Lower-Intensity Regimens and CAR T-Cell Advances Drive Progress in AML and ALL at ASH 2025

Research advances with azacitidine (Vidaza)/venetoclax (Venclexta)–based regimens in acute myeloid leukemia (AML) and CAR T-cell therapies in acute lymphoblastic leukemia (ALL) are set to steal the show during the 2025 ASH Annual Meeting, according to hematology experts.

In anticipation of the meeting, OncLive® collected exclusive commentary from:

• Harry P. Erba, MD, PhD, a professor of medicine in the Department of Medicine, Hematologic Malignancies, and Cellular Therapy and a member of the Duke Cancer Institute in Durham, North Carolina
• Marlise Rachael Luskin, MD, MSCE, associate program director of the Dana-Farber/Mass General Brigham Hematology/Oncology Fellowship Program, educational director of the Adult Leukemia Program, and a senior physician at Dana-Farber Cancer Institute in Boston, Massachusetts; as well as an associate professor of medicine at Harvard Medical School
• Eytan M. Stein MD, chief of the Leukemia Service and director of the Program for Drug Development in Leukemia in the Division of Hematologic Malignancies at Memorial Sloan Kettering Cancer Center in New York, New York
• Eunice S. Wang, MD, a professor of oncology, leader of the Leukemia Clinical Disease Team, chief of the Department of Medicine – Leukemia, and an assistant member of the Tumor Immunology Program in the Department of Immunology at Roswell Park Comprehensive Cancer Center in Buffalo, New York; as well as an associate professor in the Department of Medicine and an academic scholar at the Jacobs School of Medicine and Biomedical Sciences at State University of New York at Buffalo

“There are going to be a lot of updates on menin inhibitors [such as revumenib (Revuforj)] and other updates and combinations of menin inhibitors with standard-of-care [SOC] therapy and with other novel therapies,” Stein summarized. “There are going to be updates on triplet therapies and how triplet therapies work, and how well adding a targeted agent to a backbone of azacitidine/venetoclax works in patients with AML.”

“Every year, we make incremental progress and learn from each other, and we come back with new ideas for what to work on,” Luskin emphasized.

Read on for further insights about the AML and ALL presentations these experts are most excited to see.

AML

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

Presentation time: Sunday, December 7, 2025, 3:45-4:00 pm EST

Erba: One [study] is particularly important and may change the landscape of how we manage AML. I'm not sure if it teaches us anything different than what we already know, but this is the study that may get the highest level of attention. The [phase 2] PARADIGM trial [NCT04801797] is being presented by Amir Fathi, MD, from Massachusetts General Hospital in Boston, for a group of 9 academic centers that performed this investigator-initiated trial.

In the PARADIGM trial, patients who were eligible for intensive chemotherapy were randomly assigned to receive venetoclax with azacitidine—a less intensive therapy—or intensive chemotherapy with either 7+3 or the liposomal formulation of daunorubicin and cytarabine, CPX-351; in that cohort, it was left up to the investigator which intensive chemotherapy the patient would receive. There are important [patient] exclusions we need to consider for this study, because given that the experimental arm was venetoclax with azacitidine, [the investigators] didn't want to treat patients who were potentially curable with available treatment. They excluded patients with core binding factor leukemia—disease with translocation 8;21 and inversion 16—and they excluded patients with a FLT3 mutation because those patients could receive midostaurin [Rydapt] or quizartinib [Vanflyta] in addition to intensive chemotherapy. They also excluded patients with NPM1 mutations, if they were younger than 60 years of age. If patients were 60 years of age or older, they could be included because those patients don't have as good a prognosis as younger patients when receiving intensive chemotherapy.

The primary end point of the study was met. The [overall response rate (ORR)] statistically favored venetoclax/azacitidine. The complete response [CR] rates were a little closer [to each other], and [the difference was] not statistically different but still numerically greater with venetoclax/azacitidine. We don't yet understand all the reasons why patients may or may not have gone on to transplant, but one reason that many leukemia specialists will lean toward giving a less intensive therapy like venetoclax/azacitidine to younger, fit patients with adverse-risk genotype is that it is felt that the toxicity of a venetoclax/azacitidine regimen is less than that of intensive chemotherapy, so you may allow more patients to get to the transplant. This disparity in the rate of transplant between the 2 [PARADIGM] groups, at least at this high-level view, supports that hypothesis. More than that, multiple safety parameters favored venetoclax/azacitidine. [The authors] also included in their abstract quality of life data.

There are a lot of questions that are going to be raised by these data that are going to affect the designs of ongoing clinical trials. This is not a small trial. There are approximately 85 patients in each arm, and the study was conducted at major academic centers in the United States.

This may gather a lot of attention. We need to remember that we're focusing on the patients who don't appear to have disease that is curable with standard intensive chemotherapy. I've read this abstract, and I can't imagine a more impactful study in reality. [However], we will need to see the survival data.

Wang: [The PARADIGM trial] describes a potential paradigm-changing intervention or consideration of how we should treat patients with newly diagnosed AML. This is an open-label, multicenter, randomized study. Most of these patients had what we consider adverse-risk disease per the European LeukemiaNet 2022 risk classification criteria, meaning they were going to do poorly overall with intensive chemotherapy. These patients were randomly assigned to receive either standard intensive chemotherapy with a cytarabine/anthracycline-based regimen vs lower-intensity therapy with venetoclax/azacitidine, which until now has been reserved for older, unfit patients 75 years [of age] and older.

The data heavily favor the administration of venetoclax and azacitidine in these younger, fit patients, despite the fact that they could have received intensive chemotherapy. This has the potential to change how we treat these patients. Moving forward, adverse-risk patients, regardless of their fitness, may end up receiving a venetoclax/azacitidine-based regimen.

Venetoclax (VEN) and azacitidine (AZA) with gilteritinib (GILT) in patients with newly diagnosed (ND) FLT3mut+ Acute Myeloid Leukemia (AML) ineligible for intensive induction chemotherapy (chemo): Interim results from the phase 1/2 VICEROY study

Presentation time: Sunday, December 7, 2025, 5:45-6:00 pm EST

Ziftomenib in combination with venetoclax and azacitidine in newly diagnosed NPM1-m acute myeloid leukemia: Phase 1b results from KOMET-007

Presentation time: Monday, December 8, 2025, 11:15-11:30 am EST

Wang: The other couple abstracts I'm excited about were also using that venetoclax/azacitidine backbone [as a part of] triplet therapy. The [phase 1/2] VICEROY trial [NCT05520567] is a single-arm trial that randomly assigned patients with newly diagnosed FLT3-mutant disease to receive gilteritinib [Xospata]—a FLT3 inhibitor—at either 200 mg or 400 mg added to backbone venetoclax/azacitidine. The addition of that FLT3 inhibitor did not seem to markedly increase toxicity but enhanced the outcomes of venetoclax/azacitidine in those patients.

In [the phase 1 KOMET-007 trial (NCT05735184)], patients with newly diagnosed NPM1-mutant disease had ziftomenib [Komzifti], a newly approved menin inhibitor, added to that venetoclax/azacitidine backbone. In those patients, the ORR and composite CR [rates were high], with seemingly no increased toxicity, no QTc prolongation, and no differentiation syndrome compared with the historic use of venetoclax plus azacitidine.

These 2 abstracts have the potential to make triplet venetoclax/azacitidine-based therapy the SOC for subsets of AML, which harkens to a new age of precision medicine for the treatment of patients with AML.

ALL

First results of the Phase III GIMEMA ALL2820 trial comparing ponatinib plus blinatumomab to imatinib and chemotherapy for newly diagnosed adult Ph+ acute lymphoblastic leukemia patients

Presentation time: Sunday, December 7, 2025, 9:30-9:45am EST

Luskin: There will be updates on ongoing trials for Philadelphia chromosome–positive ALL that are trying to refine the use of TKIs and blinatumomab [Blincyto]. Our colleagues from Italy will be presenting [data from the phase 3 GIMEMA ALL2820 trial (NCT04722848)].

CD19-CAR T cell therapy as a definitive consolidation in older adults with B-ALL in CR1 is safe and induces durable MRD– remission

Presentation time: Sunday, December 7, 2025, 10:30-10:45am EST

BAFFR-CAR T cells (PMB-CT01) show promising safety and anti-leukemia efficacy in relapsed/refractory B-cell ALL patients after CD19-targeted therapy failure, including CD19-negative disease

Presentation time: Monday, December 7, 2025, 11:00-11:15am EST

Luskin: There are also trials in CAR T-cell therapy. The adoption of CAR T-cell therapy for patients with ALL who are relapsed or refractory to prior treatments has been a great advance, but there have been trials investigating using that in the upfront setting. Ibrahim Aldoss, MD, of City of Hope in Duarte, California, is presenting [some CAR T-cell therapy] abstracts.