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Lenalidomide for Relapsed Chronic Lymphocytic Leukemia Patients

Lenalidomide, given as a continuous daily oral dose, showed antitumor activity in one third of heavily pretreated CLL patients.

The application of nucleoside analogue–based chemotherapy and immunotherapy with rituximab or alemtuzumab has increased both response rates and duration in patients with chronic lymphocytic leukemia (CLL). However, because none of these therapies is curative, sequential therapeutic regimens are required.

In an industry-supported study of a potentially therapeutic agent, investigators tested the immunomodulatory drug lenalidomide (Revlimid) in relapsed CLL patients and correlated response with prognostic markers and plasma cytokine levels. The researchers evaluated 44 heavily pretreated patients (median number of prior therapies, 4; range, 1–5). Patients received lenalidomide on a continuous daily oral dosing schedule: A starting dose of 10 mg was increased by 5 mg every 28 days, based on patient tolerance.

Responses were achieved by 14 patients (32%), including 3 (7%) who had complete responses. Patients with poor-risk cytogenetics (17p or 11q) and those with unmutated immunoglobulin heavy-chain genes had overall response rates of 31% and 24%, respectively. Median plasma levels of interleukin (IL)-6, IL-10, soluble IL-2 receptor, and tumor necrosis factor receptor increased during therapy, suggesting immune activation. The median tolerable dose of lenalidomide was 10 mg; only three patients (7%) tolerated the maximum dose (25 mg) for 1 month. Grade 3–4 neutropenia and thrombocytopenia toxicities occurred in 41% and 16% of treatment courses, respectively. Two deaths from infections (pneumonia, disseminated mucormycosis) occurred during the first month of treatment, and one patient developed deep venous thrombosis. A previously reported tumor-flare reaction (painful adenopathy with fever or bone pain), observed with standard-dose lenalidomide in CLL (J Clin Oncol 2006; 24:5343), occurred in 12% of all patients in this study and in half the patients with bulky adenopathy. Patients who experienced tumor-flare reactions were treated with a short course of methylprednisolone.

Comment: Lenalidomide has a variety of biological activities, including immunomodulatory effects on T and natural killer cells, tumor microenvironment and cytokine modulation, and antiangiogenesis. However, any mechanisms of action relevant to CLL remain unknown. The authors postulate that immunomodulatory effects are of primary importance in responses to treatment, providing a rationale for continuous daily dosing. In a prior study (referenced above), when the myeloma dosing schedule of 25 mg daily for 21 days of each 28-day cycle was used to treat relapsed CLL with lenalidomide, a slightly higher overall response rate (47%) was achieved, but more patients experienced tumor-flare reactions, and some experienced tumor-lysis syndrome. In the present study, patients did not tolerate dose escalation above 10–15 mg/day when used in the continuous-dosing scheme. Taken together, these two phase II studies clearly support the activity of single-agent lenalidomide in heavily pretreated CLL patients. However, better understanding of lenalidomide’s mechanism of action and optimization of dose and schedule will be necessary before this agent can be safely integrated into current CLL therapeutic algorithms.

— Michael E. Williams, MD

Published in Journal Watch Oncology and Hematology July 8, 2008

Citation(s):

Ferrajoli A et al. Lenalidomide induces complete and partial remissions in patients with relapsed and refractory chronic lymphocytic leukemia. Blood 2008 Jun 1; 111:5291. (http://dx.doi.org/10.1182/blood-2007-12-130120)

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