Low-Dose Venetoclax (7 Days) Combined with G-CSF, Fludarabine, High-Dose Cytarabine, and Mitoxantrone (FLAG Mitox-Ven): A Safe and Efficient Regimen, and an Excellent Bridge for Allogeneic Hematopoietic Stem Cell Transplant for Relapse/Refractory Acute Myeloblastic Leukemia

Background:

Venetoclax (Ven) combined with FLAG-Ida (G-CSF, Fludarabine, Cytarabine, Idarubicin) represents an effective therapy for relapse/refractory (R/R) acute myeloblastic leukemia (AML), associated with deep remissions and high rate of transition to successful allogeneic hematopoietic stem cell transplantation (AHSCT). Lowering the cytarabine dose (to 1.5g/m2/d for 5 d) and shortening the duration of Ven administration (to 14 d in induction therapy and 7 d in consolidation) in Ven-FLAG-Ida led to lower hematological and infectious toxicities (C. DiNardo, JCO 2021). FLAG -Mitoxantrone (Mitox) was reported to be highly effective and well tolerated salvage regimen for R/R AML (Hatsum N. et al., Int. J. Hematol 2019).

Methods:

We conducted a pilot study between 6/2020 and 12/2023, involving AML pts aged ≥ 18y in first relapse or refractory to first induction therapy. Re-induction therapy FLAG-Mitox-Ven combined G-CSF (5 μg/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. Pts were evaluated after 1 cycle of re-induction. Responsive pts planned for AHSCT received a maximum of 2 cycles of consolidation therapy before AHSCT, while Pts responsive but not planned for AHSCT received a maximum of 3 cycles of consolidation. In consolidation therapy, Fludarabine and Cytarabine were given on d2-4 and G-CSF d1-5. Refractory patients were given other lines of therapy. Anti FLT3 therapy was included for patients with FLT3 mutations. The objectives of this study included the evaluation of the rate of composite complete remission (CRc) including CR, CRh, and CRi, OS and RFS after re-induction, and toxicity profile.

Results:

A total of 33 pts were included with 19 females and 14 males. The median age at relapse was 41 y (25-67). First line therapy consisted of 7+3 regimen in 20 pts, FLAG-Ida in 10 pts, and 5-azacytidine+Ven in 3 pts. AHSCT was performed in first CR in 9 pts. Anti FLT3 therapy was included in first line therapy for 7 pts. Median interval between first induction and salvage therapy was 29m (1-75). The median number of salvage therapy cycles was 2 (1-4). Anti FTL3 was included in the salvage therapy of 9 pts. All pts experienced CTCAE grade ≥3 cytopenia. Grade 3 and 4 adverse events occurring in ≥10% of pts included febrile neutropenia, pneumonia, sepsis, and gastrointestinal disorders. The 30-day mortality was 0%. Remission assessment showed CRc in 26/33 pts (78.8%) and 7 pts were refractory. Nineteen pts (58% of the total cohort, 73% of the pts in CRc) underwent AHSCT. The 14 remaining pts did not undergo AHSCT because of refractory disease (7 pts), multiple comorbidities (3 pts), and economic reasons (4 pts). Median follow up after salvage was 14m (1- 49). The 2y-OS and 2y-RFS for the whole cohort were 56% and 46% respectively. Among the 14 pts who did not undergo AHSCT, only 3pts are alive in CR at 4, 17 and 19m respectively. The 2y-OS and 2y-RFS for this group of pts were 25% and 20%, respectively, after relapse. Among the 19 pts who underwent AHSCT, 13 are alive in CR between 9 and 49m after relapse. The 2y-OS and 2y-RFS of this group of pts were 74% and 67%, respectively, significantly higher than those for the pts who did not undergo AHSCT (p=0.025 and p=0.002, respectively).

At relapse, we performed next generation sequencing (NGS) in all the pts. NGS studies identified a multitude of 21 different mutations in myeloid associated genes. Among the 26 responding pts, DNMT3A (6), TP53 (2), KIT (4), RUNX1 (5), IDH2 (3), KRAS (3), were the most common identified mutations. Among the non-responding group TP53 (5), DNMT3A (2), and BCOR (2) were the most common mutations detected. Non-responding patients were significantly more likely to harbor TP53 mutations compared to patients who responded to salvage therapy.

Summary/Conclusion

Our regimen FLAG-Mitox-Ven (7d) is a well tolerated and very efficious treatment option for R/R AML pts leading to similar CR rate (78.8%) compared to published results from the FLAG-Ida-Ven (14d) and high dose Cytarabine-Mitox-Ven (14d) regimens, with lower toxicity (Di Nardo C et al. Am J Hematol, 2022 – Rahme R et al. J Clin Med, 2024 – Ruhnke L et al. ASH, 2023). NGS findings were similar to that reported by others in this setting (Canaani J et al. Oncotarget, 2020). Our regimen is able to allow AHSCT when feasable with significant improvement in cure rate in pts with of R/R AML.