Date Published: May 8, 2012
Publisher: Hindawi Publishing Corporation
Author(s): Agostino Cortelezzi, Mariarita Sciumè, Gianluigi Reda.
The application of nucleoside analogue-based chemotherapy and immunotherapy with rituximab or alemtuzumab has increased both response rate and survival in patients with Chronic Lymphocytic Leukemia (CLL). However, because none of these therapies is curative, sequential therapeutic regimens are required. The majority of patients with relapsed or refractory CLL carry poor prognostic factors and show shorter overall survival and resistance to standard treatment. Numerous drugs have recently been approved for CLL therapy and many novel agents are under clinical investigation. The role of the tumor microenvironment and of immune dysfunction in CLL have allowed to enlarge the therapeutic armamentarium for CLL patients. This article will provide a comprehensive summary regarding mechanism of action, efficacy and safety of lenalidomide in CLL patients. Relevant clinical trials using lenalidomide alone or in combinations are discussed. Lenalidomide shows good activity also in relapsed/refractory or treatment-naive CLL patients. Definitive data from ongoing studies are needed to validate overall and progression-free survival. The toxicity profile might limit lenalidomide use because it can result in serious side effects, but largely controlled by gradual dose escalation. Further understanding of the exact mechanism of action in CLL will allow more efficacious use of lenalidomide alone or in combination regimens.
Chronic lymphocytic leukemia (CLL) shows a remarkable heterogeneity in its clinical course, from long-term survival to fast progression and early death. Previously treated patients are known to have poor overall prognosis. In such cases, the disease almost invariably becomes resistant to various subsequent chemotherapies, leading to more toxicities and deterioration of quality of life.
The precise anti-CLL mechanism of action of lenalidomide is not yet completely defined. Potential mechanisms of action include antiangiogenic effect, blockade of protumor cytokines, inhibition of prosurvival interaction between bone-marrow stromal cells and CLL cells, and enhancement of T helper and cytotoxic T cells function .
Lenalidomide proved to be effective in CLL as single agents or in combination with various chemo immunotherapeutic regimens. There were several concerns regarding toxicity, but modified protocols with low starting dose and gradual dose escalation suggest good tolerability. Myelosuppression was the predominant toxicity associated with lenalidomide. Tumor flare was also a problem with lenalidomide therapy, but it can be controlled by gradual dose-escalation and prophylactic corticosteroids in the patients who experienced tumor flare in previous cycles. However, further studies are needed to establish the most effective dose and schedule of this agent.