Eltrombopag Treatment of Thrombocytopenia in Advanced Myelodysplastic Syndromes and Acute Myeloid Leukemia: Results of the 8-Week Open-Label Part of an Ongoing Study

Patients with myelodysplastic syndromes (MDS) or acute myeloid leukemia (AML) commonly experience severe thrombocytopenia with a high risk for bleeding. Eltrombopag is an oral thrombopoietin receptor agonist indicated for treatment of chronic immune thrombocytopenia. Eltrombopag may reduce platelet transfusions and bleeding, and preclinical data suggest that it may have an anti-leukemic effect (Erickson-Miller 2008; Kalota 2010; Will 2009; Mavroudi 2010; Roth 2012). We present results of the 8-week, open-label part of an ongoing multicenter trial to evaluate the safety and efficacy of eltrombopag in patients with intermediate (int)-2 or high-risk MDS or AML (WHO criteria) with platelets <25,000/μL.

Eltrombopag was administered daily at 3 escalating dose levels, with increases every 2 weeks in patients without a platelet response: Dose Level (DL)1, 100 mg (50 mg for East Asian [EA] patients); DL2, 200 mg (100 mg for EA patients), and DL3, 300 mg (150 mg for EA patients). Platelet response was defined as on-treatment platelets ≥2x baseline and >20,000/μL for patients with baseline platelets <20,000/μL or ≥2x baseline and ≥50,000/μL for patients with baseline platelets ≥20,000/μL. Treatment with hydroxyurea was permitted.

Seventeen patients with a median age of 72 years (range, 49–91) with int-2 or high-risk MDS (n=12) or AML (n=5) were enrolled. Baseline median platelet count was 12,500/μL (range, 6,000–35,000/μL). Sixteen of 17 patients had received ≥1 prior treatment for their disease. Five, 3, and 9 patients received DL1, DL2, and DL3 as their maximum daily dose. Nine of 17 patients completed 8 weeks of treatment, 6 of whom continued to receive eltrombopag in the extension part of the study. Of the 9 patients who completed all 8 weeks of therapy, 2, 2, and 5 were receiving DL1, DL2, and DL3 at the time they completed their treatment. Ten of 17 (59%) patients had reductions in platelet transfusions during treatment with eltrombopag compared with the 4-week pre-treatment period (Table). Platelet responses were observed in 4/17 (24%) patients. Post-baseline bone marrow examinations 1–3 months after starting eltrombopag (n=11) showed no clinically meaningful changes in blast counts. The most common adverse events (AEs) were pyrexia (n=4), alanine aminotransferase (ALT) increase, diarrhea, epistaxis, headache, and pneumonia (n=3 each). Two of 3 patients with increased ALT met protocol-defined liver-stopping criteria. Both elevations occurred while patients were receiving 300 mg eltrombopag and resolved following discontinuation of eltrombopag. Three deaths were reported (2 patients with fatal AEs of sepsis, considered not related to eltrombopag treatment; 1 patient died of disease progression).

Preliminary data suggest that eltrombopag may reduce platelet transfusion requirements in thrombocytopenic patients with advanced MDS and AML. AEs were as expected for this patient population and for treatment with eltrombopag. Randomized studies assessing the potential benefits and risks of eltrombopag in this setting are ongoing.

Off Label Use: Eltrombopag is an oral TPO agonist indicated for chronic ITP being studied in MDS/AML. Garcia Delgado:Celgene: Consultancy, Speakers Bureau. Mannino:GlaxoSmithKline: Employment. Mostafa Kamel:GlaxoSmithKline: Employment, Equity Ownership. Messam:GlaxoSmithKline: Employment. Stone:GlaxoSmithKline: Employment. Chan:GlaxoSmithKline: Employment.