Inside the Clinic The CML Patient Journey: A Multidisciplinary Approach to CML Management - Episode 6
Clinical Approach to Choice of Third-Line TKI in R/R CML
Panelists discuss the critical role of mutation testing and individualized ponatinib dosing in managing resistant or relapsed chronic myeloid leukemia (CML), emphasizing frequent molecular monitoring and multidisciplinary care to balance treatment efficacy with toxicity.
When patients with CML show signs of relapse or fail to meet treatment milestones, it is crucial to perform mutation testing to guide further therapy. The standard approach involves checking the ABL kinase domain mutation status, especially because specific mutations can confer resistance to tyrosine kinase inhibitors (TKIs). Next-generation sequencing can sometimes be used, although it is not yet routine everywhere. This more comprehensive testing can reveal additional mutations that might have prognostic implications, even if they do not immediately alter treatment choices. Identifying mutations like T315I is particularly important because it limits the effectiveness of many TKIs and narrows therapeutic options.
Monitoring response to treatment in resistant or relapsed CML follows principles similar to those used at initial diagnosis. After starting a new therapy such as ponatinib, frequent checks of BCR-ABL transcript levels, particularly at 3 months, help assess how well the patient is responding. Early molecular responses predict longer-term control, so close follow-up with serial polymerase chain reaction testing is essential. Data from studies like the 5-year OPTIC trial support this strategy, showing that dose adjustments based on response can help balance efficacy and toxicity, especially with ponatinib, where doses can be lowered to minimize cardiovascular risks but must be increased again if the disease starts to progress.
In practice, ponatinib dosing is tailored to patient tolerance and risk factors. Many patients start on lower doses, such as 15 or 30 mg daily, with careful monitoring and dose adjustments as needed. Toxicities like rash or cardiovascular issues are managed proactively with supportive care and collaboration with specialists like cardio-oncology to maintain both effective treatment and quality of life. This approach emphasizes the importance of individualized therapy and vigilant monitoring to optimize outcomes in patients with resistant or relapsed CML.
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