|
Advertisement |
|
|
||
 |
|
|||||
|
|||||
|
 |
||||||
|
||||||
|
||||||
|
Originally published as JCO Early Release 10.1200/JCO.2008.18.2857 on September 8 2008 © 2008 American Society of Clinical Oncology.
Lenalidomide-Associated Tumor Flare Reaction Is Manageable in Patients With Chronic Lymphocytic Leukemia
Roswell Park Cancer Institute, Buffalo, NY To the Editor: In a case series published by Andritsos et al,1 the authors report on four patients with relapsed or refractory chronic lymphocytic leukemia (CLL) who were treated with lenalidomide at a starting dose of 25 mg/d on days 1 through 21 of each 28-day cycle. The authors highlight the adverse events observed in these patients, with particular focus on tumor flare reaction (TFR), and conclude that the toxicity with lenalidomide is unacceptable at the 25-mg dose. We observed and reported TFR first with thalidomide and then with lenalidomide.2,3 On the basis of our experience in 45 patients treated with lenalidomide for relapsed or relapsed/refractory CLL, we wish to comment specifically on drug efficacy and management of potential toxicities. Andritsos et al1 reported that all four patients in their series were treated with prophylactic corticosteroids for the first 14 days for prevention of TFR. The authors indicate further that three of four patients experienced severe TFR, which resulted in death in one patient. However, the patient who died is also described as having evidence of tumor lysis syndrome (TLS).1 The authors do not describe the grade of TFR or TLS, and it is difficult to interpret from the information recorded in the case report whether the TFR is the primary cause of death. Furthermore, the patient is reported to have a creatinine clearance of 45 mL/min at baseline. This is lower than the recommended level that is considered safe for 25-mg lenalidomide dosing and may have contributed to the enhanced toxicity observed in this patient. These data seem to contrast our experience (using a similar 25-mg dose of lenalidomide); we encountered TFR in 58% of patients (8% grade 3 or 4) with no associated deaths.2 The risk of TLS with the 25-mg dose has already been reported in a recent letter.4 In addition, we reported that TLS was observed in two of 29 patients treated with the 25-mg dose and was not observed in 16 patients treated with a lower (10 mg) starting dose that was subsequently escalated to 25 mg/d.2 This is consistent with the results of the study by Ferrajoli et al,5 which also used the lower 10-mg starting dose and did not observe TLS. Both of the patients who experienced TLS on our study had bulky disease, but maintained a creatinine clearance of more than 50 mL/min before initiating therapy with lenalidomide.2 Although the serum creatinine levels were elevated in both patients on admission for TLS (2.5 to 3.1 mg/dL), the levels returned to baseline (1.1 to 1.5 mg/dL) on discharge and resolution of TLS (1.0 to 1.7 mg/dL).
Although TFR was common in our study, it was manageable with nonsteroidal anti-inflammatory drugs. In fact, in our study, not only were there no deaths associated with TFR, but no patient discontinued lenalidomide therapy as a result of TFR. Nevertheless, as a result of the high incidence of TFR in the first 29 patients enrolled, corticosteroid prophylaxis and a lower lenalidomide starting dose (10 mg) were investigated in the subsequent 16 patients.2 Although we did not observe a lower incidence of TFR in these patients, the severity of the TFR was decreased compared with the first 29 patients (grade We also observed a higher incidence of clinical responses in patients who experienced TFR compared with patients who did not (60% v 40%, respectively), suggesting that occurrence of TFR may be related to lenalidomide efficacy in CLL patients (unpublished data). TFR is an interesting phenomenon that is unique to CLL patients treated with immune-modulating agents. Because TFR mimics disease progression, physicians need to be aware of this adverse effect and carefully monitor patients who are receiving lenalidomide therapy for TFR. Although we agree with the authors’ conclusion that a lower starting dose of lenalidomide with dose escalation seems to be safer in patients with CLL, we note that this has already been reported in the study by Ferrajoli et al.5 It is also supported by the 16 patients enrolled onto our study at this dose2 and is currently being evaluated in a large clinical study (CLL-001).4 In summary, our experience based on 45 patients indicates that, although the 25-mg dose of lenalidomide is frequently associated with TFR, the toxicity is manageable without discontinuation of therapy and it is not associated with death or unacceptable toxicity. 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: Asher A. Chanan-Khan, Celgene (C) Stock Ownership: None Honoraria: Asher A. Chanan-Khan, Celgene Research Funding: Asher A. Chanan-Khan, Celgene Expert Testimony: None Other Remuneration: None 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. Chanan-Khan A, Miller KC, Takeshita K, et al: Results of a phase 1 clinical trial of thalidomide in combination with fludarabine as initial therapy for patients with treatment-requiring chronic lymphocytic leukaemia (CLL). Blood 106:3348-3352, 2005 4. 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 5. Ferrajoli A, Lee B-N, Schlette EJ, et al: Lenalidomide induces complete and partial remissions in patients with relapsed and refractory chronic lymphocytic leukemia. Blood 111:5291-5297, 2008 6. Musial L, Miller KC, Tonelli A, et al: Low-dose prednisone decreases the severity but not the frequency of lenalidomide associated tumor flare reaction (TFR) in chronic lymphocytic leukemia (CLL) patients. Blood 108:11, 2006 (abstr 4987)
Related Correspondence
Related Reply
This article has been cited by other articles:
|
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
|
|
|||||||||||
|
|||||||||||
|
|
Copyright © 2008 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
|
2 TFR, 48% v 9%, respectively).
