A Phase I Study of CPI-613 in Combination with High-Dose Cytarabine and Mitoxantrone for Relapsed or Refractory Acute Myeloid Leukemia

作者：Pardee Timothy S^*; Anderson Rebecca G; Pladna Kristin M; Isom Scott; Ghiraldeli Lais P; Miller Lance D; Chou Jeff W; Jin Guangxu; Zhang Wei; Ellis Leslie R; Berenzon Dmitriy; Howard Dianna S; Hurd David D; Manuel Megan; Dralle Sarah; Lyerly Susan; Powell Bayard L

来源：Clinical Cancer Research, 2018, 24(9): 2060-2073.

DOI：10.1158/1078-0432.CCR-17-2282

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.

• 出版日期2018-5-1