Thromboembolic events during treatment with thalidomide

Thalidomide has been shown to be an active agent in multiple myeloma (MM), particularly in patients with advanced and chemotherapy-refractory disease.1,2 Due to its activity as a single agent, thalidomide is now being evaluated in combination therapy regimens, either with dexamethasone or polychemotherapy. Recently, Zangari et al reported on an increased risk of deep-vein thrombosis in patients with MM who were treated by a combination of thalidomide and polychemotherapy consisting of dexamethasone, vincristine, doxorubicin, cyclophosphamide, etoposide, and cisplatin.3 Deep-vein thrombosis developed in 14 of 50 patients (28%), with all thrombotic events being observed during the first 3 cycles of chemotherapy.

As is also reported by another group,4 we would like to confirm the observation of thromboembolic events in patients with MM receiving thalidomide plus chemotherapy. We have performed a phase 2 trial in advanced and chemotherapy refractory MM, in which thalidomide is combined with DCEP polychemotherapy (dexamethasone 40 mg orally, cyclophosphamide 300 mg/m², etoposide 30 mg/m², and cisplatin 15 mg/m² as continuous infusion; all drugs were administered on days 1-4, and cycles were repeated on day 35 for a maximum of 4 cycles). Thalidomide was initiated at 100 mg/d with weekly dose escalations to a maximum of 300 mg/d, which is also continued as maintenance therapy following DCEP. Among 14 patients on this protocol, 3 patients (21%) developed deep-vein thrombosis (1 patient with associated pulmonary embolism). Similar to the report by Zangari et al,3 1 patient experienced the thrombotic event prior to the second cycle of DCEP, but in the remaining 2 patients deep-vein thrombosis developed during maintenance therapy with thalidomide (29 weeks and 24 weeks, respectively, after start of therapy, corresponding to 14 weeks and 9 weeks, respectively, after completion of DCEP chemotherapy).

Because thalidomide is also being evaluated in other hematologic malignancies including non-Hodgkin lymphoma,5 we would like to report that deep-vein thrombosis and pulmonary embolism is not only restricted to patients with MM receiving thalidomide. We have initiated a phase 2 trial in patients with mantle cell lymphoma who relapsed after or did not respond to standard chemotherapy (cyclophosphamide, vincristine, and prednisone [CHOP]). Treatment consists of 4 weekly infusions with the anti-CD20 monoclonal antibody rituximab (375 mg/m²), which is concomitantly administered with thalidomide (starting dose 200 mg/d, with a dose escalation to 400 mg/d) followed by thalidomide maintenance. Two of 10 patients entered thus far on this protocol experienced a thrombotic event: in one patient, deep-vein thrombosis occurred just one week after the final infusion of rituximab; in the second patient, pulmonary embolism was diagnosed during a routine follow-up examination at week 20 when a thoracic computer tomography scan revealed thrombotic material in the pulmonary artery of the right lower lobe. This patient did not have any clinical sign or symptom of pulmonary embolism. The thrombotic events were not related to presence of a central venous catheter. During the study period, 8 patients with relapsed mantle cell lymphoma were treated with rituximab alone, but in none of these patients was venous thromboembolism observed.

In all patients reported here, occurrence of the thrombotic event was not associated with disease progression, and thalidomide could be safely readministered after appropriate anticoagulation therapy. We believe it is important to consider deep-vein thrombosis as an adverse event that may occur late in a treatment program combining thalidomide with other antineoplastic agents. Thromboembolic events associated with thalidomide do not appear to be specific for MM, which should be taken into account when thalidomide is administered to patients with other malignant disorders, in particular solid tumors, who already have a substantially increased risk of deep-vein thrombosis.