Lenalidomide Maintenance Compared With Placebo in Responding Elderly Patients With Diffuse Large B-Cell Lymphoma Treated With First-Line Rituximab Plus Cyclophosphamide, Doxorubicin, Vincristine, and Prednisone

Abstract

Purpose The standard treatment of patients with diffuse large B-cell lymphoma (DLBCL) is rituximab in combination with cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP). Lenalidomide, an immunomodulatory agent, has shown activity in DLBCL. This randomized phase III trial compared lenalidomide as maintenance therapy with placebo in elderly patients with DLBCL who achieved a complete response (CR) or partial response (PR) to R-CHOP induction. Methods Patients with previously untreated DLBCL or other aggressive B-cell lymphoma were 60 to 80 years old, had CR or PR after six or eight cycles of R-CHOP, and were randomly assigned to lenalidomide maintenance 25 mg/d or placebo for 21 days of every 28-day cycle for 24 months. The primary end point was progression-free survival (PFS). Results A total of 650 patients were randomly assigned. At the time of the primary analysis (December 2015), with a median follow-up of 39 months from random assignment, median PFS was not reached for lenalidomide maintenance versus 58.9 months for placebo (hazard ratio, 0.708; 95% CI, 0.537 to 0.933; P = .01). The result was consistent among analyzed subgroups (eg, male v female, age-adjusted International Prognostic Index 0 or 1 v 2 or 3, age younger than 70 v ≥ 70 years), response (PR v CR) after R-CHOP, and positron emission tomography status at assignment (negative v positive). With longer median follow-up of 52 months (October 2016), overall survival was similar between arms (hazard ratio, 1.218; 95% CI, 0.861 to 1.721; P = .26). Most common grade 3 or 4 adverse events associated with lenalidomide versus placebo maintenance were neutropenia (56% v 22%) and cutaneous reactions (5% v 1%), respectively. Conclusion Lenalidomide maintenance for 24 months after obtaining a CR or PR to R-CHOP significantly prolonged PFS in elderly patients with DLBCL.

Clinical heterogeneity of diffuse large B cell lymphoma following failure of front‐line immunochemotherapy

“…The Bio-CORAL study indicated that COO retains its prognostic value at relapse but this is not supported by other studies (Gu, et al 2012, Moskowitz, et al 2005, Nyman, et al 2008, Thieblemont, et al 2011). Impact of auto transplant, several different types of salvage chemotherapy, targeted treatment, such as lenalidomide and ibrutinib, with preferential activity in non-GCB DLBCL could be potential mechanisms for these findings (Hernandez-Ilizaliturri, et al 2011, Thieblemont, et al 2017, Wilson, et al 2015). Newer technologies resulting in more precise identification of COO will help clarify this in future studies.…”

Lenalidomide Maintenance after R-CHOP Therapy in Diffuse Large B-Cell Lymphoma: Can It Be a Standard of Care

“…However, in the case of lenalidomide, the dose should be chosen with caution. As mentioned above, maintenance with 25 mg of lenalidomide (on days 1-21 of each 28-day cycle) after R-CHOP seems to be associated with a high percentage of toxicity and treatment interruption (61%) [13]. Zinzani et al [21 ]reported on the outcome of a phase 2 trial combining lenalidomide and rituximab as induction therapy, followed by 20 mg of lenalidomide (for 21 days of each 28-day cycle) in patients ( n = 65) with relapsed/refractory DLBCL.…”

“…Another interesting trial, published recently by Thieblemont et al [13], reported the awaited results of the REMARC study. In this randomized, phase 3 trial, patients ( n = 650) with DLBCL who reached complete or partial remission received maintenance with either lenalidomide (25 mg/day on days 1-21 of each 28-day cycle) or placebo for 24 months after combined immune chemotherapy with 6-8 cycles of R-CHOP.…”

“…Firstly, both studies included significant numbers of patients with transformed DLBCL. In Ferreri et al [12], 22% ( n = 10) of the patients, and in the investigational arm of the REMARC study [13], 10% ( n = 31) of the patients had transformed DLBCL from indolent lymphoma, but the number of transformed lymphoma cases in the placebo group of the REMARC study was significantly lower, at only 5% ( n = 16). Of note, both arms in the REMARC study included a comparable number of patients (323 on lenalidomide vs. 327 on placebo).…”

“…Although, as per the eligibility criteria, only patients >60 years old were to be included, the number of patients who were 58-60 years old who were also enrolled (Table 1 in the original article [13]) is not mentioned. These patients and also those in the range of 60-65 years of age with relapsed/refractory DLBCL are considered in many centers as potential candidates for potentially curative high-dose chemotherapy and autologous SCT, rather than treating such patients (in partial remission) with lenalidomide which lacks an overall survival benefit, according to the REMARC study results.…”