HMA-Venetoclax Beats Chemo in AML but Not for Everyone: Amir Fathi, MD

For decades, hypomethylating agents (HMAs) have anchored treatment for older adults with acute myeloid leukemia (AML), but the biology behind their effectiveness is still not fully settled, according to Amir T. Fathi, MD, director of the leukemia program at Mass General Brigham Cancer Institute and lead author of a new PARADIGM trial (NCT04801797) analysis published in the New England Journal of Medicine.

In AML and myelodysplastic syndromes, hypermethylation can silence genes required for normal bone marrow cell maturation and differentiation. HMAs strip away those methyl groups, theoretically reactivating the genes and restoring differentiation.

“Is that truly what happens in many of the cases of response in AML? We think so, although, to be honest, I’m not sure if this is a conclusive finding,” Fathi said in an interview with The American Journal of Managed Care^®, noting the field’s understanding of HMA mechanism “continues to evolve.”

He pointed to efficacy data to explain the therapy’s clinical impact. HMA monotherapy alone produced remission rates of just 20% to 30%, well below the 60% to 70% seen with intensive chemotherapy. Adding venetoclax, the approach validated in the VIALE-A trial (NCT02993523), pushed HMA-based remission rates into that same 60%-to-70% range, with an adverse effect profile more tolerable than intensive chemotherapy for older patients.

Can PARADIGM’s Findings Apply Beyond the Trial?

Fathi cautioned that PARADIGM’s results should not be generalized to every patient with AML. The trial excluded younger patients with NPM1 mutations, core binding factor alterations, and FLT-3–mutated disease—all groups for whom targeted or transplant-sparing strategies already exist and could not ethically be randomized away from.

“These patients in general were not studied, and the data that we have should not apply to them,” Fathi said, adding that mutation testing for FLT3, NPM1, and core binding factor alterations should be considered routine in AML care. Without it, he said, clinicians risk missing an FDA-approved FLT-3 inhibitor of unnecessarily pursuing transplant in patients who could avoid it. Until dedicated trials address these subgroups, he said, PARADIGM’s conclusions apply specifically to the population enrolled.