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Blood, 1 June 2002, Vol. 99, No. 11, pp. 4247-4248
CORRESPONDENCE
To the editor:
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.
Eleonora Urbauer, Hannes Kaufmann, Thomas Nösslinger, Markus Raderer, and Johannes Drach
Correspondence: Johannes Drach, Vienna General Hospital,
Department of Internal Medicine I, Clinical Division of Oncology,
Waehringer Guertel 18-20, A-1090 Vienna, Austria; e-mail:
johannes.drach{at}akh-wien.ac.at
References
1.
Singhal S, Mehta J, Desikan R, et al.
Antitumor activity of thalidomide in refractory multiple myeloma.
N Engl J Med.
1999;341:1565-1571[Abstract/Free Full Text].
2.
Barlogie B, Desikan R, Eddlemon P, et al.
Extended survival in advanced and refractory multiple myeloma after single-agent thalidomide: identification of prognostic factors in a phase 2 study of 169 patients.
Blood.
2001;98:492-494[Abstract/Free Full Text].
3.
Zangari M, Anaissie E, Barlogie B, et al.
Increased risk of deep-vein thrombosis in patients with multiple myeloma receiving thalidomide and chemotherapy.
Blood.
2001;98:1614-1615[Abstract/Free Full Text].
4.
Osman K, Comenzo R, Rajkumar SV.
Deep vein thrombosis and thalidomide therapy for multiple myeloma.
N Engl J Med.
2001;344:1951-1952[Free Full Text].
5.
Dimopoulos MA, Zomas A, Viniou NA, et al.
Treatment of Waldenstrom's macroglobulinemia with thalidomide.
J Clin Oncol.
2001;19:3596-3601[Abstract/Free Full Text].
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