Chronic Myeloid Leukemia After Second-Line TKI Failure: What to Do Next
This protocol addresses chronic myeloid leukemia (CML) in patients who have not achieved the required molecular response milestones on a second-line tyrosine kinase inhibitor (TKI). When second-line TKI therapy falls short of those benchmarks, a further treatment step is needed.
Previous Line — Failure Condition
Second-line TKI therapy — which may include dasatinib, nilotinib, bosutinib, ponatinib, or asciminib depending on the prior treatment history and mutation profile — did not achieve the required response milestones: a BCR::ABL1IS of 10% or lower at 3 months, 1% or lower at 6 months, and 0.1% or lower at 12 months. Non-achievement of these thresholds triggers escalation to this protocol.
Treatment Goal
The response target for this line of therapy remains a BCR::ABL1IS of 1% or lower — the threshold associated with optimal survival — with milestones identical to those used in first- and second-line treatment.
Approach (Partial Overview)
Treatment at this stage draws on specific later-line TKI agents, with agent selection guided in part by the patient's BCR::ABL1 mutation profile — including whether a T315I mutation is present.
The complete agent selection criteria, sequencing algorithm, and any regimen-specific considerations are in the full protocol below.
References
DOI: 10.1038/s41375-025-02664-w
- For patients resistant to their second line drug, asciminib or ponatinib should be the first choice, co-morbidities and BCR::ABL1 mutations permitting.
- Patients with BCR::ABL1IS > 1% were randomized one of three doses of ponatinib, 45 mg, 30 mg or 15 mg, with mandatory dose reduction to 15 mg in the 45 mg and 30 mg arms once transcript levels dropped below 1%IS.
- Sub-group analyses suggest that where possible, for patients with a BCR::ABL1 mutation, particularly T315I, or for those with BCR::ABL1IS >10%, the starting dose should be 45 mg.
- Olverembatinib, a new ATP-binding site competitor, designed to have specific activity against T315I, is approved for use in 3rd and subsequent line treatment and/or for patients with T315I mutations in China.
- The milestones for response, at least to third-line TKI, should be identical to those for first- and second-line treatment.
- The definition of an acceptable response to third and subsequent line treatment is arguable, although a BCR::ABL1IS > 1% has long been considered insufficient for optimal survival.
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