Entospletinib in Combination with Induction Chemotherapy in Previously Untreated Acute Myeloid Leukemia: Response and Predictive Significance of <i>HOXA9</i> and <i>MEIS1</i> Expression.

Abstract

Spleen tyrosine kinase (SYK) signaling is a proposed target in acute myeloid leukemia (AML). Sensitivity to SYK inhibition has been linked to <i>HOXA9</i> and <i>MEIS1</i> overexpression in preclinical studies. This trial evaluated the safety and efficacy of entospletinib, a selective inhibitor of SYK, in combination with chemotherapy in untreated AML. This was an international multicenter phase Ib/II study, entospletinib dose escalation (standard 3+3 design between 200 and 400 mg twice daily) + 7+3 (cytarabine + daunorubicin) in phase Ib and entospletinib dose expansion (400 mg twice daily) + 7+3 in phase II. Fifty-three patients (<i>n</i> = 12, phase Ib and <i>n</i> = 41, phase II) with previously untreated <i>de novo</i> (<i>n</i> = 39) or secondary (<i>n</i> = 14) AML were enrolled (58% male; median age, 60 years) in this study. The composite complete response with entospletinib + 7+3 was 70%. Patients with baseline <i>HOXA9</i> and <i>MEIS1</i> expression higher than the median had improved overall survival compared with patients with below median <i>HOXA9</i> and <i>MEIS1</i> expression. Common adverse events were cytopenias, febrile neutropenia, and infection. There were no dose-limiting toxicities. Entospletinib-related skin rash and hyperbilirubinemia were also observed. Entospletinib with intensive chemotherapy was well-tolerated in patients with AML. Improved survival was observed in patients with <i>HOXA9/MEIS1</i> overexpression, contrasting published data demonstrating poor survival in such patients. A randomized study will be necessary to determine whether entospletinib was a mediator this observation.