Azacitidine/Venetoclax Combo Data Challenge Chemo in Fit Patients With AML

After more than 50 years, could induction chemotherapy be on the way out as the first treatment for patients diagnosed with acute myeloid leukemia (AML)?

Results from PARADIGM, a phase 2 trial presented Sunday at the 67th American Society of Hematology (ASH) Annual Meeting & Exposition, suggest the answer could be “yes.” Data from the study, part of the ASH plenary session, show a combination of azacitidine (Onureg; Bristol Myers Squibb) and venetoclax (Venclexta; AbbVie/Genentech) was linked to improved responses and event-free survival (EFS) compared with chemotherapy, as well as fewer infections, hospital stays, and days in intensive care.1

Azacitidine, a hypomethylating agent, and venetoclax, a BCL2 inhibitor, had been previously tested in VIALE-A, a phase 3 trial of patients ineligible for induction chemotherapy. That study established the superiority of the combination over azacitidine alone, with a median overall survival (OS) of 15 months and a composite remission rate (CRR) of 66%, which study authors said compared favorably with induction chemotherapy among the older patients in that study.2

Amir T. Fathi, MD | Image: MGH

However, it’s one thing to shift a treatment regimen for a higher-risk patient group—it’s another to scrap the 50-year standard of care for younger, fit patients with AML. VIALE-A specifically evaluated patients older than 75 years, who make up about a third of those newly diagnosed with AML, according to SEER data.3 In the investigator-initiated PARADIGM study, Amir Fathi, MD, of Massachusetts General Hospital and Harvard Medical School, and his fellow investigators sought to learn whether the azacitidine-venetoclax combination was superior to chemotherapy in that larger group of patients.

The current standard, known as “7 + 3,” consists of cytarabine, which is given for 7 consecutive days, and an anthracycline, most often daunorubicin or idarubicin, given intravenously for the first 3 days of the cycle. As Fathi noted in his plenary talk, the induction chemotherapy standard has persisted, despite the approval of 12 new drugs in AML and in the face of well-documented downsides.

“Intensive induction chemotherapy continues to yield suboptimal long-term outcomes for most," Fathi said. "As many physicians who treat leukemia know, intensive induction comes with substantial burden," including significant morbidity, prolonged bone marrow suppression, weeks of hospitalization, frequent infections and bleeding complications, mucositis, malnutrition, deleterious psychosocial effects, and an increased risk for cardiac injury.

For this new study, investigators excluded patients with core binding factor fusions, FLT3 mutations, or NPM1 mutations (unless they were at least 60 years of age). Patients were stratified whether they were older or younger than 65 years of age. The primary end point was EFS, with secondary end points including response rates, OS, toxicity, and measurable residual disease (MRD). Patients were randomized to receive azacitidine-venetoclax (the study combination) or induction chemotherapy, either 7+3 or CPX-351 (Vyxeos), which similarly combines cytarabine and daunorubicin. Each arm had 86 patients.

Results were as follows:

• The median age was 64 years among the study combination group (55% male) and 65 years for the induction chemotherapy group (60% male).
• Most patients were adverse risk per ELN 2022 criteria (72%), with 15% intermediate risk and 12% favorable risk. Distribution of risk was similar across the 2 arms, as were proportions of patients with TP53, NPM1, and IDH1/2 mutations.
• The median number of cycles completed was 4 for the study combination and 2 for chemotherapy.
• Based on the intent-to-treat analysis, the rate of overall response (OR) was significantly higher in the study combination arm (88% vs 62%; P < .001), as was composite complete remission (CCR; 81% vs 55%; P < .001).
• Complete remission rates were not significantly different between the 2 arms (59% for the study combination vs 50% for chemotherapy; P = .066)
• Procession to hematopoietic cell transplantation (HCT) favored the study combination arm, with 52 patients (61%) receiving HCT vs 34 (40%) in the chemotherapy arm.
• At a median follow-up of 16 months, 1-year EFS was 53% for azacitidine-venetoclax and 39% for those who had received chemotherapy (HR 0.61; P = .017). There was no significant age effect on these results.
• Therapy-related adverse events (AEs) of grade 3 or 4 were similar across arms. Grade 3 or 4 lung infections were seen in 12% of the study combination arm and 15% of the chemotherapy arm, and sepsis was seen in 7% of the study arm and 11% of the chemotherapy arm.
• For the study combination arm, 30- and 60-day mortality were 0%, compared with 3.5% and 4.7%, respectively, in the chemotherapy arm.
• At 2 weeks, patients receiving azacitidine-venetoclax reported better quality of life, reduced symptom burden, and lower depression scores compared with chemotherapy.

Patients from the chemotherapy arm were allowed to cross over into the study combination arm, and Fathi said this caused similar OS results between the 2 arms. When studies are designed this way, he said, EFS is the meaningful end point.

Reduced Inpatient Time Signals Significant System Savings

Patients in the azacitidine-venetoclax arm had fewer inpatient days for index hospitalization (15 vs 36; P < .001) and at the 6-month mark (41 vs 58; P < .001). The study combination patients were also less likely to need care in the intensive care unit (0 vs 9.8%) than those treated with chemotherapy. Fathi said that an analysis of the cost savings with the azacitidine-venetoclax approach is under way, and he expects this will be published separately.

Fathi said the data support changing frontline care in AML.

“Venetoclax improved event-free survival when compared to conventional induction chemotherapy and led to higher rates of overall response and composite remission,” he said. “A greater proportion of [the study combination] patients successfully proceeded to transplant following response with less early mortality, significantly improved quality of life during initial therapy, and less time in the hospital than in the intensive care unit. We, therefore, believe these data support the use of azacitidine-venetoclax in functionally fit patients eligible for transplant.”

References

1. Fathi A, Perl A, Fell G, et al. Results from PARADIGM: a phase 2 randomized multi-center study comparing azacitidine and venetoclax to conventional induction chemotherapy for newly diagnosed fit adults with acute myeloid leukemia: Presented at: 67th American Society of Hematology Annual Meeting & Exposition, December 6-9, 2025; Orlando, FL. Abstract 6.
2. DiNardo CD, Jonas BA, Pullarkat V, et al. Azacitidine and venetoclax in previously untreated acute myeloid leukemia. N Engl J Med. 2020;383(7):617-629. doi:10.1056/NEJMoa2012971
3. Klepin HD, Rao AV, Pardee TS. Acute myeloid leukemia and myelodysplastic syndromes in older adults. J Clin Oncol. 28;32(24):2541–2552. doi:10.1200/JCO.2014.55.1564