All-Oral Decitabine-Cedazuridine Plus Venetoclax Shows Good Tolerability in Newly Diagnosed AML: NEJM
USA: A phase 1-2 trial found that an all-oral combination of decitabine-cedazuridine and venetoclax was well tolerated in patients with newly diagnosed acute myeloid leukemia (AML) who were not candidates for intensive chemotherapy. The regimen did not increase higher-grade toxic effects beyond expected myelosuppressive events, highlighting its potential as an effective and more convenient treatment option for this vulnerable patient population.
The findings, published in the New England Journal of Medicine, come from a study led by Dr. Gail J. Roboz of Weill Cornell Medicine and NewYork-Presbyterian Hospital, New York, and colleagues. The researchers evaluated whether an entirely oral treatment approach could provide outcomes comparable to current hypomethylating agent-based regimens while reducing the burden associated with injectable therapies.
Older adults with AML or those unable to undergo intensive induction chemotherapy are typically treated with azacitidine or decitabine combined with venetoclax. However, these therapies require repeated parenteral administration, creating logistical challenges for patients and healthcare providers. Oral decitabine–cedazuridine has pharmacokinetic properties similar to intravenous decitabine, making it a potential alternative when combined with venetoclax.
To investigate this approach, researchers conducted the multicenter, open-label phase 1–2 ASCERTAIN-V trial involving 189 patients aged 75 years or older or those considered ineligible for intensive chemotherapy. Participants received oral decitabine–cedazuridine together with oral venetoclax. Following observations of treatment-related myelosuppression during phase 1, dosing schedules were adjusted in the pivotal phase 2b after bone marrow blast clearance to improve tolerability. The primary endpoints included assessment of drug-drug interactions and complete response rates.
Key findings from the study include:
- The trial enrolled 189 patients, including 30 in phase 1, 58 in phase 2a, and 101 in the pivotal phase 2b cohort.
- No clinically meaningful drug-drug interactions were detected between decitabine–cedazuridine and venetoclax.
- In the phase 2b cohort, the complete response rate was 47%, while the combined complete response and complete response with incomplete hematologic recovery rate reached 63%.
- Median overall survival in the pivotal phase 2b cohort was 15.5 months.
- The most common grade 3 or higher adverse events were anemia (30%), neutropenia (26%), and febrile neutropenia (25%), reflecting expected myelosuppressive effects.
- Early mortality remained relatively low, with rates of 3% at 30 days and 10% at 60 days.
The regimen showed meaningful clinical activity with an expected safety profile, primarily marked by myelosuppressive toxicities. No clinically significant drug-drug interactions were observed between decitabine–cedazuridine and venetoclax.
Overall, the findings suggest that all-oral decitabine–cedazuridine plus venetoclax may offer a convenient alternative to injectable hypomethylating agent-based therapy for patients with newly diagnosed AML who are ineligible for intensive chemotherapy, achieving complete remission in nearly half of treated patients.
Reference:
Roboz GJ, Zeidan AM, Mannis GN, Montesinos P, Arnan M, Savona MR, Odenike O, McCloskey JK, Amin HV, Fathi AT, Bernal Del Castillo T, Rodríguez-Macías G, Liesveld JL, Im AP, Cerny J, Gentile TC, Oganesian A, Chan D, Wan Y, Dijkstra M, Keer HN, Griffiths EA, DiNardo CD. All-Oral Treatment of Newly Diagnosed Acute Myeloid Leukemia. N Engl J Med. 2026 Jun 4;394(21):2107-2116. doi: 10.1056/NEJMoa2510223. PMID: 42235013.
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