Lenalidomide, a novel immunomodulatory
drug (IMiD), is a promising therapeutic strategy for patients with relapsed/refractory
chronic lymphocytic leukemia (CLL) and
B-cell lymphomas. Biologically, the mechanisms responsible for
lenalidomide activity are yet to be clearly defined. Based on preclinical models and early correlative studies conducted in parallel to clinical trials,
lenalidomide has been found to enhance natural killer (NK)- 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 of these
biological effects appear to play a role in the activity observed in CLL or
lymphoma patients treated with
lenalidomide. Given the effect in NK- and T-cell function,
lenalidomide is an alternative strategy to enhance the antitumor activity of
monoclonal antibodies (mAbs). Clinical responses have been observed in patients with relapsed/refractory CLL,
follicular lymphoma,
small lymphocytic lymphoma,
mantle cell lymphoma (MCL), and
diffuse large B-cell lymphoma (DLBCL) treated with
lenalidomide single agent. 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 CLL or CLL/
lymphoma patients with bulky
adenopathy. Correlative studies and/or retrospective analysis of
lenalidomide-treated patients had identified several
biomarkers associated with clinical endpoints in CLL (i.e. changes in
tumor necrosis factor alpha [TNF-α] or
vascular endothelial growth factor [
VEGF] levels) or DLBCL (non-GCB phenotype) patients, but need to be validated. Early studies evaluating the efficacy and toxicity of
lenalidomide in combination with
rituximab in previously untreated indolent
lymphoma are promising and warrant further study. In addition, the evaluation of
lenalidomide in the maintenance setting or in combination with other target-specific agents (i.e.
proteasome inhibitors) in aggressive
lymphomas is being addressed in ongoing clinical trials. In summary,
lenalidomide is emerging as a biologically active and novel agent in the treatment of B-cell
neoplasms. Future translational and clinical studies will further define the role of
lenalidomide in the management of de novo or relapsed/refractory CLL or
B-cell lymphomas and identify the subset of patients most likely to gain clinical benefit.