Originally published as JCO Early Release 10.1200/JCO.2005.05.0401 on November 6 2006

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Clinical Efficacy of Lenalidomide in Patients With Relapsed or Refractory Chronic Lymphocytic Leukemia: Results of a Phase II Study

Asher Chanan-Khan, Kena C. Miller, Laurie Musial, David Lawrence, Swaminathan Padmanabhan, Kenichi Takeshita, Carl W. Porter, David W. Goodrich, Zale P. Bernstein, Paul Wallace, David Spaner, Alice Mohr, Catriona Byrne, Francisco Hernandez-Ilizaliturri, Cynthia Chrystal, Petr Starostik, Myron S. Czuczman

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

	ABSTRACT

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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.

	INTRODUCTION

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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 V_H 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 AND METHODS

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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
Pretreatment screening included recording medical history, physical examination, CBCs with differential, chemistry profile (including serum creatinine, blood urea nitrogen, electrolytes, albumin, calcium, phosphate, uric acid levels, lactic dehydrogenase, AST, and ALT), and bone marrow aspirate and biopsy. Zap-70 analysis was done by flow cytometry using the technique previously described by Crespo et al.²⁸ Fluorescent in situ hybridization was used to characterize cytogenetic abnormalities; for this commercially available (Vysis Inc, Des Plaines, IL) alpha-satellite centromeric and locus-specific probes for commonly reported cytogenetic abnormalities in B-CLL were used. The panel included probes for del(13)(q14.3), del(11)(q22.3), del(17)(p13.1), and 12 centromeres. Patients with 5% of cells with a specific abnormality were considered positive. Although an effort was made to obtain Zap-70 expression and florescent in situ hybridization on all patients, this was not mandatory. Treatment was offered to all eligible patients as per recommendations outlined by Cheson et al²⁷ in the NCI Working Group 1996 guidelines.

Study Design
This is a single-institution, nonrandomized phase II study. We anticipated that prolonged treatment with lenalidomide would be required to observe maximum clinical benefit, and therefore, a cytostatic response was defined. Thus, patients with complete response (CR), partial response (PR), or stable disease (SD) on monthly evaluations were classified as having a cytostatic response and were allowed to continue treatment. Treatment was continued until achievement of molecular CR or development of unacceptable toxicity. Minimal residual disease status was determined by polymerase chain reaction using previously described methodology.²⁹ Patients who demonstrated progressive disease (PD) at anytime or SD for 2 consecutive months had intravenous rituximab added to lenalidomide therapy. These patients were also assessed monthly for response and were allowed to continue therapy until PD or maximum treatment duration of 6 months.

Treatment Schema
Lenalidomide 25 mg orally was administered once a day for 21 days on a 28-day schedule. Allopurinol 300 mg daily was initiated 2 to 3 days before treatment and continued up to 14 days in all patients for prevention of tumor lysis syndrome (TLS).

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
All patients who received any therapy were assessable for toxicity. The NCI Common Toxicity Criteria (version 3.0) was used for toxicity assessment. Starting dose of lenalidomide was 25 mg/d, which was also the maximum dose permitted. Incremental (5-mg) dose reduction was allowed for toxicity. The minimum dose permitted was 5 mg/d. Patients who could not tolerate this dose were taken off study. All patients who experienced grade 3 toxicity were taken off the study drug until resolution to grade 2. For neutropenia and/or thrombocytopenia, specific predefined dose adjustment criteria were used, as follows.

Neutropenia. Dose was held for grade 4 or grade 3 with fever (temperature 38.5°C). Treatment was resumed at the same dose (with granulocyte colony-stimulating factor support, if needed) when neutropenia resolved to grade 2.

Thrombocytopenia. Dose was held for grade 4 thrombocytopenia (platelet count < 25,000/µL). Lenalidomide was restarted without dose reduction if thrombocytopenia resolved to grade 2. For recurrent grade 4 thrombocytopenia, dose was reduced by 5 mg in subsequent cycles.

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
Any patient who received treatment was included in the intent-to-treat group. Overall response includes only CR and PR. Because we anticipated that prolonged treatment with lenalidomide may be necessary to achieve maximum response, a cytostatic response (SD or better response) was defined and used only to calculate the sample size. Patients who are currently early in treatment may eventually shift the distribution of best responses. An exact one-stage design was used to accept or reject the null hypothesis of a 55% cytostatic response rate against an alternative hypothesis of a 75% cytostatic response rate with a power of 0.8.³⁰ The significance level was P = .1. The study was designed to accrue 45 patients. Clopper-Pearson CIs were calculated for rates and proportions.

Assessment of Response
Responses were assessed and reported using the revised 1996 NCI Working Group guidelines.²⁷ Response evaluation was performed after completing each monthly cycle and included CBC with differential, chemistry profile, and physical examination. Assessable patients must have completed at least 2 months of therapy and must have maintained a response for at least 2 months. As such, all inassessable patients were considered treatment failures. Clinical CR in all patients was confirmed with bone marrow aspirate and biopsy.

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).

	RESULTS

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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.

Toxicity
Toxicity is reported for all patients (n = 45) enrolled and treated (Table 3). Fatigue (83%) and flare reaction (58%) were the most common nonhematologic adverse events reported. Pulmonary embolism was noted in two patients (5%). Details of the most relevant toxicities are provided in the following sections.

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 50,000/µL in four patients. There were no bleeding episodes, and only one patient received prophylactic platelet transfusion for a platelet count of 10,000/µL. There was no correlation between baseline platelet counts and platelet response to lenalidomide. Figure 1 reflects the overall platelet kinetics among patients treated.

View larger version (11K): [in this window] [in a new window] [PowerPoint Slide for Teaching]   Fig 1. Effect on platelet counts in chronic lymphocytic leukemia patients treated with lenalidomide. Overall effect on platelet kinetics is represented as mean platelet count at each treatment week among patients who received treatment on this study.

View larger version (11K): [in this window] [in a new window] [PowerPoint Slide for Teaching]   Fig 2. Effect on absolute neutrophil counts (ANC) in chronic lymphocytic leukemia patients treated with lenalidomide. Overall effect on neutrophil kinetics is represented as mean ANC at each treatment week among patients who received treatment on this study.

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
Using an intent-to-treat analysis, major responses were seen in 21 patients (47%; 95% CI, 32% to 62%), with four patients (9%) achieving a CR and 17 (38%) achieving a PR (Table 5). Antitumor activity of lenalidomide was evident as early as day 8 of treatment with 24 (70.5%) of 34 patients demonstrating a decrease in their peripheral-blood ALC (Table 6). Clinical responses (CR or PR) were observed in 47% of the patients with del(11)(q23) and 40% of patients with bulky disease. The median PFS time has not been reached. There have been three disease progressions (at 2.5, 2.6, and 6.2 months from start of treatment) and one death. All three patients with PD achieved a PR when rituximab was added to lenalidomide. Four patients have had a PFS time of over 12 months. The estimated probability of PFS at 1 year is 0.81.

	DISCUSSION

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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 ( grade 2 in 6% v 31%, respectively) was noted with steroid prophylaxis. None of the patients received prophylaxis for venous thromboembolism (VTE), and we observed two episodes of VTE. Our observation suggests that the risk of VTE with lenalidomide is irrespective of the underlying disease investigated, thus requiring some form of prophylaxis with the use of this agent.

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.

	Authors’ Disclosures of Potential Conflicts of Interest

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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.

Authors Employment Leadership Consultant Stock Honoraria Research Funds Testimony Other Asher Chanan-Khan Celgene Corporation Celgene Corporation Celgene Corporation Kena C. Miller Celgene Corporation Swaminathan Padmanabhan Celgene Corporation Kenichi Takeshita Celgene Corporation Celgene Corporation Zale P. Bernstein Celgene Corporation Celgene Corporation Catriona Byrne Celgene Corporation Celgene Corporation Cynthia Chrystal Celgene Corporation Celgene Corporation

	Author Contributions

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Conception and design: Asher Chanan-Khan, Kenichi Takeshita, Catriona Byrne, Cynthia Chrystal Administrative support: Asher Chanan-Khan Provision of study materials or patients: Kena C. Miller, Swaminathan Padmanabhan, Zale P. Bernstein, David Spaner, Alice Mohr, Francisco Hernandez-Ilizaliturri, Myron S. Czuczman Collection and assembly of data: Asher Chanan-Khan, Kena C. Miller, Laurie Musial, Paul Wallace Data analysis and interpretation: David Lawrence, Paul Wallace, Petr Starostik Manuscript writing: Asher Chanan-Khan, Kenichi Takeshita, Carl W. Porter, David W. Goodrich, Petr Starostik Final approval of manuscript: Asher Chanan-Khan Other: Kena C. Miller, Laurie Musial, Swaminathan Padmanabhan, Zale P. Bernstein, David Spaner, Alice Mohr, Myron S. Czuczman [Conducted trial], Catriona Byrne, Cynthia Chrystal [Regulatory and clinical trial assistance]

 

	ACKNOWLEDGMENTS

 
We thank Todd Hyde for clinical trial support and Deborah Donaldson for assistance in preparation of the manuscript.

	NOTES

 
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.

	REFERENCES

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Submitted November 22, 2005; accepted September 26, 2006.

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