DOES THE NEW BCR::ABL ASCIMINIB (ABL001) TYROSINE KINASE INHIBITOR INDUCE PLATELET ACTIVATION, INCREASE THROMBUS FORMATION AND PROMOTE A PROTHROMBOINFLAMMATORY STATE?

Abstract

Abatract Background: Chronic myeloid leukaemia (CML) is driven by the BCR::ABL1 gene, leading to the development of tyrosine kinase inhibitors (TKIs) such as Imatinib, Nilotinib, and Ponatinib. However, resistance or intolerance to ATP-competitive TKIs remains a challenge for some patients. Asciminib , a novel TKI, targets the myristoyl pocket of ABL1 instead of the ATPbinding site, reducing resistance to mutations. As Asciminib is linked to thrombocytopenia, its effects on platelet activation, endothelial function, and inflammation must be studied to assess its potential to promote thrombosis. Hypothesis: We hypothesised that Asciminib may potentiate a thromboinflammatory state over time. Aim: The main objective of this study is to determine the potential of Asciminib as a monotherapy in inducing pathological responses to platelets and endothelium over time within the vasculature. Materials and Methods: This study assessed the effects of TKIs including Asciminib on platelets and thrombotic biomarkers. Washed platelets were used to measure granule secretion, thrombus formation, surface proteins, apoptosis, and viability. Plasma from Asciminib-treated CML patients was analysed using sandwich ELISA for inflammatory and platelets-endothelial biomarkers, and thrombin generation assays were performed to study coagulation. This approach combined in vitro and ex vivo methods to explore the impact of Asciminib on platelet function and thrombotic potential Results: The study shows that Asciminib does not promote platelet activation or thrombus formation. Instead, it exhibits an inhibitory effect on thrombus formation in vitro and demonstrates anti-thromboinflammatory properties in vivo. Asciminib promotes thrombin generation over time revealing an effect on secondary haemostasis. Conclusion: Asciminib does not induce a prothrombotic or proinflammatory state, which is advantageous for CML patients on treatment to avoid adverse side effects that can be life threatening. However, the potentiation of thrombin generation over time could predispose CML patients to venous thrombosis or acute ischaemic stroke, particularly in the elderly.