Expertise-based management in essential thrombocythemia and polycythemia vera

The clinical courses of polycythemia vera (PV) and essential thrombocythemia (ET) are characterized by an increased incidence of thrombotic and hemorrhagic complications and an inherent tendency to progress into myelofibrosis or acute myeloid leukemia. Major predictors of vascular events are increasing age and previous thrombosis. Myelosuppressive drugs can reduce the rate of thromboses and hemorrhages, but there is concern that their use accelerates the rate of leukemic transformation. Thus, 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 agents are recommended in high-risk patients and hydroxyurea is the drug of choice in most patients. Interferon-alpha (IFN-alpha) or anagrelide could be considered in selected young patients or as second-line therapy in those intolerant of hydroxyurea or with refractory disease. The recent identification of the JAK2 V617F mutation in a substantial proportion of patients with PV and ET raises the possibility of a molecularly targeted therapy.     

Venous thromboembolism in patients with essential thrombocythemia and polycythemia vera

Polycythemia vera (PV) and essential thrombocythemia (ET) are myeloproliferative neoplasms (MPNs), which generally follow a benign and indolent clinical course. However, venous thromboses are common and constitute the main cause of morbidity and mortality. The discovery of the JAK2V617F mutation and other biomarkers has advanced our understanding of these diseases. There is a strong association between the presence of the JAK2V617F mutation and the development of thrombosis in ET. If venous thrombosis presents with unusual manifestations, the diagnosis of a MPN, such as PV or ET, should be part of the differentials. Treatment of venous thrombosis in MPN follows the same principle as in other patients with venous thrombosis, but careful attention to primary and secondary prophylaxis in addition to heparin-induced thrombocytopenia should be given. Cytoreductive therapy is indicated in high-risk subgroups of PV and ET patients, and alternative therapeutic agents have different effects on risk of venous thrombosis. New therapeutic approaches are emerging, and JAK2 inhibitors, histone deacetylase inhibitors and next-generation anticoagulants are in various stages of clinical development for the treatment of MPN, but their exact role in thrombosis prevention and treatment remains unclear.     

Activating mutation in the tyrosine kinase JAK2 in polycythemia vera, essential thrombocythemia, and myeloid metaplasia with myelofibrosis

Polycythemia vera (PV), essential thrombocythemia (ET), and myeloid metaplasia with myelofibrosis (MMM) are clonal disorders arising from hematopoietic progenitors. An internet-based protocol was used to collect clinical information and biological specimens from patients with these diseases. High-throughput DNA resequencing identified a recurrent somatic missense mutation JAK2V617F in granulocyte DNA samples of 121 of 164 PV patients, of which 41 had homozygous and 80 had heterozygous mutations. Molecular and cytogenetic analyses demonstrated that homozygous mutations were due to duplication of the mutant allele. JAK2V617F was also identified in granulocyte DNA samples from 37 of 115 ET and 16 of 46 MMM patients, but was not observed in 269 normal individuals. In vitro analysis demonstrated that JAK2V617F is a constitutively active tyrosine kinase.     

Progression of bone marrow fibrosis in patients with essential thrombocythemia and polycythemia vera during anagrelide treatment

Anagrelide is a second-line option for reduction of thrombocythemia in patients with chronic myeloproliferative disorders (CMPDs). A multicenter, open, phase II study of anagrelide treatment in 60 patients during 2 yr was performed by the Swedish Myeloproliferative Disorder Study Group. Adequate bone marrow biopsies were obtained from 53 of the CMPD patients [36 essential thrombocythemia (ET), 16 polycythemia vera (PV), 1 chronic idiopathic myelofibrosis (CIMF)] before treatment and compared with biopsies from 30 healthy volunteers and 34 patients with acute myeloid leukemia (AML). Higher reticulin and hyaluronan (HYA) scores were found before anagrelide therapy in the CMPD patients than in the normal controls (p<0.001 and p<0.001, respectively) and AML patients (p<0.001 and p=0.011, respectively). At the end of the study 30 CMPD patients were still on anagrelide treatment and in 19 of these patients, all diagnosed as ET (n=16) or PV (n=3), pretreatment bone marrow biopsies were compared with follow-up samples. After 2 yr of anagrelide therapy the reticulin and HYA scores were significantly higher than before treatment (p=0.02 and p=0.002, respectively). The cellularity was significantly higher (p=0.014), although the number of megakaryocytes did not change significantly. The increase of reticulin and HYA in the bone marrow after 2 yr of treatment with anagrelide indicated progression of fibrosis. Although anagrelide is a valuable drug for reduction of platelet levels, it seems unable to stop progression of bone marrow fibrosis and hypercellularity in ET and PV.     

Therapeutic effect of ranimustine (MCNU) on essential thrombocythemia and polycythemia vera

Seven patients with essential thrombocythemia and two patients with polycythemia vera were treated with ranimustine (MCNU). MCNU was given intravenously by drip infusion at a dose of 40-80 mg/m2 with intervals arranged in terns of the counts of both white blood cell and platelets. All cases with essential thrombocythemia obtained complete response, but the cases with polycythemia vera needed the combination of phlebotomy. The therapeutic effects were maintained for 2-5 months. No serious side effect was recognized except in two cases (22%) of mild nausea. Our study indicates that MCNU is useful for chemotherapy of chronic myeloproliferative disorders, especially, essential thrombocythemia.     

Treatment of polycythemia vera and essential thrombocythemia: the role of pipobroman

Pipobroman (PB) is a neutral amide of piperazine with a chemical structure close to that of alkylating agents, although the exact mechanism of action of PB has not been demonstrated. PB has well documented clinical activity in polycythemia vera (PV) and essential thrombocythemia (ET). Recent long-term follow-up studies on PV and ET patients receiving PB have facilitated the definition of the risk of late transformation into myelofibrosis with myeloid metaplasia (MMM) or acute leukemia (AL). This report gives an overview of the treatment with PB in patients with PV and ET focusing on clinical activity, administration dose and schedule, toxicity, impact on short- and long-term complications. From our experience and from the data reported in the literature the high clinical activity of PB in both PVand ET becomes evident. This drug allows, within 3 months, to attain a response in more than 90% of patients, without clinically relevant toxicities. The 10-years risk of thrombosis of patients treated with PB is about 15%, similar to that registered with hydroxyurea, the most widely used agent in PVand ET. The antiproliferative activity of PB on bone marrow megakaryocytes seems of particular value in lowering the occurrence of post-PV and post-ET MMM, whose risk (< 4% at 10 years) is the lowest registered with available treatments. The 10-year risk of acute leukemia with PB is 5% in PVand 3% in ET, which is only slightly higher than that expected as a natural evolution of the disease. In conclusion, the use of PB is a definite alternative to hydroxyurea in patients with PV and ET at high risk of thrombosis.     

Hydroxyurea: The drug of choice for polycythemia vera and essential thrombocythemia

Hydroxyurea is an old drug that is often used to control essential thrombocythemia and polycythemia vera in patients with high-risk disease. It is usually well tolerated and cheap and has been proven effective in many studies for the prevention of thrombohemorrhagic complications associated with these disorders. However, many clinicians are reluctant to use it because of the perceived risk of progression to acute leukemia. Several recent, large studies have given this drug a new lease on life. Relevant results from these studies are discussed, and the risk of leukemia is placed in perspective to demonstrate that hydroxyurea remains the drug of choice in patients with either of these disorders.     

Impaired apoptosis of megakaryocytes and bone marrow mononuclear cells in essential thrombocythemia: correlation with JAK2V617F mutational status and cytoreductive therapy

Essential thrombocythemia (ET) is a clonal myeloproliferative disorder characterized by overproduction of megakaryocytes (MKCs) and platelets. The recent discovery of the JAK2 mutation has shed a new light on the development of ET but its pathogenesis still remains unknown. One of the possible mechanisms can be deregulation of apoptosis, resulting in accumulation of bone marrow MKCs. In this study, we investigated the apoptotic profile, as well as the expression of apoptosis-regulating protein in MKCs and bone marrow mononuclear cells (BMMCs) in 43 patients with ET. We found significantly lower percentages of apoptotic MKCs and BMMCs, as measured by the rate of annexin-V+ and caspase-3+ (Cas-3+) cells in relation to healthy volunteers. Additionally, the expression of Bax protein in ET patients na?ve to cytoreductive treatment, as well as their Bax/Bcl-2 ratio, was significantly lower than in controls (p?=?<0.05 and p?相似文献   

Prognostic factors and models in polycythemia vera, essential thrombocythemia, and primary myelofibrosis

Myeloproliferative neoplasms include essential thrombocythemia (ET), polycythemia vera (PV), and primary myelofibrosis (PMF). These 3 diseases have common clinical features, such as a high risk of vascular complications, progression to secondary myelofibrosis, and clonal evolution into the blast phase. Current risk factors of ET and PV, used to predict events, are patient based: age >60 years and a history of thrombosis. Very recently, other parameters, such as leukocyte count and the presence of JAK2 (V617F) mutation, have been reported as potential risk factors. Prognosis in PMF is predicted at diagnosis by a combination of different risk factors, such as advanced age (age >60 years), anemia, leukocytosis (white blood cell count > 25 × 10(9)/L), the presence of blast cells (≥ 1%), and the presence of constitutional symptoms. This model may also predict survival when applied during follow-up.     

原发性血小板增多症骨髓病理及JAK2-V617F突变分析

目的:分析原发性血小板增多症（essential thrombocythemia,ET）患者的骨髓病理及JAK2-V617F突变特点。方法:回顾109例ET患者的临床资料,并与继发性血小板增多症(secondary thrombocythemia,ST)进行比较。结果:ET骨髓病理巨核细胞体积明显增大,核多分叶、多核易见,成簇、成片状分布,ST巨核细胞体积未见明显增大及异常分布。ET患者JAK2-V617F突变阳性率为 57.83%,ST患者JAK2-V617F突变均为阴性。JAK2-V617F突变阳性组WBC、Hb、骨髓纤维化、初诊血栓事件高于阴性组,差异有统计学意义（P<0.05)。JAK2-V617F突变阳性组年龄、Plt、骨髓粒系、红系百分比及巨核细胞计数与阴性组比较,无显著性差异（P>0.05）;JAK2-V617F突变阳性组无血栓生存率较阴性组低,差异有统计学意义（P<0.05）。结论:ET的骨髓病理特征明显,骨髓活检与JAK2-V617F基因检查相结合对ET诊断及治疗具有重要意义。     

The 2008 WHO diagnostic criteria for polycythemia vera, essential thrombocythemia, and primary myelofibrosis

Several international working groups cooperated to propose new diagnostic guidelines for polycythemia vera (PV), essential thrombocythemia (ET), and primary myelofibrosis (PMF) to the steering committee of the World Health Organization. Because JAK2 mutation status presents a decisive diagnostic test in PV, this feature was introduced as a major criterion. Minor criteria, such as characteristic bone marrow morphology, low erythropoietin level, and erythroid colony formation, were kept as supporting parameters. In PMF, major diagnostic criteria were established by histologic features independent of the presence of relevant fibrosis or myelofibrosis with myeloid metaplasia. JAK2 mutation status was restricted to positive findings to exclude reactive myelofibrosis. A decrease in the platelet level was proposed for ET, because vascular complications may occur at lower platelet counts. As with PMF, morphology plays a distinctive role in diagnosis, particularly for its differentiation from early-stage PV or prodromal PMF associated with thrombocytosis.     

真性红细胞增多症患者JAK2基因突变的临床意义

真性红细胞增多症（polycythemia vera,PV）为一种以红细胞增多为特征的骨髓增殖性肿瘤（myeloproliferative neoplasm,MPN）。PV的发病机制尚未阐明,可能和JAK2基因的功能获得性体细胞突变相关,JAK2基因突变为PV提供了分子学诊断标准。JAK2基因突变和等位基因突变负荷可推测PV患者的临床特征和发展趋势。JAK2基因突变的发现促进了分子靶向治疗的发展,JAK2抑制剂ruxolitinib已应用于临床,治疗效果和安全性均良好。JAK2等位基因突变负荷与白细胞增多、转化为骨髓纤维化（myelofibrosis,MF）密切相关,高JAK2等位基因突变负荷可能为PV患者预后不良的危险因素。本文对PV患者JAK2基因突变的临床意义进行综述。      

Patients with polycythemia vera and essential thrombocythemia with prior malignancy do not have significantly worse outcome

The clinical relevance of prior malignancy (PM) in patients with essential thrombocythemia (ET) and polycythemia vera (PV) is largely unknown. We retrospectively evaluated 437 patients (ET, n = 263; PV, n = 174) treated at MD Anderson between 1960 and 2010. Forty-four patients had PM (ET, 10%; PV, 11%), with median time to diagnosis of 66 months. PM was not associated with abnormal cytogenetics, JAK2-mutation frequency, blood-cell counts or progression to acute leukemia or myelofibrosis. In multivariate analysis, only older age and high LDH levels were associated with worse OS. In conclusion, PM does not predict worse outcomes for patients with ET and PV.