Megan Manuel

A Phase I Study of the First-in-Class Antimitochondrial Metabolism Agent, CPI-613, in Patients with Advanced Hematologic Malignancies

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 MTD, pharmacokinetics, 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 3,780 mg/m2, there were two dose-limiting toxicities (DLT). At a dose of 2,940 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 approximately 1.34 hours. Of the 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. Clin Cancer Res; 20(20); 5255–64. ©2014 AACR.

High dose cytarabine, mitoxantrone and l-asparaginase (HAMA) salvage for relapsed or refractory acute myeloid leukemia (AML) in the elderly

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.

Priapism in the oncology setting.

CASE STUDY N.L. is a 20-year-old Caucasian man with no significant medical history. He presented to the hospital with a two-day history of feeling ill with intermittent nausea, vomiting, blurred vision, and headache. He also noted slurred speech and left-upper-quadrant fullness for almost a month.

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 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.

Two case reports of MDS with chromosome 7 abnormalities after treatment of AIDS-related Burkitt lymphoma occurring in patients on HAART therapy.

e18561 Background: Burkitt lymphoma (BL) follows a rapidly progressive course, in both HIV infected and non-infected patients (pts). Non-HIV infected pts fare better with multiagent, dose intensive regimens. The role of these regimens in HIV infected pts remains unclear, particularly in the era of HAART therapy. METHODS This is an observational case report. RESULTS Case 1: 37yo HIV+ male diagnosed with Stage IIIE BL by rectal mass biopsy. Bone marrow, and CSF were negative. He was treated according to CALGB 10002. HAART was continued during therapy with good control of HIV viremia. He achieved a CR. He developed progressive cytopenias. Bone marrow 6 months after completing therapy was consistent with MDS. FISH for 7q- was positive in 15.5% of cells. The pt underwent RIC sibling donor stem cell transplant. Despite engraftment, the patient developed AML 2 months after his transplant. The patient elected not to receive induction therapy and died 2 months later due to complications of AML. Case2: 41 year old HIV+ female diagnosed with Stage IV BL by liver biopsy. She was treated according to CALGB 10002. HAART therapy was given, but despite multiple combinations the patient had persistently detectable HIV viral load. CR was achieved. She remained cytopenic after completion of chemotherapy. Bone marrow biopsy 4 months after chemotherapy showed monosomy 7 by FISH in 20% of cells, without increased blasts. The pt had ongoing CMV and HIV viremia, therefore no therapy for MDS was given. Her BL recurred one month later. She entered hospice, and died of complications of BL. CONCLUSIONS We report 2 cases of tMDS with chromosome 7 abnormalities occurring after concurrent HAART and aggressive chemotherapy for AIDS related BL. This limited series raises concern that there may be a potential interaction of HAART and chemotherapy causing increased risk of MDS. One hypothesis is that mitochondrial damage, which has been reported from nucleoside analogue antiretrovirals, could lead to increased reactive oxygen species, which could further increase the known risk of tMDS in pts treated with dose intense regimens for BL.