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To the Editor: The immunomodulatory drugs thalidomide and lenalidomide recently received US Food and Drug Administration approval for the treatment of multiple myeloma.^1-4 Venous thromboembolism (VTE) is a potentially serious complication associated with their use.^5-8 We conducted a systematic review of thromboembolism occurring with immunomodulatory drug treatment of cancer.

Methods
We reviewed incidents of thalidomide- or lenalidomide-associated VTE among patients with cancer that were reported to the US Food and Drug Administration's MEDWATCH; reported in phase 2/3 clinical trials presented at hematology/oncology conferences in the United States, Europe, and Australia; or reported as articles published between 1998 and July 2006. Databases searched included PubMed and online abstracts for national and international hematology or oncology conferences. MeSH terms included thalidomide, lenalidomide, deep vein thrombosis, thromboembolism, and pulmonary embolism. The case definition of VTE included deep vein thromboembolism or pulmonary embolism diagnosed with vascular flow studies, ultrasonography, computed tomography, or ventilation-perfusion scans.

Patients in all studies of a given treatment regimen were considered as representing a single sample. The proportion that developed VTE was calculated as the number of patients treated in each sample who developed VTE divided by the total number of patients in that sample. The 95% confidence interval for proportions for the likelihood of an event was calculated for each pooled sample using a Tozai ATC-828 manual scientific calculator. Institutional review board exemption was granted by Northwestern University.

Results
MEDWATCH included reports of 1118 thalidomide-treated patients and 8 lenalidomide-treated patients with VTE, of whom 254 (23%) and 6 (75%), respectively, had received anticoagulation therapy with warfarin, low-molecular-weight heparin, or aspirin prophylaxis. There were a total of 585 reports of VTE among 4862 thalidomide-treated patients (12%), and 110 among 1474 lenalidomide-treated patients (8%) reported in abstracts and articles that described phase 2 and phase 3 clinical trials or observational series. Prior to VTE, anticoagulation or aspirin prophylaxis had been administered to 15% of thalidomide-treated patients with multiple myeloma, 14% of thalidomide-treated patients with diseases other than multiple myeloma, and 12% of lenalidomide-treated patients with multiple myeloma. VTE rates were 27% (1 study) among patients with prostate cancer who received thalidomide-docetaxel, and a median of 13% (range, 0%-43%) among thalidomide-treated patients with renal cell cancer.

The majority of VTE reports were among patients with multiple myeloma, among whom VTE rates ranged from 0% to 40% (Table; further details of reports are available at http://www.pbm.va.gov/PBM/vamedsafe.htm). When prophylaxis was not administered, VTE rates reported in individual clinical trials were a median of 9% (range, 0%-26%) with thalidomide-dexamethasone; 12% (1 study) with thalidomide-doxorubicin; 22% (range, 10%-40%) with thalidomide-dexamethasone-doxorubicin; 14% (range, 3%-75%) with lenalidomide-dexamethasone; and less than 5% with thalidomide or lenalidomide monotherapy. With combined lenalidomide-dexamethasone, post hoc analysis in 1 study⁶ found thromboembolism rates that were 3-fold higher if erythropoietin was also administered (28% vs 9%; P=.02). VTE rates were 4% if low-dose dexamethasone (40 mg/week) was administered with lenalidomide, vs 18% if high-dose dexamethasone (40 mg on days 1-4, 9-12, and 17-20 repeated every 4 weeks) was used.^{1, 7} Among patients who received dexamethasone in conjunction with lenalidomide or thalidomide and who received prophylaxis with low-molecular-weight heparin, full-dose warfarin (international normalized ratio of 2 to 3), or aspirin, thromboembolism rates were frequently but not always less than 10%. In phase 3 clinical trials compared with the control arm, VTE rates with thalidomide treatment were 2- to 14-fold greater; with lenalidomide treatment, VTE rates were 2- to 9-fold greater.

View this table: [in this window] [in a new window] [as a PowerPoint slide]   Table. Pooled Venous Thromboembolism (VTE) Rates Among 4068 Thalidomide-Treated and 1081 Lenalidomide-Treated Patients With Multiple Myeloma*

Comment
High rates of VTE are observed when patients with multiple myeloma received thalidomide or lenalidomide in conjunction with dexamethasone, melphalan, or doxorubicin.^5-8 However, variability in sample sizes, tumor burden, concomitant chemotherapy, thromboembolism prophylaxis, and detection methods limit the precision of VTE rate estimates. In addition, untreated patients with multiple myeloma are at increased risk for VTE. Nonetheless, randomized trials have reported significantly higher VTE rates in patients receiving thalidomide- or lenalidomide-based therapy compared with standard therapies that include high-dose dexamethasone.

A black box warning was recently added to the package insert for thalidomide, indicating that patients with multiple myeloma who receive thalidomide-dexamethasone may benefit from concurrent thromboembolism prophylaxis or aspirin.⁴ A black box warning is also included in the package insert for lenalidomide indicating that lenalidomide-dexamethasone treatment for multiple myeloma is complicated by high rates of thromboembolism, the potential benefits of prophylactic anticoagulation or antiplatelet therapy are not known, and the decision to use prophylaxis should be made only after assessing an individual patient's underlying risk factors.³ Options for prophylaxis include low-molecular-weight heparin, therapeutic doses of warfarin, or daily aspirin,⁸ but clinical trials are needed to better define optimal strategies for the prevention of thrombosis.

Editor's Note: Due to potential conflict of interest, Dr Golub, JAMA’s Letters section editor, was not involved in the editorial evaluation or decision to publish this Research Letter.

Author Contribution: Dr Bennett had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.

Conception and Design: Bennett, Angelotta, Raisch.

Acquisition of Data: Bennett, Angelotta, Evens, Raisch.

Analysis and Interpretation of Data: Bennett, Angelotta, Yarnold, Evens, Zonder, Raisch, Richardson.

Drafting of the Manuscript: Bennett, Angelotta, Evens, Zonder, Raisch, Richardson.

Critical Revision of the Manuscript for Important Intellectual Content: Bennett, Angelotta, Yarnold, Evens, Zonder, Raisch, Richardson.

Statistical Analysis: Bennett, Yarnold.

Obtaining Funding: Bennett.

Administrative, Technical, or Material Support: Bennett, Angelotta.

Supervision: Bennett, Richardson.

Financial Disclosures: Dr Bennett reports being a consultant for Millennium. Dr Evens reports being on the advisory board/speakers' bureau of Genentech, IDEC, Sigma Tau, and Millennium. Dr Zonder reports being on the speakers' bureau for Celgene and Millennium. Dr Richardson reports being a member of the advisory board/speakers' bureau for Celgene and Millennium. No other authors reported disclosures.

Funding/Support: This study was supported in part by grants from the National Cancer Institute (1R01CA 102713-01 and 1K23 CA109613-01A1) and the Pattis Family Foundation.

Role of the Sponsors: The sponsors had no role in the design and conduct of the study; in the collection, management, analysis, and interpretation of the data; or in the preparation of the manuscript.

Previous Presentation: This work has been presented in part at poster sessions at the American Society of Clinical Oncology conference, June 2-6, 2006, Atlanta, Ga and the American Society of Hematology conference, December 10-13, 2005, Atlanta, Ga.

Acknowledgment: We acknowledge Martin Tallman, MD, Jayesh Mehta, MD, Seema Singhal, MD, Hau Kwaan, MD, PhD, June M. McKoy, MD, JD, MPH, Dennis P. West, PhD, Timothy Kuzel, MD, Steven M. Belknap, MD, and Steven Trifilio, RPh, all of Northwestern University, and Rita Jakiche, MS, of the VA Cooperative Studies Program for their assistance with study design, data interpretation, and report writing; Bart Barlogie, MD, PhD, and Johannes Drach, MD, of the University of Arkansas for their assistance with identification of study patients and analysis of thromboembolism prophylaxis results; Fran Cunningham, Pharm D, Bernie Good, MD, and Peter Glassman, MBBS, of the VA Healthcare System for their assistance with dissemination of the detailed reference list for this report on the VA MedSafe Project Web site; and Zehra Hussain of Swarthmore College for her assistance with abstracting and organizing data. None of the persons listed received compensation for their contributions.

Charles L. Bennett, MD, PhD, MPP
cbenne{at}northwestern.edu

Cara Angelotta, BA
Division of Hematology/Oncology

Paul R. Yarnold, PhD
Department of Emergency Medicine

Andrew M. Evens, DO, MS
Division of Hematology/Oncology
Northwestern University Feinberg School of Medicine
Chicago, Ill

Jeffrey A. Zonder, MD
Division of Hematology-Oncology
Karmanos Cancer Institute
Wayne State University
Detroit, Mich

Dennis W. Raisch, PhD
VA Cooperative Studies Program Clinical Research Pharmacy Coordinating Center
University of New Mexico
Albuquerque

Paul Richardson, MD
Division of Hematologic Malignancy
Dana-Farber Cancer Institute
Harvard Medical School
Boston, Mass

1. Richardson PG, Blood E, Mitsiades CS, et al. A randomized phase 2 study of lenalidomide therapy for patients with relapsed or relapsed and refractory multiple myeloma [published online ahead of print July 18, 2006]. Blood. 2006. http://www.bloodjournal.org/cgi/content/short/blood-2006-04-015909v1. Accessed September 15, 2006. 2. Dimopoulos M, Spencer A, Atfal M. Study of lenalidomide plus dexamethasone versus dexamethasone alone in relapsed or refractory multiple myeloma (MM): results of a phase 3 study (MM-010): American Society of Hematology. Blood. 2005;106:4050-4053. FREE FULL TEXT 3. US Food and Drug Administration Web site. Lenalidomide package insert. http://www.fda.gov/cder/foi/label/2006/021880s001.pdf. Accessed September 6, 2006.4. US Food and Drug Administration Web site. Thalidomide package insert. http://www.fda.gov/cder/foi/label/2006/021430s000,020785s031lbl.pdf. Accessed September 6, 2006.5. Bennett CL, Schumock GT, Desai AA, et al. Thalidomide-associated deep vein thrombosis and pulmonary embolism. Am J Med. 2002;113:603-606. FULL TEXT | ISI | PUBMED 6. Knight R, DeLap RJ, Zeldis JB. Lenalidomide and venous thrombosis in multiple myeloma. N Engl J Med. 2006;354:2079-2080. FREE FULL TEXT 7. Rajkumar SV, Blood E. Lenalidomide and venous thrombosis in multiple myeloma. N Engl J Med. 2006;354:2079-2080. FREE FULL TEXT 8. Zonder JA, Barlogie B, Durie BG, McCoy J, Crowley J, Hussein MA. Thrombotic complications in patients with newly diagnosed multiple myeloma treated with lenalidomide and dexamethasone: benefit of aspirin prophylaxis. Blood. 2006;108:403. FREE FULL TEXT

Letters Section Editor: Robert M. Golub, MD, Senior Editor.

JAMA. 2006;296:2558-2560.

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