Venetoclax combined with high-dose cytarabine and mitoxantrone for relapsed or refractory acute myeloid leukemia: outcomes and risk stratification

Abstract

Relapsed or refractory acute myeloid leukemia (R/R AML) remains a therapeutic challenge, with standard high‑dose cytarabine-based salvage regimens achieving complete remission (CR) rates of around 50%. In the phase 1/2 RELAX trial, adding venetoclax (VEN) to high‑dose cytarabine and mitoxantrone (HAM) was considered safe and resulted in CR or CR with incomplete hematologic recovery (CRi) in 75% of patients. Here, we performed a multicenter real‑world analysis of 128 R/R AML patients treated with HAM plus VEN (VEN 400 mg days 1-14, cytarabine 1000 mg/m² IV twice daily days 3-5, mitoxantrone 10 mg/m² IV days 5-7) between March 2023 and June 2025. The median age was 60 years (range, 20-74). Patients had a median of 1 prior therapy (range, 1-5), 38% had prior allogeneic hematopoietic cell transplantation (HCT), and 25% VEN exposure. Overall, 69% achieved CR/CRi; response rates were higher in patients with one prior therapy line (78%) and VEN-naïve patients (76%). Sixty-eight percent proceeded to HCT. After a median follow-up of 11.5 months, estimated 1‑year RFS and OS rates were 59% and 58%, respectively. In a prognostic classifier derived from pooled real-world and RELAX trial data (183 patients), TP53 mutation, complex karyotype, ≥2 prior therapy lines, and Eastern Cooperative Oncology Group performance status (ECOG PS) ≥2 predicted inferior outcomes. Patients without these features had a 1-year OS of 73%. HAM plus VEN retains high efficacy and encouraging survival outcomes in a real-world setting, supporting its use as an effective salvage and bridge-to-transplant strategy.