Lenalidomide Plus R-CHOP (R2CHOP) in Patients with Follicular Lymphoma: Data from a Phase 1/2 Study
Authors: Ayed Ayed O. , Pederson Levi , Macon William R. , Laplant Betsy R. , Reeder Craig B. , Foran James M. , Nelson Garth , Rivera Candido E. , Habermann Thomas M. , Witzig Thomas E. , Nowakowski Grzegorz S. 
Published: October 2019

Abstract
Background
Follicular lymphoma (FL) is an indolent non-Hodgkin lymphoma (NHL) with heterogeneous outcomes and remains largely incurable. Immunochemotherapy (IC) continues to be the standard therapy backbone in the frontline and relapsed settings, though novel agents are increasingly used and investigated. Lenalidomide is an immunomodulatory molecule with known single-agent activity in relapsed lymphoma. It is also active in the frontline setting and has been reported to be effective and tolerated in upfront combination regimens in FL (Fowler et al, Lancet Oncol. 2014, 15(12):1311-8). Here we report our experience with frontline use of R2CHOP (lenalidomide in combination with R-CHOP) in patients with FL.
Methods
A phase 1/2 study of R2CHOP was conducted in NHL patients with primarily diffuse large B-cell lymphoma (DLBCL). While the phase 2 study was focused on DLBCL patients, treatment-naive patients with stage II-IV, histologically-confirmed FL (grades 1, 2, and 3a) meeting criteria for therapy were eligible for the phase 1 part of the study. Additionally, FL patients were identified in the phase 2 portion of the study after central pathology review. These patients were allowed to complete therapy and were followed accordingly. Treatment consisted of 6 cycles of R2CHOP with lenalidomide given on days 1-10 and R-CHOP given in 21-day cycles. All patients received pegfilgrastim and aspirin (if not on anticoagulation) along with other supportive measures per provider discretion. Primary objectives were safety assessment and efficacy.
Results
Ten patients with FL (3 had grade 1, 3 had grade 2, and 4 had grade 3a) were enrolled in the R2CHOP phase 1/2 study at Mayo Clinic. One patient was in the phase 1 arm at dose level 2 (lenalidomide 20 mg/d) and 9 patients were in the phase 2 arm (lenalidomide 25 mg/d). The mean age was 60.8 years (range: 41-82). Eight out of ten patients were male; 5/10 had ECOG performance status of 0; 5/10 had an IPI score of intermediate or higher. All patients completed 6 cycles of planned treatment. One patient required lenalidomide dose adjustment due to toxicity. There were no lenalidomide dose interruptions. The overall response rate (ORR) was 100% and the complete response (CR) rate defined by PET imaging was 90%. Eight out of ten remain progression-free and 9/10 are alive at a median follow-up of 4.6 years (range: 2.1-5.3). Estimated progression-free survival (PFS) at 5 years was 79% (95% CI: 56-100%). The main toxicity was reversible myelosuppression with 80% treatment-related hematologic grade 3 or higher adverse events (AEs) (leukopenia 80%, neutropenia 80%, thrombocytopenia 40%, anemia 20%, transaminitis 20%). Rate of nonhematologic grade 3 or higher AEs was 20% (fatigue 10%, pneumonia 10%).
Conclusions
Frontline therapy with R2CHOP in patients with untreated FL appears to be effective and associated with acceptable toxicity. The observed PET-based CR rate and PFS were promising in this cohort. Whether R2CHOP is superior to lenalidomide/rituximab alone or standard bendamustine/rituximab will require randomized studies.
Figure Estimated PFS in FL patients treated with upfront R2CHOP. Figure. Estimated PFS in FL patients treated with upfront R2CHOP.

Disclosures
Reeder: Celgene: Research Funding; Novartis: Research Funding; BMS: Research Funding; Millennium: Research Funding. Foran:novartis: Honoraria; Millennium Pharmaceuticals, Inc.: Research Funding; pfizer: Honoraria; karyopharm: Honoraria; medscape: Honoraria; boehringer ingelheim: Research Funding; agios: Research Funding; Cellerant: Research Funding. Nowakowski:Bayer: Consultancy, Research Funding; Morphosys: Research Funding; Celgene: Research Funding.