Lenalidomide plus R-GDP (R2-GDP) in Relapsed/Refractory Diffuse Large B-Cell Lymphoma: Final Results of the R2-GDP-GOTEL Trial and Immune Biomarker Subanalysis

Abstract

Purpose: New therapeutic options are needed in relapsed/refractory diffuse large B-cell lymphoma (R/R DLBCL). Lenalidomide-based schedules can reverse rituximab refractoriness in lymphoma. Experimental Design: In the phase II R2-GDP trial, 78 patients unsuitable for autologous stem cell transplant received treatment with the following schedule: lenalidomide 10 mg Days (D)1–14, rituximab 375 mg/m2 D1, cisplatin 60 mg/m2 D1, gemcitabine 750 mg/m2 D1 and D8, and dexamethasone 20 mg D1–3, up to 6 cycles (induction phase), followed by lenalidomide 10 mg (or last lenalidomide dose received) D1–21 every 28 days (maintenance phase). Primary endpoint was overall response rate (ORR). Secondary endpoints included progression-free survival (PFS), overall survival (OS), safety, and monitorization of key circulating immune biomarkers (EU Clinical Trials Register number: EudraCT 2014-001620-29). Results: After a median follow-up of 37 months, ORR was 60.2% [37.1% complete responses (CR) and 23.1% partial responses (PR)]. Median OS was 12 months (47 vs. 6 months in CR vs. no CR); median PFS was 9 months (34 vs. 5 months in CR vs. no CR). In the primary refractory population, ORR was 45.5% (21.2% CR and 24.3% PR). Most common grade 3–4 adverse events were thrombocytopenia (60.2%), neutropenia (60.2%), anemia (26.9%), infections (15.3%), and febrile neutropenia (14.1%). Complete responses were associated with a sharp decrease in circulating myeloid-derived suppressor cells and regulatory T cells. Conclusions: R2-GDP schedule is feasible and highly active in R/R DLBCL, including the primary refractory population. Immune biomarkers showed differences in responders versus progressors.

Gemcitabine Rituximab Dexamethasone and Thalidomide as Maintenance in the Treatment of Relapse/Refractory Diffuse Large B-cell Lymphoma

“…Greater advances has been observed in the treatment of patients with DLBCL, however, primary refractory and relapse remain as a common problem, actually, only 48 to 59% of patients remain alive free disease at 10 years [14,15]. Multiple schedules has been proven, basically including anthracycline based chemotherapy with doses dense, or adding to CHOP or R-CHOP, some of the new drugs, as ibrutinib, lenalidomide, bortezomib, but some Improvement in Response Rate (ORR), DFS and OS did nor show any statistical improved in outcome.…”

“…As mentioned, the major problem is relapse, various attempts, has been employed, neither has been observed that the use of interferon, interferon and chemotherapy and rituximab, employed as maintenance or consolidative has been benefit to these patients [2][3][4][5]. Recently, et, reported that the used of lenalidomide employed during induction and followed by 18 months of lenalidomide as maintenance therapy, and an statistical difference in those patients, they employed low doses of lenalidomide, and not delayed or reduced the doses, probably in this instance not is necessary high doses, and continued low doses will be better [15]. In our institution lenalidomide is not available, or these reason we employed thalidomide at low doses, also for 18 months.…”

Novel agents in relapsed/refractory diffuse large B‐cell lymphoma

“…47 Several other studies have suggested that lenalidomide can safely be used with chemotherapy and other anti-cancer agents (Table 2). [48][49][50] Several next-generation compounds, with increased affinity for cereblon and specificity for Ikaros and Aiolos, termed CELMoDs, are in development including avadomide, iberdomide, and golcadomide.…”

“…Several other studies have suggested that lenalidomide can safely be used with chemotherapy and other anti‐cancer agents (Table 2). 48–50 …”

The progress of novel strategies on immune-based therapy in relapsed or refractory diffuse large B-cell lymphoma

“…The combination of lenalidomide plus rituximab (R 2 ) exhibited enhanced anti-tumor activity in several B-cell NHL patients regardless of front-line or R/R settings, especially in indolent lymphomas [250][251][252][253][254][255]. Lenalidomide, combined with R-CHOP as front-line therapy, showed promising ORRs and PFS in both FL and DLBCL [256,257]. The mTOR inhibitor and the immunomodulatory agent have overlapping effects within the PI3K/AKT/ mTOR axis with synergistic potential.…”