Treatment options for essential thrombocythemia and polycythemia vera

Polycythemia vera and essential thrombocythemia are the most common chronic myeloproliferative neoplasms; their molecular basis has been appreciated only recently and is briefly discussed in this article. Major causes of morbidity and mortality are represented by arterial and venous thrombosis, as well as by evolution to myelofibrosis or transformation to acute leukemia. Therapy is currently aimed at reducing the rate of thrombosis without increasing the risk of hematologic transformation that might be caused by exposure to cytotoxic drugs. A risk-oriented approach is employed for stratifying patients to the most appropriate therapeutic options. However, results of clinical trials with interferon, and the expected effects of novel drugs selectively targeting the abnormal pathways that are involved in the clonal myeloproliferation, are pushing therapeutic goals from disease control only to cure. These different issues, and current recommendations for treatment, will be discussed in the review.     

Alpha-interferon in polycythemia vera and essential thrombocythemia

Twenty-one patients with chronic myeloproliferative disorders, eleven with polycythemia vera (PV) and ten with essential thrombocythemia (ET), were treated with small doses of alpha-2a interferon (IFN). The median follow-up was, respectively, 10.8 months (range 4-22) for PV and 8.11 months (range 4-16) for ET. Six patients with PV and five with ET had been previously treated with conventional cytotoxic drugs, while the remaining patients were newly diagnosed. In four patients with PV we observed a durable normal hematocrit level (PCV less than 0.48) and a reduction of platelet count and spleen size within 4-8 weeks of treatment. Three patients achieved moderate disease control. In the others the disease remained substantially unchanged. Five out of nine evaluable patients with ET showed complete response (CR) within six weeks, one patient had a partial response (PR) and three no response (NR). In one patient with ET the IFN therapy was stopped after twelve days because neurological side effects were observed. All the other patients tolerated long-term treatment very well.     

Prevalence of polycythemia vera and essential thrombocythemia

Polycythemia vera (PV) and essential thrombocythemia (ET) are common types of myeloproliferative disorders (MPD), the prevalence of which has not been well documented in the United States. Recent breakthroughs in the molecular etiology of these disorders and the accelerated development of targeted pharmacotherapeutics to treat them underscore the need to define the affected population. In this study, we obtained health claims data from major commercial insurance payers in Connecticut and the Center for Medicare and Medicaid Services to estimate the prevalence of PV and ET. Specifically, logistic regression was utilized to develop algorithms to predict the probability that an individual with claims suggestive of MPD truly has PV or ET, and the algorithms were then applied to health claims to estimate the number of PV and ET patients in Connecticut. As of 2003, the age-standardized prevalence was 22 per 100,000 and 24 per 100,000 for PV and ET, respectively, in Connecticut. Applying the age-specific prevalence of PV and ET to the entire US population resulted in an estimated total of 65,243 patients with PV and 71,078 patients with ET in the United States in 2003. This study is the first to assess the prevalence of PV and ET in a large US population. Given the large number of individuals afflicted with these diseases and the fact that demographic changes alone will further increase the burden of     

Anagrelide-associated cardiomyopathy in polycythemia vera and essential thrombocythemia

A comprehensive database inquiry at our institutions identified 11 patients with echocardiogram-documented idiopathic cardiomyopathy that post-dated a diagnosis of either polycythemia vera or essential thrombocythemia. Anagrelide therapy was temporally associated with the particular complication in 6 patients, all of whom experienced symptomatic and/or objective improvement after drug discontinuation.     

Front-line therapy in polycythemia vera and essential thrombocythemia

Because the current therapy in polycythemia vera (PV) and essential thrombocythemia (ET) is aimed at lowering the risk of thrombosis, the risk classification system in these disorders is shaped according to thrombotic risk. Patients with either PV or ET can be stratified in a "high-risk" or "low-risk" category according to their age and previous history of thrombosis. Whether novel risk factors such as leukocytosis and JAK2 mutation may be included in the prognostic stratification requires confirmation in prospective future clinical studies. The identification and appropriate management of cardiovascular risk factors and the promotion of a healthy lifestyle in chronic myeloproliferative neoplasms (MPN), as in the general population, should be considered a cornerstone of vascular prevention. Blood hyperviscosity in PV is a major cause of vascular disturbances which severely impact on morbidity and mortality. An aggressive target of hematocrit lower than 45% in males and 42% in females has been advised by the European LeukemiaNet (ELN) group, although no convincing evidence of this recommendation is currently available. The efficacy and safety of low-dose aspirin (100mg daily) in PV has been assessed in the European Collaboration on Low-dose Aspirin in Polycythemia (ECLAP) double-blind, placebo-controlled, randomized clinical trial. Translating evidence from the positive results of ECLAP to ET may be questionable. The most commonly used front-line therapy drugs for the treatment of high-risk PV and ET patients include hydroxyurea and alpha-interferon at any age while anagrelide is recommended as second line-therapy in resistant and intolerant ET patients. Busulphan is a front-line therapy in the elderly. By definition, children with ET are a population with low vascular risk unless a major thrombotic or hemorrhagic event has occurred. ELN recommends to prescribe cytoreductive drugs in children as a last resort. No results of clinical trials with JAK-2 inhibitor drugs in PV and ET are so far available.     

Risk-adapted therapy in essential thrombocythemia and polycythemia vera

The clinical course of Polycythemia vera (PV) and Essential Thrombocythemia (ET) is marked by an high incidence of thrombotic complications, which represent the main cause of morbidity and mortality. Major predictors of vascular events are increasing age and previous thrombosis. Myelosuppressive drugs can reduce the rate of thrombosis, but there is concern that their use raises the risk of PV and ET transformation into acute leukemia. To tackle this dilemma, a risk-oriented management strategy is recommended. Low-risk patients with PV should be treated with phlebotomy and low-dose aspirin, whereas those with ET can be left untreated. Cytotoxic therapy is indicate in high-risk patients and the drug of choice is hydroxyurea because its leukemogenicity is low, if any. New therapeutic options, theoretically devoid of leukemic risk, such as alpha-interferon, anagrelide and imatinib should be reserved to selected patients and require further clinical experience.     

Platelet density in essential thrombocythemia and polycythemia vera

This study aims to compare platelet density in myeloproliferative disorders (essential thrombocythemia (ET) and polycythemia vera (PV)) with platelet density of healthy subjects. Platelet density peaks were determined using a specially designed apparatus for scanning light transmission variations along test tubes containing density-separated platelets. Eighteen patients with myeloproliferative disorders (nine ET and nine PV) were compared with a control group consisting of 12 healthy volunteers. Compared with healthy volunteers, patients with myeloproliferative disorders had significantly lower platelet peak density ( P< 0.001). It is concluded that determination of peak platelet density may be a useful tool for excluding ET and PV. A high platelet density peak makes a clonal disorder less likely and a low density peak would confirm the suspicion.     

Platelet density in essential thrombocythemia and polycythemia vera

This study aims to compare platelet density in myeloproliferative disorders (essential thrombocythemia (ET) and polycythemia vera (PV)) with platelet density of healthy subjects. Platelet density peaks were determined using a specially designed apparatus for scanning light transmission variations along test tubes containing density-separated platelets. Eighteen patients with myeloproliferative disorders (nine ET and nine PV) were compared with a control group consisting of 12 healthy volunteers. Compared with healthy volunteers, patients with myeloproliferative disorders had significantly lower platelet peak density ( P< 0.001). It is concluded that determination of peak platelet density may be a useful tool for excluding ET and PV. A high platelet density peak makes a clonal disorder less likely and a low density peak would confirm the suspicion.     

A clinical update in polycythemia vera and essential thrombocythemia

Polycythemia vera and essential thrombocythemia pose specific management issues that distinguish them from other chronic myeloproliferative disorders. They are associated with a better prognosis, as well as a variable risk of thrombohemorrhagic complications. In addition, essential thrombocythemia occurs comparatively more often in young people and women. Treatment strategies for patients with polycythemia vera and essential thrombocythemia must consider the possibility of long-term survival, morbidity from thrombotic complications, transformation into myelofibrosis with myeloid metaplasia or acute myeloid leukemia, and the effect of specific therapies on the incidence of leukemic transformation and on pregnancy. There is increasing concern about the possible leukemogenic effect of hydroxyurea. Newer therapeutic agents, including interferon alpha and anagrelide, are being used more often. Ongoing studies are reexamining the effects of low-dose aspirin in preventing thrombotic complications.     

Epidemiology of the myeloproliferative disorders polycythemia vera and essential thrombocythemia

The annual incidence of polycythemia vera (PV) and essential thrombocythemia (ET) is approximately 2 and 1.5 per 100,000 inhabitants, respectively, if based on large population surveys and adjusted to a standard population. Survival for ET patients does not differ from that of the general population. However, it appears that PV patients have a significantly higher mortality, at least for patients diagnosed before 1990.     

Differentiation between essential thrombocythemia and polycythemia vera with marked thrombocytosis

Accurate distinction between essential thrombocythemia and thrombocytotic polycythemia vera requires determination of the red cell mass in the presence of adequate iron stores, but this is not always possible. We therefore compared the clinical and laboratory features at the time of presentation of 50 patients with unequivocal essential thrombocythemia and 27 patients with thrombocytotic polycythemia vera. Univariate analysis failed to identify any single parameter capable of reliably separating the groups. A logistic regression algorithm incorporating hematocrit, white cell count, and spleen size markedly increased the diagnostic accuracy (92%) compared with predictions based on the hematocrit alone (52%). The algorithm's usefulness for patients with intermediate hematocrits was confirmed by analysis of independent samples of essential thrombocythemia and thrombocytotic polycythemia vera patients, and also by analysis of patients with probable essential thrombocythemia in whom the diagnosis could not be confirmed because of inadequate exclusion of polycythemia vera. Furthermore, comparison of survival data suggests that differentiating these disorders is prognostically important. The algorithm is recommended as an alternate method for differentiating essential thrombocythemia from thrombocytotic polycythemia vera whenever the red cell mass is unavailable or iron deficiency cannot be excluded.     

Leukocyte-platelet interaction in patients with essential thrombocythemia and polycythemia vera

OBJECTIVE: Circulating polymorphonuclear leukocyte (PMN) activation occurs in patients with essential thrombocythemia (ET) and polycythemia vera (PV). We want to define whether this phenomenon plays a role in the formation of circulating PMN-platelet aggregates in these conditions. METHODS: In 80 patients (46 ET and 34 PV) and 50 control subjects, we conducted a flow cytometric analysis to evaluate the levels of PMN-platelet aggregates (defined as the percentage of CD11b-positive PMN coexpressing a platelet-specific marker, i.e., CD42b or CD62P) and the levels of activated PMN and activated platelets. In addition, the in vitro PMN-platelet aggregate formation in response to N-formyl-methionyl-leucyl-phenylalanine (f-MLP)-induced activation of PMN was studied. RESULTS: Significantly high PMN-platelet aggregates in ET and PV patients were found and were associated with increased PMN surface CD11b and surface platelet CD62P expression. In vitro f-MLP stimulation upregulated PMN-CD11b expression and simultaneously increased CD11b/CD42b and CD11b/CD62P aggregates, without affecting platelet surface antigens. In ET patients receiving aspirin, the increments in f-MLP-induced PMN-CD11b and in PMN-platelet aggregates were significantly lower versus ET subjects not treated with aspirin. CONCLUSION: Our data show that in ET and PV patients PMN activation plays an important role in increasing circulating PMN-platelet aggregates and suggest that aspirin treatment may decrease their formation.     

Aspirin responsive platelet thrombophilia in essential thrombocythemia and polycythemia vera

Essential thrombocythemia (ET) and polycythemia vera (PV) frequently present with erythromelalgia and acrocyanotic complications, migraine-like microvascular cerebral and ocular transient ischemic attacks (MIAs) and/or acute coronary disease. The spectrum of MIAs in ET range from poorly localized symptoms of transient unsteadiness, dysarthria and scintillating scotoma to focal symptoms of transient monocular blindness, transient mono- or hemiparesis or both. The attacks all have a sudden onset, occur sequentially rather than simultaneously, last for a few seconds to several minutes and are usually associated with a dull, pulsatile or migraine-like headache. Increased hematocrit and blood viscosity in PV patients aggravate the microvascular ischemic syndrome of thrombocythemia to major arterial and venous thrombotic complications. Phlebotomy to correct hematocrit to normal in PV significantly reduces major arterial and venous thrombotic complications, but fails to prevent the platelet-mediated erythromelalgia and MIAs. Complete long-term relief of the erythromelalgic microvascular disturbances, MIAs and major thrombosis in ET and PV patients can be obtained with low dose aspirin and platelet reduction to normal, but not with anticoagulation. Skin punch biopsies from the erythromelalgic area show fibromuscular intimal proliferation of arterioles complicated by occlusive platelet-rich thrombi leading to acrocyanotic ischemia. Symptomatic ET patients with erythromelalgic microvascular disturbances have shortened platelet survival, increased platelet activation markers β-thromboglobulin (β-TG), platelet factor 4 (PF4) and thrombomoduline (TM), increased urinary thromboxane B2 (TXB2) excretion, and no activation of the coagulation markers thrombin fragments F1+2 and fibrin degradation products. Inhibition of platelet cyclooxygenase (COX1) by aspirin is followed by the disappearance and no recurrence of microvascular disturbances, increase in platelet number, correction of the shortened platelet survival times to normal, and reduction of increased plasma levels of β-TG, PF4, TM and urinary TXB2 excretion to normal. These results indicate that platelet-mediated fibromuscular intimal proliferation and platelet-rich thrombi in the peripheral, cerebral and coronary end-arterial microvasculature are responsible for the erythromelalgic ischemic complications, MIAs and splanchnic vein thrombosis. Baseline platelet P-selectin levels and arachidonic acid induced COX1 mediated platelet activation showed a highly significant increase of platelet P-selectin expression (not seen in ADP and collagen stimulated platelets), which was significantly higher in JAK2^V617F mutated compared to JAK2 wild type ET.