On May 13, the U.S. FDA granted approval to the oral combination of decitabine and cedazuridine tablets (Inqovi, Taiho Oncology, Inc.) with venetoclax for adults with newly diagnosed acute myeloid leukemia (AML) who are aged 75 years or older or have comorbidities that make them ineligible for intensive induction chemotherapy.
When Intensive AML Therapy Is Not Feasible
AML is a highly aggressive hematologic malignancy characterized by clonal proliferation of immature myeloid cells and disruption of normal hematopoiesis. AML primarily affects older adults, with a median age at diagnosis of 68-70 years. While younger patients may achieve 5-year OS rates approaching 40-50%, outcomes in older adults often remain below 10-15%.
In this population, AML is frequently associated with adverse cytogenetic and molecular features, increased comorbidity burden, frailty and reduced tolerance to intensive chemotherapy, contributing to poor clinical outcomes and major therapeutic challenges.
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How Does Decitabine/Cedazuridine Plus Venetoclax Work in AML?
Decitabine is a hypomethylating agent (HMA) widely used in AML and myelodysplastic neoplasms (MDS). By inhibiting DNA methyltransferases, it reduces aberrant methylation and reactivates genes involved in differentiation, apoptosis and cell-cycle regulation. Through epigenetic reprogramming and increased apoptotic priming, decitabine enhances leukemic sensitivity to therapies such as venetoclax.
Cedazuridine is not directly anti-leukemic but functions as a cytidine deaminase inhibitor that prevents rapid degradation of oral decitabine in the gastrointestinal tract and liver. This allows orally administered decitabine to achieve systemic exposure comparable to intravenous decitabine. Previously used in MDS and CMML, it serves as a bioavailability enhancer.
Venetoclax selectively targets BCL-2-dependent leukemic cells by restoring mitochondrial apoptotic signaling. Given the dependence of AML blasts and leukemic stem cells on BCL-2-mediated survival pathways, venetoclax has become a central component of lower-intensity AML therapy. Together with decitabine/cedazuridine, it forms a synergistic regimen that combines epigenetic modulation with targeted apoptosis.
Clinical Response and Safety Profile
Efficacy for this combination regimen was evaluated in Study ASTX727-07 (ClinicalTrials.gov identifier: NCT04657081), a single-arm, open-label trial involving 101 patients with newly diagnosed AML who were ineligible for intensive induction chemotherapy.
Key findings included:
- Complete remission (CR) rate: 41.6% (42/101 patients; 95% CI: 31.9-51.8)
- Median time to CR: 2 months (range: 0.4-15.3 months)
- Median duration of CR: not reached at the time of analysis (range: 0.5-16.3 months)
The FDA approval was based on CR and duration of CR (DoCR), defined as the time from first documented CR until relapse or death from any cause.
The prescribing information includes warnings and precautions for:
- Myelosuppression
- Embryo-fetal toxicity
Recommended Dosage and Regulatory Review
The recommended dose of Inqovi in combination with Venetoclax is one tablet containing 35 mg decitabine and 100 mg cedazuridine administered orally once daily on days 1-5 of each 28-day cycle, continued until disease progression or unacceptable toxicity, with venetoclax administered according to prescribing guidelines.
The FDA review was conducted under Project Orbis, a collaborative framework designed to facilitate concurrent international review of oncology therapeutics. For this review, the FDA collaborated with Health Canada, while applications may still be under review at other participating regulatory agencies. Decitabine and cedazuridine also received Orphan Drug Designation for this AML indication.
What Makes This Approval Significant
Although venetoclax has been available as an oral agent for AML for several years, prior venetoclax-based regimens still relied on parenteral hypomethylating agents. This approval introduces the first fully oral HMA/venetoclax combination for newly diagnosed AML.
Particularly in older adults, therapy is now evaluated not only by remission rates, but also by quality-of-life considerations and treatment burden. In this context, fully oral regimens may reduce dependence on infusion-based care, simplify treatment delivery and improve the day-to-day experience for many patients.
Healthcare professionals and patients are encouraged to report adverse events to the FDA MedWatch System.