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CME Evaluation

Oral Communication Session

Vascular Biology, Blood Cells, and Immunothrombosis

Session: Interaction with immune cells

OC 56.5 - Mechanisms of thrombogenesis in chronic myeloid leukemia (CML) patients under treatment with ponatinib and others tyrosine kinase inhibitors

Tuesday, June 25, 2024
10:30 – 10:45 ICT
Room: 111 A-C

    Presenting Author(s)

  • Sonia Aguila, PhD

    Principal Investigator
    Centro Regional de Hemodonación, IMIB-Pascual Parrilla, UCAM
    Murcia, Murcia, Spain

    • Co-Author(s)

  • JC

    José Cuenca-Zamora

    PhD student
    Centro Regional de Hemodonación, IMIB-Pascual Parrilla, UMU
    Murcia, Murcia, Spain

  • ML

    Maria Jose Lis

    MD
    Consorcio Hospital G.U. de Valencia
    Valencia, Comunidad Valenciana, Spain

  • MG

    María Carmen García-Hernández

    MD
    Hospital G. de Alicante
    Alicante, Comunidad Valenciana, Spain

  • MF

    María José Fernandez

    MD
    Hospital U. Dr Peset
    Valencia, Comunidad Valenciana, Spain

  • MN

    María Soledad Noya-Pereira

    MD
    Hospital Teresa Herrera
    A Coruña, Galicia, Spain

  • EM

    Elvira Mora Castera

    MD
    Hospital U. Politécnico La Fe
    Valencia, Comunidad Valenciana, Spain

  • LP

    Luis Ramon Palomera

    MD
    Hospital C.U. Lozano Blesa, Instituto De Investigacion Sanitaria Aragón
    Zaragoza, Aragon, Spain

  • AS

    Alicia Senin

    MD
    Hospital Duran I Reynals. Institut Català D’ Oncologia
    Barcelona, Catalonia, Spain

  • RP

    Raul Perez-Lopez

    MD
    Hospital U. Virgen de la Arrixaca
    Murcia, Murcia, Spain

  • MP

    Manual Perez-Encinas

    MD
    Hospital C.U. Santiago De Compostela
    A Coruña, Galicia, Spain

  • AA

    Ana Angona-Figueras

    MD
    Hospital U. Dr. J Trueta, Institut Català D’Oncologia
    Girona, Catalonia, Spain

  • JP

    Jose Manuel Puerta

    MD
    Hospital U. Virgen De Las Nieves,
    Granada, Andalucia, Spain

  • RV

    Rolando Vallansot

    MD
    Hospital U. Joan XXIII
    Tarragona, Catalonia, Spain

  • VC

    Venancio Conesa

    MD
    Hospital G.U. de Elche ,
    Elche, Comunidad Valenciana, Spain

  • JH

    Juan Carlos Hernandez-Boluda

    MD
    Hospital C.U. de Valencia
    Valencia, Comunidad Valenciana, Spain

  • AR

    Ana Isabel Rosell

    MD
    Hospital Virgen de la Victoria
    Malaga, Andalucia, Spain

  • ML

    María Luisa Lozano

    Hematologist
    Servicio de Hematología, Hospital General Universitario Morales Messeguer, Centro Regional de Hemodonación, Universidad de Murcia, Universidad de Murcia, IMIB-Pascual Parrilla, CIBERER-ISCIII
    Murcia, Murcia, Spain

  • VG

    Valentin Garcia-Gutierrez

    MD
    Hospital U Ramón Y Cajal,
    Madrid, Madrid, Spain

  • FF

    Francisca Ferrer-marín

    Hematologist
    Servicio de Hematología y Oncología Médica-HU Morales Meseguer-Centro Regional de Hemodonación-CIBERER-ISCIII-CB15/00055, IMIB-Pascual Parrilla, Universidad Católica de Murcia (UCAM)
    Murcia, Murcia, Spain

Background: Ponatinib, a third-generation of tyrosine kinase inhibitors (TKIs); and others have thrombosis associated with their used, but the underlying mechanisms in patients’ remains unclear.

Aims: Elucidate mechanism/s of ponatinib-associated thrombosis in order to prevent these events.

Methods: Blood was collected from CML patients recruited at GELMC hospitals (n≥20/group) and treated with imatinib, nilotinib, ponatinib (30-45mg QD); or in TKI-free remission. Hemostatic and thromboinflammatory markers were evaluated.

Results: We found no differences in biological or CML molecular parameters between groups (Table 1). Ponatinib-treated patients showed higher VWF:Ag and VWF:CB, and decreased ADAMTS13 activity compared to controls and other TKIs. For NET markers, some TKIs increased cfDNA levels, but only ponatinib increased citH3-DNA complexes. PFA-100 assay showed that ponatinib-treated patients had prolonged Col/Epi closure time, whereas others TKIs did not change it. Platelets from ponatinib patients showed reduced (50%) fibrinogen binding and P-selectin exposure following TRAP6 and CRP stimulation, as well as reduced p-Syk. However, plasma PF4 levels were similar in all CML patients, suggesting this platelet hyporeactivity is not caused by platelet activation in circulation. Luminex assay displayed elevated sE-selectin levels in imatinib and ponatinib treated patients and similar trend for thrombomodulin. Importantly, only ponatinib-treated samples had twice tissue factor levels (sTF). To investigate whether these higher TF levels were ponatinib dose-dependent, two patient subgroups treated with ponatinib 15 mg QD ± ASA after failure to discontinue was investigated and no changes in TF were found.

Conclusion(s): We describe for the first time that VWF, NETs and TF play a role in the pathogenesis of ponatinib-associated thrombosis being useful thromboinflammatory biomarkers to identify thrombotic risk. Importantly, sTF increase occurs only at high doses of ponatinib. Finally, platelets from ponatinib-treated patients are hyporeactive, therefore antiplatelet therapy might be inconsequential.