A Phase 2/3 Multicenter, Randomized, Open-Label Study to Compare the Efficacy and Safety of Lenalidomide Versus Investigator's Choice in Patients with Relapsed or Refractory Diffuse Large B-Cell Lymphoma

Abstract

Purpose: Randomized, multicenter, open-label, phase 2/3 trial investigating lenalidomide versus investigator's choice (IC) in relapsed/refractory diffuse large B-cell lymphoma (DLBCL).Experimental Design: Patients with DLBCL who received 2 prior therapies were stratified by DLBCL subtype [germinal center B-cell (GCB) vs. non-GCB; determined by immunohistochemistry (IHC)] and then randomized 1:1 to lenalidomide (25 mg/day, 21 days of 28-day cycle) or IC (gemcitabine, rituximab, etoposide, or oxaliplatin). Crossover to lenalidomide was permitted for ICtreated patients with radiologically confirmed progressive disease. The primary endpoint was overall response rate (ORR). Progression-free survival (PFS), overall survival, and subtype analysis [GCB vs. activated B-cell (ABC)] using gene expression profiling (GEP) were exploratory endpoints.Results: Stage 1: 102 DLBCL patients (by IHC: non-GCB, n ¼ 54; GCB, n ¼ 48) received 1 dose of lenalidomide or IC. Hematologic treatment-emergent adverse events with lenalidomide versus IC included neutropenia (42.6%; 36.4%), anemia (33.3%; 47.3%), thrombocytopenia (24.1%; 43.6%), and leukopenia (5.6%; 12.7%), respectively. Overall, lenalidomidetreated patients had an ORR of 27.5% versus 11.8% in IC (ORRs were similar regardless of IHC-defined DLBCL subtype). Median PFS was increased in patients receiving lenalidomide (13.6 weeks) versus IC (7.9 weeks; P ¼ 0.041), with greater improvements in non-GCB patients (15.1 vs. 7.1 weeks, respectively; P ¼ 0.021) compared with GCB (10.1 vs. 9.0 weeks, respectively; P ¼ 0.550).Conclusions: The clinical benefit of lenalidomide monotherapy in DLBCL patients was more evident in the non-GCB subtype. Exploratory analyses suggest that this preferential benefit was more pronounced in the GEP-defined ABC population, demonstrating a need for additional studies of lenalidomide in DLBCL using GEP subtyping. Clin Cancer Res; 23(15); 4127-37. Ó2017 AACR.

CC-122, a pleiotropic pathway modifier, mimics an interferon response and has antitumor activity in DLBCL

“…ABC-DLBCL patients treated with lenalidomide when compared with GCB patients showed greater improvements in overall response rate (45.5% vs 21.4%), progression-free survival (82 weeks vs 13.2 weeks), and overall survival (108.4 weeks vs 30 weeks). 26 In contrast to lenalidomide, CC-122 appears to possess broader cell autonomous activity than lenalidomide, spanning both the ABC-and GCB-DLBCL subtypes. Although the precise mechanism is not fully known, we suggest 2 possibilities to explain the differential activity of CC-122 and lenalidomide.…”

“…[24][25][26] Our previous preclinical studies also demonstrated that lenalidomide had preferential antiproliferative activity in ABC-DLBCL cell lines vs GCB-DLCBL cell lines. 16 In contrast, CC-122 exhibited antiproliferative activity in both ABC-and GCB-DLBCL cell lines; thus, we wanted to explore the potential difference in the underlying mechanisms for the differential effects exhibited by the 2 drugs.…”

Phase 1 study of lenalidomide plus dose‐adjusted EPOCH‐R in patients with aggressive B‐cell lymphomas with deregulated MYC and BCL2

“…Although early reports of treatment with DA‐EPOCH‐R in patients with MYC‐associated lymphomas are encouraging, we sought to augment this by incorporating lenalidomide specifically into the treatment of patients with DHL and DEL. Lenalidomide is an immunomodulatory drug with single‐agent activity in patients with recurrent/refractory DLBCL . In treatment‐naive settings, lenalidomide has been combined successfully with R‐CHOP and has demonstrated provocative activity, particularly in the high‐risk nongerminal center subtype of DLBCL, which encompasses the majority of patients with DEL .…”

Rituximab‐PECC induction followed by 90Y‐ibritumomab tiuxetan consolidation in relapsed or refractory DLBCL patients who are ineligible for or have failed ASCT: results from a phase II HOVON study

“…Studies with rituximab-bendamustine in patients who were ineligible for, or have failed ASCT reported ORR of 45-62% and CR rates of 15-37% (Ohmachi et al, 2013;Vacirca et al, 2014). Lenalidomide with or without rituximab was shown to induce ORR of 27% and CR rates of 10-15% in patients with relapsed/refractory DLBCL, albeit that the benefit of lenalidomide may be seen preferentially in the non-GCB DLBCL subtype (Hernandez-Ilizaliturri et al, 2011;Czuczman et al, 2017). The subjective toxicity of the R-PECC regimen was considered very mild in our patient series.…”