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

• Published in: Clinical cancer research Vol. 26; no. 22; pp. 5852 - 5859
• Main Authors: Walker, Alison R, Byrd, John C, Blachly, James S, Bhatnagar, Bhavana, Mims, Alice S, Orwick, Shelley, Lin, Tara L, Crosswell, Howland E, Zhang, Danjie, Minden, Mark D, Munugalavadla, Veerendra, Long, Lauren, Liu, Jinfeng, Pan, Yang, Oellerich, Thomas, Serve, Hubert, Rao, Arati V, Blum, William G
• Format: Journal Article
• Language: English
• Published: United States 15-11-2020
• ISSN: 1078-0432; 1557-3265
• DOI: 10.1158/1078-0432.CCR-20-1064

Spleen tyrosine kinase (SYK) signaling is a proposed target in acute myeloid leukemia (AML). Sensitivity to SYK inhibition has been linked to
and
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 (
= 12, phase Ib and
= 41, phase II) with previously untreated
(
= 39) or secondary (
= 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
and
expression higher than the median had improved overall survival compared with patients with below median
and
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
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.