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Elevated Plasma sIL-2Rα Levels in Primary Myelofibrosis Play a Distinct Role on Disease Progression in JAK2V617F and Calr Mutants

Background: Plasma soluble interleukin-2 receptor alpha (sIL-2Rα), that is released from the cell surface of activated T and B lymphocytes, is one of the best markers of immune activation. High levels of sIL-2Rα have been correlated with poor prognosis in different types of cancers. In patients with primary myelofibrosis (PMF) elevated plasma levels of the receptor are associated with risk of blast transformation and death. In this study we aimed to analyze how increased levels of sIL-2Rα mark the disease progression to improve our knowledge on the immune regulation of the disease.
 Methods: sIL-2Rα plasma concentration values were obtained by a commercial immunoassay (R&D Systems), according to the Manufacturer's Instructions, and expressed in pg/ml. Health care data of persons with PMF were obtained from the data-base of the Center for the Study of Myelofibrosis at the IRCCS Policlinico S. Matteo Foundation in Pavia. We excluded persons treated with disease-modifying drugs at any time before or on the date of base-cohort entry, and persons with acute inflammatory diseases, autoimmune diseases, other neoplasms, and severe liver or renal dysfunction. The final study cohort consisted of 300 subjects. Thirty-four healthy normal subjects matched for age and sex represented the control group. The study was approved by the local Ethic Committee, and was conducted complying with the principles of the Declaration of Helsinki.
 Results: In patients with PMF, plasma sIL-2Rα values ranged from 275 to 13,860 pg/ml, with a mean value of 1693 ± 1529 pg/mL standard deviation (SD). sIL2Rα metrics in healthy controls were: mean, 740 ± 346 pg/mL (SD), range, 207 to 1718 pg/mL. Difference in plasma sIL2Rα levels between subjects with PMF and normals was significant (P<0.001). In the analyses, we used a cut-off point of 1300 pg/mL based on the distribution of sIL-2Rα in normal subjects (upper 95th centile). Based on this cut-off, 51.1% individuals with PMF had elevated sIL-2Rα levels. At a cross-sectional analysis, in JAK2V617F mutated subjects, increasing sIL2-Rα levels were associated with clinical and hematological parameters that vary with disease progression, like decreasing hemoglobin and platelet count, increasing spleen size, white blood cell (WBC) count, frequency of circulating blood blasts and hematopoietic stem and progenitor (HSP)-CD34+ cells. The correlation coefficient of sIL-2Rα with these parameters ranged fom 0.27 to 0.41. In CALR mutated patients, the association of increased sIL-2Rα levels with decreased platelet count, increased frequency of circulating HSP-CD34+ cells, WBC count and blasts no longer remained. After a median follow-up of 61 months (range 2-178), out of the 108 patients analyzed at diagnosis, 32 (29.6%) developed severe anemia (Hb < 10 g/dL), 23 (21.3%) massive splenomegaly (spleen > 10 cm from the left costal margin), 26 (24.1%) leukocytosis (WBC >12 x109/L), and 22 (20.4%) an alarming number of HSP-CD34+ cells in PB (>100 x 106/L). Moreover, 10 (9.2%) received an allogeneic hematopoietic stem cell transplantation (HSCT), 15 (13.8%) incurred in blast transformation (BT), and 8 (7.4%) died. In patients with JAK2V617F mutation, having elevated level of sIL-2Rα gave a higher risk of incurring in severe anemia (hazard ratio (HR), 3.70, 95% CI, 1.31-10; P=0.009), large splenomegaly (HR, 8.33; 95% CI, 2.12-33.3; P=0.002) and alarming HSP-CD34+ cells (HR, 4.14; 95% CI, 1.02-20; P=0.050). Moreover, JAK2V617F mutants with elevated levels of sIL-2Rα had higher risk of death than those with non-elevated sIL-2Rα (HR, 9.09; 95% CI, 1.75-50; P=0.008). On the contrary, in CALR mutants no interaction with the levels of sIL-2Rα and risk of disease progression was evidenced. By using a composite endpoint that considered death for any cause, BT or HSCT, PMF patients with JAK2V617F mutation carrying an elevated sIL-2Rα presented a shorter time to event as compared to those with non-elevated sIL-2Rα (P=0.011), while in CALR mutants this difference disappeared (P=0.80) (Figure).
 Conclusion: The results of this study give a strong proof of concept that the immune landscape of PMF is associated with the presence/absence of JAK2V617F or CALR mutation. Acquiring direct evidence that elevated levels of sIL-2Rα represents an immune- mediated modality of disease progression in JAK2V617F but not in CALR mutated patients opens new areas of investigation towards an individualized therapeutic approach of PMF.
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 No relevant conflicts of interest to declare.
