P213 | CBL MUTATIONS AND MICROVASCULAR BLEEDING IN MYELOPROLIFERATIVE NEOPLASMS: A RETROSPECTIVE SINGLE-CENTRE CASE SERIES OF TWELVE PATIENTS

Casitas B-lineage lymphoma (CBL) mutations, affecting the negative regulation of JAK/STAT, PI3K/AKT, and RAS/MAPK pathways, are rare but intriguing lesions in myeloproliferative neoplasms (MPN). Originally associated with vascular syndromes in germline disorders, their somatic role in MPN is underexplored. Through an integrated clinical-molecular review, we identified a subset of CBL-mutated MPN patients sharing a non-thrombotic vascular phenotype characterized by microcirculatory symptoms and bleeding despite preserved or elevated platelet counts. We retrospectively collected 12 cases between 2020–2024 at our center. Five had previously been included in a thromboelastometry (ROTEM) prospective study (EHA 2023, poster #1013). Diagnoses were: myelofibrosis (n=8), polycythemia vera (n=1), and MPN/MDS overlap (n=3). Driver mutations were JAK2 (n=7), CALR (n=1), MPL (n=1), or absent (n=3). Seven patients (58%) experienced clinically relevant bleeding: intracranial hemorrhage (n=4), mucocutaneous bleeding (n=3), and alveolar hemorrhage (n=1). No patients were thrombocytopenic at the time of bleeding. ROTEM results were available in 5 cases and were globally normal except for one intrinsic imbalance. Mild factor V and X deficiencies were detected in one patient. Microcirculatory symptoms and splenomegaly were frequently observed. Six patients reported microvascular symptoms despite antiplatelet therapy, suggesting ASA-resistant vasomotor dysregulation. This was evident in 6/9 patients when considering classical MPN only (MF, PV, ET). Notably, two patients enrolled in clinical trials with PI3K inhibitors showed improvement in vascular symptoms, offering therapeutic insight. Mechanistically, CBL loss may lead to sustained activation of PI3K/AKT and MAPK pathways, contributing to endothelial hyperreactivity and pathological angiogenesis. Furthermore CBL-mutant platelets show qualitative defects, with hyperactive signaling but ineffective clot stabilization. Targeting the dysregulation with PI3K or MEK inhibitors could, in principle, restore VEGF signaling balance and reduce bleeding risk. CBL-mutated MPNs may define a distinct hemorrhagic phenotype, poorly captured by conventional tests. Deep phenotyping and targeted inhibition of aberrant signaling may open new therapeutic avenues for these patients.