Abstract 4037: In vitro cytotoxicity of CPX-351 plus venetoclax compared with hypomethylating agents or cytarabine plus venetoclax

Abstract

Abstract Introduction: Current treatment options for AML patients who are older or unfit for intensive chemotherapy are limited and associated with less than ideal outcomes, even with newly approved regimens of venetoclax plus low-dose cytarabine or DNA hypomethylating agents. CPX-351, a dual-drug liposomal encapsulation of cytarabine and daunorubicin at a synergistic ratio, was approved by the US FDA in 2017 and EMA in 2018 for treatment of adults with newly diagnosed therapy-related AML and AML with myelodysplasia-related changes. The objective of this study was to assess the cytotoxic effects of CPX-351 plus venetoclax versus combinations of venetoclax plus cytarabine, decitabine, or azacitidine. Methods: Three AML and three ALL cell lines were treated with single-agent CPX-351, venetoclax, cytarabine, decitabine, or azacitidine, or with combinations of CPX-351 plus venetoclax, venetoclax plus cytarabine, venetoclax plus decitabine, or venetoclax plus azacitidine. The cells were plated 24 hours prior to treatment and incubated with the test agents for 72 hours. Cytotoxicity was measured with a luminescent Cell Viability Assay. Results: As a single agent, all tested drugs demonstrated cytotoxicity to all cell lines, but with different potencies. CPX-351 plus venetoclax showed synergistic or additive effects in all AML and ALL cell lines tested (Table). Combinations of venetoclax with cytarabine, decitabine, or azacitidine showed variable responses (synergistic, additive, and antagonistic effects). In addition, data suggest the highest combination doses with CPX-351 may attain greater cell killing versus the other drug combinations tested. TableCICell lineCell originCPX-351 + venetoclaxCytarabine + venetoclaxAzacitidine + venetoclaxDecitabine + venetoclaxHL-60AML0.701.010.711.66SKM-1AML0.911.931.291.14KG-1AML0.530.950.590.77CCRF-CEMALL0.700.990.861.99MOLT-3ALL0.740.680.630.73Jurkat E6-1ALL0.791.331.141.40CI was calculated using the Chou and Talalay method, where CI of <1 = synergistic, 1 = additive, and >1 = antagonistic. Conclusions: These data demonstrated that the combination of CPX-351 and venetoclax is synergistic or additive in all cell lines tested. Future studies confirming these findings in in vivo hematologic malignancy models can help to design a novel dose-regimen, which may provide the best benefit with good tolerability. Citation Format: Aparna Gupta, Robin Humphreys, Derek Hanson, Qi Wang. In vitro cytotoxicity of CPX-351 plus venetoclax compared with hypomethylating agents or cytarabine plus venetoclax [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 4037.