Less-Intensive AML Regimen Offers a Better Journey: Amir Fathi, MD

Intensive induction chemotherapy has been the standard for fit patients with acute myeloid leukemia (AML) for decades, but results from the randomized phase 2 PARADIGM trial (NCT04801797) are prompting a closer look at that practice. Amir Fathi, MD, director of the leukemia program at Mass General Brigham Cancer Institute and lead author of a recent The New England Journal of Medicine analysis, believes the findings should influence how induction-eligible patients are treated. The study, he noted, was not a registrational phase 3 trial. It was designed to detect the relative efficacy of a more gentle approach vs a traditional and more intensive approach.

Azacitidine-venetoclax (HMA-ven) produced a median event-free survival (EFS) of 14.5 months compared with 6.2 months for induction chemotherapy. Fathi said the regimen was well tolerated and led to fewer or briefer hospitalizations, and patients receiving it were less likely to have refractory or persistent disease or to miss transplant. For patients with intermediate- or adverse-risk disease, whose path to cure depends on transplants, he asked, “If you can get there easier, why shouldn’t you?”

That advantage showed up in transplant rates: 60% of the HMA-ven cohort reached transplant vs 40% of the chemotherapy cohort, even though 72% of patients had adverse-risk disease. Fathi said the more obvious explanation lies in the response data. More patients responded to HMA-ven than to intensive chemotherapy, and a response is required to reach transplant. For a subset, he added, it was tolerability, as 30-day and 60-day mortality were lower with the less-intensive regimen.

Overall survival (OS) did not differ between arms, which Fathi attributed to crossover and transplant. Many patients on the intensive arm later received HMA-ven, and some in both arms reached transplant after a later line of therapy. The curves converge, but the journey does not. “Which curve do you want to sit on?” he asked.

Looking ahead, Fathi hopes future phase 3 trials move away from OS as a primary end point in AML, noting that placebo-controlled trials such as RATIFY (NCT00651261) and QuANTUM-First (NCT02668653) were less affected by crossover. Patients may not live longer, he said, “but they live better.”