A Phase I Study of CPI-613 in Combination with High-Dose Cytarabine and Mitoxantrone for Relapsed or Refractory Acute Myeloid Leukemia
Autor: | Leslie R. Ellis, Susan Lyerly, Dmitriy Berenzon, Megan Manuel, Wei Zhang, Dianna S. Howard, Timothy S. Pardee, Sarah Dralle, Bayard L. Powell, Rebecca G. Anderson, Jeff W. Chou, Scott Isom, Lance D. Miller, Kristin M. Pladna, Lais P. Ghiraldeli, Guangxu Jin, David D. Hurd |
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Rok vydání: | 2018 |
Předmět: |
Male
0301 basic medicine Oncology Cancer Research Myeloid Biopsy medicine.medical_treatment Mice 0302 clinical medicine Bone Marrow Recurrence Antineoplastic Combined Chemotherapy Protocols Cytarabine Myeloid leukemia Middle Aged Mitochondria Leukemia Myeloid Acute Leukemia Treatment Outcome medicine.anatomical_structure 030220 oncology & carcinogenesis Retreatment Female Caprylates medicine.drug Adult medicine.medical_specialty Cell Respiration Sulfides Article Cell Line Young Adult 03 medical and health sciences Oxygen Consumption Internal medicine medicine Animals Humans Aged Neoplasm Staging Chemotherapy Mitoxantrone business.industry Cancer medicine.disease 030104 developmental biology Drug Resistance Neoplasm Bone marrow Neoplasm Grading business Biomarkers |
Zdroj: | Clinical Cancer Research. 24:2060-2073 |
ISSN: | 1557-3265 1078-0432 |
Popis: | Purpose: CPI-613, a lipoate analogue 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 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 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% (11/24 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. Clin Cancer Res; 24(9); 2060–73. ©2018 AACR. |
Databáze: | OpenAIRE |
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