Background FLAG (G-CSF, Fludarabine, Cytarabine) combined with either Idarubicin (Ida) or Mitoxantrone (Mitox) were reported to be effective and well tolerated regimens in newly diagnosed (ND) or relapsed/refractory (R/R) Acute Myeloblastic Leukemia (AML). (A.K. Burnett et al. 2018 – R. Muhlneck et al. 2022). Recently, FLAG-Ida combined with Venetoclax (Ven) was reported to induce deep remissions and high rates of transition to allogeneic hematopoietic stem cell transplantation (AHSCT) in patients (pts) with ND or R/R AML (C.D. DiNardo 2022). Lowering the Cytarabine dose (to 1.5mg/m2/d for 5d) and shortening the duration of Ven administration (to 14d in induction and 7d in consolidation) in FLAG-Ida+Ven led to lower hematological and infectious toxicities (C.D. DiNardo 2025 – R Shahswar 2024). We report the outcomes of a pilot study on FLAG-Mitox+Ven (given for 7d) in ND and R/R AML pts.

Methods Between 6/2020 and 6/2025, pts fit for intensive chemotherapy aged from 18 to 60 yo with ND AML, or in first relapse/refractory were included. FLAG-Mitox +Ven regimen combined G-CSF (5μg/kg/d) on d1-7. Fludarabine (30mg/m2/d IV) and Cytarabine (1.5g/m2/d IV) on d2-5, Mitox (12mg/m2/d IV) d2,4 and Ven (100mg PO daily) given concomitantly with voriconazole d2-8. Responding pts planned for AHSCT received 1 to 2 cycles of consolidation therapy, while responding pts non planned for AHSCT received 3 cycles of consolidation. In consolidation therapy, Fludarabine and Cytarabine were given on d2-4 and G-CSF d1-5, while Mitox and Ven were given at the same schedule. Anti FLT3 therapy was given to patients with FLT3 mutations. Measurable residual disease (MRD) was assessed by flow cytometry.

The objectives included rate of composite CR (CRc: CR, CRh, CRi) and toxicity, in addition to overall survival (OS) and event-free survival (EFS).

Results Hundred and five pts were included with 55 ND and 50 R/R pts. There were 55 females and 50 males. Median age was 43yo (18–60). Among the ND pts, 11 (20%), 18 (33%), and 26 (47%) were ELN 2022 favorable, intermediate, and adverse, respectively. Sixty percent of the ND pts transitioned to AHSCT in CR1. The CRc rate after the first induction therapy (FLAG-Mitox+Ven) was 91%, with a flow MRD-negativity of 86%. The 3-y OS and 3-y EFS rates were 68% and 64%, respectively. Outcomes were not significantly different across ELN 2022 risk groups. Among the 50 R/R pts, first induction therapy consisted of 7+3 regimen in 32 pts (64%), FLAG-Ida in 15 pts (30%) and 5-Azacytidine+Ven in 3 pts (6%). AHSCT was included in first line therapy of 15 pts. The CRc rate after FLAG-Mito+Ven was 78% with a flow MRD-negativity of 74%. Sixty percent of these R/R pts transitioned to AHSCT. The 3-y OS and 3-y EFS rates were 66% and 62%, respectively, for the pts who underwent AHSCT. However, non-transplanted pts had a significantly lower 3-y OS (22%, p=0.025) and 3-y EFS (18%, p=0.002), respectively. The most frequent adverse events (grade ≥3) were hematologic, infectious (pneumonia), and gastrointestinal. The mortality rates at 30 and 60 days of FLAG-Mitox+Ven were 0% and 2.8%, respectively.

ConclusionFLAG–Mitox+Ven (7d) is a highly-effective and well-tolerated regimen for remission induction and MRD negativity in both ND and R/R AML pts. High survival outcomes were demonstrated across ELN 2022 risk groups in ND AML pts. This regimen is also an effective bridge to AHSCT when feasible.

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2025
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