P209 | COMBINATION OF PONATINIB AND ASCIMINIB IN PATIENTS WITH ADVANCED CHRONIC MYELOID LEUKEMIA

Background Progression of chronic myeloid leukemia to blast crisis (CML-BC) can occur in patients (pts) resistant to multiple tyrosine kinase inhibitors (TKIs) and is associated with poor prognosis. Despite advances with second- and third-generation TKIs, outcomes after progression remain dismal. Ponatinib is a potent multi-target TKI active against T315I and other resistant mutations, while Asciminib is a first-in-class STAMP (Specifically Targeting the ABL Myristoyl Pocket) inhibitor. The rationale for combining these agents is based on their in vitro synergistic inhibition of BCR-ABL1, through binding to distinct domains of the protein. However, clinical experience with this combination in CML remains limited. Aims To evaluate hematological, morphological, molecular response, safety and tolerability of combined Ponatinib and Asciminib in 3 pts with CML treated at a single hematology center in Italy. Methods Between 2021 and 2025, 3 Philadelphia-positive CML pts with advanced disease were treated with Ponatinib and Asciminib after failing at least 2 prior TKIs (Imatinib, Nilotinib, Dasatinib, Bosutinib). Baseline assessments included clinical characteristics, prior TKI exposure, hematologic values, bone marrow morphology, cytogenetics, molecular monitoring and transplant data when applicable. Pts received Ponatinib 45 mg QD plus Asciminib 200 mg BID, with response assessed by hematological evaluation, BCR-ABL1 Q-PCR, bone marrow morphology, cytogenetics and adverse event monitoring. Results All 3 pts obtained a complete hematological response with disappearance of peripheral blood and bone marrow blasts after 1 month of treatment. Cytogenetic remained positive while Q-PCR values decreased by 2- to 4-fold. All 3 pts could therefore undergo allogenic bone marrow transplant (BMT). One patient achieved and maintained > 3.5 years both morphological and molecular responses. The second demonstrated a complete morphological response post BMT but had detectable molecular disease and despite resuming Ponatinib and Asciminib, he progressed to CML-BC. The third just received his BMT. No severe adverse events were reported; the combined therapy was well tolerated. Conclusion This small single-center experience suggests that Ponatinib plus Asciminib appears a promising therapeutic option in transplant eligible pts with advanced CML, enabling disease control. Further studies in larger cohorts are needed to better define efficacy, safety and timing of this strategy.