Value of functional iron parameters in diagnostic re-assessment of MPN: refinement of iron-deficiency markers by zinc protoporphyrin (ZPP)

Iron deficiency assessment in myeloproliferative neoplasms is complicated by chronic inflammation, disease-related anemia, and treatment-induced changes in iron handling. We retrospectively analyzed 445 patients with MPN, including 158 with polycythemia vera, 97 with essential thrombocythemia, 44 with prefibrotic primary myelofibrosis, 127 with overt myelofibrosis, and 19 with MPN-unclassifiable, and compared conventional iron parameters with a population-based SHIP cohort of 4420 participants. ZPP was measured in the MPN cohort using quantitative fluorescence spectroscopy. Compared with SHIP, MPN patients had lower hemoglobin and higher ferritin, and the physiological positive correlation between ferritin and hemoglobin observed in SHIP was reversed in MPN patients, with R = 0.27, 95% CI 0.24 to 0.30, p < 0.001 in SHIP versus R = - 0.45, 95% CI - 0.52 to - 0.36, p < 0.001 in MPN. Median ZPP in the MPN cohort was 43.0 µmol/mol heme, with 123 of 445 patients (27.6%) showing ZPP values > 65 µmol/mol heme and 59 of 445 patients (13.3%) showing values > 100 µmol/mol heme. ZPP differed significantly between MPN entities, with median values of 35.0 µmol/mol heme in ET, 49.4 µmol/mol heme in PV, 36.5 µmol/mol heme in pre-PMF, 54.7 µmol/mol heme in overt MF, and 46.0 µmol/mol heme in MPN-U (p < 0.001). ZPP correlated inversely with hemoglobin in MPN patients (R = - 0.26, 95% CI - 0.35 to - 0.16, p < 0.001), whereas its association with ferritin was weak (R = - 0.10, 95% CI - 0.20 to - 0.00, p = 0.045). Among 80 patients with CTCAE grade ≥ 2 anemia, 58 (73%) had ZPP values above the upper limit of normal. In exploratory multivariable analysis, PV, overt MF, and phlebotomy were independently associated with higher ZPP, whereas CRP and time from diagnosis were not. In JAK2-mutated PV versus ET, ZPP was significantly higher in PV (48.5 versus 37.5 µmol/mol heme, p = 0.010), complementing lower transferrin saturation and higher JAK2 variant allele frequency. These data indicate that ZPP provides a functional readout of iron-restricted heme synthesis in MPN, adds information beyond ferritin and transferrin saturation, and may refine diagnostic reassessment and therapeutic monitoring, particularly in PV and overt MF.