The emerging role of lenalidomide in the management of mantle cell lymphoma (MCL).

Mantle cell lymphoma (MCL) is considered an aggressive and incurable B-cell malignancy despite current available treatments that include the incorporation of rituximab, bortezomib, high-dose cytarabine, and for those eligible, high dose chemotherapy and autologous bone marrow transplant (HDC-ASCT). Patients with relapsed/refractory MCL represent a challenge for the treating physician stressing the need to develop therapeutic agents. Lenalidomide, a novel inmmunomodulatory drug (IMiD), is a promising therapeutic strategy for patients with relapsed/refractory B-cell lymphoma. Biologically, the mechanisms responsible for lenalidomide activity are yet to be clearly defined. Based on pre-clinical models and early correlative studies conducted parallel to clinical trials, lenalidomide has been found to enhance NK-cell and T-cell activity against tumor cells, alter the balance of pro- and anti-inflammatory cytokines in the tumor bed, inhibit angiogenesis, and to a lesser degree, induce cell cycle arrest and apoptosis in cancer cells. Together, all these biological effects appear to play a role in the activity observed in lymphoma patients treated with lenalidomide. Given the effect in NK- and T-cell function, lenalidomide is an alternative strategy to enhance the anti-tumor activity of monoclonal antibodies (mAbs). Clinical responses have been observed in patients with relapsed/refractory chronic lymphocytic leukemia (CLL), follicular lymphoma, small lymphocytic lymphoma, diffuse large B-cell lymphoma (DLBCL), and MCL. The favorable toxicity profile and route of administration made the use of lenalidomide an attractive therapy for certain types of patients (i.e. elderly, chemotherapy unfit, etc.). The erratic but serious incidence of tumor lysis syndrome and/or tumor flare reactions provides challenges in the incorporation of lenalidomide in the management of previously untreated lymphoma patients with bulky adenopathy. Early studies evaluating the efficacy and toxicity of lenalidomide in combination with steroids or rituximab/bendamustine in MCL are promising and warrant further study. In addition, the evaluation of lenalidomide in the maintenance setting (i.e. post HDC-ASCT) or in combination with other target specific agents (i.e. proteasome inhibitors) in MCL is being addressed in ongoing clinical trials. We provide a general overview of the clinical development of lenalidomide in MCL. Future translational and clinical studies will further define the role of lenalidomide in the management of de novo or relapsed/refractory MCL and may assist in the identification of subset of MCL patients most likely to gain clinical benefit from this exiting agent.