title: Circulating interleukin (IL)-8, IL-2R, IL-12, and IL-15 levels are independently prognostic in primary myelofibrosis: a comprehensive cytokine profiling study.
abstract: OBJECTIVE
  Abnormal cytokine expression accompanies myelofibrosis and might be a therapeutic target for Janus-associated kinase (JAK) inhibitor drugs. This study describes the spectrum of plasma cytokine abnormalities in primary myelofibrosis (PMF) and examines their phenotypic correlates and prognostic significance.
  
  
  METHODS
  Patients included in this study were required to have archived plasma, bone marrow biopsy, and cytogenetic information available at the time of first referral to the Mayo Clinic. Multiplex biometric sandwich immunoassay was used to measure plasma levels of 30 cytokines.
  
  
  RESULTS
  In total, 127 PMF patients were studied; comparison with normal controls (n = 35) revealed significantly increased interleukin-1β (IL-1β), IL-1RA, IL-2R, IL-6, IL-8, IL-10, IL-12, IL-13, IL-15, tumor necrosis factor α (TNF-α), granulocyte colony-stimulating factor (G-CSF), interferon alfa (IFN-α), macrophage inflammatory protein 1α (MIP-1α), MIP-1β, hepatocyte growth factor (HGF), IFN-γ-inducible protein 10 (IP-10), monokine induced by IFN-γ (MIG), monocyte chemotactic protein 1 (MCP-1), and vascular endothelial growth factor (VEGF) levels and decreased IFN-γ levels. In treatment-naive patients (n = 90), increased levels of IL-8 (P < .001), IL-2R (P < .001), IL-12 (P < .001), IL-15 (P = .001), and IP-10 (P = .003) were independently predictive of inferior survival. A similar multivariable analysis that included all 127 study patients confirmed the prognostic value of these five cytokines, and IL-8, IL-2R, IL-12, and IL-15 remained significant when risk stratification, according to the recently revised Dynamic International Prognostic Scoring System (DIPSS plus), was added to the multivariable model. Leukemia-free survival was predicted by IL-8, which was also the only cytokine associated with ≥ 1% circulating blasts. Other cytokine-phenotype associations included increased IL-8 and constitutional symptoms; IL-2R, IL-12, and transfusion need; IL-2R, IL-8, and leukocytosis; IP-10 and thrombocytopenia; HGF, MIG, IL-1RA, and marked splenomegaly; and IL-1RA, IL-2R, IP-10, MIP-1β, and JAK2V617F. A two-cytokine (IL-8/IL-2R) -based risk categorization delineated prognostically different groups within specific DIPSS plus risk categories.
  
  
  CONCLUSIONS
  This study signifies the presence of specific cytokine-phenotype associations in PMF and a prognostically relevant plasma cytokine signature that might prove useful as a laboratory tool for predicting and monitoring treatment response.
authors.affiliation: Mayo Clinic, 200 First St SW, Rochester, MN 55905, USA. tefferi.ayalew@mayo.edu
authors.forename: Ayalew
authors.initials: A
authors.lastname: Tefferi
authors.forename: Rakhee
authors.initials: R
authors.lastname: Vaidya
authors.forename: Domenica
authors.initials: D
authors.lastname: Caramazza
authors.forename: Christy
authors.initials: C
authors.lastname: Finke
authors.forename: Terra
authors.initials: T
authors.lastname: Lasho
authors.forename: Animesh
authors.initials: A
authors.lastname: Pardanani
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D014408:Biomarkers, Tumor / Q000097:blood*; D001706:Biopsy; D001856:Bone Marrow Examination; D016022:Case-Control Studies; D016009:Chi-Square Distribution; D020732:Cytogenetic Analysis; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D005838:Genotype; D006801:Humans; D018664:Interleukin-12 / Q000097:blood*; D019409:Interleukin-15 / Q000097:blood*; D016209:Interleukin-8 / Q000097:blood*; D053614:Janus Kinase 2 / Q000235:genetics; D053208:Kaplan-Meier Estimate; D008297:Male; D008875:Middle Aged; D008910:Minnesota; D009154:Mutation; D010641:Phenotype; D011237:Predictive Value of Tests; D055728:Primary Myelofibrosis / Q000097:blood / Q000235:genetics / Q000276:immunology* / Q000473:pathology; D011379:Prognosis; D016016:Proportional Hazards Models; D040081:Protein Array Analysis / Q000379:methods; D015375:Receptors, Interleukin-2 / Q000097:blood*; D018570:Risk Assessment; D012307:Risk Factors; D015854:Up-Regulation
chemical_list: D014408:Biomarkers, Tumor; C508606:CXCL8 protein, human; D019409:Interleukin-15; D016209:Interleukin-8; D015375:Receptors, Interleukin-2; D018664:Interleukin-12; C507924:JAK2 protein, human; D053614:Janus Kinase 2