AML and CML Highlights From ASH 2025

Jorge Cortes, MD Georgia Cancer Center | Rahul Gosain, MD, MBA Wilmot Cancer Institute | Rohit Gosain, MD Roswell Park Comprehensive Cancer Center

Key Points

• The PARADIGM study showed azacitidine plus venetoclax may have some value for fit patients with acute myeloid leukemia (AML) otherwise eligible for induction chemotherapy.

• A shortened dosing schedule for venetoclax combined with decitabine demonstrated comparable efficacy and improved safety in newly diagnosed AML.

• Ziftomenib combined with azacitidine and venetoclax showed encouraging activity in newly diagnosed and relapsed or refractory NPM1–mutated AML populations in the KOMET-007 trial.

• Data updates from the ASC4FIRST and ASC2ESCALATE trial further supported the efficacy and favorable safety profile of asciminib in the treatment of chronic myeloid leukemia (CML).

ASH 2025 AML and CML Trials

On the Oncology Brothers podcast, cohosts Rahul Gosain, MD, MBA, of Wilmot Cancer Institute, and Rohit Gosain, MD, of Roswell Park Comprehensive Cancer Center, invited Jorge Cortes, MD, of Georgia Cancer Center, to discuss key presentations in AML and CML from the 2025 American Society of Hematology Annual Meeting and Exposition (ASH 2025). 

For the AML space, the doctors discussed azacitidine plus venetoclax versus chemotherapy in PARADIGM, ziftomenib combinations in KOMET-007, and retrospective data on shortened courses of venetoclax. For CML, the doctors reviewed the ASC4FIRST and ASC2ESCALATE trials on asciminib.

PARADIGM: Azacitidine Plus Venetoclax in Fit Patients With AML

The phase 2 PARADIGM study compared azacitidine plus venetoclax with conventional induction chemotherapy in fit patients with AML. The study excluded patients with core binding factor fusions, FLT3 mutations, or NPM1 mutations (unless aged 60 years or older). The chemotherapy arm included chemotherapy consolidation, and both arms were allowed to proceed to hematopoietic cell transplantation (HCT).

Compared with standard chemotherapy, azacitidine plus venetoclax improved overall response rate (88% vs 62%; P < .001) and composite remission rate (81% vs 55%; P < .001). More patients in the azacitidine plus venetoclax arm proceeded to HCT versus the chemotherapy arm (61% vs 40%; P = .009). The 1-year rates of event-free survival (EFS) were 53% and 39% with azacitidine plus venetoclax and chemotherapy, respectively. Overall EFS was significantly improved in the azacitidine plus venetoclax arm (HR, 0.61; P = .017).

The PARADIGM data support the applicability of azacitidine plus venetoclax in chemotherapy-eligible patients. While induction chemotherapy remains the preferred treatment for fit, low-risk patients with AML for now, the treatment paradigm will likely move towards azacitidine plus venetoclax in the future, said Dr. Cortes.

Retrospective Analysis of Shortened Venetoclax Course

In real-world practice, the dosing schedule for venetoclax is often shortened from the full 28 days to avoid cytopenias and infections. At ASH 2025, researchers from the University of Alabama at Birmingham presented a retrospective study on patients with newly diagnosed AML who received a shortened course of 10 days of venetoclax plus 5 days of decitabine per cycle. The shortened regimen yielded “comparable efficacy” to published data, even in higher-risk subgroups, as well as a potentially improved safety profile, the authors reported.

The report supports the real-world practice of modifying the dosing schedule for venetoclax. While more data are needed to refine an optimal schedule for venetoclax, “it is evident that we probably don’t need the full schedule for every patient, particularly the most fragile patients,” said Dr. Cortes.

Ziftomenib Across AML Populations in KOMET-007

The phase 1a/1b KOMET-007 trial evaluated the menin inhibitor ziftomenib in combination with azacitidine and venetoclax in newly diagnosed NPM1–mutated AML and in relapsed or refractory NPM1–mutated or KMT2A–rearranged AML. Researchers presented separate analyses for the newly diagnosed and relapsed/refractory populations at ASH 2025. 

The newly diagnosed analysis covered 39 patients with a median follow-up of 16.3 weeks (range, 1.6-41.1). In total, 29 patients (74%) had grade 3 or higher treatment-emergent adverse events (AEs), most commonly neutropenia (31%) and thrombocytopenia (23%). Fourteen (36%) patients had grade 3 or higher AEs related to ziftomenib, most commonly neutropenia (15%) and thrombocytopenia (13%). No patients discontinued ziftomenib because of AEs. Among 31 response-evaluable patients, the composite complete remission (CRc) rate was 84%, with a median time to first CRc of 3.5 weeks (range, 2.4-9.4).

The relapsed or refractory analysis included 80 patients with NPM1–mutated or KMT2A–rearranged AML. Overall, 71 patients (89%) had grade 3 or higher treatment-emergent AEs, most commonly febrile neutropenia (9%) and anemia (8%), and 6 patients discontinued ziftomenib because of AEs. For NPM1–mutated and KMT2a–rearranged patients specifically, the overall response rates were 65% and 33%, the CRc rates were 49% and 22%, and the median times to first CRc were 4.9 weeks (range, 2.7-15.6) and 5.5 weeks (range, 2.6-18.9), respectively.

While comparative studies are needed for ziftomenib, the KOMET-007 data are encouraging, especially in the relapsed or refractory setting, said Dr. Cortes. 

Asciminib Data Grows With ASC4FIRST and ASC2ESCALATE

The FDA granted accelerated approval to asciminib for patients with newly diagnosed CML on October 29, 2024, after it improved efficacy outcomes compared with investigator-selected tyrosine kinase inhibitors (TKIs) in the ASC4FIRST trial. At ASH 2025, investigators presented 96-week patient-reported outcomes from ASC4FIRST.

In the trial, investigators preselected imatinib or a second-generation TKI for all patients prior to randomization. Among patients selected for imatinib, 37.5% of those randomized to asciminib versus 17.7% of those randomized to TKI reported improvements in global health status and quality of life (QoL). Among patients selected for a second-generation TKI, 58.9% of those randomized to asciminib and 28.6% of those randomized to a TKI reported improvements. The data reinforce the place of asciminib as standard of care for CML, and the improved QoL is an important benefit for patients who are not likely to be able to stop therapy, said Dr. Cortes.

ASH 2025 also featured a presentation from the ASC2ESCALATE study, which evaluated second-line asciminib in patients with CML who previously received a TKI. Overall, asciminib induced a major molecular response in 56.1% and 55.6% of evaluable patients at week 24 and week 48, respectively. The safety profile was comparable with asciminib outcomes in the first-line. The findings fill a data gap for asciminib in the second-line setting, and allow oncologists to better select the optimal therapy for each line based on patient and disease characteristics, said Dr. Cortes.