Pharmacological boosting of azacitidine/venetoclax in acute myeloid leukemia

Azacitidine/venetoclax is the standard treatment for patients with acute myeloid leukemia (AML) unfit for intensive chemotherapy. Cytochrome P450 3A4 (CYP3A4) is the major metabolizing enzyme for venetoclax, and its inhibition can boost venetoclax. In the HOVON 171 phase 2 trial, patients with AML were treated with azacitidine/venetoclax/cobicistat. This 2-stage, open-label, multicenter phase 2 trial included a crossover run-in phase followed by an ongoing extension phase. In cycle 1, patients received standard-dose azacitidine/venetoclax. In cycle 2, cobicistat was added, and venetoclax was reduced to 50 mg. The primary end point was pharmacokinetic equivalence, defined as 90% confidence interval (CI) of geometric mean ratios (GMRs) >0.8 for area under the curve over 24 hours (AUC_0-24h) and maximum plasma concentration (C_max). Polymorphisms in genes encoding for CYP enzymes were determined. In vitro assays were performed to assess cobicistat's impact on the antileukemic effect of azacitidine/venetoclax in AML cell lines. In 13 evaluable patients, cobicistat-boosted venetoclax at 50 mg achieved higher exposure than standard 400-mg dosing. GMRs were 2.0 (90% CI, 1.4-2.8) for AUC_0-24h and 1.4 (90% CI, 1.0-2.0) for C_max. In the intention-to-treat population, 65% achieved complete remission (CR) or CR with incomplete hematologic recovery. Interpatient variability in venetoclax exposure because of CYP3A4 polymorphisms was reduced by cobicistat. No unexpected toxicities were observed. In in vitro, cobicistat enhanced azacitidine/venetoclax antileukemic effects. In conclusion, cobicistat enhances and optimizes venetoclax exposure, enabling an eightfold dose reduction while maintaining efficacy. The potentiated antileukemic activity positions cobicistat as a promising complementary agent in AML therapy. This trial was registered at www.clinicaltrials.gov as NCT06014489.