ASH 2025 CML Highlights: Asciminib, Ponatinib Optimization, and Treatment Sequencing

Sawyer Bawek, DO University at Buffalo | Fadi Haddad, MD MD Anderson Cancer Center

Key Points

• The ASC4FIRST trial establishes asciminib as a highly effective frontline option in newly diagnosed chronic myeloid leukemia (CML), particularly for patients aiming for deep molecular response and treatment-free remission.

• Ponatinib dose-optimization strategies from the OPTIC trial allow maintenance of efficacy while reducing cardiovascular toxicity in refractory CML.

• Additional myeloid mutations, such as ASXL1, are associated with poorer outcomes with tyrosine kinase inhibitors (TKIs), highlighting the need for biologically informed treatment strategies.

At the 2025 ASH Annual Meeting, Sawyer Bawek, DO, of Roswell Park Comprehensive Cancer Center, discussed key advances in the management of CML, with a particular focus on treatment selection in newly diagnosed disease and sequencing strategies after treatment failure, in an interview with Fadi Haddad, MD, of The University of Texas MD Anderson Cancer Center. 

Over the past decade, outcomes for patients with CML have dramatically improved, with most patients now achieving near-normal life expectancy. As a result, treatment selection has increasingly shifted beyond survival alone toward individualized goals, including treatment-free remission, long-term tolerability, and comorbidity management. Data presented at ASH 2025 reinforce the importance of aligning therapeutic choice with patient priorities and biologic risk.

Frontline Treatment Selection and the ASC4FIRST Trial

The ASC4FIRST trial evaluated asciminib, a first-in-class STAMP (specifically targeting the ABL myristoyl pocket) inhibitor, against investigator’s choice of a TKI (imatinib or a second-generation TKI) in patients with newly diagnosed CML. Results demonstrated asciminib’s superiority in achieving higher rates of major molecular response and deep molecular responses, along with a more favorable safety profile.

Dr. Bawek emphasized that defining the patient’s treatment goal is central to frontline decision-making. For patients interested in achieving deep molecular remission quickly—such as those who are younger, planning pregnancy, or motivated to pursue treatment-free remission—a more potent agent like asciminib may be preferred. In contrast, patients whose primary goal is disease control with lifelong therapy can expect excellent long-term survival with any approved TKI, making tolerability and comorbidities key factors in selection. Cardiovascular disease, pulmonary disease, and baseline risk profiles should guide individualized therapy, with dasatinib generally avoided in patients with underlying lung disease and imatinib or bosutinib favored in those with cardiovascular concerns.

Ponatinib Optimization, Genomic Risk, and Sequencing Strategies

Ponatinib remains a highly effective option for patients with multiply relapsed or refractory CML, but concerns about cardiovascular toxicity have historically limited its use. Updated results from the OPTIC trial support a dose-optimization strategy, starting at 30 to 45 mg daily and reducing to 15 mg once a complete cytogenetic response or BCR-ABL1 of 1% or less is achieved. This approach preserves efficacy while reducing toxicity. Dr. Bawek also noted his institutional practice of using cardiovascular prophylaxis with low-dose aspirin and statins in selected patients, although this strategy is not yet universally adopted.

Another major theme at ASH 2025 was the impact of additional myeloid mutations, particularly ASXL1, which are present in about 20% of patients with newly diagnosed CML. Data from ASC4FIRST showed that ASXL1 mutations were associated with lower molecular response rates, higher treatment failure, and increased acquisition of ABL1 kinase domain mutations. While asciminib demonstrated clear benefit over other TKIs in patients without ASXL1 mutations, outcomes were inferior across all treatments when ASXL1 was present, underscoring the need for improved risk stratification and novel approaches in this subgroup.

To conclude the interview, Dr. Bawek highlighted data examining second-line therapy after failure of a second-generation TKI. Patients who failed frontline dasatinib, nilotinib, or bosutinib and switched to newer agents such as asciminib or ponatinib achieved substantially higher molecular response rates than those who switched to an alternative second-generation TKI.