LAUSR

Serum erythropoietin (EPO) level below the normal reference range is widely accepted as a minor diagnostic criterion for polycythemia vera (PV) and has retained its value in the revised 2016 World Health Organization (WHO) classification scheme of myeloid neoplasms. While over 80% of PV patients exhibit subnormal EPO values, very little is known about the incidence, phenotypic connotation, or prognostic significance of serum EPO levels in essential thrombocythemia (ET). Studies on this subject remain, in fact, exceedingly rare. Previous reports limited to small patient populations have suggested that subnormal EPO levels may be more prevalent than expected in ET, up to 50% in some series. Furthermore, one study comprising 39 untreated ET patients revealed a heightened risk of vascular events and significantly shorter time to initiation of myelosuppressive therapy in those exhibiting subnormal EPO values. These observations, albeit preliminary, raise the possibility that serum EPO may be relevant, perhaps even prognostically impactful in ET. Accordingly, after securing a diagnostically pure cohort of untreated strictly WHO-defined chronic phase ET patients, we documented serum EPO measurements, laboratory and clinical features, and overall, myelofibrosis-free, and polycythemia vera-free survival stratified by EPO level. The current study was approved by the Mayo Clinic Institutional Review Board. Diagnosis of ET was in strict accordance with the 2016 WHO criteria. ET patients with available EPO measurements at diagnosis or during their chronic phase (March 1994–November 2017) were considered under the following strict provisions: (i) all patients were in chronic phase with no evidence of myelofibrotic or leukemic transformation; (ii) all patients were untreated with cytoreductive agents at the time of sample collection and those with EPO levels drawn at diagnosis were also previously untreated with cytoreductive agents; (iii) all patients had hemoglobin levels above sex-adjusted values for anemia (no more than two standard deviations below the mean or >13.5 g/dL in men and >12.0 g/dL in women), thus excluding anemia as a potential confounding variable; and (iv) all patients with hemoglobin values exceeding the threshold for PV criteria had clinical and morphological parameters carefully assessed and all cases of masked PV systematically excluded. Few individuals with hemoglobin values exceeding the threshold for PV but without meeting PV criteria were found to have either transient elevations in hemoglobin or clear underlying causes of secondary polycythemia such as hypoxia, smoking, or elite athletic training, among others. Serum erythropoietin levels were obtained using standard immunoenzymatic assay methods with reference range between 4 and 21mIU/mL. Reasons for EPO draw were varied and included primarily diagnostic work-up or monitoring of chronic phase disease. Laboratory, clinical, and cytogenetics data corresponding to time of EPO sample collection and/or diagnosis were abstracted. Screening for driver mutation status was performed using conventional methods. Risk stratification was based on the three-tiered prognostic model international prognostic score for ET (IPSET).