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

Background Dual translocation of MYC and BCL2 or the dual overexpression of these proteins in patients with aggressive B‐cell lymphomas (termed double‐hit lymphoma [DHL] and double‐expressor lymphoma [DEL], respectively) have poor outcomes after chemoimmunotherapy with the combination of rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R‐CHOP). Retrospective reports have suggested improved outcomes with dose‐intensified regimens. In the current study, the authors conducted a phase 1 study to evaluate the feasibility, toxicity, and preliminary efficacy of adding lenalidomide to dose‐adjusted etoposide, prednisone, vincristine, cyclophosphamide, and doxorubicin with rituximab (DA‐EPOCH‐R) in patients with DHL and DEL. Methods The primary objective of the current study was to determine the maximum tolerated dose of lenalidomide in combination with DA‐EPOCH‐R. A standard 3+3 design was used with lenalidomide administered on days 1 to 14 of each 21‐day cycle (dose levels of 10 mg, 15 mg, and 20 mg). Patients attaining a complete response after 6 cycles of induction therapy proceeded to maintenance lenalidomide (10 mg daily for 14 days every 21 days) for 12 additional cycles. Results A total of 15 patients were enrolled, 10 of whom had DEL and 5 of whom had DHL. Two patients experienced dose‐limiting toxicities at a lenalidomide dose of 20 mg, consisting of grade 4 sepsis. The maximum tolerated dose of lenalidomide was determined to be 15 mg. The most common nonhematologic grade ≥3 adverse events included thromboembolism (4 patients; 27%) and hypokalemia (2 patients; 13%) (toxicities were graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events [version 4.0]). The preliminary efficacy of the regimen was encouraging, especially in the DEL cohort, in which all 10 patients achieved durable and complete metabolic responses with a median follow‐up of 24 months. Conclusions The combination of lenalidomide with DA‐EPOCH‐R appears to be safe and feasible in patients with DHL and DEL. These encouraging results have prompted an ongoing phase 2 multicenter study. The current phase 1 trial of lenalidomide added to the combination of dose‐adjusted etoposide, prednisone, vincristine, cyclophosphamide, and doxorubicin with rituximab (DA‐EPOCH‐R) in patients with double‐hit lymphoma and diffuse large B‐cell lymphoma with dual overexpression of MYC and BCL2 identified 15 mg of lenalidomide as the recommended phase 2 d