Entospletinib in Combination With Induction Chemotherapy in Previously Untreated Acute Myeloid Leukemia: Response and Predictive Significance of HOXA9 and MEIS1 expression.

Purpose Spleen tyrosine kinase (SYK) signaling is a proposed target in acute myeloid leukemia (AML). Sensitivity to SYK inhibition has been linked to HOXA9 and MEIS1 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. Methods This was an international multicenter phase 1b/2 study: entospletinib dose escalation (standard 3+3 design between 200 mg and 400 mg BID) + 7+3 (cytarabine + daunorubicin) in phase 1b, and entospletinib dose expansion (400 mg BID) + 7+3 in phase 2. Results Fifty-three patients (n=12 phase 1b, n=41 phase 2) with previously untreated de novo (n=39) or secondary (n=14) AML enrolled (58% male, median age 60 years). The composite complete response with entospletinib + 7+3 was 70%. Patients with baseline HOXA9 and MEIS1 expression higher than the median had improved overall survival compared to patients with below median HOXA9 and MEIS1 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. Conclusion Entosplentib with intensive chemotherapy was well tolerated in AML patients. Improved survival was observed in patients with HOXA9/MEIS1 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.