Lenalidomide Has Activity in CLL
Abstract & Commentary
By Andrew Artz, MD, Division of Hematology/Oncology, University of Chicago, Chicago, IL. Dr. Artz reports no financial relationship to this field of study.
Synopsis: Lenalidomide is an immunomodulatory oral thalidomide derivate with activity in a variety of hematologic malignancies. Ferrajoli and colleagues explored lenalidomide at a starting dose of 10mg daily without interruption for relapsed and refractory CLL. Among 44 patients, 25% achieved a PR and 7% achieved a CR for an overall response rate of 32%. Best responses occurred on average 6 to 9 months after initiation. Myelosuppresion was the most common toxicity. Lenalidomide has activity in advanced CLL warranting further exploration.
Source: Ferrajoli A, et al. Lenalidomide induces complete and partial remissions in patients with relapsed and refractory chronic lymphocytic leukemia. Blood. 2008;vol. 111:5291-5297.
Fludarabine based chemotherapy regimens show considerable and often prolonged responses for chronic lymphocytic leukemia (CLL). Unfortunately, once the disease relapses, especially after a short interval, the prognosis is poor and effective treatment options limited. Lenalidomide is an oral thalidomide derivate possessing immunomodulatory activity and potently inhibits tumor necrosis-factor alpha.1 Lenalidomide has shown robust responses in multiple myeloma and 5q minus myelodysplastic syndrome.2,3 The drug may also have activity in CLL.4 The mechanism of activity remains poorly understood but may include both immunomodulation and inhibition of angiogenesis.
Ferrajoli and colleagues analyzed 44 patients enrolled on a phase II trial of lenalidomide for relapsed and refractory CLL. Lenalidomide started at 10 mg daily and was escalated by 5 mg increments as tolerated. Partial remissions occurred in 25% and CR in 7% for an overall response rate of 32% with the time to best response ranging from 6 to 9 months. The median follow-up was 14 months. None of the patients achieving CR relapsed during this follow-up. Further evidence of activity arose from the finding that 46% of patients had a 50% decrease in the lymphocyte count. The response rate was 31% for those with adverse prognostic factors of deletions of 11q23 and/or 17 p. The median tolerable dose was 10 mg with only 3 patients able to tolerate 25 mg daily. Intolerance was primarily related to myelosuppression as neutropenia occurred in 41% of treatment courses. One deep venous thrombosis occurred in a patient also receiving an erythropoietin stimulating agent. Tumor flare developed in 12% of patients but was not predictive of response.
Commentary
Purine analogues such as fludarabine or pentostatin combined with cyclophosphamide and/or rituximab induce high response rates as initial therapy in chronic lymphocytic leukemia (CLL). Some patients cannot tolerate these myelosuppressive regimens and require less immunosuppressive therapy. Nevertheless, relapsed or refractory disease usually develops and subsequently, treatment options rarely enable long-term disease control.5
Lenalidomide is an emerging therapy and has activity in lymphoid malignancies. Previously, Chanan-Khan demonstrated that lenalidomide can induce responses in relapsed and refractory CLL 4. Among 45 patients dosed at 25 mg daily for 3 out of 4 weeks, the overall response rate of 47%, and 9% achieved CR. However, 70% of patients experienced grade 3 to 4 neutropenia. This report of approximately the same number of patients from MD Anderson Cancer Center tested an initial dose of 10 mg daily without interruption in similar patients. They found an overall response rate of 32% and CR rate of 7%. The time to best response was 6 to 9 months, indicating that a prolonged course should be given if tolerated. Although dose escalation was planned, neutropenia in 41% of courses as well as other cytopenias prevented dose escalation or resulted in dose reductions; ultimately, 10 mg daily was the median dose administered. Interestingly, both of these series showed that tumor flare reactions can occur with lenalidomide, although they were much less frequent in the present series compared to the report by Chanan-Khan.
Taken together, lenalidomide certainly has activity in relapsed and refractory CLL. Questions of optimal initial dosing and whether to use intermittent or continuous therapy will have to be addressed. Determining the role of lenalidomide requires studies comparing lenalidomide to other treatments (eg, alemtuzumab). Lenalidomide's unique mechanism of action and suggestion of activity in poor-risk patients raises interest in combination therapy both for initial therapy and relapsed disease. Even more interesting may be lenalidomide as maintenance therapy since responses are slow but could be maintained with continuous dosing. These are exciting times as numerous other treatments have shown promise for CLL such as flavopiridol, oblimerson, and newer monoclonal antibodies.6,7 Add one more drug to the growing arsenal of potential treatments for CLL.
References
1. Hideshima T, et al. Thalidomide and its analogs overcome drug resistance of human multiple myeloma cells to conventional therapy. Blood. 200;96:2943-2950.
2. List A, et al. Efficacy of lenalidomide in myelodysplastic syndromes. N Engl J Med. 2005;352:549-557.
3. Dimopoulos M, et al. Lenalidomide plus dexamethasone for relapsed or refractory multiple myeloma. N Engl J Med. 2007;357:2123-2132.
4. Chanan-Khan A, et al. Clinical efficacy of lenalidomide in patients with relapsed or refractory chronic lymphocytic leukemia: results of a phase II study. J Clin Oncol. 2006;24:5343-539.
5. Tam CS, et al. Long term results of the fludarabine, cyclophosphamide & rituximab regimen as initial therapy of chronic lymphocytic leukemia. Blood. 2008.
6. O'Brien S, et al. Randomized phase III trial of fludarabine plus cyclophosphamide with or without oblimersen sodium (Bcl-2 antisense) in patients with relapsed or refractory chronic lymphocytic leukemia. J Clin Oncol. 2007;25:1114-1120.
7. Byrd JC, et al. Treatment of relapsed chronic lymphocytic leukemia by 72-hour continuous infusion or 1-hour bolus infusion of flavopiridol: results from Cancer and Leukemia Group B study 19805. Clin Cancer Res. 2005;11:4176-4181.
Lenalidomide is an immunomodulatory oral thalidomide derivate with activity in a variety of hematologic malignancies. Ferrajoli and colleagues explored lenalidomide at a starting dose of 10mg daily without interruption for relapsed and refractory CLL.You have reached your article limit for the month. Subscribe now to access this article plus other member-only content.
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