ASH 2025: Key Anticipated Updates in the Leukemia Landscape

The 2025 American Society of Hematology (ASH) Annual Meeting & Exposition in Orlando, Florida, is rapidly approaching. Clinicians from around the world are preparing for the newest data that may signal the rise of novel therapeutic strategies across hematologic malignancy management.

On top of late-breaking abstracts and presentations in diseases such as lymphoma and multiple myeloma, this year’s meeting will feature plenty of critical updates in the treatment of patients with different types of leukemia. From studies exploring alternatives for the standards of intensive chemotherapy and continuous treatment to trials assessing novel therapeutic classes like menin inhibitors, here is a sample of the presentations to watch out for in the leukemia landscape.

Abstract 1: Fixed-duration versus continuous targeted treatment for previously untreated chronic lymphocytic leukemia: Results from the randomized CLL17 trial.¹

Presentation: December 7, 2:05 – 2:20 PM EST by Othman Al-Sawaf, MD, PhD

Among the anticipated presentations at this year’s meeting is a readout of data from the investigator-initiated phase 3 CLL17 trial (NCT04608318), in which patients with previously untreated chronic lymphocytic leukemia (CLL) were assigned to receive ibrutinib (Imbruvica), fixed-duration venetoclax (Venclexta) plus obinutuzumab (Gazyva), or fixed-duration venetoclax plus ibrutinib. Data from this trial may elucidate the efficacy of different fixed-duration regimens in CLL compared with continuous treatment until disease progression.

“[CLL17 is] the first study that has compared this continuous therapy with the other novel targeted agents. The study is going to be a bit of a challenge to interpret once it’s completed because when it was designed, ibrutinib was the standard BTK inhibitor that most [patients] used. Now, with acalabrutinib [Calquence] and zanubrutinib [Brukinsa], most [patients] use these next-generation inhibitors,” Deborah Stephens, DO, an associate professor of Medicine, director of the CLL and Richter’s Program, and physician leader of the CLL and Lymphoma Research Program at the University of North Carolina School of Medicine, stated in an interview with CancerNetwork® regarding the trial and other updates in the CLL landscape. “It’s going to be an important study because it looks at all-targeted, time-limited therapies vs indefinite therapy. There are some weak spots because ibrutinib is the BTK inhibitor that was used, but it will still provide important data.”

Abstract 6: 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.²

Presentation: December 7, 3:45 – 4:00 PM EST by Amir Fathi, MD

As part of a visit to Georgia Cancer Center in Augusta, Georgia, CancerNetwork sat down with Daniel Peters, MD, to discuss critical advancements in leukemia research and management. When prompted about the potential next steps for the field, Peters highlighted research slated for presentation at the 2025 ASH meeting that may “change the treatment paradigm” in acute myeloid leukemia (AML).

“I think the field is moving towards leaving this old paradigm of 7+3 intensive chemotherapies for newly diagnosed patients with AML who are young and fit, and [some studies are] looking at some of these other regimens, particularly azacitidine [Vidaza] and venetoclax,” Peters, an assistant professor of Hematology and Oncology in the Department of Medicine at the Medical College of Georgia of Augusta University and bone marrow transplant & cellular therapy faculty member at Georgia Cancer Center, said. “The field [may] move towards a less intensive approach and a less toxic approach up front.”

One such study exploring this shift away from the intensive induction standard is the phase 2 PARADIGM trial (NCT04801797), in which a cohort of fit patients with newly diagnosed AML were assigned to receive venetoclax/azacitidine or chemotherapy. Findings from this trial may demonstrate the feasibility and efficacy of offering an alternative to upfront intensive chemotherapy for a select AML population.

Abstract 5669: Zanubrutinib + venetoclax for treatment-naive chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL), including patients with del(17p) and/or TP53 mutation and unmutated immunoglobulin heavy-chain variable status: 3-year results from SEQUOIA arm D.³

Presentation: December 8, 6:00 – 8:00 PM by Mazyar Shadman, MD, MPH

One key poster presentation will detail updated results from arm D of the phase 3 SEQUOIA trial (NCT03336333), in which patients with CLL or small lymphocytic leukemia (SLL) received zanubrutinib plus venetoclax. Of note, this analysis will disclose outcomes among a population that includes those with del(17p) and/or TP53 mutations and unmutated immunoglobulin heavy-chain variable status after a median follow-up of 38.5 months.

In a previous presentation of findings from arm D of the SEQUOIA trial at the 2025 American Society of Clinical Oncology (ASCO) Annual Meeting, study investigator Mazyar Shadman, MD, MPH, noted that “zanubrutinib plus venetoclax has a robust efficacy and produces deep and durable responses in treatment-naïve CLL regardless of the presence of [17p deletions] or TP53 mutations.”⁴ Shadman is an associate professor of Clinical Research and medical director of Cellular Immunotherapy at the Fred Hutch Cancer Center.

Abstract 764: Ziftomenib in combination with venetoclax and azacitidine in relapsed/refractory NPM1-m or KMT2A-r acute myeloid leukemia: updated phase 1a/b safety and clinical activity results from KOMET-007.⁵

Presentation: December 8, 11:45 AM – 12:00 PM EST by Amir Fathi, MD

Abstract 766: Ziftomenib in combination with venetoclax and azacitidine in newly diagnosed NPM1-m acute myeloid leukemia: phase 1b results from KOMET-007.⁶

Presentation: December 8, 11:15 – 11:30 AM EST by Gail Roboz, MD

Evaluation of the investigational menin inhibitor ziftomenib (Komzifti) plus venetoclax and azacitidine is ongoing among patients with NPM1-mutated or KMT2A-rearranged AML as part of the phase 1a/1b KOMET-007 trial (NCT05735184). Different presentations at this year’s ASH meeting will focus on study outcomes across different treatment settings. Updated findings may show the activity of the ziftomenib-based combination among patients with relapsed/refractory disease as well as those who were newly diagnosed with AML.

In November 2025, the FDA approved ziftomenib monotherapy for those with relapsed/refractory AML based on data from the phase 1b/2 KOMET-001 trial (NCT04067336).⁷ Additional investigations like the KOMET-007 trial may reveal the potency of combining ziftomenib with other agents in AML management.

References

1. Al-Sawaf O, Stumpf J, Zhang C, et al. Fixed-duration versus continuous targeted treatment for previously untreated chronic lymphocytic leukemia: results from the randomized CLL17 trial. To be presented at the 2025 American Society of Hematology (ASH) Annual Meeting & Exposition; December 6-9, 2025; Orlando, FL. Abstract 1.
2. 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. To be presented at the 2025 American Society of Hematology (ASH) Annual Meeting & Exposition; December 6-9, 2025; Orlando, FL. Abstract 6.
3. Shadman M, Munir T, Ma S, et al. Zanubrutinib + venetoclax for treatment-naive chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL), including patients with del(17p) and/or TP53 mutation and unmutated immunoglobulin heavy-chain variable status: 3-year results from SEQUOIA arm D. To be presented at the 2025 American Society of Hematology (ASH) Annual Meeting & Exposition; December 6-9, 2025; Orlando, FL. Abstract 5669.
4. Shadman M, Munir T, Ma S, et al. Combination of zanubrutinib (zanu) + venetoclax (ven) for treatment-naive (TN) CLL/SLL: results in SEQUOIA arm D. J Clin Oncol. 2025;43(suppl 16):7009. doi:10.1200/JCO.2025.43.16_suppl.7009
5. Issa G, Fathi A, Zeidan A, et al. Ziftomenib in combination with venetoclax and azacitidine in relapsed/refractory NPM1-m or KMT2A-r acute myeloid leukemia: updated phase 1a/b safety and clinical activity results from KOMET-007. To be presented at the 2025 American Society of Hematology (ASH) Annual Meeting & Exposition; December 6-9, 2025; Orlando, FL. Abstract 764.
6. Roboz G, Wang E, Fathi A, et al. Ziftomenib in combination with venetoclax and azacitidine in newly diagnosed NPM1-m acute myeloid leukemia: phase 1b results from KOMET-007. To be presented at the 2025 American Society of Hematology (ASH) Annual Meeting & Exposition; December 6-9, 2025; Orlando, FL. Abstract 766.
7. FDA approves ziftomenib for relapsed or refractory acute myeloid leukemia with a NPM1 mutation. News release. FDA. November 13, 2025. Accessed December 4, 2025. https://tinyurl.com/2mcsxzuv