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

Abstract

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 purineanalog 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 Յ 2, 50% and grade Ն 3, 8%) and TLS in 5% (all grade 3) of the patients. Ferrajoli et al reported 37% of TFR (grade Յ 2, 30% and grade Ն 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 antiinflammatory 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 TL...

Lenalidomide-induced upregulation of CD80 on tumor cells correlates with T-cell activation, the rapid onset of a cytokine release syndrome and leukemic cell clearance in chronic lymphocytic leukemia

“…[4][5][6][7]17 A major concern in CLL has been the occurrence of tumor flare reactions, the etiology of which is not understood. Here, we provide an explanation for the exacerbated reaction to lenalidomide in CLL.…”

“…3 Significant morbidity and fatal adverse events have been attributed to tumor flare reaction, often in conjunction with tumor lysis syndrome. 4,5 Based on these observations, clinical trials have been modified to include lower starting doses and close monitoring. In contrast, lenalidomide 30 mg daily in multiple myeloma and 25 mg daily in relapsed or refractory aggressive non-Hodgkin's lymphoma has not caused tumor flare reaction or tumor lysis syndrome.…”

Approaches to Managing Safety With Lenalidomide in Hematologic Malignancies

“…Tumor lysis syndrome was seen in 7/260 CLL patients (3%) receiving lenalidomide in a review of the Celgene Corporation database conducted in 2007, with all cases developing during the first 15 days of treatment (Moutouh-de Parseval et al, 2007). Acute renal failure and/or cardiac arrhythmia were seen in 3/7 patients.…”

“…Patients had a median age of 65 years; 69% had bulky lymphadenopathy (> 5 cm), and 48% had high-risk genomic abnormalities. Four serious cases of TLS were observed in the first 18 patients, leading to a protocol amendment to identify the maximum tolerated dose (MTD, defined as the highest dose of a treatment that does not cause unacceptable side effects) escalation level with lower initial lenalidomide, added TLS prophylaxis, increased TLS/TFR monitoring, and the exclusion of any patients with severe renal dysfunction, who were defined as those having a history of renal failure that required dialysis (Moutouh-de Parseval, Weiss, DeLap, Knight, & Zeldis, 2007). Dose escalation from 2.5 mg/day lenalidomide, increasing in 5-mg increments every 28 days, achieved safe titration to 20 mg/day without reaching the MTD (Wendtner et al, 2012b).…”

The Treatment of Relapsed Refractory Chronic Lymphocytic Leukemia

“…24 Furthermore, administration of lenalidomide to this patient population can be challenging, requiring initiation at a very low dose and slow escalation to avoid potentially life-threatening tumor flare reactions. 25,26 Significant myelosuppression is also often dose limiting; in the final report of the CLL-001 study presented at ASH 2010, 73% of relapsed/refractory patients were unable to escalate lenalidomide above 5 mg/d, and the ORR was 12%. 27 These results suggest some efficacy of lenalidomide in this patient population, but poor tolerability in many patients and, again, no long-term control of the disease.…”