SUMMARY: The FDA on May 13, 2026, approved an oral combination of Decitabine and Cedazuridine tablets (INQOVI®) with Venetoclax for the treatment of newly diagnosed Acute Myeloid Leukemia (AML) in adults 75 years or older, or who have comorbidities that preclude the use of intensive induction chemotherapy.
The American Cancer Society estimates that in 2026, 22,720 new cases of Acute Myeloid Leukemia (AML) will be diagnosed in the United States and 11,500 patients will die of the disease. AML is one of the most common types of leukemia in adults and can be considered as a group of molecularly heterogeneous diseases with different clinical behavior and outcomes. A significant percentage of patients with newly diagnosed AML are not candidates for intensive chemotherapy or have disease that is refractory to standard chemotherapy.
Advancing Convenience Without Compromising Efficacy
The treatment landscape for older adults with AML who are not candidates for intensive induction chemotherapy has evolved significantly with the introduction of Venetoclax-based combinations. However, despite improved outcomes, current standards of care still rely heavily on parenteral HypoMethylating Agents (HMAs), requiring frequent visits to healthcare facilities and creating substantial logistical and quality-of-life challenges for patients and caregivers.
Findings from the Phase 1–2 ASCERTAIN-V trial offer compelling evidence that an entirely oral regimen consisting of Decitabine–Cedazuridine (INQOVI®) and Venetoclax (VENCLEXTA®) may provide a clinically effective alternative, while reducing the treatment burden associated with injectable therapies. The study evaluated the safety, pharmacokinetics, and efficacy of this oral combination in patients with newly diagnosed AML who were either 75 years of age or older or considered unsuitable for intensive chemotherapy due to significant comorbidities.
The Rationale for an All-Oral Approach
Venetoclax combined with Azacitidine or Decitabine has become the established frontline treatment for patients with AML who are ineligible for intensive chemotherapy. While these regimens have demonstrated meaningful survival benefits, they require repeated administration of intravenous or subcutaneous HMAs over several days during each treatment cycle.
Decitabine–Cedazuridine was developed to address this challenge by delivering oral Decitabine exposure comparable to IV administration. Cedazuridine inhibits cytidine deaminase, preventing premature degradation of Decitabine in the gastrointestinal tract and allowing therapeutic systemic exposure through oral dosing. Previous studies have demonstrated pharmacokinetic equivalence between oral Decitabine–Cedazuridine and intravenous Decitabine, paving the way for evaluation in AML.
The ASCERTAIN-V investigators sought to determine whether combining oral Decitabine–Cedazuridine with oral Venetoclax could maintain the efficacy expected from HMA-Venetoclax therapy while improving treatment convenience and potentially enhancing patient experience.
Study Design and Patient Population
ASCERTAIN-V was a multicenter, open-label, nonrandomized Phase 1–2 study conducted across 34 academic and community treatment centers in the United States, Canada, and Spain.
The trial enrolled patients with newly diagnosed AML who met one of two criteria:
- Age 75 years or older, or
- Younger patients with significant comorbidities that precluded intensive chemotherapy.
Qualifying comorbid conditions included severe cardiac or pulmonary disease, impaired renal function, moderate hepatic dysfunction, or reduced performance status.
All participants received:
- Oral Decitabine–Cedazuridine (35 mg/100 mg) on days 1–5 of each 28-day cycle
- Oral Venetoclax, initiated with a standard ramp-up schedule and continued at 400 mg daily
A total of 189 patients were enrolled across the study, including 101 patients in the pivotal Phase 2b cohort that served as the primary efficacy population.
Pharmacokinetic Findings Confirm Combination Feasibility
A key objective of the study was to determine whether coadministration of Venetoclax altered exposure to Decitabine–Cedazuridine or vice versa.
Results demonstrated no clinically meaningful drug–drug interactions between the two agents. Pharmacokinetic analyses showed that systemic Decitabine exposure remained consistent with previous studies evaluating oral Decitabine–Cedazuridine alone, supporting the feasibility of combining the two oral therapies without compromising drug delivery. These findings are particularly important because maintaining predictable drug exposure is essential when replacing established IV regimens with oral alternatives.
Encouraging Clinical Activity in a High-Risk Population
The pivotal Phase 2b cohort met its predefined efficacy objective and demonstrated substantial antileukemic activity.
Among evaluable patients:
- Complete remission (CR) was achieved in 47% of patients.
- The combined rate of Complete Remission and Complete Remission with incomplete hematologic recovery (CR + CRi) reached 63%.
- Median Overall Survival was 15.5 months.
- Among patients achieving Complete Remission, 75% maintained their response at 12 months.
Minimal Residual Disease (MRD) analyses, although exploratory and not standardized, also provided encouraging signals. More than half of responding patients achieved MRD negativity by multiparameter flow cytometry, a finding often associated with deeper remissions and improved long-term outcomes.
Managing Myelosuppression Through Adaptive Treatment Strategies
As expected with Venetoclax-based AML therapy, myelosuppression remained the principal toxicity observed during treatment.
The most common grade 3 or higher adverse events in the pivotal phase 2b cohort included Anemia (30%), Neutropenia (26%) and Febrile neutropenia (25%). Early mortality remained within expected ranges for this older and medically complex population, with 30-day and 60-day mortality rates of 3% and 10%, respectively.
Importantly, the investigators incorporated treatment modifications during the Phase 2b portion of the study to reduce prolonged cytopenias. Early bone marrow assessments were used to confirm blast clearance before completion of a full 28-day course of Venetoclax. Once remission was documented, Venetoclax exposure was shortened and treatment schedules for both agents were adjusted to facilitate hematologic recovery.
This strategy appeared successful. As treatment progressed, the duration of Venetoclax administration decreased, accompanied by reductions in serious adverse events and febrile neutropenia. Similarly, Decitabine–Cedazuridine exposure was individualized over time, supporting a treatment paradigm that emphasizes intensive disease control during induction followed by tailored maintenance of remission.
Clinical Implications for Practice
The ASCERTAIN-V results reinforce the growing recognition that effective AML treatment can potentially be delivered outside traditional infusion-based settings.
For clinicians, the findings highlight several practical considerations:
- Early bone marrow evaluation may help identify patients who can benefit from abbreviated Venetoclax exposure.
- Dose modifications should be incorporated proactively to mitigate prolonged cytopenias.
- Growth factor support should be considered in patients with severe or persistent neutropenia.
- Venetoclax dosing must be adjusted appropriately when azole antifungal prophylaxis is required.
- Close monitoring remains essential despite the convenience of oral administration.
The trial also underscores the importance of adherence monitoring, as treatment success with oral regimens depends on consistent medication use. Investigators reported high adherence rates through the use of patient diaries and pill counts.
A Potential Alternative to Infusion-Based HMA-Venetoclax Therapy
Cross-trial comparisons should be interpreted cautiously, particularly given the single-arm design of ASCERTAIN-V. Nevertheless, the observed remission rates, overall survival outcomes, and safety profile appear broadly comparable to those reported historically with Azacitidine-Venetoclax and IV Decitabine-Venetoclax combinations.
Given that oral Decitabine–Cedazuridine achieves systemic exposure equivalent to intravenous Decitabine, the study supports the concept that an all-oral HMA-Venetoclax regimen can deliver clinically meaningful outcomes without introducing new safety concerns.
Beyond efficacy, the potential reduction in travel, clinic visits, caregiver burden, and treatment-associated disruption may represent a significant advantage for older patients who often face mobility limitations and competing medical challenges.
Looking Ahead
The ASCERTAIN-V trial marks an important step toward more patient-centered AML care. By demonstrating meaningful remission rates, durable responses, and survival outcomes with a fully oral treatment strategy, the study provides evidence that convenience and clinical efficacy do not necessarily need to be mutually exclusive.
While randomized comparative studies and formal Quality-of-Life assessments would further strengthen the evidence base, these findings suggest that oral Decitabine–Cedazuridine plus Venetoclax may emerge as a valuable frontline option for patients with newly diagnosed AML who are not candidates for intensive chemotherapy.
As the AML treatment landscape continues to evolve, the ability to deliver effective therapy through a fully oral regimen has the potential to reshape care delivery and improve the treatment experience for a vulnerable patient population.
All-Oral Treatment of Newly Diagnosed Acute Myeloid Leukemia. Roboz GJ, Zeidan AM, Mannis GN, et al. N Engl J Med 2026;394:2107-2116.
