eCase - Chronic Myeloid Leukemia Treatment

CME

Chronic Myeloid Leukemia: Optimizing Use of TKIs to Individualize Treatment Across the Disease Spectrum

Physicians: Maximum of 1.00 AMA PRA Category 1 Credit™

Released: August 15, 2024

Expiration: February 14, 2025

CME/CE Information

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Introduction Overview of CML Personalized Initial Therapy for A Young Patient with Newly Diagnosed CML and a Goal of TFR Personalized Initial Therapy for an Older Patient With Newly Diagnosed CML and Multiple Comorbidities Personalizing Therapy for Patients With Intolerance to Initial Therapy Personalizing Therapy for Patients with Suboptimal Response to Initial Therapy Personalizing Therapy for Patients with Loss of Response to Previous TKI Therapy Concluding Thoughts References

Summary: The State of CML Treatment in 2024

In 2024, CML treatment primarily involves targeted therapies, particularly TKIs, which have revolutionized management of the disease. For frontline therapy, the choices of TKI include imatinib, dasatinib, bosutinib, and nilotinib. The choice of frontline agent can depend on the goal of treatment (survival or TFR), patient comorbidities, comedications, CML risk category, and cost.² If frontline therapy fails, it is important to reassess the treatment strategy and determine whether failure is due to nonadherence, treatment toxicities, or disease resistance. For many patients whose waning response is due to nonadherence because of treatment-related AEs, dose reductions of TKIs are an excellent approach that can help maintain efficacy and improve tolerability.

Resistance to frontline therapy should be confirmed with molecular monitoring that shows a clear loss of response and a mutation analysis. Choice of later-line TKI therapies is then based on mutation profile and TKI side effect profiles together with any relevant patient comorbidities. Dasatinib, nilotinib, or bosutinib are reasonable choices if resistance to frontline imatinib or frontline second-generation TKIs is identified, tailored to the patient’s comorbidities and ABL1 mutational status. Ponatinib has demonstrated efficacy against the T315I mutation and other resistance mutations. The STAMP inhibitor asciminib has demonstrated efficacy in resistant CML and provides an option with a novel mechanism of action. Regular monitoring and personalized treatment adjustments are crucial for optimizing outcomes in patients with resistant CML.

The recent results from the ASC4FIRST trial demonstrated the superiority of asciminib over imatinib and second-generation TKIs in the frontline setting of patients with chronic-phase CML, with higher MMR rates at 48 weeks. These positive results may lead to the approval of asciminib for use in patients with newly diagnosed CML. However, with the availability of generic imatinib and soon second-generation generic TKIs, the price of asciminib is a significant consideration and barrier to its use in the frontline setting. Furthermore, long-term safety data need to be established for asciminib before it can replace first- or second-generation TKIs in patients with newly diagnosed CML. Previously, frontline nilotinib showed a favorable safety profile after 5 years of follow-up, but the 10-year follow-up showed a 25% cumulative incidence of cardiovascular events.¹⁵

Despite the significant improvement in outcomes with the approved third-generation TKIs, resistance still occurs. Patients with resistance to asciminib and/or ponatinib should be referred for clinical trials with newer-generation TKIs and should be considered for allogeneic stem cell transplantation.

Finally, TFR is an important goal of therapy in patients with CML. Multiple combination strategies have been evaluated but failed to improve the rates of TFR. It is preferable that patients attempting TFR achieve MR^4.5for 5 years or more before stopping TKI therapy.

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