AML remains a complex and difficult-to-treat cancer, with poor long-term outcomes. Despite therapeutic advances, the five-year survival rate for patients with AML remains low.

Across the Phase I (n = 30), Phase IIA (n = 58), and Phase IIB (n = 101) portions of the trial, the complete remission (CR) rates were 40.0%, 37.9%, and 46.5%, respectively. The rates of CR with incomplete hematologic recovery (CRi) were 23.3%, 27.6%, and 16.8%, while CR with partial hematologic recovery (CRh) was observed in 16.7%, 20.7%, and 5.0% of patients, respectively.

Additional efficacy data showed that the combined CR+CRi rates were 63.3% in Phase I, 65.5% in Phase IIA, and 63.4%  in Phase IIB. The CR+CRh rates were 56.7%, 58.6%, and 51.5% in Phases I, IIA, and IIB, respectively. The combined CR+CRi+CRh rates were identical to the CR+CRi rates across all three Phases: 63.3%, 65.5%, and 63.4%, respectively.

Although oral decitabine monotherapy provides pharmacokinetic exposure (AUC) comparable to the intravenous formulation, overall survival (OS) outcomes were lower, with a median OS of 9.0 months. Pharmacokinetic analyses demonstrated no drug-drug interaction between oral decitabine and cedazuridine (DEC-C) and venetoclax in either the Phase I or Phase IIA portions. The geometric least squares mean ratio was 102.0% for AUC₀–₂₄ and 97.30% for Cₘₐₓ. Median follow-up durations were 34.3 months in Phase I, 26.0 months in Phase IIA, and 11.2 months in Phase IIB.

Median time to CR was 1.9 months in Phase I, 2.4 months in Phase IIA, and 2.4 months in Phase IIB. At 9 months, the proportion of responders who remained in CR was 75.0% in Phase I, 76.2% in Phase IIA, and 80.0% in Phase IIB. Median OS was 6.8 months in Phase I, 14.5 months in Phase IIA, and 15.5 months in Phase IIB.

Among 49 patients in Phase IIB who achieved CR, CRi, or CRh, minimal residual disease (MRD) was assessed by local multiparameter flow cytometry. Of these, 55.1% (n = 27) achieved MRD negativity at any time. Among MRD-negative patients, median OS was not estimable, compared to 15.5 months in MRD-positive patients.

Regarding safety, all but one patient experienced at least one adverse event (AE). Grade ≥3 AEs occurred in 86.7%, 91.4%, and 98.0% of patients in Phases I, IIA, and IIB, 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%). Non-hematologic TRAEs were mostly low-grade and gastrointestinal in nature, including nausea (any Grade, 19.0%; Grade ≥3, 0%), decreased appetite (16.4%; 0.5%), and constipation (12.7%; 0.5%).

In Phase IIB, the 30-day and 60-day mortality rates were 3.0% and 9.9%, respectively. These deaths were attributed to adverse events (30-day, n = 3; 60-day, n = 7) and disease progression (n = 3).

AEs leading to treatment discontinuation occurred in 10.3% of patients in Phase IIA and 8.9% in Phase IIB. Rates of treatment interruption were 46.7% in Phase 1, 65.5% in Phase IIA, and 68.3% in Phase IIB. Dose reductions occurred in 23.3%, 8.6%, and 13.9% of patients, respectively, while death was reported in 10.0%, 12.1%, and 15.8% across the three Phases.

KOL insights: 

“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.” – Expert Opinion

Conclusion: 

For over four decades, intensive chemotherapy (IC) has remained the standard treatment for younger, fit patients with acute myeloid leukemia (AML). This approach typically involves a combination of the pyrimidine analog cytarabine and an anthracycline, most commonly in the "7+3" regimen—seven days of cytarabine plus three days of daunorubicin. Response rates with this regimen are around 60–80% in patients under 60 years old, with long-term survival rates of 30–40%.

The B-cell lymphoma 2 (BCL-2) protein is a critical factor in AML cell survival, as it regulates the mitochondrial pathway of apoptosis. Venetoclax, a BCL-2 inhibitor, combined with azacitidine or decitabine, has shown good tolerability and consistent safety profiles across dose-escalation and expansion phases in older patients with newly diagnosed AML who are not candidates for standard induction chemotherapy.