Chronic Myeloid Leukemia (CML), Chronic Phase

Evidence-based treatment sequencing for newly diagnosed chronic-phase CML, integrating frontline selection between the STAMP inhibitor asciminib and standard TKIs (imatinib, dasatinib, nilotinib, bosutinib), with mutation-guided salvage for resistance or the T315I gatekeeper mutation.

Frontline TKI selection for newly diagnosed Ph+ CML in chronic phase

• Asciminib preferred frontline → Asciminib (STAMP allosteric inhibitor)
• Standard TKI by risk score / comorbidity → Standard TKI — imatinib, dasatinib, nilotinib, or bosutinib

1L: Asciminib (STAMP allosteric inhibitor)

Preferred frontline option based on superior major molecular response and improved tolerability versus imatinib and investigator-selected 2G-TKIs in ASC4FIRST. Its off-target-sparing STAMP mechanism reduces the vascular and metabolic toxicities that limit 2G-TKIs. Monitor CBC, lipase/amylase, and for arterial events.

• Resistance, failure, or intolerance → BCR-ABL1 kinase-domain mutation analysis on resistance or intolerance

1L: Standard TKI — imatinib, dasatinib, nilotinib, or bosutinib

Established frontline options chosen by baseline risk score (Sokal/ELTS), treatment goal (e.g. pursuit of treatment-free remission favors a 2G-TKI), and comorbidity profile — dasatinib carries pleural-effusion/PAH risk, nilotinib vascular/metabolic risk, bosutinib GI/hepatic risk, imatinib the most benign long-term profile.

• Resistance, failure, or intolerance → BCR-ABL1 kinase-domain mutation analysis on resistance or intolerance

BCR-ABL1 kinase-domain mutation analysis on resistance or intolerance

• T315I mutation or multi-TKI resistance → Ponatinib or asciminib (T315I or multi-TKI resistance)
• Non-T315I resistance or intolerance → Alternative second/third-generation TKI (mutation-guided)

2L: Ponatinib or asciminib (T315I or multi-TKI resistance)

The T315I gatekeeper mutation confers resistance to all first/second-generation TKIs. Ponatinib (response-based dose reduction per OPTIC to mitigate arterial-occlusive risk) and asciminib (at the higher 200 mg twice-daily T315I dose) retain activity. Aggressive cardiovascular risk-factor management is essential with ponatinib.

• Subsequent progression → Allogeneic stem cell transplant or clinical trial

2L: Alternative second/third-generation TKI (mutation-guided)

For non-T315I resistance or intolerance, switch to an alternative TKI guided by the specific kinase-domain mutation (e.g. avoid nilotinib for Y253H/E255K/F359V; avoid dasatinib for F317L/V299L) and by the prior agent's toxicity.

• Subsequent progression → Allogeneic stem cell transplant or clinical trial

3L+: Allogeneic stem cell transplant or clinical trial

For multi-refractory chronic-phase disease, disease that has progressed to accelerated/blast phase, or compound-mutation resistance, evaluate for allogeneic hematopoietic stem cell transplantation and prioritize clinical-trial enrollment.