SHORT REPORT

Thromboembolic events in patients with myelodysplastic

syndrome receiving thalidomide in combination

with darbepoietin-alpha

Michael Steurer, Irene Sudmeier, Reinhard Stauder and Gunther Gastl Division of Haematology and

Oncology, Innsbruck University Hospital, Innsbruck, Austria

Received 19 November 2002; accepted for publication 11 December 2002

Summary. A phase II trial was conducted to explorethe efficacy and tolerability of combining thalidomide(100 mg/d p.o.) with an erythropoietic growth factor (dar-bepoietin-alpha 2Æ25 lg/kg/d s.c.) in patients with low-to-intermediate-risk myelodysplastic syndromes (MDS).However, the trial had to be discontinued early because of anunexpectedly high incidence of thromboembolic events. Ofthe first seven patients enrolled, two developed deep-veinthrombosis and one died of massive pulmonary embolism. We

concluded that thalidomide might significantly increase thethromboembolic risk of erythropoietic proteins in MDSpatients. Careful clinical surveillance and thrombosisprophylaxis (heparin or oral anticoagulation) should beconsidered for MDS patients undergoing combined treatmentwith thalidomide and erythropoietic growth factors.

Keywords: myelodysplastic syndrome, thalidomide, darbe-poietin, thrombosis.

Thalidomide appears to be a promising new agent for thepalliative treatment of myelodysplastic syndromes (MDS).Several phase II trials point to its efficacy as a single drug(Raza et al, 2001; Musto et al, 2002; Strupp et al, 2002).As enhanced and premature apoptosis within the clonalerythropoietic precursor cell compartment represents amajor pathogenic event for MDS, there is a soundrationale for combining thalidomide with erythropoieticgrowth factors. Notably, about 20–30% of patients withlow-risk MDS respond to erythropoietin alone (Rose et al,1995). Based on these data, we designed a phase II trial inwhich thalidomide was co-administered with darbepoie-tin-alpha in patients with low-to-intermediate-risk MDSaccording to the International Prognostic Scoring System(IPSS). Darbepoetin-alpha is a novel, highly sialylatederythropoiesis-stimulating protein with prolonged serumhalf-life and increased in vivo biological activity whencompared with recombinant human erythropoietin (Smith,2002).

Recently, the thrombogenic potency of thalidomide hasbeen described as a major complication in patients withmultiple myeloma (Cavo et al, 2002; Zangari et al,2002), non-Hodgkin’s lymphoma (Urbauer et al, 2002)

and renal cell carcinoma (Escudier et al, 2002) receiv-ing concomitant chemotherapy. In contrast with thesemalignancies, MDS per se is not associated with an ele-vated risk for thromboembolic events. We herein describea thrombophilic disorder induced by combination therapywith thalidomide and darbepoietin-alpha in patients withMDS.

PATIENTS AND METHODS

A clinical phase II study was performed to assess theefficacy and tolerability of thalidomide combined withdarbepoeitin-alpha in patients with low-to-intermediate-risk MDS according to the IPSS. The study protocol wasapproved by the Institutional Ethics Committee, andpatients gave their written informed consent before studyentry. Eligibility criteria were as follows: (1) establisheddiagnosis of primary low-to-intermediate-risk MDS accord-ing to the IPSS; (2) absence of any previous or co-existentmalignant disease; and (3) absence of any significant organdysfunction. Patients were scheduled to receive thalidomide(Myrin�; Lipomed, Basel, Switzerland) 100 mg/d p.o. anddarbepoietin-alpha (Aranesp�; Amgen, Thousand Oaks,CA, USA) 2Æ25 lg/kg/week s.c., on an outpatient basis.Clinical and laboratory assessment was performed every4 weeks. Seven patients were enrolled between March andJune 2002.

Correspondence: Michael Steurer, MD, Division of Haematology and

Oncology, Innsbruck University Hospital, Anichstr. 35, A-6020

Innsbruck, Austria. E-mail: michael.steurer@uibk.ac.at

British Journal of Haematology, 2003, 121, 101–103

� 2003 Blackwell Publishing Ltd 101

RESULTS AND DISCUSSION

Three months after start-up, the trial had to be discontinuedbecause the first three, of a total of seven patients enrolled atthat time, had developed deep-vein thrombosis, one ofwhom had succumbed because of severe pulmonaryembolism (Table I). The thrombotic events occurred after6, 8 and 11 weeks of therapy respectively. The fatal case(patient 2) had a history of previous deep-vein thrombosisseveral years before the diagnosis of MDS was established.No evidence was found for the presence of inheritedthrombotic risk factors, including factor V Leiden, pro-thrombin gene abnormalities (G20210A), protein S andprotein C deficiencies, in any of these patients. The patientsdid not display any signs of paroxysmal nocturnal haemo-globinuria, and there were no additional thromboembolicrisk factors present such as hormonal manipulation, surgi-cal procedure or indwelling catheter. In the three patientswith thrombotic complications, platelet counts remainedstable during therapy and ranged between 92 and123 · 109/l. Notably, haemoglobin levels rose significantly(> 1 g/dl) in three of the seven patients within a treatmenttime of 6 to 11 weeks (Table I); only one of these patients(patient 1) with a haemoglobin response experienced athrombotic event.

Recently, the thrombogenic activity of thalidomide hasbeen recognized in patients with multiple myeloma (Cavoet al, 2002; Zangari et al, 2002) or renal cell carcinoma(Escudier et al, 2002). In myeloma patients, the rate ofthromboembolic events increased further from approxi-mately 10% to up to 30% when patients received thalido-mide in combination with an anthracycline-basedchemotherapy or steroids (Cavo et al, 2002; Zangari et al,2002). In contrast to myeloma or solid tumours, MDS is nota priori associated with a thrombophilic state. Whenthalidomide alone was administered to MDS patients,thrombotic events reportedly occurred in only two of atotal of 137 patients (1Æ5%) (Raza et al, 2001; Musto et al,2002; Strupp et al, 2002). Moreover, recombinant humanerythropoietin (rhuEPO) as a single drug did not increasethe rate of thromboembolic events in MDS (Rose et al, 1995;Terpos et al, 2002). The safety profile of darbepoietin-alpha

in regard to thrombosis risk has been reported to beidentical to that of rhuEPO or placebo in patients withmalignant disease (Vansteenkiste et al, 2002). We thusassume that a particular interaction between erythropoieticproteins and thalidomide may cause an unexpectedly highthrombotic risk in MDS. rhuEPO has been shown to directlyactivate endothelial cells and to interact with platelets,thereby increasing platelet reactivity. In addition, rhuEPOreduced serum levels of protein S in humans (Stohlawetzet al, 2000). The mechanism by which rhuEPO or othererythropoietic agents and thalidomide interact and perhapsfurther exaggerate thrombogenicity remains to be investi-gated.

We conclude that thalidomide can induce or increase athrombogenic state in patients with MDS. When combinedwith erythropoietic compounds in any kind of haematolog-ical malignancy or solid neoplasm, careful clinical sur-veillance is warranted and thrombosis prophylaxis withlow-molecular-weight heparin or oral anticoagulationshould be considered. For this purpose, we amended ourprotocol by excluding MDS patients with a pre-existingthrombophilic risk and introducing a thrombosis prophy-laxis with low-molecular-weight heparin or low-dose oralanticoagulation.

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Table I. MDS patients undergoing treatment with thalidomide and darbepoietin-alpha.

Patient AgeSerum haemoglobin (g/dl)

Number of RBC Duration of Thromboembolic

number (years) Baseline During therapy transfusions therapy (weeks) events

1 66 8Æ3 9Æ8* none 11 DVT

2 67 9Æ9 10Æ7 6 8 fatal PE

3 63 10Æ9 12Æ1* none 6 DVT

4 62 9Æ1 10Æ9* none 6 none

5 69 6Æ8 8Æ0 5 6 none

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7 66 10 9Æ5 none 3 none

*Haemoglobin response > 1 g/dl.

DVT, deep-vein thrombosis; PE, pulmonary embolism.

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