|
Advertisement |
|
|
||
 |
|
|||||
|
|||||
|
 |
||||||
|
||||||
|
||||||
|
Originally published as JCO Early Release 10.1200/JCO.2005.05.0401 on November 6 2006 © 2006 American Society of Clinical Oncology. Clinical Efficacy of Lenalidomide in Patients With Relapsed or Refractory Chronic Lymphocytic Leukemia: Results of a Phase II Study
From the Departments of Medicine, Pharmacology and Therapeutics, Biostatistics, and Pathology, Roswell Park Cancer Institute, Buffalo, NY; Celgene Corporation, Summit, NJ; and Toronto Sunnybrook Regional Cancer Center, Toronto, Ontario, Canada Address reprint requests to Asher Chanan-Khan, MD, Department of Medicine, Roswell Park Cancer Institute, Elm and Carlton St, Buffalo, NY 14263; e-mail: asher.chanan-khan{at}roswellpark.org
PURPOSE: Patients with relapsed or refractory chronic lymphocytic leukemia (CLL) have profound immune defects and limited treatment options. Given the dramatic activity of lenalidomide in other B-cell malignancies and its pleotropic immunomodulatory effects, we conducted a phase II trial of this agent in CLL. PATIENTS AND METHODS: Patients with relapsed or refractory B-cell CLL (B-CLL) were eligible if they required treatment as per the National Cancer Institute Working Group 1996 guidelines. Lenalidomide was administered orally at 25 mg on days 1 through 21 of a 28-day cycle. Response was assessed after each cycle. Patients were to continue treatment until disease progression, unacceptable toxicity, or complete remission. Rituximab was added to lenalidomide on disease progression. RESULTS: Forty-five patients were enrolled, with a median age of 64 years. Sixty-four percent of the patients had Rai stage III or IV disease, and 51% were refractory to fludarabine. The overall response rate was 47%, with 9% of the patients attaining a complete remission. Fatigue, thrombocytopenia, and neutropenia were the most common adverse effects noted in 83%, 78%, and 78% of the patients, respectively. CONCLUSION: Lenalidomide is clinically active in patients with relapsed or refractory B-CLL. These findings are encouraging and warrant further investigation of this agent in the treatment of this disorder.
Chronic lymphocytic leukemia (CLL), the most common hematologic malignancy in the Western hemisphere, remains incurable.1 Patients with symptomatic disease have compromised survival ranging from 1.5 to 6 years and require treatment.1,2 Acceptable initial therapeutic options include fludarabine, alkylating agents (chlorambucil or cyclophosphamide), or their combination with the anti-CD20 monoclonal antibody rituximab.3-5 Several phase II clinical trials have demonstrated improved clinical responses when chemotherapy is combined with monoclonal antibodies,4-6 one retrospective analysis demonstrated an improvement in progression-free survival (PFS) and possibly overall survival.7 All patients eventually experience disease relapse, and there are limited treatment options, especially for patients who are refractory to fludarabine. Recent advances have brought new insight into CLL biology; specific genetic features such as del(17)(p13.1), del(11)(q22.3), p53 mutation, and unmutated Ig VH genes can now identify patients with clinically aggressive disease and suboptimal responses to current treatments.8 Also, the evolving understanding of the role of tumor cell microenvironment in the pathogenesis of CLL is leading to promising new therapeutic avenues.9-16 Several aberrant cytokine networks have been reported that support growth and survival of the malignant CLL clone. CLL cells not only produce but also express cell surface receptors for these prosurvival cytokines such as tumor necrosis factor alpha and vascular endothelial growth factor, forming an autocrine growth-promoting signaling network.17-19 Also, increased production of some cytokines, such as interleukin-10, has an immunosuppressive effect on T cells. Thus, the malignant cytokine microenvironment supports prolonged CLL cell survival, immune evasion, and resistance to therapy. Interrupting these prosurvival effects of the malignant cytokine microenvironment is a potential new approach in treating patients with CLL. Lenalidomide, a thalidomide analog, is an immunomodulating drug (IMiDs) with antitumor activity reported in various malignant disorders including multiple myeloma and myelodysplastic syndrome (MDS).20-24 Two phase III studies in myeloma and one randomized phase II study in MDS resulted in approval of lenalidomide by the US Food and Drug Administration. Preclinically, lenalidomide has demonstrated the ability to decrease the production of several prosurvival cytokines, including tumor necrosis factor alpha, vascular endothelial growth factor, and interleukin-6. Lenalidomide is also reported to modulate an immune effector cell response through activation of the T and natural killer cells25 and directly induce apoptosis in tumor cells.26 These properties encouraged us to investigate the antileukemic effects of lenalidomide in patients with relapsed or refractory B-cell CLL (B-CLL). Results of this phase II clinical trial are presented here.
Patients All patients were enrolled and treated at Roswell Park Cancer Institute (Buffalo, NY) on an institutional review board–approved clinical study. All patients gave written informed consent. Patients with an immunophenotypically confirmed diagnosis of B-CLL, who either had Rai stage III or IV disease or required treatment for Rai stage I or II disease as defined in the National Cancer Institute (NCI) 1996 guidelines were eligible.27 Eligible patients must have received at least one prior therapy and have experienced relapse after or have been refractory to the last therapy. Entry criteria included the following: age  18 years, Eastern Cooperative Oncology Group performance status of  2, absolute neutrophil count 1.5 x 109/L, platelet count 30 x 109/L, serum creatinine 1.5 mg/dL, total bilirubin 1.5 mg/dL, and ALT and AST 2x upper limit of normal. Patients must not have received any therapy for B-CLL within 4 weeks before initiating treatment on this study.
Pretreatment Evaluation
Study Design
Treatment Schema As a result of occurrence of TLS in two of the first 29 patients, the treatment protocol was revised to allow slow dose escalation in subsequent patients enrolled (n = 16). In these patients, lenalidomide was started at 5 mg and escalated by 5 mg every 1 to 2 weeks (maximum of 25 mg). For patients receiving combination therapy, lenalidomide was administered at the same schedule, whereas rituximab (375 mg/m2) was administered intravenously on days 1, 8, and 15 of combination cycle 1 and on days 1 and 15 of combination cycles 2 to 6.
Toxicity Assessment and Management
Neutropenia.
Dose was held for grade 4 or grade 3 with fever (temperature
Thrombocytopenia.
Dose was held for Flare reaction. Flare reaction clinically presents with sudden onset of tender enlargement of the lymph nodes and/or spleen associated with low-grade fever and/or rash. Some patients can experience an increase in WBCs. Flare reaction was treated with a nonsteroidal anti-inflammatory agent (ibuprofen 400 mg orally every 6 hours for the duration of the reaction). Treatment was not stopped or dose reduced for flare reaction. Note that no prophylaxis was used in the first 29 patients. Subsequent patients (n = 16) received prophylaxis with prednisone (20 mg orally for 7 days followed by 10 mg for 7 days).
Statistical Analysis
Assessment of Response Patients who achieved SD or a better response remained on the treatment protocol until disease progression, unacceptable toxicity, or achievement of molecular CR. Patients achieving a CR who had persistent disease determined by either flow cytometry or polymerase chain reaction were allowed to continue therapy until clearance of minimal residual disease. After completion of treatment, patients were re-evaluated at 1 month and then at 3-month intervals with complete restaging as mentioned earlier (except bone marrow aspirate/biopsy).
Patients were accrued from September 2004 through May 2006. Baseline characteristics of these patients are listed in Table 1, and information regarding prior treatments is listed in Table 2.
Forty-five patients were enrolled, and 29 are assessable for response. Median age was 64 years (range, 42 to 75 years), and advanced Rai stage (III or IV) disease was noted in 64%. The median number of prior therapies given was three (range, one to 10 therapies), with 51% of the patients refractory to fludarabine (Table 2).
Toxicity
Fatigue. Fatigue was reported in 13 patients (29%) on study entry and in 33 patients (73%) during the study. Grade 3 or 4 fatigue was noted in four patients (10%); two had complete resolution within 2 months of initiating therapy, and two continue to have fatigue while on study drug. There was no correlation between fatigue and the flare reaction. Dose was not reduced or held in any patient for fatigue.
Thrombocytopenia.
Grade 3 or 4 thrombocytopenia was observed in 45% of the patients. Twenty-nine patients (64%) had thrombocytopenia before starting therapy. However, among the patients with baseline thrombocytopenia, thrombocytopenia improved in 18 patients (62%) and worsened in 11 patients (38%) after the first cycle. A more than 50% decrease in platelet counts from baseline was noted in four patients (9%), with absolute counts
Neutropenia. The incidence of grade 3 or 4 neutropenia was 70%, with six episodes of febrile neutropenia (Table 3). Treatment was held until resolution of neutropenia, as described previously, and granulocyte colony-stimulating factor was used at the treating physician’s discretion. Figure 2 reflects the neutrophil kinetics during treatment.
TLS. Two patients had TLS. One patient with stage III bulky disease presented with fever at day 9 of cycle 1. Laboratory work-up demonstrated hyperuricemia, hyperphosphatemia, uremia, and renal failure (Table 4), consistent with grade 3 TLS. This patient was discharged after 4 days with complete resolution of TLS. During the second cycle, lenalidomide dose was reduced (15 mg). Grade 3 TLS was again noted at day 7 of treatment and lasted 12 days with complete resolution at time of discharge. This patient (with a pre-existing cardiac disease) subsequently developed congestive heart failure (while off lenalidomide for 25 days) and died of cardiac causes.
The second patient had stage IV bulky disease with a baseline absolute lymphocyte count of 339 cells/µL. On day 9 of cycle 1, this patient presented with shortness of breath, peripheral edema, generalized weakness, sweating, fever, and tachycardia. Laboratory work-up showed hyperuricemia, hyperphosphatemia, uremia, and worsening serum creatinine. He was discharged after 7 days with complete resolution of TLS (Table 4). Flare reaction. Overall incidence of flare reaction was 58%, with 8% of patients having grade 3 or 4. Onset was usually within 24 hours of the first dose, with a median duration of 14 days. Except in two patients, flare reaction was only noted during the first cycle. The initial 29 patients did not receive any prophylaxis, and on development of the flare reaction, ibuprofen was used for treatment; however, few patients required additional oral morphine for pain control. The high incidence of flare reaction prompted us to investigate oral prednisone for prophylaxis in the subsequent 16 patients enrolled. None of the patients (with or without the prophylaxis) required interruption, discontinuation, or dose reduction of therapy because of flare reaction. No obvious predisposing clinical features could be identified to predict development of the flare reaction. We also could not establish any correlation with either the extent of disease or response to therapy.
Response
Inassessable Patients Twelve patients were inassessable for response. Among these patients, five withdrew consent, and seven could not complete two cycles as a result of toxicity (two because of thrombocytopenia, one because of pulmonary embolism, one because of pulmonary pneumonitis, two because of neutropenia, and one died, as mentioned earlier).
The IMiDs, thalidomide and lenalidomide, are clinically active antitumor compounds.20,23,24,31,32 Three clinical trials investigated the role of thalidomide in patients with CLL.33-35 In treatment-naïve patients, we reported enhanced efficacy of fludarabine when combined with thalidomide compared with historical control.33 In contrast, Furman et al34 noted only a modest activity of this combination in the relapsed or refractory CLL population. The role of single-agent thalidomide was investigated by Kay et al,35 who did not observe any major responses except disease stabilization in 71% of the patients. The results of this study demonstrate for the first time that the immunomodulating agent lenalidomide is clinically active in CLL. From a relatively large phase II cohort, we demonstrate that 47% of patients attain a PR or CR to lenalidomide after use of this therapy. Antileukemic effects were noted as early as 7 days of therapy, with incremental responses with extended therapy. As an oral therapy, administration of lenalidomide was, in general, well tolerated and associated with typical side effects seen with many therapeutics used in the treatment of refractory CLL. Although neutropenia and thrombocytopenia were observed in a subset of patients, neither opportunistic nor bacterial infections were problematic in this heavily pretreated group of patients. Collectively, these data provide strong support for further pursuit of lenalidomide in confirmatory phase II studies and in combination with other agents currently used to treat CLL.
The antitumor activity of lenalidomide noted in this study is exciting; however, the hematologic toxicity observed remains a concern at the 25-mg starting dose. This was also the most common reason for dose reduction, with 14 patients (31%) requiring dose modification during the course of therapy. Slow dose escalation resulted in improved tolerability and suggests a better way to deliver this agent. We observed three episodes of possible TLS. The clinical and laboratory features in these cases were confounding and may be a result of renal failure, precluding a definitive diagnosis. Another unusual but common side effect noted with lenalidomide was the flare reaction. Although this was commonly seen during the first cycle, awareness of this phenomenon is important as it mimics disease progression. We were able to effectively manage the flare reaction with nonsteroidal agents and, in some cases, with more potent analgesics. Our experience with the use of steroid prophylaxis is limited to small population of patients. Although we did not observe a decrease in the incidence of the flare reaction among patients treated with or without prophylaxis (81% v 83%, respectively), a definite decrease in the severity of flare reaction ( There are many potential impacts of our novel observation regarding lenalidomide single-agent activity in B-CLL. Given that this therapy represents an oral therapeutic with demonstrable efficacy, confirmation of our data in a large phase II study is warranted. Additionally, the dose and schedule of administration of lenalidomide is derived from MDS and multiple myeloma studies emphasizing consideration of pursuing alternative schedules of administration. Given the high responses observed when an alternative IMiD, thalidomide, was combined with fludarabine, combination studies with other agents active in CLL should be considered. Finally, the immune-activating properties of lenalidomide make it an attractive therapeutic to add to rituximab, and this approach is currently being pursued by our group.
Although all authors completed the disclosure declaration, the following authors or their immediate family members indicated a financial interest. No conflict exists for drugs or devices used in a study if they are not being evaluated as part of the investigation. 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.
We thank Todd Hyde for clinical trial support and Deborah Donaldson for assistance in preparation of the manuscript.
published online ahead of print at www.jco.org on November 6, 2006. Supported by Celgene Corporation, Summit, NJ. Presented in part at the XI International Workshop on Chronic Lymphocytic Leukemia, September 16–18, 2005, Brooklyn, NY; the 47th Annual Meeting of the American Society of Hematology, December 10–13, 2005, Atlanta, GA; and the 41st Annual Meeting of the American Society of Clinical Oncology, May 13–17, 2005, Orlando, FL. Authors’ disclosures of potential conflicts of interest and author contributions are found at the end of this article.
1. Rai KR, Sawitsky A, Cronkite EP, et al: Clinical staging of chronic lymphocytic leukemia. Blood 46:219-234, 1975 2. Binet JL, Lepoprier M, Dighiero G, et al: A clinical staging system for chronic lymphocytic leukemia: Prognostic significance. Cancer 40:855-864, 1977[CrossRef][Medline] 3. Rai KR, Peterson BL, Appelbaum FR, et al: Fludarabine compared with chlorambucil as primary therapy for chronic lymphocytic leukemia. N Engl J Med 343:1750-1757, 2000 4. Byrd JC, Peterson BL, Morrison VA, et al: Randomized phase 2 study of fludarabine with concurrent versus sequential treatment with rituximab in symptomatic, untreated patients with B-cell chronic lymphocytic leukemia: Results from Cancer and Leukemia Group B 9712 (CALGB 9712). Blood 101:6-14, 2003 5. Keating MJ, O’Brien S, Albitar M, et al: Early results of a chemoimmunotherapy regimen of fludarabine, cyclophosphamide, and rituximab as initial therapy for chronic lymphocytic leukemia. J Clin Oncol 23:4079-4088, 2005 6. Wierda W, O’Brien S, Wen S, et al: Chemoimmunotherapy with fludarabine, cyclophosphamide, and rituximab for relapsed and refractory chronic lymphocytic leukemia. J Clin Oncol 23:4070-4078, 2005 7. Byrd JC, Rai K, Peterson BL, et al: Addition of rituximab to fludarabine may prolong progression-free survival and overall survival in patients with previously untreated chronic lymphocytic leukemia: An updated retrospective comparative analysis of CALGB 9712 and CALGB 9011. Blood 105:49-53, 2005[Medline] 8. Byrd JC, Gribben JG, Peterson BL, et al: Select high-risk genetic features predict earlier progression following chemoimmunotherapy with fludarabine and rituximab in chronic lymphocytic leukemia: Justification for risk-adapted therapy. J Clin Oncol 24:437-443, 2006 9. Bartik MM, Welker D, Kay NE: Impairments in immune cell function in B cell chronic lymphocytic leukemia. Semin Oncol 25:27-33, 1998[Medline] 10. Gorgun G, Holderried TA, Zahrieh D, et al: Chronic lymphocytic leukemia cells induce changes in gene expression of CD4 and CD8 T cells. J Clin Invest 115:1797-1805, 2005[CrossRef][Medline] 11. Caligaris-Cappio F, Hamblin TJ: B-cell chronic lymphocytic leukemia: A bird of a different feather. J Clin Oncol 17:399-408, 1999 12. Hoffbrand AV, Panayiotidis P, Reittie J, et al: Autocrine and paracrine growth loops in chronic lymphocytic leukemia. Semin Hematol 30:306-317, 1993[Medline] 13. Lagneaux L, Delforge A, Bron D, et al: Chronic lymphocytic leukemic B cells but not normal B cells are rescued from apoptosis by contact with normal bone marrow stromal cells. Blood 91:2387-2396, 1998 14. Panayiotidis P, Jones D, Ganeshaguru K, et al: Human bone marrow stromal cells prevent apoptosis and support the survival of chronic lymphocytic leukaemia cells in vitro. Br J Haematol 92:97-103, 1996[CrossRef][Medline] 15. van Kooten C, Rensink I, Aarden L, et al: Cytokines and intracellular signals involved in the regulation of B-CLL proliferation. Leuk Lymphoma 12:27-33, 1993[Medline] 16. Trentin L, Zambello R, Agostini C, et al: Expression and regulation of tumor necrosis factor, interleukin-2, and hematopoietic growth factor receptors in B-cell chronic lymphocytic leukemia. Blood 84:4249-4256, 1994 17. Waage A, Espevik T: TNF receptors in chronic lymphocytic leukemia. Leuk Lymphoma 13:41-46, 1994[Medline] 18. Kay NE: The angiogenic status of B-CLL B cells: Role of the VEGF receptors. Leuk Res 28:221-222, 2004[CrossRef][Medline] 19. Kay NE, Bone ND, Tschumper RC, et al: B-CLL cells are capable of synthesis and secretion of both pro- and anti-angiogenic molecules. Leukemia 16:911-919, 2002[CrossRef][Medline] 20. List A, Kurtin S, Roe DJ, et al: Efficacy of lenalidomide in myelodysplastic syndromes. N Engl J Med 352:549-557, 2005 21. Tohnya TM, Ng SS, Dahut WL, et al: A phase I study of oral CC-5013 (lenalidomide, Revlimid), a thalidomide derivative, in patients with refractory metastatic cancer. Clin Prostate Cancer 2:241-243, 2004[Medline] 22. Barlogie B: Thalidomide and CC-5013 in multiple myeloma: The University of Arkansas experience. Semin Hematol 40:33-38, 2003[CrossRef][Medline] 23. Bartlett JB, Michael A, Clarke IA, et al: Phase I study to determine the safety, tolerability and immunostimulatory activity of thalidomide analogue CC-5013 in patients with metastatic malignant melanoma and other advanced cancers. Br J Cancer 90:955-961, 2004[CrossRef][Medline] 24. Richardson PG, Schlossman RL, Weller E, et al: Immunomodulatory drug CC-5013 overcomes drug resistance and is well tolerated in patients with relapsed multiple myeloma. Blood 100:3063-3067, 2002 25. Mitsiades CS, Mitsiades N: CC-5013 (Celgene). Curr Opin Investig Drugs 5:635-647, 2004[Medline] 26. Dredge K, Horsfall R, Robinson SP, et al: Orally administered lenalidomide (CC-5013) is anti-angiogenic in vivo and inhibits endothelial cell migration and Akt phosphorylation in vitro. Microvasc Res 69:56-63, 2005[CrossRef][Medline] 27. Cheson BD, Bennett JM, Grever M, et al: National Cancer Institute-sponsored Working Group guidelines for chronic lymphocytic leukemia: Revised guidelines for diagnosis and treatment. Blood 87:4990-4997, 1996 28. Crespo M, Bosch F, Villamor N, et al: ZAP-70 expression as a surrogate for immunoglobulin-variable-region mutations in chronic lymphocytic leukemia. N Engl J Med 348:1764-1775, 2003 29. Trainor KJ, Brisco MJ, Wan JH, et al: Gene rearrangement in B- and T-lymphoproliferative disease detected by the polymerase chain reaction. Blood 78:192-196, 1991 30. Korn EL, Arbuck SG, Pluda JM, et al: Clinical trial designs for cytostatic agents: Are new approaches needed? J Clin Oncol 19:265-272, 2001 31. Bartlett JB, Tozer A, Stirling D, et al: Recent clinical studies of the immunomodulatory drug (IMiD) lenalidomide. Br J Cancer 93:613-619, 2005[CrossRef][Medline] 32. Rajkumar SV, Hayman SR, Lacy MQ, et al: Combination therapy with lenalidomide plus dexamethasone (Rev/Dex) for newly diagnosed myeloma. Blood 106:4050-4053, 2005 33. 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 leukemia (CLL). Blood 106:3348-3352, 2005 34. Furman R, Leonard J, Allen S, et al: Thalidomide alone or in combination with fludarabine are effective treatments for patients with fludarabine-relapsed and refractory CLL. J Clin Oncol 24:595s, 2005 (suppl; abstr 6640) 35. Kay N, Geyer S, Yaqoob I, et al: Thalidomide (Td) treatment in chronic lymphocytic leukemia (CLL): A North Central Cancer Treatment Group (NCCTG) Study. Blood 102:5162a, 2003 (abstr) Submitted November 22, 2005; accepted September 26, 2006. Related Correspondence
This article has been cited by other articles:
|
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
|
|
|||||||||||
|
|||||||||||
|
|
Copyright © 2006 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
|
<
TOP
ABSTRACT
INTRODUCTION
