PARADIGM Trial: Rethinking Induction Therapy in Fit Patients With AML

The phase 2, investigator-initiated PARADIGM trial, presented at the 2025 ASH Meeting, challenges the longstanding paradigm that medically fit patients with AML require intensive induction chemotherapy. Regimens such as “7+3” or CPX-351 have been standard for fit, newly diagnosed AML, but these are associated with significant treatment-related morbidity, prolonged hospitalizations, and early mortality. While azacitidine plus venetoclax (aza/ven) is well established in older or unfit patients, as demonstrated in VIALE-A, it had not been prospectively evaluated against intensive chemotherapy in fit patients, a knowledge gap PARADIGM was designed to address.

“This was a really exciting ASH abstract. It was a plenary this past year, 2025. It’s really appropriately named. It really did change the treatment paradigm in AML,” Dr. Tiffany Tanaka, a hematologist/medical oncologist at UC San Diego Health, tells SurvivorNet Connect.

What Did PARADIGM Find?

PARADIGM was a randomized, multicenter phase 2 study enrolling 172 transplant-eligible adults with newly diagnosed AML considered fit for intensive therapy. Key exclusion criteria included favorable-risk cytogenetics (core-binding factor alterations), acute promyelocytic leukemia, FLT3 mutations, and NPM1 mutations in patients under 60 years, focusing the trial on a higher-risk cohort in whom the benefit of intensive chemotherapy is less clear. Patients in both arms could proceed to allogeneic stem cell transplantation after induction.

“So this was actually something we’ve all been wondering about. There are patients out there who are probably going to be chemo resistant or chemo refractory, but they’re younger,” Dr. Tanaka explains. “It was a phase two study looking at traditional intensive induction chemo versus hypomethylating agent plus Venetoclax in AML.”

The trial met its primary endpoint, demonstrating a significant improvement in event-free survival (EFS) for patients treated with aza/ven compared with intensive chemotherapy.

• Median EFS was 14.6 months in the aza/ven arm versus 6.2 months with chemotherapy, with one-year EFS rates of 53% versus 36%.
• Composite response rates were higher with aza/ven, and a greater proportion of patients were able to bridge to transplant (61% vs 40%).

While composite remission rates (CR + CRi) were clearly higher with aza/ven, the benefit in strict CR was smaller and less consistent, reflecting that many patients achieved marrow remission even without full hematologic recovery. Overall survival was numerically higher with aza/ven, although interpretation is confounded by subsequent therapies and transplantation, highlighting EFS as the most reliable primary endpoint. Measurable residual disease (MRD) was included as a secondary endpoint, with detailed results pending.

Most patients enrolled had intermediate or adverse risk AML, reflecting real-world populations where fit patients with high-risk features often fare poorly with intensive chemotherapy alone.

While the trial balanced risk categories and mutational profiles across arms, detailed subgroup analyses, including outcomes for monocytic AML, have not yet been reported.

Safety & Side Effects

Clinical questions remain regarding intermediate-risk patients, some of whom may achieve long-term remission with chemotherapy alone, and not all end up proceeding to transplant. Whether aza/ven can cure a subset of these patients without transplant remains to be clarified, underscoring the need for longer follow-up and more granular analyses.

“It felt a little bit odd to not give them intensive chemo, but we now have the paradigm study to support that aza/ven is indeed more effective in certain mutation subgroups,” Dr. Tanaka explains.

In terms of safety, aza/ven was associated with lower early mortality, fewer infections, shorter hospital stays, and improved patient-reported outcomes relative to intensive chemotherapy. Hematologic toxicity was similar between arms, but non-hematologic complications were less frequent with aza/ven, translating to meaningful differences in quality of life and healthcare utilization.

“Compared to your traditional intensive chemo, patients on aza/ven don’t have such a traumatic course, they’re not getting terrible mucositis, they’re not losing their hair, and the GI effects aren’t quite as severe,” Dr. Tanaka explains.

“But what is very similar between the two regimens is they still can have a very deep blood count need. They can still take a month to recover blood counts. So it’s not uncommon for patients on aza/ven to be hospitalized for that entire induction chemo month and to have some of the same challenges that we see with 7+3,” she adds. “They could still be very transfusion dependent and face infection and bleeding risk. So it’s really important they still get all the same leukemia care that they would with 7+3.”

Future Directions

As a phase 2 study, PARADIGM was exploratory and not powered for definitive overall survival comparisons, limiting its ability to establish aza/ven as superior to intensive chemotherapy for all fit patients. The trial excluded favorable-risk subgroups, restricting generalizability. Subgroup analyses, including outcomes for intermediate-risk patients, monocytic AML, and molecularly defined cohorts, remain incomplete, and MRD data are still pending. The open-label design and allowance for subsequent therapies and transplantation may further confound interpretation of overall survival, emphasizing the need for longer follow-up and prospective phase 3 validation.

Overall, PARADIGM demonstrates that a lower-intensity backbone can outperform traditional induction chemotherapy in fit patients with intermediate or adverse risk AML. Increased composite remission rates, improved EFS, and more frequent transitions to transplant were achieved without compromising overall survival, suggesting a potential paradigm shift.

“This study really supports using aza/ven in younger, transplant-eligible patients,” Dr. Tanaka says, “offering effective disease control and a higher likelihood of bridging to transplantation, while potentially providing a more tolerable treatment option compared with intensive chemotherapy.”