Eltrombopag for low to intermediate-2 risk myelodysplastic syndrome

Eltrombopag, an oral thrombopoietin receptor agonist, can increase platelets in patients with chronic immune thrombocytopenic purpura and produces trilineage responses in patients with refractory aplastic anemia. Because management of persistent cytopenias in MDS patients remains unsatisfactory, we initiated a pilot, phase II study of eltrombopag in low to Int-2 risk MDS subjects, following failure of standard therapies, or as an initial therapy (NCT00961064). Eltrombopag was initiated at 50 mg/day, increasing every two weeks to 150mg/day. The primary endpoint assessed at 16 weeks was defined as: (a) platelets ≥ 20,000/μL above baseline or stable platelet counts with transfusion independence for a minimum of 8 weeks in transfusion dependent subjects; or (b) in anemic subjects (Hb < 9 g/dL pretreatment) ≥ 1.5g/dL increase in Hb without transfusion support, or a reduction in the units of PRBC transfusions by at least 50%; or (c) in neutropenic subjects (ANC <0.5 x 109/L pretreatment) ≥ 0.5 x 109/L increase in ANC, or ≥ 100% increase. Responding subjects could continue to receive eltrombopag on an extension arm. Eighteen subjects are evaluable to date, with a median age 65 years (range 35 - 85), a male predominance (11/18), and refractory cytopenia with unilineage dysplasia (RCUD) as the most common subtype (8/18). At baseline, 9 subjects had normal cytogenetics, and 7 had abnormalities including deletion 13q, trisomy 6, deletion 20q, and trisomy 15. Bone marrow blasts were <5% in all subjects pre-treatment. Severe thrombocytopenia was the qualifying cytopenia in 9 subjects, severe anemia in 3, and 6 were bicytopenic. Eltrombopag was well tolerated by all subjects, with only one grade 3 adverse event (hepatotoxicity) that resolved without dose-reduction. All but one subject reached the full dose of 150mg/day. 56% (10/18) of patients achieved a response at 16 weeks, and most were eventually bi- or tri-lineage, with continued improvement in counts with longer duration of treatment beyond the 16 week endpoint. Eltrombopag was discontinued in 3 subjects who essentially normalized counts (Hb >10 g/dL and platelets >50,000/μL and ANC>1000/μL) during the extension arm, with maintenance of improved blood counts off drug for a median of 4 months (range 3 - 24). Only one subject (a responder) had progression of MDS on eltrombopag, with marrow blasts of 8% noted at 9 months. Accrual to the study is continuing, and preliminary results indicate eltrombopag is a promising, welltolerated and effective drug to improve cytopenias of all lineages in MDS patients.