Increased Pentraxin-3 Correlates with the Activity of the Neoplastic Clone in Primary Myelofibrosis

Background: Primary myelofibrosis (PMF) refers to a fatal myeloproliferative neoplasm characterized by progressive bone marrow (BM) fibrosis. A well-described feature of PMF is an increase in circulating cytokines, which induce a systemic inflammatory state with debilitating constitutional symptoms. Treatment with JAK inhibitors has significantly improved the quality of life of PMF patients, acting predominantly through the inhibition of cytokine production. However, the effects of such agents on the reversal of the BM fibrosis have remained limited. Recently, members of the pentraxin family of circulating immune proteins have been associated with the regulation of tissue remodeling in the BM of PMF patients. Specifically, pentraxin-3 (PTX3) has been shown to promote the differentiation of monocytes to collagen-producing fibrocytes in vitro and in vivo . In contrast to the liver-secreted short pentraxins, PTX3 is produced by myeloid, mesenchymal and endothelial cells, suggesting a potentially paramount role in inducing the BM fibrosis. Here, we tested the hypothesis that the plasma levels of PTX3 are increased in the PMF patients and that they can be correlated with the activity of the neoplastic clone over the course of the disease.

Methods: Peripheral blood samples were obtained from 140 well-characterized patients with PMF and 30 healthy controls. Patients were diagnosed according to the revised WHO criteria and the BM fibrosis grade was assessed following the current European consensus criteria. Plasma cocentrations of PTX3 were measured by the quantitative sandwich enzyme immunoassay according to the manufacturer's instructions.

Results: Our results showed a significantly higher concentration of PTX3 plasma levels in PMF patients compared to healthy controls (median: 4.150 vs. 0.532 ng/mL; p < 0.0001). Remarkably, PTX3 levels significantly positively correlated with the JAK2^V617F allele frequency, total leukocyte count and the plasma LDH concentration among all patients (p= 0.004; p < 0.0001; p < 0.0001, respectively), as well as in those diagnosed within 6 months of presentation (n = 68; p= 0.012; p= 0.011; p= 0.002). Furthermore, PTX3 levels increased with the time from the diagnosis over the median follow-up period of 6.95 years (p= 0.041). Conversely, patients previously treated with cytoreductive agents or JAK inhibitors showed a clear downward trend compared to the treatment-naïve patients (p= 0.048). Even though apparent, a non-significant difference was observed when we stratified the patients according to the BM fibrosis grade. Nonetheless, spleen size and plasma CRP concentration significantly correlated with the PTX3 plasma levels (p < 0.0001; p= 0.002), and PTX3 was considerably higher among patients who presented with constitutional symptoms and worse performance status (p= 0.120; p= 0.003). Whereas we did not observe a significant association between PTX3 and survival in our cohort of PMF cases (median OS: 4.5 years, 95% CI, 3.3 - 5.7), PTX3 correlated with the DIPSS risk score (p= 0.043) indicating its prognostic relevance.

Conclusions: For the first time we report an abundance of PTX3 in the plasma of PMF patients and observe a strong association of this protein with the activity of the neoplastic clone. Of particular note is the correlation of PTX3 with markers of a systemic inflammatory response (CRP, spleen size, constitutive symptoms), some of which have been correlated with outcomes. In contrast to pro-fibrotic pentraxin PTX3, a decrease in the anti-fibrotic pentraxin serum amyloid P component (SAP) has been previously reported in PMF, motivating the development of novel therapeutic agents in these patients. Collectively, our data suggests that a significant disbalance in pentraxin levels in favour of PTX3 could be driving the main disease process in PMF. Deciphering the distinct roles of these humoral immune proteins presents a viable approach in understanding the pathogenesis of BM fibrosis in myeloproliferative neoplasia.