Comparable efficacy of venetoclax 50mg with posaconazole versus venetoclax 400mg in newly diagnosed AML patients: A prospective study of pharmacokinetics, toxicity, and clinical outcomes.

Abstract

6530 Background: Metabolism of Venetoclax(VEN) by CYP3A enzymes gives a unique opportunity to administer it at a lower dose with a CYP3A inhibitor. Azoles are strong CYP3A inhibitors & they are commonly used for antifungal prophylaxis during AML induction. Current data suggest that VEN 100mg with posaconazole achieves comparable clinical efficacy but is associated with higher myelotoxicity. We prospectively explored further dose reduction of VEN to 50 mg with posaconazole & compared it with VEN 400 mg with respect to pharmacokinetics, response rates & toxicity. Methods: We conducted an open-label, prospective study & enrolled 31 AML patients unfit for intensive chemotherapy. Patients received either VEN 50 mg with posaconazole (VEN50 cohort, n=20) or VEN 400 mg without posaconazole (VEN400 cohort, n=11). Pharmacokinetic parameters, including C0, Cmax, & AUC(0–24), were assessed using high-performance liquid chromatography. Clinical outcomes: overall response rate (ORR), composite complete response (CRc), measurable residual disease (MRD), & hematological recovery time-were analysed. Results: The median age of patients was 50 years (IQR: 35.5–60). Under the ELN2024 model, 74% of VEN50 patients & 63.6% of VEN400 patients were favourable-risk, while 26% & 36.4% were intermediate-risk, respectively. The ORR was 80% in the VEN50 cohort & 81.8% in the VEN400 cohort. CRc rates were comparable between the VEN50 (60%) & VEN400 (63.6%) cohorts, with similar MRD negativity rates (30% vs. 36.3%). Pharmacokinetic analysis revealed significantly lower systemic drug exposure in the VEN50 cohort [AUC(0–24):17.88 µg·h/mL vs. 48.05 µg·h/mL, p=0.002] with C0 levels of 0.42 µg/mL vs. 1.08 µg/mL (p=0.004) & Cmax levels of 1.435 µg/mL vs. 3.63 µg/mL (p=0.002). Patients in VEN50 cohort experienced shorter neutropenic phase (17.5 vs. 24 days). Adverse events, including febrile neutropenia (60% vs. 72.7%, p=0.501) & culture-positive infections (20% vs. 27.2%, p=0.569), were comparable between the two cohorts. No treatment-related death occurred in either of the group. Conclusions: Our findings suggest that lower plasma levels achieved with VEN50 can lead to comparable CR rate & MRD negative rate in comparison with VEN400 with lesser myelotoxicity. Comparison of baseline characteristics and outcomes. Category VEN 50mg + Posaconazole) VEN 400 mg P-Value Median Age (IQR) 50 (35–59) 39 (35–52) 0.32 ECOG (0–2) (%) 90 91 0.29 C0 (µg/mL, Median) 0.42 (0.17–1.57) 1.08 (0.4–2.78) 0.004 Cmax (µg/mL, Median) 1.435 (0.54–5.51) 3.63 (1.27–6.92) 0.002 AUC0-24 (µg·h/mL, Median) 17.88 (8.09–81.47) 48.05 (19.96–94.79) 0.002 Overall Response Rate (ORR) (%) 80 81.8 1.0 CRc (CR + CRi) (%) 60 63.6 1.0 MRD Negativity (%) 30 36.3 0.98 Febrile Neutropenia (%) 60 72.7 0.501 Neutropenia Recovery (days, Median) 17.5 24 0.4 Culture-Positive Infections (%) 20 27.2 0.569