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Serum YKL-40 levels are elevated in primary and secondary myelofibrosis and may be affecting their survival

Background Primary and secondary myelofibrosis (PMF and SMF) are clonal hematopoietic stem cell disorders characterized by myeloproliferation, bone marrow fibrosis, splenomegaly and a strong inflammatory milieu. Glycoprotein YKL–40 emerged as an important biomarker of inflammation, angiogenesis, tissue remodeling, cell proliferation and differentiation. Serum YKL-40 levels were shown to be higher in PMF patients when compared to healthy controls. However, the clinical significance of this finding is unknown. Aims The aim of our study was to investigate serum YKL-40 levels in PMF and SMF patients and to assess its clinical correlations. Methods Using commercially available ELISA kit (R&D Systems Europe, Abingdon, UK) we analyzed serum YKL-40 levels in 30 myelofibrosis patients (13 PMF and 17 SMF) and in 25 sex- and age–matched healthy controls. Correlations with clinical parameters were made. Optimal cut - off for survival analyses was determined using the ROC curve analysis. The Kruskal-Wallis analysis of variance, the Mann-Whitney U test, the Spearman rank correlation, the log rank test and the Cox regression analysis was used. P values <0.050 were considered statistically significant for all analyses. Results Serum YKL-40 levels significantly differed between patients and controls (p=0.006): both PMF (median 685.3 pg/mL, range 220 – 4000) and SMF (median 1797.8 pg/mL, range 58 – 4000) patients had higher serum YKL-40 levels in comparison to controls (median 560 pg/mL, range 117 – 1137 ; p<0.050 for both comparisons), whereas there was no statistically significant difference between PMF and SMF patients. Higher serum YKL-40 levels were statistically significantly associated with presence of constitutional symptoms (median 465.1 pg/mL vs 3694.5 pg/mL for patients with or without constitutional symptoms ; p=0.001), higher Eastern Cooperative Oncology Group (ECOG) performance status (median 685.3 pg/mL vs 3413.2 pg/mL for patients with 0-1 and 2-4 performance status, respectively ; p=0.047), higher platelet count (rho 0.390 ; p=0.033), larger spleen (rho 0.750 ; p<0.001), lower serum lactate dehydrogenase (LDH) (rho -0.380 ; p=0.039) and less prominent bone marrow fibrosis grade (rho -0.480 ; p=0.007). Patients receiving ruxolitinib had lower serum YKL-40 levels (median 552.9 pg/mL) than those on hydroxycarbamide therapy (median 4000 pg/mL ; p=0.005). In univariate survival analysis, patients with higher serum YKL-40 levels (>2311.15 pg/mL) had inferior overall survival in comparison to patients presenting with lower YKL-40 levels (≤2311.15 pg/mL) (HR 2.91 ; p=0.034). This association remained significant in the multivariate Cox regression model after adjusting for sex, age, DIPSS score and ruxolitinib therapy (HR 5.59 ; p=0.029). Conclusion This is the first study to report clinical associations and strong prognostic properties of increased serum YKL-40 levels in patients with parimary and secondary myelofibrosis. Serum YKL-40 levels might represent a state of pronounced inflammation and increased tumor burden in myelofibrosis, as they are significantly associated with presence of constitutional symptoms, poor performance status and parameters indicative of stronger myeloproliferation. Additional studies are needed to more precisely elucidate the cell(s) of YKL–40 origin and to clarify the role of YKL-40 in promoting disease progression and bone marrow fibrosis. Prognostic properties of YKL-40 also need to be confirmed in larger prospective cohorts of uniformly treated myelofibrosis patients. Nevertheless, our results identify YKL-40 as a potential prognostic biomarker in myelofibrosis.

Cytokine, Myelofibrosis, Myeloproliferative disorder

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