Purpose The lipoate derivative CPI-613 is a first-in-class agent that targets mitochondrial metabolism. This study determined the effects of CPI-613 on mitochondrial function and defined the maximally tolerated dose (MTD), pharmacokinetics (PKs), and safety in patients with relapsed or refractory hematologic malignancies. Experimental Design Human leukemia cell lines were exposed to CPI-613 and mitochondrial function was assayed. A phase I trial was conducted in which CPI-613 was given as a 2-hour infusion on days 1 and 4 for 3 weeks every 28 days. Results CPI-613 inhibited mitochondrial respiration of human leukemia cells consistent with the proposed mechanism of action. In the phase I trial, 26 patients were enrolled. CPI-613 was well tolerated with no marrow suppression observed. When the infusion time was shortened to 1 hour renal failure occurred in 2 patients. At 3780 mg/m2, there were 2 dose-limiting toxicities (DLTs). At a dose of 2940 mg/m2 over 2 hours, no DLTs were observed, establishing this as the MTD. Renal failure occurred in a total of 4 patients and resolved in all but 1, who chose hospice care. CPI-613 has a triphasic elimination with an alpha half-life of ~1.34 hours. Of 21 evaluable, heavily pretreated, patients, 4 achieved an objective response and 2 achieved prolonged stabilization of disease for a clinical benefit rate of 29%. Following drug exposure, gene expression profiles of peripheral blood mononuclear cells from responders demonstrated immune activation. Conclusion CPI-613 inhibits mitochondrial function and demonstrates activity in a heavily pretreated cohort of patients.

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. 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. 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. The addition of CPI-613 to chemotherapy is a promising approach in older patients and those with poor-risk cytogenetics. .

Background The hypomethylating agents (HA), azacitidine and decitabine, have emerged as an alternative to initial and salvage therapy in patients with AML. Little is known about how AML responds to hypomethylating agents after standard therapy and the activity of these agents in a real world setting is not well studied. Methods We retrospectively examined data for 75 consecutive AML patients at Wake Forest from 2002–2011 treated with HAs either as 1st line (n=34), salvage (n=28) or consolidation (n=13). We collected data on age, gender, race, Charlson Comorbidity index (CCI), cytogenetics, type of treatment, Complete Remission (CR), Complete Remission with incomplete count recovery (CRi), and survival. Statistical analysis was performed using Kaplan-Meier estimates and cox proportional hazards models. Results Frontline response rate (CR+CRi) was 26.5%, median overall survival (OS) was 3.4 (95% CI 1.3–7.4) months, with 18% alive at one year. In the salvage cohort, the response rate was significantly lower compared to frontline (3.6% versus 26.5%, p=0.017). Despite the reduced response, OS from time of HA treatment was longer than frontline at 8.2 (CI 4.8–10.3) months. In the consolidation cohort OS was 13.8 (CI 8.0 – 21.6) months with one patient in remission more than 30 months from diagnosis. Conclusion These data suggest prior cytotoxic therapy decrease marrow response rates to HAs but not survival. Furthermore, use of hypomethylating agents for consolidation resulted in a median overall survival over one year in a cohort of older patients. This suggests that hypomethylating agents have activity in all phases of AML treatment.

Standardized phase angle (SPhA) is a tool used to estimate body composition and cell membrane integrity. Standardized phase angle has been shown to predict survival in solid malignancies and hematopoietic stem cell transplant patients. We investigated the predictive value of SPhA on 60‐day mortality, overall survival (OS), and length of hospital stay (LHS) for adults with acute myelogenous and lymphoblastic leukemia (AML and ALL). Consecutive patients ≥18 years with newly diagnosed acute leukemia receiving intensive chemotherapy were enrolled. Phase angle measurements were taken on day 1 of therapy for all patients and on the day of nadir marrow for AML patients. Measurements were standardized by BMI, gender, and age to calculate the SPhA. The difference between SPhA at nadir bone marrow compared to day 1 of induction was used to calculate change in SPhA. A cutoff of 25th percentile was used to dichotomize baseline SPhA. Among 100 patients, 88% were AML, 56% were female, and mean age was 59 years. Though not statistically significant, OS by Kaplan‐Meier analysis was shorter for those below the 25th percentile SPhA compared to those above (median OS: 11.0 months vs 19.5 months; P = .09). Lower baseline SPhA was associated with increased incidence of 60‐day mortality in univariable (odds ratio [OR] = 5.25; 1.35, 20.44; P = .02) but not multivariable analysis (OR = 3.12; 0.67, 14.48; P = .15) adjusted for age, creatinine, and cytogenetics. Increased change in SPhA was associated with worse OS (hazard ratio = 1.15; 1.00,1.33; P = .05) in multivariable analysis. Standardized phase angle is a rapid, noninvasive, and objective measure that may be used to inform risk stratification.

Acute myeloid leukemia (AML) is an aggressive malignancy that affects older patients. The role of salvage therapy in the elderly is controversial and there is little data on efficacy. Outcomes for 94 relapsed or refractory AML patients who received salvage HAMA therapy were analyzed. Of the 94 patients 66 were ≥60, including 26 patients ≥70, and 28 were <60 years old. Early mortality (30-day) was 14% (4% <60, 18% ≥60 years old). Overall, 27% of patients died during hospitalization or were discharged to hospice (11% <60, 33% ≥60 years old). CR/CRi was achieved in 41% of patients (61% <60, 33% ≥60 years old). Median survival was 6.1 months (15.7 <60, 5.2 ≥60). Patients ≥60 who achieved a CR/CRi had a median survival of 11.7 months. At 12 months 56% of patients <60 were alive versus 24% of patients ≥60. At 24 months these numbers fell to 40% and 2% respectively. In those <60 years old, 50% went on to allogeneic hematopoietic stem cell transplant (HSCT) whereas 14% of patients in the ≥60 cohort did so. In conclusion, HAMA salvage therapy results in a 33% response rate in patients ≥60 years old with acceptable toxicity.