For Patients with Adverse-Risk Acute Myeloid Leukemia, Frontline FLAG Ida with Venetoclax Is Safe and Efficacious

Introduction: FLAG-Ida venetoclax (FIV) is a highly intensive chemotherapy regimen combining the BCL-2 inhibitor Venetoclax (400 mg daily, days 1-14) and is commonly used in the relapse/refractory setting for patients with acute myeloid leukemia (AML).. Recently, this regimen has emerged as a promising option for inducing remission in the frontline setting for patients with adverse-risk AML (DiNardo., JCO, 2021). This retrospective study evaluates the outcomes of patients with adverse-risk AML treated with frontline FIV.

Methods: Twenty-nine patients with adverse-risk AML were treated with frontline FIV. Adverse-risk AML was defined based on cytogenetic and molecular data (according to ELN 2022 criteria) and/or by a history of hematologic malignancy (secondary AML) or prior chemotherapy exposure (chemotherapy-related AML). Patients were treated at two large tertiary care centers between February 2022 and June 2024. The FIV regimen was administered to patients with adverse-risk AML who were fit for intensive chemotherapy, given the low remission rates associated with other protocols.

The primary outcome was the rate of complete remission (CR) or complete remission with incomplete hematologic recovery (CRi) at the end of induction therapy. Secondary outcomes included 30-day and 60-day mortality rates, relapse-free survival (RFS), and overall survival (OS). Measurable residual disease (MRD) was assessed using multiparameter flow cytometry.

Results: The median age of patients treated with frontline FIV was 54.6 years. Ten patients were aged 60 years or older. 18 (62%) are males .. All patients were considered fit with an ECOG performance status of 0-1. Sixteen patients had secondary or therapy-related AML, 4 had a history of myelodysplastic syndrome and 7 had myeloproliferative neoplasms. Fifteen patients (52%) had a complex karyotype, and 9 patients (31%) had TP53 mutations, del(17p), or both.

CR/CRi status was determined by flow cytometry. Twenty-six patients (90%) achieved CR/CRi, with 58% achieving MRD-negative status. These responses were achieved after one cycle of induction therapy; none of the patients required a second cycle of FIV.

One patient died by day 60 of the study period; no deaths occurred by day 30. The median time to an absolute neutrophil counts greater than 500/µL was 25 days, and the median time to platelet recovery (greater than 50,000/µL) was 27 days. The average duration of hospitalization was 30 days.

Of the 26 patients who achieved CR/CRi, 25 proceeded to receive allogeneic stem cell transplants. The median follow-up period was 7 months. The median OS and RFS have not yet been reached, though longer follow-up is needed. For patients diagnosed before August 1, 2023 (16 patients), the 1-year OS rate was 57%.

Discussion: Patients with adverse-risk AML typically have a poor outcome. Induction of remission and hematopoietic stem cell transplantation are currently the only curative options. Previous studies have shown that remission induction in these patients is achieved in less than half of the patients.

In this study, the frontline FIV regimen appears to achieve a high remission rate in adverse-risk AML, even in the presence of mutations and cytogenetic abnormalities associated with chemoresistance, such as complex karyotype and TP53 mutations. The depth of remission achieved enabled patients to undergo stem cell transplantation at first complete remission (CR1), potentially benefiting from a graft-versus-leukemia effect to prevent relapse and improve survival. Although not directly comparable, the remission rates observed in this report are higher than those reported in similar studies for fit patients treated with CPX-351 or FLAG-Ida (Lancet, JCO 2018; Othman, Blood Adv 2023), with 1-year survival rates at least comparable. Longer follow-up is needed to determine whether the high remission and MRD-negative rates will translate into improved long-term survival. In summary, FIV is a safe and effective frontline chemotherapy regimen for patients with adverse-risk AML, leading to high remission rates and encouraging survival outcomes.