Efficacy and Safety of Low-Dose Venetoclax Combined with Voriconazole Inpatients with Acute Myeloid Leukemia Unfit for Intensive Chemotherapy

Background: Venetoclax combined with hypomethylating agents is the standard regime for elderly patients with acute myeloid leukemia unfit for intensive induction therapy. Nevertheless, many patients struggle with finances and forgo treatments due to the high costs of venetoclax. Concurrent application of venetoclax and CYP3A4 inhibitors such as voriconazole in low-income patients maybe is a feasible strategy to reduce the dose of ventoclax. Methods: We conducted a single-institutional, non-randomized, open-label, prospective study. Between June 2020 and March 2023, 57 elderly or unfit patients with newly diagnosed acute myeloid leukemia at the first affiliated hospital of Anhui medical university were enrolled. Twenty-three patients received low-dose venetoclax plus voriconazole plus azacitidine (cohort 1), whereas another 34 patients received standard dose venetoclax plus azacitidine (cohort 2). The efficacy of the two regimes between cohorts was analyzed and compared, the peak venetoclax concentration (C max) and side effects of the patients were also detected. Results: Totally, there were 35 males and 22 females, with a median age of 67 (range 46-91) years old. 86% (49/57) of patients were adverse/intermediate risk in the whole cohort. The baseline characteristics were all balanced differently between the two cohorts. The venetoclax Cmax in cohort 1 was 1930±225ng/mL, whereas the venetoclax Cmax in cohort 2 was 2371±274ng/mL, there was no significant difference between the two cohorts ( P＝0.3138). The overall response rates were 91% (21/23) and 85% (29/34) in cohort 1 and cohort 2, respectively ( P＝0.0834). At a median of 16 months of follow-up, the median progression-free survivals were 16 and 12 months in two cohorts, respectively ( P＝0.2651) with a hazard ratio of 0.6507. The median overall survivals were not reached and 14 months in the two cohorts, respectively ( P＝0.4636) with a hazard ratio of 0.7466. The most common hematological adverse events were neutropenia, thrombocytopenia, and anemia, whereas the most frequent non-hematological adverse events include infections, vomiting, diarrhea, and hypokalemia. Conclusions: The combination of low-dose venetoclax and voriconazole is well tolerated and effective in unfit AML patients. Concurrent application of venetoclax provided a feasible and sustainable strategy for low-income patients. Keywords: Venetoclax, low-dose, voriconazole, Unfit, Acute myeloid leukemia No relevant conflicts of interest to de