Immune and cytokine landscape of cytopenic and proliferative PMF

Results from a retrospective, single-center, observational study analyzing clinical, molecular, transcriptomic, and cytokine data from 140 patients with primary myelofibrosis (PMF) were published in Therapeutic Advances in Hematology by Lee et al. Patients were stratified into those with cytopenic (n = 62) and proliferative (n = 78) phenotypes. The aim of this study was to determine whether differential activation of immune and inflammatory pathways contribute to the phenotypic heterogeneity of PMF.

Key data: Proliferative PMF harbored a greater prevalence of JAK2 driver mutations vs cytopenic PMF (80.5% vs 63.3%; p = 0.025). Compared with the proliferative phenotype, cytopenic PMF was associated with significantly inferior overall survival (OS; hazard ratio [HR], 6.58; 95% confidence interval [CI], 3.13–13.85; p < 0.001), higher ASXL1 (37.3% vs 15.8%; p = 0.011) and EZH2 mutation rates (11.8% vs 1.8%; p = 0.035), and upregulated tumor necrosis factor α (TNFα)–nuclear factor κB (NFκB; p = 0.010) and interleukin (IL)-2–signal transducer and activator of transcription 5 (STAT5) (p = 0.040) signaling pathways. IL-8 (p = 0.021) and granulocyte colony-stimulating factor (G-CSF; p = 0.007) remained independently associated with the cytopenic phenotype after adjusting for fibrosis severity. A greater proportion of patients with cytopenic vs proliferative PMF were classified as high-risk by the Genetically Inspired Prognostic Scoring System (GIPSS; p = 0.002) and showed more advanced disease features, including elevated lactate dehydrogenase (LDH; p < 0.001), higher blast counts (p < 0.001), and more frequent overt fibrosis (p < 0.001).

Key learning: In this study, cytopenic PMF represented a biologically distinct, clinically aggressive phenotype; these findings support further investigation into therapeutic strategies targeting modulation of inflammatory and cytokine pathways in this high-risk subgroup.