The thrombosis happened in a combo trial with dexamethasone.
Here's the NEJM letter:
Volume 344:1951-1952 June 21, 2001 Number 25
Deep Venous Thrombosis and Thalidomide Therapy for Multiple Myeloma
To the Editor: Thalidomide is effective for the treatment of refractory myeloma.1 Its role in the initial treatment of the disease is under active investigation.2,3 We report the occurrence of deep venous thrombosis with the use of thalidomide in combination with other active agents in patients with newly diagnosed myeloma.
We initiated a phase 2 trial of treatment with thalidomide, doxorubicin, and dexamethasone in previously untreated patients with symptomatic stage 2 or 3 myeloma at the Memorial Sloan-Kettering Cancer Center. The trial was supported by Celgene, which manufactures thalidomide. Thalidomide was administered orally at a dose of 100 mg for 2 weeks, and the dose was then increased to 200 mg; doxorubicin (36 mg per square meter of body-surface area) was administered as an intravenous bolus on the first day of each 28-day cycle, and dexamethasone (40 mg per day) was given daily on days 1 through 4, 9 through 12, and 17 through 20 of each cycle. We planned a total of four cycles of therapy with this regimen. As of February 2001, we had enrolled 15 patients, and symptomatic deep venous thrombosis had developed in 4 of the 15 (27 percent). The incidence of deep venous thrombosis was much higher than we had previously noted in the treatment of patients with newly diagnosed myeloma, and therefore, in February 2001, the trial was suspended. At that time, five patients could be evaluated, all of whom had responses to the study regimen. One had a complete response, three had very good partial responses, and one had a partial response.
A separate phase 2 trial of thalidomide and dexamethasone for the treatment of patients with newly diagnosed myeloma is ongoing at the Mayo Clinic. As of February 2001, 45 patients had been enrolled in the study, and 3 (7 percent) had had thrombotic events. Two patients had documented deep venous thrombosis; acute dyspnea developed in the third patient, who died within an hour in a hospital emergency room, with a clinical diagnosis of pulmonary embolism.
Arterial thrombosis and venous thrombosis after thalidomide therapy have been reported in a case series of five patients: four with lupus erythematosus and one with severe atopic dermatitis.4 Thalidomide is an effective and important agent in the treatment of myeloma. Given the frequency of thrombotic events, however, we do not recommend combining thalidomide with other chemotherapeutic agents in patients with newly diagnosed myeloma outside of approved clinical trials. A safe dose and schedule of administration should be established, and a clearer understanding of the thrombophilia obtained.
Keren Osman, M.D.
Raymond Comenzo, M.D.
Memorial Sloan-Kettering Cancer Center
New York, NY 10021
The following abstract I found suggests this may be specifically related to the combination:
Thromb Haemost 1992 Jul 6;68(1):69-73
Inhibition of fibrinolytic activity in-vivo by dexamethasone is counterbalanced by an inhibition of platelet aggregation.
van Giezen JJ, Jansen JW.
Solvay Duphar B. V., Dept. Vascular Pharmacology, Weesp, The Netherlands.
Dexamethasone decreases the fibrinolytic activity in cultured medium of several cell types by an induction of PAI-1 synthesis. As a result of this enhanced PAI-1 synthesis a prothrombotic state is expected in patients treated with dexamethasone. However, such a prothrombotic state is not reported as a major adverse effect. We have studied the effects of dexamethasone (dose range: 0.1-3.0 mg/kg) on the fibrinolytic system of rats after a 5 day pretreatment period. It appeared that dexamethasone dose dependently decreased the fibrinolytic activity (a dose of 1 mg/kg showed a reduction of about 40%). This reduced fibrinolytic activity could be functionally translated into an increased thrombus size as measured with a venous thrombosis model: thrombus size was increased by 50% with 1 mg/kg dexamethasone. No effects could be measured on the coagulation system, but it appeared that ex-vivo measured platelet aggregation was dose dependently inhibited by dexamethasone treatment. This effect resulted in-vivo in prolonged obstruction times as measured with a modified aorta-loop model. These results indicate that the expected prothrombotic state due to a diminished fibrinolytic activity caused by dexamethasone is counterbalanced by an inhibition of platelet aggregation.
I lightened up a little near the open, but I still hold some.
Peter |
