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

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 ch...

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Published inClinical 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
LanguageEnglish
Published United States 15.11.2020
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Summary: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.
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ISSN:1078-0432
1557-3265
DOI:10.1158/1078-0432.CCR-20-1064