ASTX727 + Venetoclax combination (CMML / MDS-MPN)

Current understanding

Oral decitabine/cedazuridine (ASTX727) combined with the BCL-2 inhibitor venetoclax is being evaluated in a randomized phase II trial against ASTX727 monotherapy in patients with chronic myelomonocytic leukemia (CMML) and MDS/MPN with excess blasts. The rationale mirrors the established HMA + venetoclax backbone used in AML, but uses an all-oral HMA platform and targets the CMML/MDS-MPN overlap population specifically. Evidence is currently trial-early.

Evidence log

• 2026-09-21 — Metronomic Decitabine-Cedazuridine and Venetoclax in R/R AML, HR-MDS, HR/AP MPN: Cross-reference: a parallel phase 2 trial (trial-early) is evaluating the same ASTX727 + venetoclax doublet but with a metronomic (low-dose continuous) ASTX727 schedule in R/R AML, HR-MDS, and HR/AP MPN, extending the doublet beyond the CMML/MDS-MPN overlap population and testing an alternative dosing schedule. (novelty: 3)
• 2026-06-11 — Venetoclax in Combination With ASTX727 for the Treatment of Treatment-Naive High-Risk Myelodysplastic Syndrome or Chronic Myelomonocytic Leukemia: Phase I/II trial (trial-early) evaluating safety, optimal dosing, and efficacy of venetoclax + ASTX727 specifically in treatment-naive high-risk MDS or CMML, extending the doublet’s evaluation into the frontline setting for this overlap population. (novelty: 3)
• 2026-06-05 — A Phase II Study of Cladribine and Low Dose Cytarabine in Combination With Venetoclax, Alternating With Azacitidine and Venetoclax, in Patients With Higher-risk Myeloproliferative Chronic Myelomonocytic Leukemia or Higher-risk Myelodysplastic Syndromes With Excess Blasts: Cross-reference: a parallel phase II trial in higher-risk CMML/MDS with excess blasts is testing cladribine + low-dose cytarabine + venetoclax alternating with azacitidine + venetoclax, intensifying the HMA + BCL-2 backbone with cytotoxic chemotherapy compared to this all-oral ASTX727 + venetoclax doublet. (novelty: 3)
• 2026-06-05 — Venetoclax and Azacitidine for the Treatment of Relapsed or Refractory High-Risk Myelodysplastic Syndrome or Chronic Myelomonocytic Leukemia: Cross-reference: a parallel phase I/II trial is evaluating the injectable analog — azacitidine + venetoclax — in relapsed/refractory high-risk MDS or CMML, providing comparator data for the HMA + BCL-2 backbone in the overlap/MDS population that this oral ASTX727 + venetoclax study targets. (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: the same ASTX727 + venetoclax doublet is being repurposed as post-transplant maintenance (alongside an azacitidine + venetoclax maintenance arm) in a phase I/II trial that also adds venetoclax to FluBu conditioning for AML/MDS/CMML/MDS-MPN-U, extending the oral HMA + BCL-2 platform into the post-allo-SCT setting. (novelty: 3)

Open questions

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