Chronic myeloid leukemia
ICD-10 C92.1 · ICD-11 2B33.2

CML with BCR::ABL1 T315I Gatekeeper Mutation — When First-Line Targeted Therapy Fails to Achieve Transcript Reduction

Clinical Scenario

This protocol addresses patients with chronic myeloid leukemia who carry the BCR::ABL1 T315I gatekeeper mutation — a variant that confers resistance to most available targeted agents — and whose first-line therapy has not achieved the required depth of response.

The T315I Gatekeeper Mutation

The T315I mutation displays resistance to all currently available TKIs except a small subset of specifically active agents. When even these agents fail to suppress disease to target levels, this specific escalated pathway applies.

First-Line Failure — Escalation Trigger

Patients in this setting were previously treated with a first-line agent active against the T315I mutation — ponatinib, asciminib, or olverembatinib — with the goal of reducing BCR::ABL1 transcripts (IS) to ≤1%. This protocol is indicated when that transcript reduction target was not achieved.

Treatment Approach (Partial Overview)

The approach for this situation centres on a transplant-based strategy, preceded by a short course of targeted therapy intended to improve disease control ahead of the procedure. The complete algorithm — including eligibility, sequencing, and full options — is available in the structured protocol.

Instant Access to Structured Evidence-Based Regimens

References

DOI: 10.1002/ajh.27443

One important mutation, T315I, known as the "gatekeeper" mutation, displays resistance to all currently available TKIs except ponatinib, asciminib, and olverembatinib.

For T315I-mutated CML, allo-HSCT (one-time procedure; cost range $20 000–500 000) may be the best curative option following a short course of ponatinib (3–6 months) to induce better disease control.

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