Efficacy of a 14-day venetoclax regimen in combination with a hypomethylating agent for Acute Myeloid Leukemia: A single-center retrospective analysis

Abstract Background : Venetoclax in combination with a hypomethylating agent has become the current standard of care in elderly or unfit patients with acute myeloid leukemia (AML). The VIALE-A trial, which demonstrated a high complete response (CR) rate of 65% using 28 days of venetoclax in patients with AML, had a significant side effect profile, including high rates of neutropenic fever and myelosuppression, which raises tolerability concerns in sicker patients. Emerging evidence has shown potentially similar CR rates with an improved safety profile using a shorter regimen of venetoclax as compared to the VIALE-A trial. In our study, we examine the safety and outcomes of a 14-day regimen of venetoclax in combination with azacitidine or decitabine for treatment of AML at our institution. Methods: In this single-center retrospective study, we screened all adults (≥18 y) with either newly diagnosed or relapsed/refractory AML admitted between April 2019 to June 2024 at Baylor St. Luke's Medical Center. Patients were included if they received a 14-day course of venetoclax in combination with azacitidine or decitabine. Patients received this shortened venetoclax course by physician discretion. The primary outcome of the study was 4-week all-cause mortality. Secondary endpoints included overall survival, neutropenic fever rates, time to count recovery, and overall response rate. Kaplan-Meier analysis was used to estimate survival while reverse Kaplan-Meier was used for median follow-up. Results: Fifty patients were included in our study (median age 71 years, range 44–87; 62% male; 22% Hispanic, 18% Black, 4% Asian or Pacific Islander). Median performance status was Eastern Cooperative Oncology Group (ECOG) Grade 1 (range 0-4), with 6 (12%) of our population having an ECOG Grade of 3 or 4. Forty-six (92%) were newly diagnosed AML, while the remainder had relapsed/refractory disease. Seven (14%) patients had secondary or therapy-related AML. Patients had a median presenting white blood cell (WBC) count of 3.5 × 10⁹/L (range 0.5–277), median hemoglobin of 7.75 g/dL (range 5.3–14), median platelet count of 49 × 10⁹/L (range 5–500), and a median bone marrow blast percent of 43% (range 7–96). The most common adverse cytogenetics included -5/-5q (13; 26%), -7/7q (11; 22%) and inv3 (1; 2%). Fifteen (30%) patients had diploid cytogenetics and 15 (30%) had a complex karyotype. The most common adverse somatic mutations included TP53 (16; 32%), ASXL1 (8; 16%), RUNX1 (6; 12%), and FLT3 (4; 8%). The median dose of venetoclax was 200mg (range 70–400), adjusted based on concomitant azole therapy to account for CYP3A-mediated drug interactions. Four (8%) patients received an allogeneic stem cell transplant. Neutropenic fever occurred in 28 (56%) patients, with the most common infections including pneumonia in 11 (39%) and bacteremia in 9 (32%). Complete remission (CR) or complete remission with incomplete count recovery (CRi) was induced in 26 patients (52%); of these, eight patients (31%) were minimal residual disease negative. The overall response rate was 70% (35/50 patients). Although we did not have count recovery data for all patients, hemoglobin recovery was in a median 33 days (range 22–91, 20 patients), neutrophil recovery in a median 35 days (range 26–116, 21 patients), and platelet recovery to greater than 100 × 10⁹/L in a median 27 days (range 11–91, 33 patients). After a median follow-up of 32.6 months (95% CI 16.3–not reached), median overall survival was 9.2 months (6.6–26.7). Four-week mortality in our patient cohort was 14% (7/50). Conclusions: A shortened 14-day course of venetoclax induction therapy provided comparable rates of overall response, complications, and 4-week mortality as those who received the full 28-day regimen in the pivotal VIALE-A trial. Differing from previous literature, our cohort also included patients with relapsed/refractory AML. Our study is unique in including a more diverse patient population with increased comorbidities; unlike the VIALE-A trial, our study included a greater than 40% minority population and a significant number of ECOG Grade 3 and 4 patients. Our population also had higher rates of complex karyotypes and TP53 mutations. Limitations of our study include a small, single-center cohort and venetoclax dosing length was assigned by physician discretion. A prospective randomized study is warranted to determine the ideal length of venetoclax therapy in patients with AML.