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Originally published as JCO Early Release 10.1200/JCO.2008.18.3400 on September 8 2008 © 2008 American Society of Clinical Oncology.
In Reply:
Department of Internal Medicine, Division of Hematology and Oncology, Comprehensive Cancer Center, The Ohio State University, Columbus, OH
Department of Internal Medicine, Division of Hematology and Oncology, and Division of Medicinal Chemistry, College of Pharmacy, Comprehensive Cancer Center, The Ohio State University, Columbus, OH The unacceptable toxicities seen in all four chronic lymphocytic leukemia (CLL) patients treated with lenalidomide at a starting dose of 25 mg/d at The Ohio State University, combined with our laboratory investigation of this agent to understand the drug-induced tumor flare observed, prompted our report in Journal of Clinical Oncology.1 All four patients treated at The Ohio State University met National Cancer Institute criteria for treatment and, therefore, would have met eligibility criteria for the trial reported previously by Chanan-Khan et al.2 Chanan-Khan et al raise the important point that the patient in our report1 who died had a creatinine clearance of less than 60 mL/min, a factor now recognized to potentially increase the toxicity of lenalidomide. This patient did have a component of tumor lysis; however, the proximate cause of his demise was a dramatic rapid tumor expansion documented on laboratory and imaging studies as well as postmortem examination. Therefore, he died of complications directly attributable to tumor flare. A previous letter in Journal of Clinical Oncology on tumor lysis and tumor flare authored by Moutouh-de Parseval et al3 and referred to by Chanan-Khan et al provides little detail in describing the primary events that occurred in these patients. Moreover, the actual frequency of early death as a result of rapid disease progression, which might represent tumor flare, was unclear. Insurance of patient safety in clinical trials and in related care that might be applied off study, based on published phase II reports when protocol options are not available, is a public health issue. Our report1 provides a warning that lenalidomide tumor flare and other toxicities seen at the 25-mg/d starting dose can be severe and provides caution that the ideal dose and schedule of this exciting agent in CLL are yet to be determined. The findings in this report are not in isolation; a second study in previously untreated CLL patients by Chen et al4 also demonstrated that the 25-mg/d dose initially reported by Chanan-Khan et al2 is associated with excessive toxicity including a patient death. Likewise, on the basis of recommendations from an independent data safety monitoring committee, Celgene (Summit, NJ) has significantly modified the starting dose of the CLL-01 trial,3 which Chanan-Khan et al refer to in their letter, as a result of safety concerns of tumor flare and tumor lysis. Outside of the important warning regarding the potential toxicity of lenalidomide at high dose, our report provides laboratory evidence that B-cell activation of the tumor cell may contribute to development of tumor flare in vivo.1 At the present time, it is uncertain whether development of tumor flare is necessary for response to lenalidomide in CLL; Ferrajoli et al5 suggest that it is not because they did not note an association of improved response with the development of tumor flare. Likewise, it is unclear whether corticosteroids or other means to reduce tumor flare might blunt clinical response to lenalidomide. Additionally, a recent publication has demonstrated that lenalidomide also activates T cells in vivo from patients with CLL.6 Sorting out the contributing roles of B-cell activation, T-cell activation, and other innate immune effector cells to the mechanism of action of lenalidomide is of great importance. At the present time, the use of lenalidomide should be limited to clinical trials with a starting dose less than the 25-mg/d dose initially reported by Chanan-Khan et al2 so that the experience observed can be applied to improve the safety and efficacy of this agent as it matures as a potential alternative therapy for CLL. AUTHORS’ DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST Although all authors completed the disclosure declaration, the following author(s) indicated a financial or other interest that is relevant to the subject matter under consideration in this article. Certain relationships marked with a "U" are those for which no compensation was received; those relationships marked with a "C" were compensated. For a detailed description of the disclosure categories, or for more information about ASCO's conflict of interest policy, please refer to the Author Disclosure Declaration and the Disclosures of Potential Conflicts of Interest section in Information for Contributors. Employment or Leadership Position: None Consultant or Advisory Role: Leslie A. Andritsos, Celgene (U); Thomas S. Lin, Celgene (C); John C. Byrd, Celgene (U) Stock Ownership: None Honoraria: None Research Funding: William Blum, Celgene Expert Testimony: None Other Remuneration: None ACKNOWLEDGMENTS Supported by the National Cancer Institute (Grant No. P01 CA95426; CLL Research Consortium Grant No. P01 CA81534-02), The Leukemia and Lymphoma Society, and The D. Warren Brown Foundation. NOTES published online ahead of print at www.jco.org on September 8, 2008 REFERENCES
1. Andritsos LA, Johnson AJ, Lozanski G, et al: Higher doses of lenalidomide are associated with unacceptable toxicity including life-threatening tumor flare in patients with chronic lymphocytic leukemia. J Clin Oncol 26:2519-2525, 2008 2. Chanan-Khan A, Miller KC, Musial L, et al: Clinical efficacy of lenalidomide in patients with relapsed or refractory chronic lymphocytic leukemia: Results of a phase II study. J Clin Oncol 24:5343-5349, 2006 3. Moutouh-de Parseval LA, Weiss L, DeLap RJ, et al: Tumor lysis syndrome/tumor flare reaction in lenalidomide-treated chronic lymphocytic leukemia. J Clin Oncol 25:5047, 2007 4. Chen CI, Harminder P, Mariela P, et al: A phase II study of lenalidomide in previously untreated, symptomatic chronic lymphocytic leukemia (CLL). Blood 110:2042, 2007 (abstr) 5. Ferrajoli A, Keating MJ, Wierda WG, et al: Lenalidomide is active in patients with relapsed/refractory chronic lymphocytic leukemia (CLL) carrying unfavorable chromosomal abnormalities. Blood 110:754, 2007 (abstr) 6. Ramsay AG, Johnson AJ, Lee AM, et al: Chronic lymphocytic leukemia T cells show impaired immunological synapse formation that can be reversed with an immunomodulating drug. J Clin Invest 118:2427-2437, 2008[Medline]
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Copyright © 2008 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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