At the 2025 ASH Annual Meeting & Exposition in Orlando, Florida, Ibrahim Aldoss, MD, City of Hope, Los Angeles, California, discussed results from the phase 2 PARADIGM trial, which compared azacitidine plus venetoclax with intensive chemotherapy for newly diagnosed, fit adults with acute myeloid leukemia (AML).

The results showed a significant improvement in event-free survival, along with higher response rates, lower early mortality, and better quality-of-life outcomes for treatment with azacitidine-venetoclax. 

Dr Aldoss concluded, “Patients receiving azacitidine-venetoclax required substantially fewer inpatient and ICU days during initial therapy. Underscoring its more favorable tolerability and healthcare utilization profile.”

Transcript:

Hi, everyone. I'm Dr. Ibrahim Aldoss from the Division of Leukemia Department of Hematology and Stem Cell Transplant at City of Hope. Today I will be commenting on Dr. Fathi presentation results from PARADIGM, a phase 2 randomized multicenter study comparing azacitidine and venetoclax to conventional induction chemotherapy for newly diagnosed fit adults with AML. That will be presented in ASH in the plenary session.

For many decades, intensive chemotherapy with 7+3 regimen has been the standard frontline therapy for fit patients with AML. However, the intensive chemotherapy is associated with significant short and long-term toxicity, prolonged hospitalization, as well as some optimal long-term survival outcomes. Venetoclax and azacitidine produce high response rates, and [are] associated with less toxicity than intensive chemotherapy. This motivated us to design a prospective study evaluating whether azacitidine and venetoclax could outperform intensive chemotherapy in fit patients with newly diagnosed AML and potentially can redefine the current standard of care in AML.

The PARADIGM study was an open-label, multicenter phase 2 randomized study. It was investigator-initiating trial led by Massachusetts General Hospital and City of Hope. It was designed to compare the therapeutic activity of conventional intensive chemotherapy with azacitidine and venetoclax in intensive chemotherapy eligible adults, age 18 and above. We excluded patients with core-binding factors, patients with FLT3 mutations and younger patients with NPM1 mutations. The primary end point was event-free survival and key secondary endpoints including response rate, overall survival toxicity, MRD response, hospitalization metrics, and quality of life. Randomization was stratified by age as well as pre-randomization selection of 7+3 versus CPX-351 within the intensive chemotherapy arm.

We are at a total of 172 patients across 9 US centers, and patients were randomized evenly between the 2 arms. The median age was comparable between the 2 arms and the majority of patients they had adverse risk disease biology as per the ELN 2022. The distribution of risk categories, including some key prevalent mutations were comparable between the 2 arms.

The study met the primary endpoint with a median follow-up of 16 months. One-year event-free survival was 53% with azacitidine and venetoclax compared to 39% with intensive chemotherapy. Overall, event-free survival was significantly superior in the azacitidine venetoclax arm with a hazard ratio of 0.61 and P value of 0.017.

By intent-to-treat analysis, overall response, as well as composite CR, were higher with the venetoclax-azacitidine compared to intensive chemotherapy. We have observed greater proportion of patients treated with azacitidine-venetoclax, able to proceed with allogenic stem cell transplant following response compared to intensive chemotherapy. Grade 3 and 4 treatment related adverse events were predominantly hematologic and occurred that similar rates between the 2 arms. However, we observed less 30 and 60-day mortality in the venetoclax-azacitidine arm compared to the intensive chemotherapy arm.

Patient reported outcomes also favor azacitidine-venetoclax at 2 weeks. Patient receiving azacitidine-venetoclax reported significantly better quality of life, lower symptom burden, and fewer depression symptoms. Azacitidine-venetoclax patients were less likely to require ICU care and had substantially fewer inpatient days, both during the index hospitalization and over the first 6 months of therapy.

In conclusion, the study made the primary end point demonstrating that azacitidine venetoclax significantly improved event-free survival compared to intensive chemotherapy in younger intensive chemotherapy eligible patient. Azacitidine-venetoclax was also associated with higher overall response and composite CR rates. A greater proportion of patients treated with azacitidine-venetoclax were able to proceed to transplant after achieving a response compared to those receiving intensive chemotherapy.

In addition, azacitidine-venetoclax was associated with meaningful improvement in early quality of life measures as well as symptom burden. Patients receiving azacitidine-venetoclax required substantially fewer inpatient and ICU days during initial therapy. Underscoring its more favorable tolerability and healthcare utilization profile. Thank you.

Source:

Fathi A, Perl A, Fell G, et al. Results from paradigm - a phase 2 randomized multi-center study comparing azacitidine and venetoclax to conventional induction chemotherapy for newly diagnosed fit adults with acute myeloid leukemia. Dec 6-9, 2025; Orlando, FL. Abstract: 6