Myeloproliferative neoplasms are divided into essential thrombocythemia (ET), polycythemia vera (PV) and primary myelofibrosis (PMF). Although ruxolitinib was proven to be effective in reducing symptoms, patients rarely achieve complete molecular remission. Therefore, it is relevant to identify new therapeutic targets to improve the clinical outcome of patients. Bcl‐xL protein, the long isoform encoded by alternative splicing of the Bcl‐x gene, acts as an anti‐apoptotic regulator. Our study investigated the role of Bcl‐xL as a marker of severity of MPN and the possibility to target Bcl‐xL in patients. 129 MPN patients and 21 healthy patients were enrolled in the study. We analysed Bcl‐xL expression in leucocytes and in enriched CD34+ and CD235a+ cells. Furthermore, ABT‐737, a Bcl‐xL inhibitor, was tested in HEL cells and in leucocytes from MPN patients. Bcl‐xL was found progressively over‐expressed in cells from ET, PV and PMF patients, independently by JAK2 mutational status. Moreover, our data indicated that the combination of ABT‐737 and ruxolitinib resulted in a significantly higher apoptotic rate than the individual drug. Our study suggests that Bcl‐xL plays an important role in MPN independently from JAK2 V617F mutation. Furthermore, data demonstrate that targeting simultaneously JAK2 and Bcl‐xL might represent an interesting new approach.

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Background: Patients with MDS are at high risk of developing infections, which still represent the most frequent complications and the main cause of mortality and morbidity. We conducted a retrospective study with the aim of evaluating incidence, characteristics and outcome of infectious events in patients with myelodysplastic syndromes (MDS) and the risk factors associated with them. Patients and methods: 200 patients with MDS or LMMC followed by the Ancona Hematology Clinic in the last 15 years were included. In this group, we evaluated severe infectious episodes and associated risk factors, relating to patient, disease and therapy. Results: In a cohort of 200 patients, we detected 65 cases of infections of higher than third grade according to WHO. Pneumonia is the most frequent infection, especially on a bacterial basis. Risk factors that have shown significant association with infections ≥ G3 are: comorbidity (p = 0.0086), hemoglobin level (P = 0.0111), neutropenia (P = 0.0152), transfusion dependence during the course of disease (P <0.0001) and hypomethylating therapy (P = 0.0014). A subanalysis confirmed comorbidities as risk factors for the development of pneumonia (P = 0.0322) and azacitidine therapy as a risk factor for sepsis (P = 0.0038). The overall survival of the cohort is approximately 7.5 months and the predictive factors of survival are patient age (P = 0.0005), WHO disease class (P = 0.001), R-IPSS (P <0.0001) and transfusion-dependence during the course of the disease (P <0.0001). Multivariate analysis confirmed age (P = 0.0002), R-IPSS (P = 0.0043) and transfusion-dependence (P = 0.0006) as predictors of survival. Infections above grade 3 do not impact survival. Otherwise, there was a trend of reduced survival in patients who had pneumonia (P = 0.0612) or sepsis (P = 0.0927). Conclusion: Patients with MDS have a high probability of encountering an infectious problem in the course of the natural history of the disease. In one out of five cases, there are more than one infectious event. Particularly at risk of infection are patients with comorbidities, neutropenia (PMN <800 / mm³), significant transfusion needs and on therapy with hypomethylating agents. These patients should be carefully monitored for infectious complications. Disclosures No relevant conflicts of interest to declare.

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