Azole-adjusted venetoclax-based regimens in unfit AML patients: A real-world brazilian experience from a resource-limited setting

Abstract Background: Venetoclax-based regimens have become the standard of care for patients with newly diagnosed acute myeloid leukemia (AML) unfit for intensive chemotherapy. In resource-limited settings, Venetoclax availability is limited and dose adjustments due to azole prophylaxis have been adopted as a cost-saving strategy in some centers. Although this approach has been supported by prior studies, additional real-world evidence is needed to better characterize its clinical outcomes. This retrospective study explored the efficacy and complications of Venetoclax-based regimens with azole-adjusted dosing in AML patients treated in a resource-limited setting. Methods: We performed a retrospective analysis of all newly diagnosed adult AML cases treated at our public center in Brazil between 2014 and 2025. Demographic, clinical, and laboratory data were collected from electronic medical records of 230 patients, with a focus on those considered unfit for intensive chemotherapy due to clinical status and comorbidities (n=119). Since Venetoclax only became available at our center in 2020, patients considered unfit for intensive chemotherapy were previously treated with either Cytarabine 20 mg/m² SC for 10 days (LoDAC) or received best supportive care (BSC). After 2020, unfit patients were treated with Venetoclax-based regimens (n=54), either combined with Azacitidine 75 mg/m²/day SC for 7 days (AZA-VEN) or with low-dose Cytarabine 20 mg/m²/day SC for 10 days (LoDAC-VEN). All patients received, after ramp-up, azole-adjusted dosing of Venetoclax: 100 mg when combined with Voriconazole or 200 mg with Fluconazole. The primary outcome was median overall survival (OS) from treatment start. Secondary endpoints included overall response (CR, CRh or CRi) after one or two cycles, as well as Measurable Residual Disease (MRD) status by flow cytometry. We also evaluated the number of cycles and duration of Venetoclax administration, treatment-related toxicities, and reasons for discontinuation. Results: Among the 119 patients unfit for intensive chemotherapy, 80 had de novo AML and 39 had secondary or therapy-related AML. The median age at diagnosis was 68 years (range 61–75), with 50.9% male. Charlson Comorbidity Index (CCI) was 3-4 in 30.3% of patients and >4 in 47.1% of the cases. According to ELN 2022 risk stratification, 40.7% were classified as adverse risk. In terms of treatment, 54 patients (45.3%) received azole-adjusted AZA-VEN or LoDAC-VEN and 65 cases (54.6%) were managed with LoDAC or BSC. The median OS in the Venetoclax azole-adjusted group was 156 days (95% CI 121-242) compared with 29 days (95% CI 24-54) for those treated with LoDAC or BSC (HR=0.50; 95% CI 0.33-0.76; p=0.001). There were 91 deaths, 41.8% in Venetoclax patients. A post-hoc analysis comparing AZA-VEN versus LoDAC-VEN regimens was performed, showing no OS difference between regimens (HR=0.93; 95% CI 0.42-2.05; p=0.975). There were no statistically significant differences between groups in age at diagnosis or CCI. Among the 54 patients in the Venetoclax azole-adjusted group, 62.9% received Venetoclax 100mg daily plus Voriconazole 200mg twice daily, while 37.1% received Venetoclax 200mg daily plus Fluconazole 300mg daily. The median number of cycles was 2 (range 1-4), with a median Venetoclax duration of 28 days per cycle (range 11-28 days). The most common treatment-related toxicities included grade III/IV neutropenia complicated by bacterial infection (29.9%) and severe hemorrhage (7.4%). Early mortality rates were 12.9% at 30 days and 24.9% at 60 days. An overall response to Venetoclax was observed in 54% of patients, while 21% were considered refractory, and 25% could not be evaluated for response due to early death or loss to follow-up. Among responders, 77% achieved MRD negativity. For consolidation, 48.1% proceeded to allogeneic transplantation, while 16.7% received intermediate-dose Cytarabine. Conclusions: In this real-world study, Venetoclax-based regimens with azole-adjusted dosing showed better outcomes in unfit AML patients compared to LoDAC or BSC, reinforcing the applicability of such regimens in resource-limited settings. While overall survival in our cohort was lower than reported in pivotal trials, likely due to infectious complications and limited access to supportive care, response rates were comparable. These results support broader incorporation of this approach across diverse healthcare systems.