P1013: cbl mutation may be associated with the onset of myeloproliferative neoplasms with microvascular disorders: a single-centre experience

Topic: 15. Myeloproliferative neoplasms - Biology & Translational Research Background: Casitas B lineage lymphoma (CBL) is a cancer-predisposing gene that encodes for adaptor proteins, involved in cancer onset and progression, hematopoietic development and T cell receptor regulation. Germline mutations configure the “CBL syndrome”, a RASopathy similar to Noonan syndrome, while somatic CBL mutations are reported in solid and hematological tumors, specially myeloid neoplasms (firstly in juvenile myelomonocytic leukemia, but also in 5-10% of chronic myelomonocytic leukemia and acute leukemia secondary to myelodysplastic syndromes). Three main molecular pathways are regulated by CBL: the JAK2, EGFR and PI3K/AKT signaling cascades. Of note is the association of CBL mutations with a spectrum of non-malignant conditions: vascular disease due to uncontrolled VEGF and RAS-MAPK overstimulation (eg Takayasu arteritis and Moyamoya disease), autoimmune manifestations (rheumatoid arthritis, uveitis, Evans Syndrome), splenomegaly and coagulative disorders (elevated kaolin clotting time ratio, antiphospholipid antibodies persistent positivity). Interestingly, the vascular manifestations may be corrected with MAPK targeted therapy. The prognostic impact of CBL mutations in myeloid malignancies is still controversial, but a potential benefit of therapeutic CBL targeting is hypothesized. Aims: Clinical, molecular and global coagulation characterisation of myeloproliferative neoplasms (MPNs) patients (pts) with CBL mutation. Methods: 53 pts affected by MPNs, naïve from any therapy, with the only exception of ASA were enrolled. We performed assays of genetics (30-gene panel in NGS - SOPHiA Myeloid SolutionTM, SOPHiA Genetics, Switzerland) and thromboelastometry (ROTEM® Delta, Werfen, Spain) for INTEM, EXTEM, FIBTEM parameters. Data on bone marrow histology, microcirculatory disturbances and history of vascular events were collected. Results: The overall results of the study have been previously described (EHA 2022 - P992, submitted paper). Herein, we focused on pts with a point mutation of CBL detected by NGS, present in our case series with an unexpectedly high frequency (5/53, 9.4%). Remarkably, all cases had similar histological and clinical features: 4/5 CBL (80%) mutated pts had early MF but with palpable splenomegaly and constitutional symptoms, and one patient had a JAK2 negative masked-PV. 100% of the pts reported ASA-resistant microcirculatory disturbances. 2/5 (40%) of the pts had haemorrhagic events (incoercible epistaxis, intracranial hemorrhage) in their history. The subject with recurrent epistaxis, despite normal coagulation times, showed slight deficits of coagulation factors V and X, already described associated to CBL. As regards ROTEM, CBL mutated pts did not show statistically significant differences compared to non-mutated ones, probably due to sample size. The masked-PV patient showed a marked imbalance of clotting times (CT) in INTEM and EXTEM, with a preferential utilization of the intrinsic pathway. Two MF patients are benefiting from a combination trial with PI3K inhibitor. Summary/Conclusion: We would like to shine a light on the role of CBL in MPNs, given the high frequency in our case study. We can speculate its role as a co-driver mutation, in the peculiar clinical and histological entity of early MF, with microvascular symptoms but also a tendency to bleeding. CBL could further explain why MPNs are historically considered as vascular disease, with both a high thrombotic and hemorrhagic risk. Of growing interest, the implication in clinical management: CBL could represent a promising therapeutic target, regulating the downstream signaling cascades of JAK/STAT and PI3K.Keywords: Myeloproliferative disorder, Bleeding, Thrombelastograph, Thrombosis