Phase I Study of Escalating Doses of Lenalidomide Combined with R-CHOP (R2-CHOP) for Front-Line Treatment of B-Cell Lymphomas

Abstract 1632

R-CHOP is the standard front-line treatment for most patients (pts) with B-cell lymphoma. Single-agent studies of lenalidomide in relapsed/refractory lymphoma have demonstrated a significant activity in both indolent and aggressive lymphomas. We conducted a phase I study to determine the recommended dose of lenalinomide when given in combination with R-CHOP-21 for patients with previously untreated CD20+ B-cell lymphoma.

Pts received oral lenalidomide on days 1–14 with R-CHOP (rituximab 375 mg/m2, cyclophosphamide 750 mg/m2, doxorubicin 50 mg/m2, vincristine 1.4 mg/m2, all on day 1, prednisone 100 mg/m2 days 1–5) given every 3 weeks for 6 cycles. Lenalidomide dose was increased from 5 mg to 25 mg (5 mg per dose level), using a 3+3 escalation design. Pegfilgrastim was administered on day 4 and oral aspirin prophylaxis (100 mg) was given daily during the treatment. Maximum tolerated dose was determined by the number of dose limiting toxicities (DLT) during the first 2 cycles. DLT was defined as grade 3 or more nonhematological toxicity, grade 3 hematological toxicity lasting more than 7 days, or grade 4 hematological toxicity lasting more than 3 days.

Twenty-seven pts were enrolled in the study from January 2009 to June 2010. Eighteen pts had follicular lymphoma, 4 pts diffuse large B-cell lymphoma, 3 pts mantle cell lymphoma and 2 pts indolent B-cell lymphoma. Twenty-five pts had a disseminated disease. Two hematological DLTs were observed in 6 pts of the 20mg cohort allowing escalating the dose to 25mg. At this dose, 2 DLTs occurred (1 hepatic, 1 hematological) in 6 pts, during the first two cycles. Therefore, 25mg was considered as the recommended dose and that cohort was expanded to a total of 12 patients. Hematological toxicity was the most frequent adverse event with 59% grade 3–4 neutropenia (7 % of patients with grade 3 or 4 febrile neutropenia) and 30% grade 3–4 thrombocytopenia. Grade 1–2 peripheral neurotoxicity was observed in 48% of the pts and was not related to a particular lenalidomide dose level. No grade 3–4 neurotoxicity occurred. One patient had pulmonary embolism of moderate severity and one patient has a deep vein thrombosis. lenalidomide was stopped in five pts due to toxicity according to protocol defined criteria. Six pts experienced delay in the administration of R2-CHOP. No death occurred on study. Complete remission (CR + CRu) was observed in 20 pts and 6 pts had PR. One patient with follicular lymphoma had rapid progression after the fifth cycle of R2-CHOP.

The combination of 25mg of lenalidomide during 14 days with 21-day R-CHOP cycles has an acceptable safety profile in patients with B-cell lymphoma. A phase 2 study of the combination in patients with high burden follicular lymphoma is now ongoing.