Management of polycythaemia vera: a critical review of current data

Polycythaemia vera (PV) is a chronic blood cancer; its clinical features are dominated by myeloproliferation (erythrocytosis, often leucocytosis and/or thrombocytosis) and a tendency for thrombosis and transformation to myelofibrosis or acute myeloid leukaemia. In the past 10 years the pathophysiology of this condition has been defined as JAK/STAT pathway activation, almost always due to mutations in JAK2 exons 12 or 14 (JAK2 V617F). In the same time period our understanding of the optimal management of PV has expanded, most recently culminating in the approval of JAK inhibitors for the treatment of PV patients who are resistant or intolerant to therapy with hydroxycarbamide. It has also been demonstrated that life expectancy for many patients with PV is not normal, nor is their quality of life. We critically explore these findings and discuss their impact. In addition, we highlight persisting gaps in our current management strategy; for example, what is the optimal first line cytoreductive therapy and, indeed, which patients need cytoreductive drugs.     

Coexistence of sarcoidosis and myeloproliferative disease: a case of sarcoidosis preceding polycythaemia vera with a literature review

A patient with the chronic active type of sarcoidosis developed polycythaemia vera 20 years later. A review of the literature shows that sarcoidosis preceding myeloproliferative disease tends to be of the chronic active variety. The same pattern is observed in associations of sarcoidosis with malignant lymphoproliferative disease and solid tumours, in which sarcoidosis appears to be the underlying cause of the subsequent malignancy.     

Homocysteine levels in polycythaemia vera and essential thrombocythaemia

Patients with polycythaemia vera (PV) or essential thrombocythaemia (ET) have an increased risk of arterial and venous thromboembolic complications. Since hyperhomocysteinaemia (HHC) is a risk factor for vascular disease, we investigated the frequency of HHC in these disorders and analysed a possible association of elevated plasma homocysteine levels with vascular complications. In the cohort of 134 patients from Vienna (69 female, 65 male, median age 65.5 years, range 21-91 years) with PV (n = 74) or ET (n = 60), plasma homocysteine levels were significantly higher compared to 134 healthy controls. Median homocysteine level was 12.3 micromol/l (range 3.5-48.4 micromol/l) in patients with PV or ET and 8.9 micromol/l (range 4.8-30.5 micromol/l) in normal controls (P < 0. 0001). In addition to the 134 patients from Vienna, 48 patients (28 female, 20 male; median age 66.5 years, range 24-82) from Vicenza with PV (n = 25) or ET (n = 23) were included to evaluate the impact of HHC on the risk of thrombosis. Of 59 patients with HHC (44 from Vienna and 15 from Vicenza) 18 (31%) had a history of arterial and 10 (17%) of venous thrombosis. Of 123 patients with normal homocysteine levels, 30 (24%) had arterial and 16 (13%) had venous thromboses. The difference between the two groups was statistically not significant. Even though mild to moderate HHC occurred in a larger number of patients with PV or ET and thrombosis, it can presently not be regarded as an additional risk factor for thrombosis.     

Development of polycythaemia vera in a patient with myelofibrosis

In March 1981, a 53-year-old man presented with itching and was diagnosed as having myelofibrosis. There was gradual enlargement of the spleen over the following 5 yr. His spleen had to be removed in February 1986 because of physical discomfort. 3 months post-splenectomy he became polycythaemic. Bone marrow examination was consistent with severe myelofibrosis. It was possible to demonstrate erythropoietin-independent BFU-E from peripheral blood, and ferrokinetic studies showed that erythropoiesis was localised to the liver with little bone marrow activity. Thus, despite severe marrow fibrosis, liver erythropoiesis was now polycythaemic, suggesting the coexistence of myelofibrosis and polycythaemia vera.     

Studies of neutrophil and monocyte oxidative responses in polycythaemia vera and related myeloproliferative disorders

Summary. We have previously reported that polymorphonuclear granulocyte (PMN) chemiluminescence (CL) and superoxide anion production are abnormally low in patients with polycythaemia vera (PV) after simulation with n-formylmethionyl-leucyl-phenylalanine (fMLP). but normal when elicited by phorbol myristate acetate (PMA). This study documents that both fMLP and PMA induced CL was normal in PMN from patients with chronic myelogenous leukaemia (CML) and essential thrombocythaemia (ET). Furthermore, we monitored intracellular hydrogen peroxide (H₂O₂) production in PMN and monocytes from patients with PV, CML and ET by flow cytometry. H₂O₂) production in resting and PMA-stimulated cells was normal in all diseases. So also was fMLP induced H₂O₂ generation in ET PMN and monocytes. In contrast, fMLP-induced H₂O₂ production was significantly lower both in PV PMN (1.8 ± 0.7 mean fluorescence intensity units in PV compared to 8.4 ± 3.4 in healthy controls; P < 0.02), and in PV monocytes (0.3 ± 0.5 compared to 2.5 ± 0.7 in controls; P < 0.02). A less pronounced reduction of fMLP stimulated H₂O₂ production was noted in CML PMN (3.8 ± 3.1 compared to 8.4 ± 3.4 in controls; P < 0.05), and monocytes (1.3 ± 0.6 compared to 2.5 ± 0.7 in controls: P < 0.05). The reduction of H₂O₂ generation in PV and CML PMN was not attributed to subpopulations of less responsive cells. However, one ET and one CML patient showed a subpopulation of less responsive PMN. Thus intracellular H₂O₂ (as well as extracellular release of superoxide ions) is reduced in fMLP-stimulated PV PMN and monocytes but normal after PMA stimulation, a phenomenon that is not consistently found in other myeloproliferative disorders.     

Molecular analysis of the erythropoietin receptor system in patients with polycythaemia vera

Summary Erythropoietin (EPO) is a potent regulator of the viability, proliferation and differentiation of erythroid progenitor cells. Its effect is mediated by binding to the erythropoietin receptor (EPO-R), a member of a new cytokine receptor family. Alterations of the EPO/EPO-R system have recently been shown to be involved in the pathogenesis of familial erythrocytosis and polycythaemia vera (PV). In order to define whether genetic changes in the EPO-R gene and its ligand play a role in the development of PV, the structure and expression levels of the EPO-R and EPO genes were examined in samples from bone marrow and/or peripheral blood mononuclear cells of 24 patients with PV. As expected, EPO serum levels were low and no detectable level of EPO mRNA was found by reverse polymerase chain reaction (RT-PCR) in the peripheral blood mononuclear cells of our PV patients. To search for structural alterations of the EPO-R, cDNA samples were subjected to PCR and SSCP analysis as well as sequencing. Heterogenous expression of EPO-R mRNA was observed without any structural changes, as revealed by RT-SSCP analysis using overlapping primers spanning the whole coding region of the EPO-R gene. Structural integrity of the EPO-R was further confirmed by sequencing of cloned PCR products. These data suggest that the mechanisms for the development of PV do not involve structural changes of the EPO-R gene.     

In vitro platelet adhesion to vascular subendothelium: studies in patients with polycythaemia vera

In this work we studied platelet adhesion to subendothelial surfaces in 10 patients with polycythaemia vera and 10 healthy volunteers at 40% Hct (corresponding to the mean value of our control group) and 55% Hct (a value roughly corresponding to the mean Hct in polycythaemic patients). Platelet concentration was kept constant at 2.0-2.5 X 10(11)/l. The results indicate that there was a statistically significant increase in adhesion both in controls and in patients with Hct varying from 40% to 55%. The contribution of the higher Hct in promoting platelet adhesion was comparable in the two groups. When red blood cells (RBC) from the patients were tested with platelets from healthy volunteers in cross-over experiments, they promoted adhesion in the same way as control RBC. Similarly, when patients' platelets were mixed with control RBC, adhesion was the same as control platelets. These data indicate that platelet and RBC contribution to this parameter are not significantly modified in this group of polycythaemic patients, provided that platelet and RBC values are adjusted to control range.     

ASXL1 mutations,previous vascular complications and age at diagnosis predict survival in 85 WHO-defined polycythaemia vera patients

Polycythaemia vera (PV) patients have an overall comparatively favourable prognosis, but disease progression is very heterogeneous and life-threatening thrombosis and bleedings are frequent complications in untreated disease. Moreover, transformation to more severe secondary myelofibrosis and acute myeloid leukaemia can occur. The aim of this study was to identify gene mutations that could be used together with clinical data as prognostic markers to guide treatment decisions in PV patients. A well-characterized WHO-defined cohort of PV patients was used. Clinical data and blood values were evaluated and a myeloid sequencing panel was used to screen for additional mutations other than the diagnostic JAK2 V617F and JAK2 exon 12 mutations. In 78% of the PV patients, at least one mutation additional to JAK2 V617F was detected. Additional mutations in genes coding for epigenetic modifiers, like TET2, DNMT3A and ASXL1, were most frequent. When correlated to overall survival, mutations in ASXL1 were significantly associated with inferior survival. In an attempt to obtain prognostic guidance in a larger number of patients, the presence of ASXL1 mutations was combined with age and vascular complications prior to diagnosis. Based on these data we were able to define three risk groups that predicted survival.     

The measurement of venous haematocrit in patients with polycythaemia vera

Abstract. Andréasson B, Wahlström E, Jacobsson S, Björkholm M, Samuelsson J, Birgegård G, Wadenvik H, Kutti J (Medical Clinic, Kärnsjukhuset, Skövde; Sahlgrenska University Hospital, Göteborg; Karolinska Hospital, Stockholm; Huddinge University Hospital, Huddinge; and Akademiska Hospital, Uppsala, Sweden). The measurement of venous haematocrit in patients with polycythaemia vera. J Intern Med 1999; 246: 293–297. Objective. In clinical practice, patients with polycythaemia vera (PV) are monitored by measurement of venous packed cell volume (PCV). However, whereas treatment recommendations are still based upon studies in which the results were obtained with the centrifuged microhaematocrit, currently in most instances automated blood cell counters are used to calculate PCV. In a group of patients with polycythaemia we therefore compared the results obtained by the microhaematocrit method with PCV calculated by haematology analysers. Design. The study was carried out on a prospective basis. Duplicate venous blood samples were collected. The centrifuged microhaemotocrit was obtained by using an IEC Micro-MB Centrifuge. Depending on different routine methods used in the participating hospitals, the blood cell counter PCV was calculated using Coulter STKS, Bayer Technicon H2 or H3. Setting. Patients were included from four Swedish university hospitals: Akademiska (Uppsala), Huddinge and Karolinska (Stockholm) and Sahlgrenska (Göteborg). Subjects. Seventy-four patients with PV and 10 patients with secondary polycythaemia were included and a total of 150 duplicate blood samples were analysed from these subjects. Results. In the 150 measurements the mean blood cell counter calculated PCV was 0.448 ± 0.037; the mean for centrifuged microhaematocrit was 0.467 ± 0.037 and the difference between means was highly significant (P = 6.8 × 10^–25). The means for centrifuged haematocrit and calculated PCV differed significantly in the groups of PV patients treated with phlebotomy only, hydroxyurea or radiophosphorous (P < 0.0001, respectively). In PV patients treated with α-interferon and in patients with secondary polycythaemia the difference in means did not reach statistical significance (P = 0.07 and P = 0.13, respectively). The groups of patients with MCV <80 fL and ≥80 fL both presented significant differences between means for calculated PCV and centrifuged haematocrit. Conclusions. If PV patients are monitored with blood cell counter calculated PCV it appears that the therapeutic goal should be to maintain the calculated PCV below 0.43, provided the local differences in calculated PCV and centrifuged haematocrit are of the same magnitude as in this study.     

Cytogenetic conversion in a case of polycythaemia vera treated with interferon-alpha

Summary Polycythaemia vera is a clonal disorder of the haemopoietic stem cell causing a pathologic expansion of the erythroid and sometimes the megakaryocytic and myeloid elements. In order to avoid the possible mutagenic effects of radioactive phosphorus, alkylating agents and hydroxyurea, since 1988 α-IFN has been used for the treatment of PV and has been shown to induce and maintain haematological remission. We describe a 24-year-old PV patient with chromosomal abnormalities who achieved not only a reduction of the proliferation of erythroid elements and reticulin content in the bone marrow, but also a complete cytogenetic remission after IFN treatment.     

A retrospective analysis of the impact of treatments and blood counts on survival and the risk of vascular events during the course of polycythaemia vera

Vascular and non‐vascular complications are common in patients with polycythaemia vera. This retrospective study of 217 patients with polycythaemia vera aimed to determine whether blood counts with respect to different treatments influenced the complication rate and survival. We found that 78 (36%) patients suffered from at least one complication during follow‐up. Older age and elevated lactate dehydrogenase at diagnosis were found to be risk factors for vascular complications. When the vascular complication occurred, 41% of the patients with a complication had elevated white blood cells (WBC) compared with 20% of patients without a complication (P = 0·042). Patients treated with hydroxycarbamide (HC; also termed hydroxyurea) experienced significantly fewer vascular complications (11%) than patients treated with phlebotomy only (27%) (P = 0·013). We also found a survival advantage for patients treated with HC, when adjusted for age, gender and time period of diagnosis (Hazard ratio for phlebotomy‐treated patients compared to HC‐treated patients at 5 years was 2·42, 95% confidence interval 1·03‐5·72, P = 0·043). Concerning survival and vascular complications, HC‐treated patients who needed at least one phlebotomy per year were not significantly different from HC‐treated patients with a low phlebotomy requirement. We conclude that complementary phlebotomy in HC‐treated patients in order to maintain the haematocrit, is safe.