Clinical and experimental studies in Philadelphia chromosome negative chronic myeloproliferative disorders

Abstract

The present thesis deals with various aspects on the (a) epidemiology, (b) diagnosis, and (c) molecular biology in Philadelphia chromosome negative (Ph-) chronic myeloproliferative disorders (MPD). First, the incidence of the three Ph- MPD, polycythaemia vera (PV), essential thrombocythaemia (ET) and idiopathic myelofibrosis (IMF) was investigated in the city of Göteborg, Sweden during the years 1983-1999 (Paper I). A total of 416 patients with Ph- MPD were identified. There were 205 patients with PV, 153 with ET, 34 with IMF, and 24 with unclassifiable Ph- MPD. The annual incidence rate for PV, when adjusted for the European Standard Population, was 1.97/100,000 inhabitants; the corresponding figures for ET and IMF were 1.55 and 0.30/100,000 inhabitants, respectively. There was a significant increase of the annual incidence for ET (p=0.008); no such increase was recorded for either PV or IMF. The second part of the study investigated how the diagnosis of PV was assessed in the Western Swedish Health Care Region (Paper II). A total of 2 University Hospitals (UH) and 4 County Hospitals (CH) participated, and a detailed survey of 129 PV patients diagnosed at these hospitals during a 5-year period (1994-1998) was carried out. The red-cell mass (RCM) had been measured in almost all patients at UH but only in a minority of patients at CH. As regards assessment of spleen size and plasma erythropoietin concentrations (p-EPO) the difference between UH and CH was less conspicuous. On the other hand, bone marrow biopsies had been obtained from most patients at UH as well as CH. The aim of a subsequent study (Paper III) was to assess how the measurement of 3 variables, i.e., RCM, spleen size and p-EPO could be used for the differentiation between PV and apparent polycythaemia (AP). The results obtained from 31 consecutive patients with PV and 38 with AP were compared. Measurements of RCM confirmed the presence of absolute erythrocytosis in all PV patients; RCM was within normal limits in all patients with AP. In AP the mean spleen scan area obtained by gamma camera scintigraphy was identical to the mean reference value. In PV gamma camera imaging displayed various degrees of splenomegaly. Subnormal or not measurable p-EPO was present in all PV patients; only 3/38 AP patients demonstrated slightly subnormal values for p-EPO. In the third part of the study we investigated polycythaemia rubra vera-1 (PRV-1) positivity, i.e., PRV-1 mRNA overexpression in patients with ET (Papers IV and V). In 58 ET patients in whom p-EPO had been measured prior to the institution of any myelosuppressive treatment (Paper IV) there was a significant association between subnormal p-EPO and PRV-1 positive results (p=0.001). In a subsequent study (Paper V) PRV-1 overexpression was quantified in 70 ET patients; 17 of them were found to be PRV-1 positive. Ten of the 17 PRV-1 positive ET patients had experienced thrombo-embolic complications compared with 14 of the 53 PRV-1 negative patients; this difference was statistically significant (p=0.02).