Thalidomide- and Lenalidomide-Associated Thromboembolism Among Patients With 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.

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.