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Splenomegaly s a hallmark ol primary (PMF) and secondary myelofibrosis {;SMF};, developing mostly due to extramedullary hematopoiesis. It represents tumour burden and correlates with unfavourable disease features. PMF and SMF may have distinct molecular profiles and differ in the duration on of the myeloproliferative disease prior to the diagnosis, exposure to prior specific therapies and associated risks. Due to biological differences, distinct prognostic scores (although utilizing similar parameters) have been developed for PMF and SMF.

Primary myelofibrosis (PMF), post-polycythemia vera (post-PV) and post-essential thrombocythemia (post-ET) secondary myelofibrosis (SMF) are chronic myeloproliferative neoplasms (MPNs) characterized by bone marrow fibrosis, splenomegaly and debilitating constitutional symptoms. Despite clinical similarities, PMF and SMF harbor different mutational backgrounds [1] and optimal prognostication of risk of death is achieved utilizing specialized prognostic scores (DIPSS [2] and Mysec-PM [3], respectively). PMF and SMF patients also suffer from a substantial risk of thrombotic events that might be comparable to PV and ET patients [4], and is probably modulated by similar factors. Nevertheless, thrombotic risk in myelofibrosis patients is often overlooked and risk-factors for thrombosis are less well characterized. In this report we aimed to assess potential differences in thrombotic risk between PMF, post-PV and post-ET SMF in our multicentric cohort of patients with myelofibrosis.

Background: Serum uric acid (SUA) can promote inflammation and is associated with increased cardiovascular morbidity. Primary (PMF) and secondary myelofibrosis (SMF) are myeloproliferative neoplasms characterized by high cellular turnover and substantial risk of thrombosis and death. Methods: We have retrospectively investigated SUA in 173 patients with myelofibrosis (125 PMF ; 48 SMF) and 30 controls. Results: The PMF patients had significantly higher SUA in comparison to SMF and controls. In both PMF and SMF higher SUA was significantly associated with arterial hypertension and decreased renal function. Among PMF patients, higher SUA was significantly associated with older age, larger spleen, higher white blood cell counts, higher lactate dehydrogenase, lower immunoglobulin G levels, allopurinol use and non-smoking. Among SMF patients, higher SUA was associated with male sex (P < 0.05 for all analyses). In PMF higher SUA was univariately associated with inferior survival (> 427 μmol/L hazard ratio (HR) = 2.22 ; P = 0.006) and shorter time to thrombosis (> 444 μmol/L HR = 5.05 ; P = 0.006), which could be shown separately for arterial (> 380 μmol/L ; HR = 4.9 ; P = 0.013) and venous thromboses (> 530 μmol/L ; HR = 17.9 ; P < 0.001). In multivariate analyses, SUA remained significantly associated with inferior survival independent of the Dynamic International Prognostic Staging System and with shorter time to thrombosis independent of age in PMF patients ; however, the prognostic significance of SUA was diminished after including serum creatinine in the models. SUA was not prognostic in SMF patients. Conclusion: The PMF patients present with higher SUA levels, which are associated with features of more advanced disease and higher risks of arterial and venous thrombosis and death.

Purpose This cohort study aimed to determine patterns of glycemic fluctuation and changes in metabolic parameters during and after corticosteroid administration in newly diagnosed diffuse large B-cell lymphoma (DLBCL) patients treated with R-CHOP chemotherapy. Patients and methods The study was performed in 20 patients of whom 11 had diabetes and 9 were nondiabetics. Anthropometric parameters were collected, and blood samples were taken four times during the study to analyze metabolic parameters. Capillary glucose was measured seven times a day (fasting, before mean meals, postprandial, and before bedtime) to evaluate the glycemic profile. Results In all 20 patients, acute glucocorticoid administration resulted in the elevation of average glucose levels, dominantly postprandial in the afternoon which correlates with corticosteroid peak action. In 7 out of 11 diabetics, prandial insulin was started during corticosteroid administration and discontinued afterward. Although none of our nondiabetic patients met diabetes criteria, evident is the elevation in average glycemia levels six weeks after corticosteroid administration. Potentially, even transient corticosteroid administration reduces insulin sensitivity and contributes to later glycemic disturbances. HbA1c levels were higher at the end of the study while fructosamine levels were higher during the study. Conclusion Patients and health-care professionals need to be aware of corticosteroid-induced hyperglycemia. We recommend identifying risk factors, measuring glycemia before, during, and after corticosteroid administration, and starting the adequate therapy as soon as possible.

Context: Blood plasma experiences substantial changes in both volume and composition in patients with chronic myeloproliferative neoplasms (MPN) and represents a large reservoir of cytokines and other mediators of inflammation. Higher estimated plasma volume status (ePVS) has recently been shown to correlate with increased thrombotic risk in polycythemia vera patients. Objective: To estimate clinical and prognostic associations of ePVS in patients with myelofibrosis. Design: Retrospective cohort study. Setting: 6 hematology centers. Patients: 238 myelofibrosis patients, 168 with PMF, 34 with post-PV SMF and 36 with post-ET SMF. Interventions: ePVS was calculated using the Strauss derived Duarte formula: (100-hematocrit (%)/hemoglobin (g/dL) and expressed as dl/g. Main outcome measures: Overall survival (OS) and time to thrombosis (TTT). Results: Median ePVS was 5.8 dl/g and it did not significantly differ between PMF and SMF patients. Among other associations, higher ePVS was significantly associated with higher degree of bone-marrow fibrosis, absence of JAK2-mutation, lower white blood cells (WBC), platelets and hemoglobin, presence of circulatory blasts, higher C-reactive protein, higher lactate dehydrogenase, lower albumin and higher Charlson comorbidity index in an overall cohort, as well as with more pronounced splenomegaly and higher Dynamic International Prognostic Scoring System (DIPSS) risk in primary myelofibrosis (PMF) and higher Mysec-PM risk in secondary myelofibrosis (SMF) patients (P5.6 dl/g) was associated with shorter overall-survival (OS) in PMF (HR=2.8, P7 dl/g, HR=4.1, P=0.009) patients. Associations with overall survival diminished in multivariate analyses after adjustments for DIPSS and Mysec-PM, respectively. Association with TTT remained significant independently of JAK2, WBC and chronic kidney disease. Conclusions: Myelofibrosis patients with more advanced disease features and more pronounced inflammation have higher ePVS, indicative of expanded plasma volume. Higher ePVS is associated with impaired survival in PMF and SMF and higher thrombotic risk in PMF patients.

Elevated red blood cell distribution width (RDW) has recently gained attention in patients with myeloproliferative neoplasms (MPN) as it was shown to be associated with reduced survival in myelofibrosis [1] and conflicting information has been reported for thrombotic risk in treatment- naïve and exposed polycythemia vera (PV) patients [2, 3, 4]. Due to uncertain implications of this parameter on the thrombotic risk in MPN, we aimed to evaluate RDW and associated thrombotic risk in a multicentric cohort of patients with primary (PMF) and secondary myelofibrosis (SMF).

Background: Cell-division-cycle-25c (CDC25c) is a gene coding a phosphatase controlling entry into mitosis upon activation through Polo-like-kinase-1 (PLK1) and serves as a key regulator of cell division. CDC25c was reported to be dysregulated in some malignant diseases, but its role in myelofibrosis has not yet been elucidated. Methods: We have retrospectively investigated CDC25c mRNA expression in bone marrow aspirates of 43 patients with myelofibrosis (28 primary/PMF, 15 secondary myelofibrosis/SMF) and 12 controls. Results: CDC25c mRNA expression did not significantly differ between PMF, SMF and controls (median ΔCT 3.08 vs 2.86 vs 2.29 for PMF, SMF and controls, respectively ; P=0.162). Patients presenting with higher CDC25c mRNA expression were of older age (P=0.037), had statistically significantly higher white-blood-cells (P=0.017), larger liver size (P=0.022), higher absolute neutrophil (P=0.010), monocyte (P=0.050), basophil (P=0.012), and eosinophil counts (P=0.013). Patients presenting with high CDC25c mRNA expression had statistically significantly inferior overall survival compared to low CDC25c expression group (HR=2.99 ; P=0.049). Median overall survival was not reached in patients with low and was 44 months in patients with high CDC25c expression. Conclusion: Our data suggest that CDC25c might be implicated in disease pathogenesis and could represent interesting novel therapeutic target in myelofibrosis. Future studies investigating these interesting associations are warranted.

We retrospectively investigated psoas muscle area (PMA)at vertebra L3 level from baseline and 6- month CT scans of myelofibrosis patients from two Croatian hematology centers that were treated with ruxolitinib due to high or intermediate-2 risk disease. Data for a total of 13 patients were available. PMA improvement of 10% was associated with higher baseline hemoglobin level (median 117 vs 95 g/L ; P = 0.034) and lower International Prognostic Scoring System (IPSS) score (2 vs 4 ; P = 0.019)Improvement in PMA was significantly correlated with decline in the longest spleen diameter (Rho = − 0.57 ; P = 0.042). Patients with less advanced disease were more likely to achieve better PMA improvement favoring early start of ruxolitinib therapy.

We retrospectively investigated a cohort of 176 myelofibrosis patients (128 primary-PMF ; 48 secondary-SMF) from five hematology centers. The presence of chronic kidney disease (CKD) was determined in addition to other clinical characteristics. CKD was present in 26.1% of MF patients and was significantly associated with older age (P < 0.001), higher WBC (P = 0.015), and its subsets (neutrophil, monocyte, and basophil counts), higher platelets (P = 0.001), lower albumin (P = 0.018), higher serum uric acid (P = 0.001), higher LDH (P = 0.022), and the presence of CV risk factors (P = 0.011). There was no significant association with driver mutations, degree of bone marrow fibrosis, PMF/SMF, or DIPSS risk categories (P > 0.05 for all analyses). The presence of CKD was significantly associated with shorter time to arterial (HR = 3.49 ; P = 0.041) and venous thrombosis (HR = 7.08 ; P = 0.030) as well as with shorter overall survival (HR 2.08 ; P = 0.009). In multivariate analyses, CKD (HR = 1.8 ; P = 0.014) was associated with shorter survival independently of the DIPSS (HR = 2.7 ; P < 0.001) ; its effect being more pronounced in lower (HR = 3.56 ; P = 0.036) than higher DIPSS categories (HR = 2.07 ; P = 0.023). MF patients with CKD should be candidates for active management aimed at the improvement of renal function. Prospective studies defining the optimal therapeutic approach are highly needed.

Aurora-kinase-A (AURKA), BORA and Polo-like-kinase-1 (PLK1) are regulating cell-cycle control and promotion of mitosis entry. AURKA contributes to Janus-kinase-2 (JAK2) activation and increased AURKA protein levels were reported in CD34+ and CD41+ cells of myeloproliferative neoplasm patients, leading to aneuploidy and aberrant megakaryopoiesis. We aimed to investigate AURKA, BORA and PLK1 mRNA expression in unfractionated bone-marrow aspirates of 43 patients with myelofibrosis (28 primary-/PMF, 15 secondary-myelofibrosis/SMF) and 12 controls and to assess their clinical correlations. AURKA expression did not significantly differ between myelofibrosis and controls (P = 0.466). Higher AURKA expression was significantly associated with higher absolute monocyte-count (P = 0.024) and shorter overall survival (HR = 3.77; P = 0.012). Patients with both PMF and SMF had lower BORA expression than controls (P = 0.009). Higher BORA expression was significantly associated with absence of constitutional symptoms (P = 0.049), absence of circulatory blasts (P = 0.047), higher monocyte- (P = 0.040) and higher eosinophil-counts (P = 0.016) and had neutral effect on survival (P > 0.05). PLK1 expression did not significantly differ between myelofibrosis and controls (P = 0.103). Higher PLK1 expression was significantly associated with higher white-blood-cell-count (P = 0.042) and inferior overall survival (HR = 5.87; P = 0.003). In conclusion, AURKA, BORA and PLK1 are involved in pathogenesis of myelofibrosis and may affect survival. Future studies investigating these interesting associations are warranted.

We retrospectively investigated C reactive protein to albumin ratio (CAR) in a cohort of 142 patients with myelofibrosis [101 primary (PMF) ; 41 secondary (SMF)] and compared it to hematological and clinical parameters. Among other associations, higher CAR was significantly associated with higher grade of bone marrow fibrosis, lower frequency of Calreticulin (CALR) mutations, presence of constitutional symptoms, massive splenomegaly, transfusion dependency, blast phase disease, lower hemoglobin, lower platelets, higher ferritin and higher lactate dehydrogenase (LDH) (p < .05 for all analyses). Higher CAR was able to predict inferior survival in PMF independently of DIPSS [hazard ratio (HR)¼2.17 ; p ¼ .015 for high CAR and HR¼ 2.05 ; p < .001 for DIPSS] and in SMF independently of Mysec-PM (HR¼ 6.48 ; p ¼ .022 for high CAR and HR¼ 2.63 ; p ¼ .013 for Mysec-PM) demonstrating its good prognostic potential. CAR seems to be an independent and prognostically relevant parameter, both in PMF and SMF, and might aid in timely recognition of most vulnerable patients.

Prolonged steroid premedication and/or reduction of lymphocyte count with Clb prior to administering first dose of G might result in a lower frequency of severe infusion reactions observed in our series In contrast to rituximab, the combination of G with higher-doses of Clb frequently results in premature stopping of the latter, especially in patients with serious comorbidities. This prevents the delivery of the intended total dose of Clb and reduces the possibility to improve efficacy over G þ Clb pulses.