Giuseppe Saglio at LeukO 2026: Managing TKI Resistance in CML

Giuseppe Saglio at LeukO 2026: Evaluating Resistance and Mutation Testing in Chronic Myeloid Leukemia

When chronic myeloid leukemia stops responding to tyrosine kinase inhibitors, switching treatments too early can expose patients to unnecessary toxicity, according to Giuseppe Saglio, Emeritus Professor of Hematology and Internal Medicine at the University of Turin, Italy. Speaking at LeukO 2026: Global Virtual Congress on Leukemias, organized by OncoDaily, Saglio addressed the complex mechanisms of resistance driven by BCR::ABL1 mutations and outlined how modern molecular testing helps clinicians decide when to maintain therapy or transition to alternative agents.

The Tech TL;DR:

• Molecular Monitoring: Next-generation sequencing detects low-frequency BCR::ABL1 mutations before resistance becomes clinically apparent.
• Treatment Customization: Patient age, comorbidities, and specific kinase domain mutations dictate TKI selection rather than rigid time-bound thresholds.
• Alternative Inhibitors: Agents like asciminib target the ABL1 myristoyl pocket, though secondary resistance mutations can still emerge outside the binding site.

Age Influences Initial TKI Drug Selection

Tyrosine kinase inhibition remains the foundational approach for managing chronic myeloid leukemia, allowing most patients to secure long-term disease control. However, clinical practice data presented by Saglio at LeukO 2026 and highlighted by Oncodaily revealed distinct prescription patterns across different demographics.

Age heavily influences initial drug selection. Physicians predominantly prescribed second-generation TKIs to younger patients—with a mean age of approximately 51 years—where achieving a deep molecular response and attempting treatment-free remission served as primary clinical goals. Conversely, older patients, with a mean age of roughly 66 years, were more frequently treated with imatinib. While newer TKIs generate faster and deeper molecular responses, comparative clinical trials have not consistently demonstrated an overall survival advantage over imatinib in first-line settings. Consequently, for older individuals with significant comorbidities, maintaining long-term tolerability takes precedence over securing the deepest possible molecular drop.

Discontinuation Patterns and Toxicity Versus Resistance

Data from more than 1,500 patients illustrated divergent discontinuation profiles among available inhibitors. Approximately 30% of patients receiving imatinib or dasatinib discontinued their initial treatment during follow-up, whereas nilotinib exhibited higher persistence rates. The underlying drivers of discontinuation varied significantly between compounds.

Dasatinib cessation was frequently linked to intolerance, particularly pleural effusion manifesting after years of continuous therapy. Intolerance affected roughly 20% of dasatinib-treated patients compared to 10% for nilotinib. Resistance displayed the inverse trend, occurring more frequently with imatinib than with second-generation alternatives. Differentiating between toxicity-driven discontinuations and resistance-driven treatment failure remains essential for selecting subsequent therapies.

Updated Criteria Partition Molecular Response Outcomes

The 2025 European LeukemiaNet recommendations established a more individualized framework for interpreting molecular response milestones. Previous clinical guidelines often classified results missing specific thresholds as absolute treatment failure. The updated criteria instead partition outcomes into three distinct categories:

• Favorable: Therapy functions as expected, rendering a switch unnecessary.
• Warning: Response falls below optimal levels, demanding closer monitoring and potential regimen adjustments.
• Unfavorable: Elevated risk of resistance dictates a preference for switching therapies after evaluating the clinical context.

Long-term findings from the German CML Study IV demonstrated that missing early molecular milestones does not automatically preclude favorable long-term survival. Patients exhibiting BCR::ABL1 transcript levels between 1% and 10% at later evaluations occasionally achieved positive outcomes when their molecular trajectory remained stable or improving. Persistent disease burdens exceeding 10% after 12 months, however, correlated with substantially worse outcomes, necessitating treatment modification.

Mutations Dictate Choice of Subsequent Therapy

When resistance develops, identifying specific BCR::ABL1 kinase domain mutations dictates the choice of subsequent therapy. Mutations alter the kinase structure, preventing standard ATP-competitive inhibitors from binding effectively. Well-characterized alterations such as T315I render conventional TKIs ineffective, though ponatinib or higher-dose asciminib offer alternative pathways depending on patient cardiovascular profiles.

Asciminib introduces a distinct mechanism by binding to the ABL1 myristoyl pocket rather than the ATP-binding site, stabilizing an inactive conformation. Despite this alternative binding site, resistance can still develop. Research identified that certain mutations, including M244V and F359V, locate outside the myristoyl pocket yet alter protein conformation enough to disrupt asciminib-mediated inhibition. Compound mutations involving two or more alterations within the same BCR::ABL1 molecule can confer simultaneous resistance to multiple TKIs, meaning doctors must perform early molecular assessments and consider stem cell transplantation quickly for refractory cases.