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Tumor Lysis Syndrome/Tumor Flare Reaction in Lenalidomide-Treated Chronic Lymphocytic Leukemia

Celgene Corporation, Summit, NJ

To the Editor:

Lenalidomide is a novel immune modulating drug (IMiD) that has demonstrated impressive antitumor activity in previously treated multiple myeloma and International Prognostic Scoring System low-risk and intermediate-1 risk deletion 5q myelodysplastic syndromes. The antileukemic effects of lenalidomide in patients with relapsed or refractory chronic lymphocytic leukemia (CLL) were recently reported in two ongoing phase II studies.^1,2 In the first study by Chanan-Khan et al, lenalidomide was given orally with a cyclic 25-mg regimen (day 1 to 21 of a 28-day cycle) in 45 patients with relapsed or refractory CLL; the overall response rate (ORR) was 47% with 9% of the patients attaining complete remission. In the other study by Ferrajoli et al, oral lenalidomide was administered at 10 mg daily for 28 days and dose escalated up to a maximum of 25 mg daily, in 45 patients with relapsed CLL who had received at least one purine–analog based regimen. The first 35 patients assessable for response had an ORR of 38% with 9% attaining complete remission. In both studies notable adverse reactions included tumor flare reaction (TFR) and tumor lysis syndrome (TLS). In the study by Chanan-Khan et al, TFR occurred in 58% (grade 2, 50% and grade 3, 8%) and TLS in 5% (all grade 3) of the patients. Ferrajoli et al reported 37% of TFR (grade 2, 30% and grade 3, 7%) and no TLS.

We summarize here the development of TLS and TFR during lenalidomide therapy in CLL. TFR during lenalidomide therapy has been observed in CLL and small lymphocytic lymphoma (SLL). TFR occurs in the majority of lenalidomide-treated CLL patients, and is usually not severe and generally well managed with nonsteroidal anti-inflammatory agents or steroids.

Seven TLS episodes were observed among 260 CLL patients treated with lenalidomide to date. All seven patients had onset of TLS of varying severity during the first 15 days of treatment. Two patients also had concomitant TFR characterized by severe back and bone pain. TLS was complicated by acute renal failure and/or cardiac arrhythmia in three patients. Metabolic abnormalities and renal dysfunction resolved with supportive therapy in five patients; however, two patients died. Bulky disease, moderate renal insufficiency, and increased uric acid levels before therapy distinguished these seven patients from those who did not have TLS.

Due to these findings, Celgene Corporation (Summit, NJ) temporarily suspended enrollment to its sponsored CLL trial (CC-5013-CLL-001) and an independent data monitoring committee (DMC) reviewed the data. The DMC recommended that, given the evidence of lenalidomide's significant activity in CLL in this and other trials,^1,2,5 the CLL-001 study should continue, but with modifications to define a better-tolerated lenalidomide dosing regimen. The DMC noted that similar reactions occurred with other immune modulating agents in CLL.^3,4 The use of low-dose-intensity regimens at the initiation of therapy and aggressive TLS prophylaxis and monitoring decreased the incidence of TLS with these other therapies. The revised study will include; (1) a lower starting dose of lenalidomide followed by a closely monitored dose escalation scheme; (2) increased frequency of safety monitoring for TLS and TFR; (3) TLS prophylaxis with hydration and allopurinol; and (4) exclusion of patients with a history of renal failure requiring dialysis. When the study resumes, a small cohort of patients will be enrolled, and if the modified lenalidomide regimen is well tolerated, the study will be expanded.

Lenalidomide is not currently approved by any regulatory agency for CLL. Until adequate data are available from this amended trial and other ongoing experiences in CLL, treatment of CLL with lenalidomide outside of a well-monitored clinical trial is discouraged.

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: Laure A. Moutouh-de Parseval, Celgene Corporation (C); Lilia Weiss, Celgene Corporation (C); Robert J. DeLap, Celgene Corporation (C); Robert D. Knight, Celgene Corporation (C); Jerome B. Zeldis, Celgene Corporation (C), Celgene Corporation (C) Consultant or Advisory Role: None Stock Ownership: Laure A. Moutouh-de Parseval, Celgene Corporation; Lilia Weiss, Celgene Corporation; Robert J. DeLap, Celgene Corporation; Robert D. Knight, Celgene Corporation; Jerome B. Zeldis, Celgene Corporation Honoraria: None Research Funding: None Expert Testimony: Jerome B. Zeldis, Celgene Corporation (U) Other Remuneration: Jerome B. Zeldis, Celgene Corporation

REFERENCES

1. 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[Abstract/Free Full Text]

2. Ferrajoli A, O'Brien S, Faderl SH, et al: Lenalidomide is an active agent in relapsed and treatment-refractory chronic lymphocytic leukemia. Haematologica 92 , 2007 (suppl; abstr 363)

3. Yang H, Rosove MH, Figlin RA: Tumor lysis syndrome occurring after the administration of rituximab in lymphoproliferative disorders: High-grade non-Hodgkin's lymphoma and chronic lymphocytic leukemia. Am J Hematol 62 : 247 -250, 1999[CrossRef][Medline]

4. Byrd JC, Lin TS, Dalton JT, et al: Flavopiridol administered using a pharmacologically derived schedule is associated with marked clinical efficacy in refractory, genetically high-risk chronic lymphocytic leukemia. Blood 109 : 399 -404, 2007[Abstract/Free Full Text]

5. Ferrajoli A, O'Brien S, Faderl SH, et al: Lenalidomide induces complete and partial responses in patients with relapsed and treatment-refractory chronic lymphocytic leukemia (CLL). Blood 108 , 2006 (suppl; abstr 305)

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