Ponatinib plus asciminib in myeloid blast-phase CML harboring a phased BCR::ABL1 Y253H/T315I compound mutation: a...

Compound BCR::ABL1 mutations, particularly those including T315I in combination with P-loop substitutions, represent a major therapeutic challenge in advanced-phase chronic myeloid leukemia (CML). Clinical evidence supporting dual ATP-site and allosteric inhibition in this setting remains limited. We report a heavily pretreated patient with myeloid blast-phase CML in whom next-generation sequencing at blast transformation identified Y253H, T315I, and a low-level Y253_E255delinsHGK variant. Importantly, phasing analysis demonstrated that Y253H and T315I were present on the same BCR::ABL1 allele, confirming a true compound mutation. Given the aggressive disease biology, limited therapeutic options, and transplant intent, the patient received ponatinib 45 mg once daily plus asciminib 200 mg twice daily as an individualized bridge strategy. After 4 weeks of treatment, bone marrow evaluation showed a transient reduction in blast burden. However, treatment exposure was brief and interrupted by pancreatitis, no molecular response was documented, and rapid relapse occurred before planned allogeneic transplantation. This case should therefore not be interpreted as evidence of efficacy. Rather, it provides a cautious, hypothesis-generating clinical observation suggesting possible short-term activity of dual ATP-site and allosteric inhibition in a highly resistant setting. This case also highlights the potential value of long-read sequencing-based mutation profiling with phasing in advanced-phase CML, where distinguishing true compound mutations from separate subclones may be clinically relevant.