Pharmacological boosting of azacitidine/venetoclax in acute myeloid leukemia

1 Cobicistat allowed an 8-fold reduction in venetoclax while optimizing exposure, demonstrating a cost-effective strategy for AML treatment. 2 Cobicistat potentiated anti-leukemic activity of azacitidine/venetoclax and positions it as a promising complementary agent in AML therapy. Azacitidine/venetoclax is the standard treatment for acute myeloid leukemia (AML) patients 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, AML patients were treated with azacitidine/venetoclax/cobicistat. Here, we describe the pharmacokinetic results and the potential enhancing effects of cobicistat on venetoclax and azacitidine. This two-stage, open-label, multicenter phase 2 trial (NCT06014489) included a cross-over 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 reduced to 50 mg. Primary endpoint was pharmacokinetic equivalence defined as geometric mean ratios (GMRs) >0.8 for AUC 0-24h and C max . Polymorphisms in genes encoding for CYP enzymes were determined. In vitro assays were performed to assess cobicistat’s impact on the anti-leukemic effect of azacitidine/venetoclax in AML cell lines. In 13 evaluable patients, cobicistat-boosted venetoclax 50 mg achieved higher exposure than standard 400 mg dosing. GMRs were 2.0 1.4–2.8 for AUC 0–24h and 1.4 1.0–2.0 for C max . In the intention-to-treat population, 65% achieved complete remission (CR) or CR with incomplete hematologic recovery (CRi). Interpatient variability in venetoclax exposure due to CYP3A4 polymorphisms was strongly reduced by cobicistat. No unexpected toxicities were observed. In vitro, cobicistat enhanced azacitidine/venetoclax anti-leukemic effects. In conclusion, cobicistat enhances and optimizes venetoclax exposure, enabling 8-fold dose reduction while maintaining efficacy. The potentiated anti-leukemic activity positions cobicistat as a promising complementary agent in AML therapy.