 60% or greater), and for the 29 patients with 2 or more adverse prognostic factors, the ORR was 59% with 31% in CR. There was no unexpected new toxicity, but nephrotoxicity was still a concern with DHAP and suggests that the substitution of cisplatin to an alternative platinum such as oxaliplatin may be of benefit.5 The number of transplants performed was 34 (55%), a borderline increase from CORAL. The evaluation of response was the main end point. However, in DLBCL, determining response is often difficult due to the presence of residual masses6 with analysis of survival the only confirmatory demonstration of efficacy. A significant difference in overall survival has been reported in another recent lymphoma study between 2 regimens despite an apparent similar response rate.7 In the current study, it is hard to predict survival. With a short follow-up, for patients with an saaIPI of 2 or 3, the median progression-free survival of 177 days was still low compared with the 189 days in the CORAL study. For patients with CR <12 months, the median PFS was 261 days, compared with 164 days for CORAL. With the many limitations inherent in such studies, only randomized studies will determine if the approach reported indeed represents an advance in treatment.
Several other anti-CD20 are in development (especially obinutuzumab, which also has activity in rituximab-resistant lymphoma8 ) and may also be candidates for future study. Multiple new agents targeting various pathways have also shown clinical activity in lymphoma. The ORR in relapsed DLBCL was in the order of 30%, with a few complete remissions of short duration. Their true benefit may be only detectable when they are combined with standard regimens.9
Matasar et al report the first phase 2 study combining a novel anti-CD20 to salvage chemotherapy. The investigators claimed that, because of the selection of a higher percentage of poor-prognosis patients, these results are superior to those obtained with R-ICE or R-DHAP. The data are encouraging and give the basis for the ongoing randomized study with rituximab vs ofatumumab DHAP regimens.
Conflict-of-interest disclosure: C.G. received research funding from Roche Pharma.
