Oral Venetoclax Combo Elicits Responses, Survival in Newly Diagnosed AML

“In newly diagnosed patients with AML ineligible for intensive chemotherapy, the all-oral regimen of decitabine and venetoclax represents a potential new standard of care for these patients," according to study author Gail J. Roboz, MD.

Among those with newly diagnosed acute myeloid leukemia (AML) who are ineligible to receive intensive chemotherapy, complete responses (CRs) and encouraging survival outcomes occurred following treatment with all-oral venetoclax (Venclexta) plus decitabine/cedazuridine (DEC-C), according to a presentation on data results from the ASCERTAIN-V (ASTX727-07) trial (NCT04975919) during the 2025 European Hematology Association Congress.¹

Across the phase 1 (n = 30), phase 2A (n = 58), and phase 2B (n = 101) portions of the trial, the CR rates were 40.0% (95% CI, 22.7%-59.4%), 37.9% (95% CI, 25.5%-51.6%), and 46.5% (95% CI, 36.5%-56.7%), respectively. The CR with incomplete hematologic recovery (CRi) rates were 23.3%, 27.6%, and 16.8%; the CR with partial hematologic recovery (CRh) recovery rates were 16.7%, 20.7%, and 5.0%, respectively.

Further efficacy data showed that in phase 1, the CR+CRi rate was 63.3% (95%, 43.9%-80.1%); in phase 2A this was 65.5% (95% CI, 51.9%-77.5%), and was 63.4% (95% CI, 53.2%-72.7%) in phase 2B. The CR+CRh rates were 56.7% (95% CI, 37.4%-74.5%), 58.6% (95% CI, 44.9%-71.4%), and 51.5% (95% CI, 41.3%-61.6%), respectively. The CR+CRi+CRh rates were 63.3% (95% CI, 43.9%-80.1%), 65.5% (95% CI, 51.9%-77.5%), and 63.4% (95% CI, 53.2%-72.7%), respectively.

“Oral decitabine and venetoclax resulted in comparable safety response and survival rates to parenteral [azacitidine] and venetoclax as described in VIALA-A [NCT02993523], although of course, cross-trial comparisons cannot really be made,” lead study author, Gail J. Roboz, MD, professor of medicine and director of the Clinical and Translational Leukemia Program at the Weill Medical College of Cornell University and the NewYork-Presbyterian Hospital, of Weill Cornell Medicine in New York, NY, said in an oral presentation of the data. “In newly diagnosed patients with AML ineligible for intensive chemotherapy, the all-oral regimen of decitabine and venetoclax represents a potential new standard of care for these patients.”

Combinations with venetoclax and azacitidine, decitabine, or low-dose cytarabine for patients aged 75 years or older with AML and are ineligible for intense induction chemotherapy have accelerated approvals in the United States and European Union, based on phase 1/2 studies.^2,3 Outcomes were found to be similar with venetoclax plus either azacitidine and decitabine in newly diagnosed patients; however, optimal duration of venetoclax dosing is unclear, and Roboz emphasized the parenteral decitabine or azacitidine is linked with significant treatment burden, leading to the ASCERTAIN-V investigation.

Although oral decitabine alone has a similar pharmacokinetic area under the curve (AUC) exposure to the intravenous formulation, data showed that survival outcomes were lower, with a median overall survival (OS) of 9.0 months.⁵

In the open-label, multicenter, nonrandomized interventional ASCERTAIN-V trial, investigators evaluated an all-oral regimen of decitabine and venetoclax in elderly patients with newly diagnosed AML or with comorbidities precluding first-line intensive induction chemotherapy.

Dosing was differentiated in the phase 1/phase 2A and phase 2B portions. In cycle 1 of phase 1 and phase 2, decitabine/cedazuridine (DEC-C) plus 100 mg of venetoclax at a ramp-up dose was given on day 1, followed by DEC-C plus 200 mg of venetoclax on day 2, DEC-C plus 400 mg of venetoclax on days 3 to 5, and venetoclax alone at 400 mg on days 6 to 28. In cycles 2 and beyond, DEC-C plus 400 mg of venetoclax was given on days 1 to 5, followed by 400 mg of venetoclax alone on days 6 to 28. Dosing continued until disease progression or unacceptable toxicity.

Cycles 1 and 2 and beyond of the phase 2B section was the same dosing as the phase 1/2A sections.

All cycles were 28 days each. Pharmacokinetic studies occurred in cycles 1 and 2 and beyond in the phase 2B section vs cycle 2 alone in the phase 1/2A sections.

The primary end point in phase 1 were effects on DEC-C on venetoclax pharmacokinetic exposures, with secondary end points being venetoclax’s effects on DEC-C pharmacokinetics, CR, CRi, CRh, OS, and safety. In the phase 2A portion, the coprimary end points were DEC-C effects on venetoclax pharmacokinetic exposures and CR rate, based on European LeukemiaNet (ELN) 2017 criteria, with secondary end points being CR, CRi, CRh, OS, duration of response (DOR), and safety. Finally, in the phase 2B section, the primary end point was CR rate based on ELN 2017 criteria; secondary end points were venetoclax effect on DEC-C pharmacokinetics in cycles 1 to 3, CRi, CRh, OS, DOR, and safety.

Across the phase 1 (n = 30), phase 2A (n = 58), and phase 2B (n = 101) portions, the median age was 78 years (range, 66-87), 75 years (range, 56-91), and 78 years (range, 63-88). More than half of patients overall had an ECOG performance status of 1 (51%), and 40.6% were classified as intermediate risk via ELN 2017. No mutation profiling via next-generation sequencing was done at baseline in phase 1; in phases 2A and 2B, TP53 was reported in 5.2% and 16.8% of patients, respectively. There was also FLT3 (3.4% and 11.9%), IDH1 (10.3% and 5.9%), IDH2 (10.3% and 11.9%), and NPM1 (13.8% and 12.9%), respectively.

Pharmacokinetic results showed that there were no drug-drug interactions between DEC-C and venetoclax in both the phase 1 and phase 2A portions. Specifically, the geometric least squares mean ratio was 102.0% (90% CI, 87.25%-119.3%) for the AUC_0-24 parameters and 97.30% (90% CI, 85.31-111.0) for the C_max parameter. These data met the primary end point for phase 1 and a secondary end point for phase 2, Roboz said.

The median follow-up in phase 1 was 34.3 months, 26.0 months in phase 2A, and 11.2 moths in phase 2B.

Additional efficacy results showed that in phases 1, 2A, and 2B, the median time to CR was 1.9 months (range, 0.9-9.6), 2.4 months (range, 0.8-12.2), and 2.4 months (range, 0.7-15.3), respectively. Responders continued to be in CR at 9 months in 75.0% (95% CI, 40.8%-91.2%), 76.2% (95% CI, 51.9%-89.3%), and 80.0% (95% CI, 63.9%-89.5%) across the phase 1, 2A, and 2B portions, respectively.

Roboz added that a subgroup analysis of the phase 2B section showed consistent CR rates across prespecified subgroups, including age, sex, region, baseline ECOG performance status, prior systemic treatment, and cytogenetic classification.

The median OS in the phase 1 portion was 6.8 months (95% CI, 4.3-19.5); in the phase 2A portion, the median OS was 14.5 months (95% CI, 8.1-18.2) and, in the phase 2B portion, this was 15.5 months (95% CI, 7.6-not estimable).

Forty-nine patients in the phase 2B portion with CR/CRh/CRi were evaluated for minimal residual disease (MRD) by local multiparameter flow cytometry. Data showed that 55.1% (n = 27) of patients achieved MRD negativity at any time; for those who were MRD negative, the median OS was NE (95% CI, 12.1-NE) and was 15.5 months (95% CI, 7.4-NE) for those who were MRD negative.

“It should be caveated right away that neither the time point nor the methodology for MRD was standardized, but we are doing our best to provide this important data,” Roboz cautioned.

Dose adjustments were also studied as part of the analysis. Patients completed a median 4 (range, 1-33), 5 (range, 1-26), and 4 (range, 1-15) cycles of treatment in the phase 1, 2A, and 2B portions, respectively. Roboz noted that the 3.3% of patients in phase 1 underwent bone marrow examination, which then increased to 15.5% in phase 2A and to 31.7% of patients in phase 2B.

Regarding safety, all but 1 patient experienced any adverse event (AE); grade 3 or higher AEs occurred in 86.7%, 91.4%, and 98.0% of patients on phase 1, phase 2A, and phase 2B, respectively.

The most common treatment-related adverse events (TRAEs) across all phases were anemia (25.9%), neutropenia (21.2%), febrile neutropenia (20.6%), and thrombocytopenia (14.3%). The most common non-hematological TRAEs were low-grade and gastrointestinal-related, comprising nausea (any-grade, 19%; grade ≥3, 0%), decreased appetite (16.4%; 0.5%), constipation (12.7%; 0.5%). The 30- and 60-day mortality rates were 3.0% and 9.9%, respectively, in phase B. These were due to AE (30-day, n = 3; 60-day, n = 7), and disease progression (n = 3).

AEs that led to treatment discontinuation occurred in 10.3% of patients on phase 2A and 8.9% of patients on phase 2B, treatment interruption (phase 1, 46.7%; phase 2A, 65.5%; phase 2B, 68.3%), dose reduction (23.3%; 8.6%; 13.9%), and death (10.0%; 12.1%; and 15.8%).

Disclosures: Roboz cited industry affiliations with Abbvie, Amgen, AstraZeneca, Astellas, Bristol Myers Squibb, Caribou Biosciences, Celgene, Daiichi Sankyo, Ellipses Pharma, Genoptix, Gilead, GlaxoSmithKline, Geron, Glycomimetics, Janssen, Jasper Pharmaceuticals, Jazz Pharmaceuticals, Molecular Partners, Morphosys, Neogenomics, Novartis, Oncoprecision, Oncoverity, Pfizer, Rigel, Roche, Servier, Telix, Syndax.

References

1. Roboz GJ, Zeidan AM, Mannis GN, et al. All-oral decitabine-cedazuridine (DEC-C) + venetoclax (VEN) in patients with newly diagnosed acute myeloid leukemia (AML) ineligible for induction chemotherapy: phase 1/2 clinical trial results. Presented at: European Hematology Association Congress; June 12-15, 2025; Milan, Italy. Abstract S135.
2. DiNardo CD, Pratz KW, Letai A, et al. Safety and preliminary efficacy of venetoclax with decitabine or azacitidine in elderly patients with previously untreated acute myeloid leukaemia: a non-randomised, open-label, phase 1b study. Lancet Oncol. 2018;19(2):216-228. doi:10.1016/S1470-2045(18)30010-X
3. Wei AH, Strickland SA, Hou J-Z, et al.Venetoclax combined with low-dose cytarabine for previously untreated patients with acute myeloid leukemia: results from a phase Ib/II study. J Clin Oncol. 2019;37(15):1277-1284. doi:10.1200/JCO.18.01600
4. Zeidan AM, Platzbecker U, Garcia-Manero G, et al. Longer-term benefit of luspatercept in transfusion-dependent lower-risk myelodysplastic syndromes with ring sideroblasts. Blood. 2022;140(20):285-290. doi:10.1182/blood.2022016171
5. Geissler K, Koristek Z, Del Castillo TB, et al. Oral decitabine/cedazuridine versus intravenous decitabine for acute myeloid leukaemia: A randomised, crossover, registration, pharmacokinetics study. Br J Haematol. 2024;205(5):1734-1745. doi:10.1111/bjh.19741