Acute myeloid leukemia (AML) is especially hard to treat in older adults and in patients who cannot tolerate intensive chemotherapy. Despite therapeutic progress, long-term survival is still limited, with a 5-year relative survival rate near 32%. Intensive chemotherapy has long been in the standard frontline, but advanced age, poor performance status and comorbidities rule this out for many newly diagnosed patients.
Venetoclax combined with a hypomethylating agent offers a lower-intensity frontline alternative for these patients. The randomized VIALE-A trial demonstrated the benefit of venetoclax plus azacitidine over azacitidine alone, showing improved response rates and OS, with extended follow-up continuing to confirm this and no new safety concerns.
Clinical trial data alone, though, cannot fully capture how a treatment performs in everyday practice. Patients treated outside trials tend to carry more comorbidities, follow different treatment patterns, and represent broader biological diversity. Real-world studies of ven-based therapy have generally reported response rates around 60% and median OS of roughly 10-15 months. Much of this evidence, though, comes from small, single-center or single-country cohorts, often lacking properly matched control groups.
The AML Real World EvidenCe Initiative was designed to address this gap, testing whether the effectiveness of venetoclax plus a hypomethylating agent seen in clinical trials holds up in routine practice.
Methods and Design
This international retrospective study included 17 academic centers across the United States, Israel, and Canada. Adults with newly diagnosed AML received first-line venetoclax plus azacitidine or decitabine, or a non-venetoclax regimen. Venetoclax treatment could have started from April 2016 and control therapy from May 2015, with data collected through August 2024.
Controls were matched 1:1 by age (<60, 60-74, or ≥75 years) and European LeukemiaNet 2017 risk. The main analysis included patients ineligible for intensive chemotherapy by Ferrara criteria (age ≥75 years or ≥1 relevant comorbidity), although these factors were not matching criteria. Additional analyses examined patients aged ≥75 and ≥80 years and stratified controls by treatment intensity; the ≥80-year subgroup was not specifically age-matched.
Key outcomes were treatment response, OS, and transfusion independence. Composite CR included CR, CR with partial hematologic recovery, and CR with incomplete marrow recovery. OS was measured from treatment initiation until death or end of follow-up. Transfusion independence was defined as ≥56 consecutive days without red blood cell or platelet transfusions, with maintenance and conversion from baseline transfusion dependence also assessed.
Patient Population and Treatment Characteristics
The study included 576 patients: 288 treated with venetoclax plus a hypomethylating agent and 288 matched controls. Of the venetoclax-treated patients:
- 66.7% were ineligible for intensive chemotherapy
- 44.8% were aged ≥75 years
- 74.5% had at least one relevant comorbidity
In this matched subgroup, most patients were from the US, 63.5% had adverse-risk disease, and about one-third had secondary acute myeloid leukemia.
Molecular features were broadly similar. TP53 mutations were present in 21.2% of venetoclax-treated patients vs 13.4% of controls, and IDH1/2 mutations in 21.2% vs 17.9%, NPM1 and FLT3-ITD frequencies were comparable. None of these differences were statistically significant.
Among intensive-chemotherapy-ineligible patients, 72.9% received venetoclax plus azacitidine and 27.1% venetoclax plus decitabine. Of the matched controls, 58.9% received high-intensity therapy and 41.1% low-intensity therapy, most commonly azacitidine or decitabine alone. Mean first-line treatment duration was longer with venetoclax-based therapy (7.2 vs 3.7 months), and hematopoietic cell transplantation was uncommon in both groups (7.3% vs 10.4%).
Venetoclax-Based Therapy Produced Higher Remission Rates
Among patients with available response assessments, composite CR was significantly higher with venetoclax plus a hypomethylating agent than with matched controls (63.7% vs 46.0%).
The difference was most pronounced against low-intensity therapy, with composite CR rates of 56.8% vs 17.9%. In contrast, response rates were similar when venetoclax-based therapy was compared with high-intensity treatment (68.5% vs 65.8%). The advantage was most apparent versus conventional low-intensity therapy, while response rates with venetoclax-based treatment were comparable to high-intensity regimens in this cohort.
Time to composite CR was similar between groups (2.3 vs 1.6 months), as was median DOR (11.0 vs 12.9 months), with no significant differences.
Benefit Was Maintained in the Oldest Patients
The response advantage remained evident with increasing age. Composite CR was significantly higher with venetoclax plus a hypomethylating agent than with control therapy in patients aged ≥75 years (60.8% vs 27.1%) and ≥80 years (56.8% vs 18.5%). These findings support the activity of venetoclax-based therapy even in very old patients with limited treatment options.
Overall Survival
Among patients ineligible for intensive chemotherapy, median OS was numerically longer with venetoclax plus a hypomethylating agent than with matched controls (17.4 vs 13.6 months). The difference was more pronounced against low-intensity therapy (14.0 vs 7.6 months), although it was not statistically significant. At 12 months, OS was significantly higher with venetoclax-based therapy (59.2% vs 34.9%).
The survival trend was also maintained in older patients. Among those aged ≥75 years, median OS was 14.6 months with venetoclax-based therapy versus 8.5 months with control treatment, with 24-month OS rates of 26.8% vs 18.0%. Similar numerical trends were seen in patients aged ≥80 years, although statistical significance was not reached.
Transfusion Independence and Supportive-Care Burden
At baseline, approximately 59% of evaluable patients in both groups were transfusion dependent. During first-line therapy, transfusion independence was achieved by 63.7% of patients receiving venetoclax plus a hypomethylating agent vs 53.2% of controls, though the difference was not statistically significant.
Among patients transfusion independent at baseline, 75.4% maintained independence with venetoclax-based therapy vs 67.7% of controls. Among those initially transfusion dependent, 55.4% vs 43.5% converted to transfusion independence.
Venetoclax-treated patients required significantly fewer transfusion episodes per patient per month (5.2 vs 6.7). Similar favorable trends were observed in patients aged ≥75 and ≥80 years. Reduced transfusion requirements may be particularly meaningful in older or medically vulnerable patients by lowering supportive-care burden and improving quality of life.
Comparison With Previous Evidence
The findings support the effectiveness of venetoclax plus a hypomethylating agent in routine clinical practice and are broadly consistent with VIALE-A. Against low-intensity therapy, composite CR was ~57% vs 18% in this study, compared with 66% vs 28% with venetoclax + azacitidine and azacitidine alone in VIALE-A.
Response rates were also somewhat higher than in previous real-world studies, where composite CR with venetoclax plus azacitidine ranged from ~43% – 58%, possibly reflecting access to specialized leukemia care, advanced diagnostics, and supportive resources at academic centers.
Survival findings were similarly consistent with previous evidence. VIALE-A reported median OS of 14.7 vs 9.6 months with venetoclax + azacitidine and azacitidine alone, while a community-based study reported 9.2 vs 5.7 months with venetoclax plus a hypomethylating agent and a hypomethylating agent alone. Shorter follow-up, more frequent transplantation, and a slightly younger population than in VIALE-A may partly explain the relatively favorable survival outcomes.
Previous retrospective studies have produced mixed survival results, although one sensitivity analysis found identical median OS of 17.5 months with venetoclax + azacitidine and 7+3 chemotherapy, while a recent meta-analysis favored venetoclax plus a hypomethylating agent, particularly in NPM1-mutated disease. These data should not be interpreted as evidence for replacing intensive chemotherapy in fit patients, as retrospective treatment selection and differences in patient fitness introduce substantial confounding.
The favorable transfusion outcomes were also consistent with VIALE-A and are clinically relevant in older or medically vulnerable patients, in whom reducing transfusion dependence may lower supportive-care burden and improve quality of life. Outcomes also appeared favorable in patients with IDH1/2, NPM1, and FLT3-ITD/NPM1 alterations, though no formal statistical comparisons were performed for the mutation-defined groups.
Bottom Line
These findings extend the benefit demonstrated in VIALE-A to routine clinical practice. Because this was a retrospective study with relatively short follow-up and a predominantly academic-center population, the findings don’t establish equivalence or superiority to intensive chemotherapy. Further real-world evidence with longer follow-up, including safety and molecular subgroup analyses, may provide a clearer understanding of long-term outcomes and which patients are most likely to benefit.
