期刊
CLINICAL CANCER RESEARCH
卷 24, 期 9, 页码 2060-2073出版社
AMER ASSOC CANCER RESEARCH
DOI: 10.1158/1078-0432.CCR-17-2282
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类别
资金
- Bioinformatics Shared Resource
- [1R01CA197991-01A1]
- [P30CA012197]
Purpose: CPI-613, a lipoate analogue that inhibits pyruvate dehydrogenase (PDH) and alpha-ketogluterate dehydrogenase (KGDH), has activity in patients with myeloid malignancies. This study explored the role of mitochondrial metabolism in chemotherapy response and determined the MTD, efficacy, and safety of CPI-613 combined with high-dose cytarabine and mitoxantrone in patients with relapsed or refractory acute myeloid leukemia. Experimental Design: The role of mitochondrial response to chemotherapy was assessed in cell lines and animal models. A phase I study of CPI-613 plus cytarabine and mitoxantrone was conducted in patients with relapsed or refractory AML. Results: Exposure to chemotherapy induced mitochondrial oxygen consumption that depended on PDH. CPI-613 sensitized AML cells to chemotherapy indicating that mitochondrial metabolism is a source of resistance. Loss of p53 did not alter response to CPI-613. The phase I study enrolled 67 patients and 62 were evaluable for response. The overall response rate was 50% (26CR_5CRi/62). Median survival was 6.7 months. In patients over 60 years old, the CR/CRi rate was47%(15/32) with a median survival of 6.9 months. The response rate for patients with poor-risk cytogenetics also was encouraging with 46% (11/24 patients) achieving a CR or CRi. RNA sequencing analysis of a subset of baseline bone marrow samples revealed a gene expression signature consistent with the presence of B cells in the pretreatment marrow of responders. Conclusions: The addition of CPI-613 to chemotherapy is a promising approach in older patients and those with poor-risk cytogenetics. (C) 2018 AACR.
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