Azacitidine + Venetoclax + Gilteritinib combination

Current understanding

Triple combination layering the FLT3 inhibitor gilteritinib onto the azacitidine + venetoclax doublet for FLT3-mutated relapsed/refractory AML, CMML, and high-risk MDS/MPN. A phase I/II trial (trial-early evidence) is testing whether triplet therapy improves outcomes versus the established hypomethylating + BCL-2 inhibitor doublet in this molecularly defined subgroup.

Evidence log

• 2026-09-21 — Metronomic Decitabine-Cedazuridine and Venetoclax in R/R AML, HR-MDS, HR/AP MPN: Cross-reference: a phase 2 trial (trial-early) of metronomic oral ASTX727 + venetoclax in R/R AML, HR-MDS, and HR/AP MPN provides a doublet comparator (without FLT3 inhibition) using an all-oral HMA platform and a metronomic dosing schedule in overlapping salvage populations. (novelty: 3)
• 2026-05-29 — Azacitidine With or Without Lenalidomide or Vorinostat in Treating Patients With Higher-Risk Myelodysplastic Syndromes or Chronic Myelomonocytic Leukemia: Cross-reference: a randomized phase II/III trial (trial-late) is testing azacitidine ± lenalidomide or vorinostat in higher-risk MDS/CMML, providing a contemporaneous comparator for HMA-combination strategies (IMiD or HDAC inhibitor add-on) versus the HMA + BCL-2 + FLT3i triplet approach in the MDS/MPN-overlap subgroup. (novelty: 3)
• 2026-05-20 — Venetoclax Added to Fludarabine + Busulfan Prior to Transplant and to Maintenance Therapy for AML, MDS, and MDS/MPN: Cross-reference: a phase I/II trial is using the azacitidine + venetoclax doublet (without gilteritinib) as one arm of post-transplant maintenance in AML/MDS/CMML/MDS-MPN-U after venetoclax-augmented FluBu conditioning, providing a peri-transplant deployment of the same HMA + BCL-2 backbone. (novelty: 3)
• 2026-04-16 — Azacitidine and Quizartinib for the Treatment of Myelodysplastic Syndrome or Myelodysplastic/Myeloproliferative Neoplasm With FLT3 or CBL Mutations: Cross-reference: parallel phase I/II of azacitidine + quizartinib (FLT3 inhibitor) in FLT3/CBL-mutated MDS/MPN provides a doublet-with-FLT3i comparator for whether adding venetoclax to an HMA + FLT3i backbone improves outcomes in the FLT3-mutated MDS/MPN-overlap subgroup. (novelty: 3)
• 2026-03-05 — Azacitidine Combined With Venetoclax in Patients With Higher-risk Chronic Myelomonocytic Leukemia (AVENHIR): AVENHIR phase II single-arm multicenter trial (trial-early) evaluates the underlying azacitidine + venetoclax doublet specifically in higher-risk CMML, providing comparator context for whether adding gilteritinib offers benefit over the doublet backbone in the FLT3-mutated MDS/MPN-overlap subgroup. (novelty: 3)
• 2026-04-16 — Azacitidine, Venetoclax, and Gilteritinib in Treating Patients With Recurrent/Refractory FLT3-Mutated Acute Myeloid Leukemia, Chronic Myelomonocytic Leukemia, or High-Risk Myelodysplastic Syndrome/Myeloproliferative Neoplasm: cross-connection with navitoclax-venetoclax-decitabine-combination: Both are HMA + venetoclax-based triplets for advanced myeloid neoplasms; they differ in the third agent (FLT3 inhibition via gilteritinib vs. BCL-XL inhibition via navitoclax) and patient selection (FLT3-mutated subgroup vs. unselected advanced myeloid). (novelty: 3)

Open questions

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