Background: The last decade witnessed the emergence of several therapeutic options for patients with chronic lymphocytic leukemia (CLL) for first-line and relapsed settings. The vast majority of patients with relapsed or refractory CLL carry poor prognostic features, which are strong predictors of shorter overall survival and resistance to first-line treatment, particularly fludarabine-based regimens. Methods: This article highlights the current role of immunomodulatory drugs (IMiDs) and active immunotherapy as treatment options for this select group. The rationale of using IMiDs is discussed from the perspective of lenalidomide as a novel active agent. Relevant clinical trials using IMiDs alone or in combinations are discussed. New immunotherapeutic experimental approaches are also described. Results: As a single agent, lenalidomide offers an overall response rate of 32% to 47% in patients with relapsed/ refractory disease. Recent studies have shown promising activity as a single agent in treatment-naive patients. The combination of lenalidomide with immunotherapy (rituximab and ofatumumab) has also shown clinical responses. Encouraging preclinical and early clinical data have been observed with different immunotherapeutic approaches. Conclusions: The use of IMiDs alone or in combination with immunotherapy represents a treatment option for relapsed/refractory or treatment-naive patients. Mature data and further studies are needed to validate overall and progression-free survival. The toxicity profile of lenalidomide might limit its use and delay further studies. Immunotherapy offers another potential alternative, but further understanding of the immunogenicity of CLL cells and the mechanisms of tumor flare reaction is needed to improve the outcomes in this field.
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