Scientific programme

PS09  Plenary Session
THERAPY-1: CURRENT OPTIONS

05-May-2017 10:30 12:00
 
 
Abstract:
ELTROMBOPAG IN COMBINATION WITH AZACITIDINE FOR FIRST-LINE TREATMENT OF MDS PATIENTS WITH THROMBOCYTOPENIA: THE RANDOMIZED, PLACEBO-CONTROLLED, PHASE III, SUPPORT STUDY

Introduction: First-line treatment of MDS patients with hypomethylating agents (HMA) can exacerbate pre-existing thrombocytopenia. Relieving thrombocytopenia may reduce platelet transfusion requirements and mortality from bleeding complications, and allow optimal azacitidine dosing. SUPPORT investigated platelet supportive care effects of the oral thrombopoietin receptor agonist eltrombopag in MDS patients with thrombocytopenia receiving azacitidine.

Methods: Adults without previous HMA exposure, baseline platelets <75x109/L, and IPSS Int-1/Int-2/High-risk MDS were randomized 1:1 to eltrombopag/azacitidine or placebo/azacitidine. Azacitidine was administered at 75mg/m2 sc once/day for 7 days, every 28 days, plus eltrombopag or placebo at 200mg/day, escalating by 100mg to maximum 300mg/day (doses 50% reduced for East Asians [EA]). Primary endpoint: proportion of platelet-transfusion independent patients during azacitidine cycles 1–4. Disease progression was a secondary endpoint.

Results: 356 patients (median age 70 [range 24–89] years) received eltrombopag (n=179; n=64 Int-1, n=77 Int-2, n=38 High-risk) or placebo (n=177; n=61 Int-1, n=83 Int-2, n=33 High-risk). Median time on azacitidine/eltrombopag or azacitidine/placebo was 83 (range 1–477) versus 149 (8–503) days. Median eltrombopag doses were 113 (range 60–148) mg/day (EA) and 200 (65–293) mg/day (non-EA).

Following a planned interim assessment, the independent data monitoring committee recommended premature termination, because outcomes crossed the predefined futility threshold and for safety reasons. At final analysis, 28/179 (16%) eltrombopag and 55/177 (31%) placebo patients were platelet-transfusion independent during azacitidine cycles 1–4 (OR: 0.37, 95% CI: 0.21–0.65; one-sided P=1.000).

Fifty-three (15%) patients had AML progression by central (eltrombopag: n=21 [12%]; placebo: n=10 [6%]) or investigator-assessment (eltrombopag: n=27 [15%]; placebo: n=16 [9%]) Table 1). Table 2 shows the proportion of AML progression and disease progression by baseline blast count and IPSS risk category.

Conclusions: Analyses are ongoing to understand the futility and apparent imbalance in AML progression, which is contrary to previous eltrombopag studies. Hypotheses include baseline blast count imbalance between arms, eltrombopag-azacitidine pharmacodynamic interaction and transient stimulatory effects on specific MDS/AML clones involving bone marrow progenitor expansion rather than true leukemic transformation/progression. Short eltrombopag and azacitidine exposure makes assessment of causality difficult; a follow-up study is planned.

 
Co-authors
M. Dickinson 1, H. Cherif 2, P. Fenaux 3, M. Mittelman 4, A. Verma 5, M.S.O. Portella 6, P. Burgess 7, U. Platzbecker 8
1Peter MacCallum Cancer Centre, Haematology Department, Melbourne, Australia
2Uppsala University Hospital, Department of Medical Sciences, Uppsala, Sweden
3Assistance Publique-Hopitaux de Paris/University Paris XIII, Hopital Avicenne, Bobigny, France
4Tel Aviv University, Tel Aviv Sourasky Medical Center, Tel Aviv, Israel
5Albert Einstein College of Medicine, Division of Medical Oncology- Department of Medicine, New York, USA
6Novartis Pharmaceuticals Corporation, Oncology Clinical Development, East Hanover, USA
7Novartis Pharma AG, Global Drug Development, Basel, Switzerland
8University Hospital Carl Gustav Carus- Technische Universität Dresden, Department of Internal Medicine I, Dresden, Germany