Advances in Acute Myeloid Leukemia Explored at ASH 2025

Like many cancers, acute myeloid leukemia (AML) has been a major beneficiary of the introduction of targeted therapies into the oncology treatment landscape. In fact, one of the earliest uses of targeted therapy in oncology was all-trans retinoic acid, which targets the retinoic acid receptor in acute promyelocytic leukemia. Eventually, the combination of all-trans retinoic acid with arsenic trioxide led to the cure of nearly all patients with what was previously a feared malignancy. In the ensuing years, many targeted therapies have entered the AML treatment armamentarium, including gemtuzumab ozogamicin (targeting CD33; Mylotarg), FLT3 inhibitors, IDH1 and IDH2 inhibitors, the BCL2 inhibitor venetoclax (Venclexta), and menin inhibitors.

At the 67th American Society of Hematology (ASH) Annual Meeting in December 2025, we saw further advances in targeted therapy for AML. The plenary session featured the PARADIGM trial (NCT04801797), which asked whether the novel combination of azacitidine and venetoclax could replace intensive chemotherapy (the standard for the past 50 years) in younger, fit patients with high-risk AML. This phase 2 study randomly assigned 172 adults with newly diagnosed AML to receive azacitidine plus venetoclax, conventional intensive induction with the 7+3 regimen, or CPX-351. Patients with FLT3 mutations (in whom FLT3 inhibitors were deemed essential) and those with NPM1 mutations under age 60 or core-binding factor AML (whose prognosis was deemed to be favorable with conventional therapy) were excluded, leaving a high-risk population, with 72% of patients categorized as adverse risk by European LeukemiaNet 2022 criteria. Patients treated with azacitidine-venetoclax had a better median event-free survival (14.6 months vs 6.2 months), a higher response rate (88% vs 62%), and a higher likelihood of getting to allogeneic hematopoietic cell transplant (61% vs 40%), as well as a lower 30-day mortality rate (0% vs 3.5%). Median overall survival was not significantly different between the groups (21.5 months vs 18.6 months), perhaps because of crossover. Quality of life was better with azacitidine-venetoclax, as measured by fewer days in the hospital, lower rates of admission to intensive care units, better quality-of-life scores, and lower symptom burden. These findings suggest that the lower-intensity, targeted regimen has the potential to become the new standard induction therapy in fit patients with high-risk AML. Of note, the combination of azacitidine and venetoclax has not been compared with a venetoclax-containing, intensive induction regimen.

Additional targeted agents reported at ASH included several menin inhibitors and bispecific antibodies. Examples include studies of revumenib (Revuforj) combined with decitabine/cedazuridine and venetoclax in an all-oral triplet for newly diagnosed AML; revumenib combined with 7+3 chemotherapy; ziftomenib (Komzifti) combined with azacitidine and venetoclax; the FLT3 × CD3 bispecific antibody CLN-049 in relapsed AML; and the CD123 × CD3 bispecific antibody mipletamig combined with azacitidine and venetoclax as frontline therapy.