Entospletinib in Combination with Induction Chemotherapy in Previously Untreated Acute Myeloid Leukemia: Response and Predictive Significance of HOXA9 and MEIS1 Expression
| Autor: | Bhavana Bhatnagar, Arati V. Rao, James S. Blachly, Tara L. Lin, Alison Walker, Howland E. Crosswell, William Blum, Jinfeng Liu, Veerendra Munugalavadla, Lauren Long, Danjie Zhang, Mark D. Minden, Yang Pan, Hubert Serve, John C. Byrd, Alice S. Mims, Thomas Oellerich, Shelley Orwick |
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| Rok vydání: | 2020 |
| Předmět: |
0301 basic medicine
Oncology Cancer Research medicine.medical_specialty Daunorubicin medicine.medical_treatment Syk 03 medical and health sciences 0302 clinical medicine hemic and lymphatic diseases Internal medicine medicine Chemotherapy business.industry Myeloid leukemia Induction chemotherapy medicine.disease Rash 030104 developmental biology 030220 oncology & carcinogenesis Cytarabine medicine.symptom business Febrile neutropenia medicine.drug |
| Zdroj: | Clinical Cancer Research. 26:5852-5859 |
| ISSN: | 1557-3265 1078-0432 |
| Popis: | 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 and Methods: 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. |
| Databáze: | OpenAIRE |
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