In a new trial, patients newly diagnosed with acute myeloid leukemia (AML) fared significantly better with a combined regimen of azacitidine and venetoclax compared with conventional induction chemotherapy. The azacitidine–venetoclax combination (known as aza-ven) is the standard of care for older adults who are not fit enough for intensive chemotherapy. The trial is the first to test the superiority of this regimen to intensive induction chemotherapy, the current standard for fit patients.
Our study met its primary endpoint, demonstrating that aza-ven improves event-free survival. It also leads to higher rates of overall response and composite complete response than intensive induction chemotherapy in younger, intensive-chemotherapy-eligible patients. A greater proportion of patients successfully proceeded to transplant following response with less early mortality, significantly improved quality of life during initial treatment, and less time in the hospital."
Amir Fathi, MD, lead study author, director of the Center for Leukemia at Mass General Brigham Cancer Institute and associate professor of medicine, Harvard Medical School, Boston
AML is a cancer of the bone marrow that causes an overabundance of abnormal white blood cells and impedes the production of healthy blood cells. Hematopoietic stem cell transplantation can cure AML, but this option is not available to everyone, and almost all patients must undergo initial treatments to reduce cancer in the bone marrow before proceeding to transplant. Intensive induction chemotherapy with cytarabine and anthracyclines has long stood as the standard frontline treatment, but this treatment requires patients to spend about a month in the hospital and carries a high risk of infection, bleeding, and other complications and side effects.
Azacitidine is a chemotherapy drug that has been used for years, in injectable forms, for older patients with AML. Venetoclax is an oral targeted therapy that inhibits the BCL-2 protein, which is involved in cancer cell survival. The two agents are generally well tolerated and can be administered and managed safely on an outpatient basis over time.
In the trial, 172 adult patients were randomly assigned to receive either aza-ven or standard intensive induction chemotherapy. The results were significantly better in the aza-ven arm for the trial's primary endpoint, event-free survival (EFS), with events defined as relapse, disease progression, disease refractoriness prompting change in therapy, or death. With a median follow-up of just under 22 months, EFS was significantly longer in the aza-ven arm; the median EFS was more than 14 months among those receiving aza-ven compared with a median of just over six months for those receiving induction chemotherapy. The effect of aza-ven remained protective even after adjusting for other variables, and at one year, 53% of those in the aza-ven arm met criteria for EFS compared with 36% of those in the control arm.
Patients whose cancer had certain characteristics, including core binding factor fusions, FLT3 mutations, or NPM1 mutations (unless age 60 or over), were excluded from the trial. As a result, the study reflects a patient population of predominantly intermediate-to-high-risk AML, although all patients were fit enough to undergo intensive induction chemotherapy.
"I believe the data support the use of this treatment in this population," said Dr. Fathi. "It applies to adverse risk and intermediate risk patients who don't have FLT3 mutations. That doesn't mean that other patient populations may not benefit, but they require their own focused study."
Participants receiving aza-ven experienced a higher overall response to treatment than those receiving induction chemotherapy, with 88% of those in the aza-ven arm seeing an overall response and 78% seeing a composite complete response, compared with 62% and 54% in the control arm, respectively. They were also more likely to progress to a transplant, which occurred in 61% of those receiving aza-ven and 40% of those receiving induction chemotherapy.
The rate of grade 3 or 4 therapy-related adverse events was similar between study arms. No patients who received aza-ven died within 60 days, while 5% of those in the control group died by this timepoint. Hospitalization was also longer among patients in the control group. Ten percent of patients in the induction arm required admission to the intensive care unit during their index hospitalization, compared with zero in the aza-ven arm. Patients in the aza-ven arm also reported a lower symptom burden and lower rates of depression at two weeks, according to quality of life assessments.
The researchers plan to conduct further analyses to compare costs, the rate of infectious complications, and other factors that may inform treatment decisions for this patient population. In addition, they will assess the use of measurable residual disease status to provide key prognostic and predictive information across arms of the study and inform the optimal amount of treatment needed for aza-ven prior to transplant.
The study was investigator-initiatied; Genentech and AbbVie Inc. (maker of venetoclax), provided the study drug and funding to support research staff.
Amir Fathi, MD, of Mass General Brigham Cancer Institute and Harvard Medical School will present this study on Sunday, December 7, 2025, at 3:45 p.m. Eastern time during the Plenary Scientific Session in West Hall D2 of the Orange County Convention Center.
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