All-Oral Decitabine and Cedazuridine Plus Venetoclax Demonstrates Strong Clinical Activity in Newly Diagnosed Acute Myeloid Leukemia

Clinical Summary:

• Design/Population: This phase 1/2 trial evaluated an all-oral regimen of decitabine and cedazuridine plus venetoclax in older adults and patients with newly diagnosed acute myeloid leukemia (AML) who were ineligible for intensive induction chemotherapy. 
• Key Outcomes: The combination demonstrated no clinically meaningful drug–drug interactions and achieved a complete response rate of 47%, and a complete response/complete response with incomplete hematologic recovery rate of 63% in the pivotal phase 2b cohort. The safety profile was characterized primarily by expected myelosuppressive toxicities.
• Clinical Relevance: These findings support this all-oral regimen as a potential treatment option for patients who are ineligible for intensive chemotherapy, offering a more convenient alternative to parenteral hypomethylating agent-based therapy. 

Results from the phase 1/2 ASCERTAIN-V trial demonstrated that an all-oral regimen of decitabine and cedazuridine plus venetoclax produced meaningful clinical activity without clinically significant drug-drug interactions in patients with newly diagnosed acute myeloid leukemia (AML) who were ineligible for intensive chemotherapy, supporting a more convenient treatment approach.

“For patients with AML who are 75 years of age or older or who are ineligible for intensive induction chemotherapy, azacitidine or decitabine plus venetoclax is the standard of care, but parenteral administration imposes a burden on patients and providers,” stated Gail Roboz, MD, Weill Cornell Medicine, New York, New York, and coauthors. “Oral decitabine–cedazuridine, approved in Europe for AML, has pharmacokinetic properties equivalent to those of intravenous decitabine but provides limited survival benefit as monotherapy.”

In this multicenter, open-label trial, 189 patients who were ≥75 years of age or ineligible for intensive chemotherapy received oral decitabine and cedazuridine plus venetoclax. To reduce treatment-related myelosuppression observed during phase 1 (n = 30), schedule modifications were encouraged in the pivotal phase 2b cohort (n = 101) after bone marrow blast clearance. 

The primary end points were venetoclax pharmacokinetics with and without decitabine and cedazuridine during phase 1/2a and complete response during phases 2a (n = 58) and 2b. 

At analysis, no clinically meaningful drug-drug interactions were observed between decitabine, cedazuridine, and venetoclax. 

In the phase 2b cohort, the complete response rate was 47%, and the combined complete response or complete response with incomplete hematologic recovery rate was 63%. Median overall survival was 15.5 months. 

The most common grade ≥3 adverse events in the phase 2b cohort included anemia (30%), neutropenia (26%), and febrile neutropenia (25%). The mortality rate was 3% at 30 days and 10% at 60 days.

“All-oral decitabine–cedazuridine plus venetoclax caused no drug interactions and resulted in a complete response in nearly half the patients, with myelosuppressive effects,” concluded Dr Roboz et al. 

Source:

Roboz GJ, Zeidan AM, Mannis GN, et al. All-oral treatment of newly diagnosed acute myeloid leukemia. N Engl J Med. Published online June 3, 2026. doi: 10.1056/NEJMoa2510223