A phase I study of CPI-613 in combination with high dose cytarabine and mitoxantrone for relapsed or refractory acute myeloid leukemia

Purpose: CPI-613, a lipoate analog that inhibits pyruvate dehydrogenase (PDH) and α-ketogluterate dehydrogenase (KGDH) has activity in patients with myeloid malignancies. This study explored the role of mitochondrial metabolism in chemotherapy response, determined the maximally tolerated dose, efficacy and safety of CPI-613 combined with high dose cytarabine and mitoxantrone in patients with relapsed or refractory acute myeloid leukemia. Methods: 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 was 47% (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 of 24 patients) achieving a CR or CRi. RNA sequence 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. Conclusion: The addition of CPI-613 to chemotherapy is a promising approach in older patients and those with poor risk cytogenetics.

from #ORL-AlexandrosSfakianakis via ola Kala on Inoreader http://ift.tt/2BioAGw