Highlights
- Oral decitabine/cedazuridine combined with venetoclax offers a fully oral, effective induction and consolidation regimen for older or unfit patients with newly diagnosed AML.
- Long-term follow-up demonstrates encouraging overall response rates (ORR) and measurable residual disease (MRD) negativity, particularly in de novo AML, with median overall survival (OS) around 12-13 months in this high-risk population.
- Secondary AML, often with adverse genomics and prior hypomethylating treatment exposure, shows lower response rates and shorter survival, underscoring the need for innovative strategies in this subgroup.
- Oral administration improves patient convenience and reduces healthcare resource burden, with favorable safety profiles consistent with previous intravenous hypomethylating agent plus venetoclax studies.
Background
Acute myeloid leukemia (AML) is predominantly a disease of older adults, with median age at diagnosis around 68 years. Many patients are unfit for intensive induction chemotherapy due to age, frailty, or comorbidities. Hypomethylating agents (HMAs) such as azacitidine and decitabine combined with venetoclax, a selective BCL-2 inhibitor, have become the standard frontline care for these patients, substantially improving remission rates and survival over HMA monotherapy. However, traditional HMA administration is parenteral, requiring frequent clinic visits and posing a significant burden on elderly or frail patients.
The development of an oral formulation of decitabine combined with cedazuridine, a cytidine deaminase inhibitor that increases oral bioavailability, enables an entirely oral HMA regimen. Early-phase studies demonstrate pharmacokinetic equivalence to intravenous decitabine. Moreover, the combination of oral decitabine/cedazuridine with oral venetoclax aims to further improve accessibility and convenience while maintaining efficacy.
Key Content
Clinical Development and Evidence for Oral Decitabine/Cedazuridine Plus Venetoclax
Oral decitabine/cedazuridine received regulatory approval in Europe for AML and myelodysplastic syndrome based on pharmacokinetic and clinical data establishing equivalence to intravenous decitabine. The phase 1-2 ASCERTAIN-V trial explored the combination of oral decitabine/cedazuridine with oral venetoclax in patients aged ≥75 or ineligible for intensive induction. No pharmacokinetic drug interactions were observed, confirming compatibility. In the pivotal phase 2b cohort (N=101), a complete remission (CR) rate of 47% and composite CR (CR + CRi) of 63% were seen, with median overall survival (OS) of 15.5 months and manageable myelosuppressive toxicities (N Engl J Med. 2026;394(21):2107–2116) [PMID: 42235013].
Long-term Follow-up of Oral Decitabine/Cedazuridine Plus Venetoclax: Real-World Phase II Data
The recent single-center phase II trial led by Htut et al. (Haematologica, 2026) reports extended follow-up outcomes in 68 older or unfit patients with newly diagnosed AML receiving oral decitabine/cedazuridine plus venetoclax. Median age was 79 years, with over half of patients having ECOG performance status ≥2, reflecting a high-risk cohort.
The study stratified outcomes by AML subtype — 32 patients had de novo AML and 36 had secondary AML (post myelodysplastic syndrome or prior hypomethylating agent exposure in 16%). The overall response rate (ORR) was 75% in de novo AML versus 58% in secondary AML. MRD negativity among responders was comparable (58% vs 56%). Median OS was 12.7 months (95% CI, 9.1–20.3) for de novo AML and 7.2 months (95% CI, 3.6–29.9) for secondary AML (P=0.61). Relapse-free survival (RFS) was similar between groups (9.2 vs 11.7 months, P=0.56). No significant differences were observed in relapse rates or non-relapse mortality.
These findings reinforce the clinical activity and tolerability of an all-oral regimen, highlighting the particular vulnerability and therapeutic challenge of secondary AML where novel agents and combination strategies warrant exploration.
Comparative and Complementary Studies
Several studies have compared venetoclax with HMAs to conventional intensive induction in various populations. For younger, fit patients, randomized trials demonstrate that venetoclax plus decitabine yields noninferior remission rates and improved safety over intensive chemotherapy (Blood 2025; 145(22):2645-2655) [PMID: 40009498].
In elderly relapsed/refractory AML, venetoclax with azacitidine demonstrates comparable efficacy but increased rash and diarrhea compared to decitabine-based D-CAG regimens (Chinese J Hematol, 2026) [PMID: 41991313]. Additionally, VD-CAG (venetoclax plus decitabine, cytarabine, aclarubicin, G-CSF) shows high remission rates even in secondary AML, warranting further validation in larger cohorts (Ann Hematol, 2024) [PMID: 39589493].
The prognostic importance of achieving MRD negativity with venetoclax-HMA regimens has been consistently demonstrated, associating with longer remission duration and overall survival (Blood Adv 2021;5(7):1876-1883) [PMID: 33792630]. This supports MRD-guided treatment modifications in this population.
Mechanistic and Translational Insights
Decitabine and cedazuridine inhibit DNA methyltransferases, leading to hypomethylation and reactivation of tumor suppressor genes, while venetoclax targets the BCL-2 anti-apoptotic pathway, disrupting leukemic cell survival. Their combination synergistically induces apoptosis in AML blasts, including those with adverse-risk mutations.
Prior exposure to HMAs and complex genomic features in secondary AML may confer resistance through epigenetic and apoptotic pathway alterations, explaining reduced response rates and emphasizing the need for novel agents or combination therapies addressing these mechanisms.
Expert Commentary
The availability of a fully oral combination of decitabine/cedazuridine plus venetoclax represents a significant advance for older or unfit AML patients who often face logistical challenges with parenteral therapy. The favorable pharmacokinetic profile and absence of drug interactions facilitate outpatient management and may improve quality of life.
While response rates and survival outcomes approximate those reported for intravenous regimens, this approach particularly benefits patients with de novo AML. Secondary AML patients, with more complex disease biology and prior HMA exposure, continue to experience inferior outcomes, underscoring an unmet clinical need.
The long median follow-up in the recent phase II study advances our understanding of durability and safety over time. MRD negativity remains a valuable biomarker for prognosis and should be incorporated into routine clinical assessment to guide therapeutic decision-making.
Limitations include the single-center design and limited sample size for subgroup analyses. Larger randomized trials comparing oral versus intravenous hypomethylating agent regimens combined with venetoclax are warranted to validate findings and optimize schedules, including modifications to reduce myelosuppression.
Guideline bodies such as NCCN now incorporate venetoclax with HMAs as frontline therapy for patients unfit for intensive induction; oral regimens may soon be integrated with appropriate dosing and monitoring recommendations.
Conclusion
Oral decitabine/cedazuridine combined with venetoclax offers an effective, safe, and convenient all-oral frontline therapeutic option for older or unfit patients with newly diagnosed AML. Response rates and long-term survival outcomes in de novo AML are encouraging, with manageable safety profiles and substantial MRD negativity rates.
However, secondary AML remains a challenging subgroup with lower response rates and survival despite this therapy, emphasizing the need for continued research into novel agents and personalized treatment strategies.
The oral regimen has the potential to improve patient quality of life and reduce healthcare resource use, aligning with the broader trend toward outpatient and patient-centered oncology care.
Future directions include larger multicenter studies, MRD-driven treatment adaptations, and exploration of combination approaches to further enhance outcomes, particularly in high-risk AML subtypes.
References
- Htut TW et al. Long-term follow-up of oral decitabine/cedazuridine plus venetoclax for older or unfit patients with newly diagnosed acute myeloid leukemia. Haematologica. 2026 Jul 2. PMID: 42389833.
- Wang ES et al. All-Oral Treatment of Newly Diagnosed Acute Myeloid Leukemia. N Engl J Med. 2026 Jun 4;394(21):2107-2116. PMID: 42235013.
- DiNardo CD et al. Venetoclax plus azacitidine or decitabine in patients with newly diagnosed acute myeloid leukemia: Long term follow-up from a phase 1b study. Am J Hematol. 2021 Feb;96(2):208-217. PMID: 33119898.
- Kadia TM et al. Venetoclax and decitabine vs intensive chemotherapy as induction for young patients with newly diagnosed AML. Blood. 2025 May 29;145(22):2645-2655. PMID: 40009498.
- Sun Y et al. Comparison of efficacy and safety of venetoclax plus azacitidine versus D-CAG regimen in elderly patients with relapsed or refractory AML. Zhonghua Xue Ye Xue Za Zhi. 2026 Mar;47(3):262-269. PMID: 41991313.
- Feng M et al. Venetoclax plus D-CAG for elderly or unfit patients with newly diagnosed AML: a multicenter prospective study. Ann Hematol. 2024 Dec;103(12):5315-5323. PMID: 39589493.
- Swerdlow SH et al. Prognostic value of measurable residual disease after venetoclax and decitabine in AML. Blood Adv. 2021 Apr 13;5(7):1876-1883. PMID: 33792630.