PF667 THE ROLE OF HEPCIDIN AND DYSREGULATED IRON HOMEOSTASIS IN THE PATHOGENESIS OF ANEMIA IN MYELOFIBROSIS

Abstract

Background:Myelofibrosis (MF) is a stem cell disorder with impaired hematopoiesis and complex pathogenesis. Anemia in MF is a result of a multifactorial process, which is incompletely understood. The central pathogenetic mechanism is replacement of normal hemopoietic tissue by fibrotic stroma. However, the ineffective erythropoiesis, inflammation and iron overload have an additional impact on development and worsening of the anemia, suggesting the role of dysregulated iron homeostasis and hepcidin.Aims:to analyze hepcidin, IL‐6, IL‐8 levels and parameters of iron metabolism in a random cross‐section of patients with different forms and stages of myelofibrosis.Methods:We analyzed 36 patients with MF – 75 % with primary MF(PMF) (prefibrotic PMF – 38,9% and overt PMF – 36,1%) and 25% with secondary MF (post‐PV −11,1% and post‐ET – 13,9%); median age of the group was 68,5 years (range 39–88); male: female ratio‐ 1,57:1. According to DIPSS: 5,6% were Low; 52,8% were Intermediate 1; 33,3% were Intermediate 2 and 8,3% were High risk. Regarding treatment 30,6% of the patients received hydroxyurea, 8,3% ‐ Interferon, 19,4% ‐ Ruxolitinib and 41,7% ‐ best supportive care. Patients who were transfused with ≥3 RBC units/month were 19,5% and those receiving <3 RBC units/month ‐ 80,5%. All patients were divided in 3 groups according to the time from diagnosis: newly diagnosed (30,6%), 1 to 5 years (47,2%) and > 5 years (22,2%) from diagnosis. Serum ferritin, Fe, TIBC and parameters of CBC were measured as a part of routine clinical assessment. Serum hepcidin and serum concentrations of IL 6 and IL8 were measured in duplicate by ELISA (My BioSource, San Diego, USA) in all patients and 14 healthy controls.Results:In our study the levels of hepcidin in MF patients are not found statistically different from levels in healthy controls. No difference is found in hepcidin level within the three risk groups according to DIPSS (Intermediate 1, Intermediate 2 and High), neither between the subtypes of disease (proliferative or fibrotic stage of primary myelofibrosis and secondary myelofibrosis). However, we find significant difference between hepcidin levels within the three groups according to disease duration. Patients with newly diagnosed MF have higher levels of hepcidin compared to those with prolonged evolution (F = 7,09, R = −0,476, R2 = 0,226, p = 0,003). Patients receiving > 3 RBC transfusions/month present with lower hepcidin compared to transfusion independent patients (10,10 ± 6,67; 31,15 ± 44,37; p < 0,05). We also find significantly lower hepcidin level in patients receiving cytoreductive or target treatment compared to patients without any therapy (17,74 ± 21,99; 43,05 ± 58,46; p < 0,05). In all risk groups hepcidin positively correlates with leukocytosis and age. Unexpectedly, higher levels of ferritin and serum iron are associated with low hepcidin. In multivariate analysis a significant straight correlation between hepcidin level and IL6 (R = 0,427, p = 0,009) and between IL6 and IL8 levels in the whole cohort (R = 0,500, p = 0,002) is found.Summary/Conclusion:The hepcidin regulation is complex and multifactorial. Its role in pathogenesis of anemia in myelofibrosis is controversary. Probably it has a higher impact in early stages of the disease and depends on treatment and transfusions. A further analysis, including labile iron, would better clarify the precise mechanisms of anemia in a heterogeneous disorder like MF.