Entospletinib in Combination with Induction Chemotherapy in Previously Untreated Acute Myeloid Leukemia: Response and Predictive Significance of HOXA9 and MEIS1 Expression.
Clin Cancer Res
; 26(22): 5852-5859, 2020 11 15.
Article
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| MEDLINE
| ID: mdl-32820015
ABSTRACT
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. PATIENTS ANDMETHODS:
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.RESULTS:
Fifty-three patients (n = 12, phase Ib and n = 41, phase II) with previously untreated de novo (n = 39) or secondary (n = 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 HOXA9 and MEIS1 expression higher than the median had improved overall survival compared with 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.CONCLUSIONS:
Entospletinib with intensive chemotherapy was well-tolerated in patients with AML. 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.
Texto completo:
1
Bases de datos:
MEDLINE
Asunto principal:
Pirazinas
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Leucemia Mieloide Aguda
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Proteínas de Homeodominio
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Proteína 1 del Sitio de Integración Viral Ecotrópica Mieloide
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Indazoles
Tipo de estudio:
Clinical_trials
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Prognostic_studies
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Risk_factors_studies
Límite:
Adult
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Female
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Humans
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Male
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Middle aged
Idioma:
En
Revista:
Clin Cancer Res
Asunto de la revista:
NEOPLASIAS
Año:
2020
Tipo del documento:
Article