Shifting Therapeutic Urgency and TKI Strategy

EP: 1.NCCN Guidelines and Early Response Monitoring in Chronic Myeloid Leukemia

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EP: 2.Shifting Therapeutic Urgency and TKI Strategy

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Asciminib represents a breakthrough in CML treatment as the first inhibitor specifically targeting the ABL myristoyl pocket, offering a unique allosteric binding mechanism distinct from traditional ATP-competitive TKI inhibitors. This innovative approach provides therapeutic advantages, particularly for patients who have treatment failure with other TKIs with similar mechanisms of action. Understanding these different binding mechanisms helps clinicians select optimal treatments based on individual patient resistance patterns and treatment history.

TKI therapy success depends heavily on understanding off-target receptor effects that contribute to medication adverse effects and treatment tolerability. These off-target interactions often explain cardiotoxicity and fluid retention observed with different CML medications, making adverse effect profiles crucial considerations in treatment selection. Although some off-target effects prove beneficial for treating other malignancies, in CML treatment, they primarily influence adverse event profiles and patient quality of life, requiring careful therapeutic selection based on individual patient risk factors.

CML treatment strategies must adapt based on disease presentation phase, with patients with advanced-phase disease requiring more aggressive approaches, including combination induction chemotherapy alongside BCR-ABL targeted therapy. Second-generation or higher TKIs are preferred for advanced-phase CML due to their superior response rates and higher target affinity. Even patients with chronic-phase disease with intermediate to high-risk Sokal scores warrant consideration for second-generation TKIs to prevent transformation to advanced disease phases and achieve faster, more durable responses.