Assess response milestones (BCR::ABL1 IS)
Assess the BCR::ABL1 molecular response trajectory and determine whether there is an inadequate response or loss of a previously achieved response. Key molecular response milestones: 3 months: BCR::ABL1 IS ≤10% is favorable; >10% is a warning and becomes unfavorable if confirmed within 1–3 months. 6 months: ≤1% is favorable; >1–10% is a warning; >10% represents established resistance. 12 months: ≤0.1% is favorable; >0.1–1% is a warning; >1% is unfavorable. At any time: loss of a previous response, a resistant BCR::ABL1 mutation, or high-risk additional cytogenetic abnormalities should raise concern for resistance. Do not base a treatment switch on a single unexpected PCR result alone. Review the molecular trajectory together with adherence, dose interruptions or reductions, drug interactions, comorbidities, and potential laboratory variability.
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Rule out pseudo-resistance
Before confirming true TKI resistance, reassess potentially reversible causes of an inadequate molecular response: Non-adherence Drug–drug interactions Dose interruptions or dose reductions Laboratory / assay variability If the molecular trajectory is unexpected, repeat or confirm BCR::ABL1 testing as clinically appropriate before declaring true resistance. Address reversible causes whenever possible before changing therapy.
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Mutation testing (NGS preferred)
Perform BCR::ABL1 kinase-domain mutation testing when TKI resistance is suspected or when a persistent warning or unfavorable molecular response is present. Targeted BCR::ABL1 NGS is preferred when available because it provides greater sensitivity for detecting emerging resistant clones. Use the mutation profile to: identify TKIs that are unlikely to be effective; guide selection of the next TKI; identify T315I or other clinically relevant resistance-associated mutations. Consider conventional cytogenetic analysis when resistance is suspected to assess for additional chromosomal abnormalities or disease progression.
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Select next TKI
Select the next TKI according to: prior TKI exposure; BCR::ABL1 mutation profile; prior intolerance versus true resistance; comorbidities and drug-specific toxicity; treatment goals and patient preference. After imatinib failure Consider a second-generation TKI or asciminib, guided by mutation profile and comorbidities. After resistance to a second-generation TKI Consider asciminib or ponatinib, when clinically appropriate. T315I mutation Ponatinib or asciminib Multi-TKI-resistant disease or resistance to ponatinib or asciminib Refer for allo-HCT evaluation Consider a clinical trial when available. Key principle: unfavorable response reflects inadequate depth or loss of response → reassess exposure and adherence, test for resistance mutations, and change therapy when appropriate.