The combination of azacitidine and venetoclax more than doubled event-free survival compared with standard induction chemotherapy among fit patients with previously untreated acute myeloid leukemia (AML), according to a phase 2 trial.

Patients in the trial, dubbed PARADIGM, had high-risk disease and were eligible for chemotherapy induction. The half treated with azacitidine-venetoclax instead had longer event-free survival, at a median of 14.5 months vs 6.2 months with chemotherapy.

They also had fewer serious adverse events, higher rates of remission, and a greater likelihood of proceeding to hematopoietic stem cell transplant, according to findings reported in The New England Journal of Medicine.

“These data support the use of azacitidine-venetoclax in fit patients who are eligible for transplantation and have nonfavorable-risk, FLT3-nonmutated AML,” wrote investigators led by Amir Fathi, MD, of Mass General Brigham Cancer Institute in Boston.

The findings challenge the current first-line standard of care for AML: 7 + 3 induction chemotherapy — 7 days of cytarabine with three daily infusions of an anthracycline, usually daunorubicin — for patients who can tolerate it. Severe bone marrow suppression, prolonged hospitalizations, infections, bleeding complications, and other substantial toxicities are common.

Azacitidine-venetoclax is gentler, with fewer and less-severe side effects. Currently, it’s held in reserve for older patients and others who can’t tolerate 7 + 3 induction, but there has been a long-standing question as to whether patients who would normally receive intensive chemotherapy can instead be treated with azacitidine-venetoclax.

PARADIGM may offer an answer, at least for higher-risk patients like those in the trial.

“This study is practice-changing for the subset of AML patients who were enrolled,” Navneet Majhail, MD, physician-in-chief of blood cancers at Sarah Cannon Cancer Network in Nashville, Tennessee, told Medscape Medical News.

For many patients with high-risk AML, Majhail noted, the only curative therapy is allogeneic hematopoietic cell transplantation. “A significantly greater proportion of patients on the azacitidine-venetoclax arm received a transplant compared to patients on the induction chemotherapy arm,” he said.

A press release from Mass General Brigham said the findings could change the initial treatment for many patients with AML.

“Less-intensive treatment does not necessarily mean less-effective treatment,” Fathi said in the release. “Our findings suggest that some of these patients may do better with a less-intensive approach.”

Nearly three quarters of patients in PARADIGM had genetic features predictive of poorer prognosis according to the European LeukemiaNet 2022 classification. The trial excluded patients with core binding factor, NPM1, and FLT3 mutations because they have targeted treatment options.

The azacitidine-venetoclax group received a median of four treatment cycles, and the chemotherapy group had a median of two.

At a median follow-up of 22 months, median event-free survival, the primary endpoint, was 14.5 months vs 6.2 months with azacitidine-venetoclax vs chemotherapy — corresponding to a hazard ratio for event or death of 0.57 (95% CI, 0.39-0.84).

Overall, 78% of azacitidine-venetoclax vs 53% of chemotherapy patients had a composite complete remission, and more patients on the less-intensive regimen went on to stem cell transplant (68% vs 40%).

As for safety, grade 3 or worse infections occurred in 28% vs 41% of patients in the azacitidine-venetoclax vs chemotherapy arm. Similarly, the rate of grade 3 or higher hemorrhages was 2% vs 12% with azacitidine-venetoclax vs chemotherapy. In the month following randomization, patients on the drug combination spent a mean of 12.5 days in the hospital compared with 27 days in the chemotherapy group.

An accompanying editorial noted that the findings are consistent with a Chinese trial that randomly assigned 188 patients younger than 60 years to venetoclax with an alternative hypomethylating agent, decitabine, or 7 + 3 induction. The primary endpoint was composite complete remission.

In the venetoclax-decitabine arm, patients aged 40 years or older had a higher composite complete remission rate (91% vs 75%), as did patients with adverse-risk disease (91% vs 42%) and epigenetic mutations (91% vs 67%). Patients on the drug combination also had fewer grade 3 or worse infections (32% vs 67%) and shorter durations of severe thrombocytopenia (median, 13 vs 19 days).

However, composite complete remission was lower in patients who carried the favorable RUNX1::RUNX1T1 fusion (44% vs 88%).

“Larger trials with longer follow-up are needed to verify whether these and other hints of differential effectiveness in cytogenetically or molecularly defined subgroups are correct,” wrote editorialist Charles Schiffer, MD, retired hematologist-oncologist at Wayne State University in Detroit.

He noted there are at least five ongoing trials with designs similar to that of PARADIGM, although in diverse patient populations.

In PARADIGM, there was no apparent difference between treatment groups in median overall survival (21.5 months vs 18 months with azacitidine-venetoclax vs chemotherapy), but the trial was not designed to formally assess that outcome. In the Chinese trial, both progression-free and overall survival were similar between the two arms, at a median follow-up of 12.1 months.

PARADIGM received funding from AbbVie and Genentech, who jointly developed venetoclax. Fathi reported being a consultant to both companies and others. Schiffer reported no relevant disclosures.

M. Alexander Otto is a physician assistant and award-winning journalist. He is also an MIT science journalism fellow. Email: aotto@medscape.net