Does Venetoclax/Azacitidine Make Chemotherapy Obsolete in AML?

The phase 2 PARADIGM trial (NCT04801797) excluded patients with core binding factor fusions, FLT3 mutations, or NPM1 mutations unless the patient was 65 years or older, since standard-of-care options specific to those subgroups could not be incorporated into the trial’s arm assessing azacitidine (Vidaza) plus venetoclax (Venclexta).

Lead study author Amir T. Fathi, MD, director of the Leukemia Program at the Massachusetts General Brigham Cancer Institute in Boston and a professor of medicine at Harvard Medical School, spoke with CancerNetwork^® about whether these results mean induction chemotherapy becomes a second-line or niche option for fit patients with AML. Although the data support the use of a gentler therapeutic option in certain contexts, Fathi emphasized that the findings do not completely render induction chemotherapy obsolete.

Transcript:

CancerNetwork: How do you see these results changing the day 1 conversation with a patient with newly diagnosed, fit AML? Does induction chemotherapy become a second-line or niche option rather than the default?

Fathi: It’s important to say here…that we did not study every single [patient with] AML. Important key subsets of patients were excluded from the study because we had to. For example, [patients with] FLT3 mutations were excluded. Why? Because right now, the standard of care is intensive chemotherapy plus a FLT3 inhibitor. We could not randomly [assign] a patient to a hypomethylating agent [HMA]–venetoclax arm that didn’t have a FLT3 inhibitor because no such combination is approved. Those patients, because of regulatory considerations, had to be excluded.

We could not include core-binding factor AML, which is oftentimes seen in younger patients and who are favorable risk. Why? Because, similarly, gemtuzumab ozogamicin [Mylotarg], that antibody-drug conjugate, is approved for use in patients with that subtype of AML, and we could not add it to the HMA arm. Therefore, we could not really consider it ethically in that arm, so we had to exclude those patients. [Regarding patients who are younger with] NPM1 mutations, a lot of these patients are cured with intensive chemotherapy and a nontransplant approach. We decided to include patients who had intermediate and adverse-risk disease whom we thought were bound for transplant and would find a way to potentially get there in a better-tolerated way.

When you ask me, does this make intensive induction chemotherapy obsolete? No, because it only applies to the patients that we studied. That, I grant, is a sizable subset of [patients with] AML, and in those patients, I think our data support the use of a gentler option. For patients who have AML that falls within the categories we excluded, intensive chemotherapy, in my view, currently remains the standard of care. Over time, clinical trials that look at targeted therapies and incorporate them into HMA-based regimens can do randomized studies specifically in those subsets, and hopefully, over time, more gentle approaches can become relevant for them as well.

Reference

Fathi AT, Perl AE, Fell GG, et al. Azacitidine-venetoclax or induction chemotherapy for acute myeloid leukemia. N Engl J Med. 2026;395(9):845-858. doi:10.1056/NEJMoa2602804