今日の臨床サポート

真性多血症(PV)

著者: 桐戸敬太 山梨大学医学部附属病院 血液・腫瘍内科

監修: 木崎昌弘 埼玉医科大学総合医療センター

著者校正/監修レビュー済:2020/03/26
参考ガイドライン:
  1. 日本血液学会:造血器腫瘍診療ガイドライン2018年版
患者向け説明資料

概要・推奨   

  1. 骨髄生検は、真性多血症と他の骨髄増殖性腫瘍との鑑別のために重要である(推奨度1)。
  1. EPO濃度の測定は、真性多血症(PV)と二次性赤血球増加症との鑑別において有用である(推奨度1
  1. 末梢血検体を用いてJAK2V617F変異解析を行う(推奨度1
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薬剤監修について:
オーダー内の薬剤用量は日本医科大学付属病院 薬剤部 部長 伊勢雄也 以下、林太祐、渡邉裕次、井ノ口岳洋、梅田将光による疑義照会のプロセスを実施、疑義照会の対象については著者の方による再確認を実施しております。
※薬剤中分類、用法、同効薬、診療報酬は、エルゼビアが独自に作成した薬剤情報であり、
著者により作成された情報ではありません。
尚、用法は添付文書より、同効薬は、薬剤師監修のもとで作成しております。
※薬剤情報の(適外/適内/⽤量内/⽤量外/㊜)等の表記は、エルゼビアジャパン編集部によって記載日時にレセプトチェックソフトなどで確認し作成しております。ただし、これらの記載は、実際の保険適用の査定において保険適用及び保険適用外と判断されることを保証するものではありません。また、検査薬、輸液、血液製剤、全身麻酔薬、抗癌剤等の薬剤は保険適用の記載の一部を割愛させていただいています。
(詳細はこちらを参照)
著者のCOI(Conflicts of Interest)開示:
桐戸敬太 : 講演料(ノバルティスファーマ株式会社,武田薬品工業)[2021年]
監修:木崎昌弘 : 講演料(ブリストル・マイヤーズスクイブ,ヤンセンファーマ,ノバルティスファーマ,セルジーン,MSD,小野薬品,武田薬品,大日本住友製薬),研究費・助成金など(武田薬品),奨学(奨励)寄付など(協和キリン,中外製薬,武田薬品,小野薬品,第一三共)[2021年]

改訂のポイント:
  1. JAK2V617F遺伝子変異解析について、一般臨床でも検査可能となった点を中心に加筆、修正を行った。

病態・疫学・診察

疾患情報  
  1. 真性多血症(PV)とは、造血幹細胞レベルの異常によって生ずる 骨髄増殖性腫瘍 の1つである。有効造血の亢進によりすべての血球の増加を認めるが、中でも赤血球の増加が顕著である。90%以上の症例にJAK2遺伝子変異(V617F変異)を認める。血栓症の合併を予防することが最も重要である。
  1. 診断のためにはJAK2変異解析が不可欠である。
  1. エリスロポエチン(EPO)濃度の上昇がないことも、診断には有用な情報である。
  1.  血栓症 および出血の合併が高く、特に年齢(60歳以上)および血栓・出血の既往があることの2点が血栓・出血のリスク因子とされる。
  1. 上記リスク因子がない場合には、瀉血によるヘマトクリットのコントロールと低用量アスピリンの併用が推奨される。(図アルゴリズム
  1. 上記リスク因子を有する場合には、さらに細胞減少治療を併用する。(図アルゴリズム
  1. 数%の症例は、 急性白血病 や 骨髄線維症 へ移行する。
問診・診察のポイント  
  1. まず反応性多血症との鑑別を行う必要がある。

これより先の閲覧には個人契約のトライアルまたはお申込みが必要です。

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文献 

著者: Jasper H Smalberg, Lidia R Arends, Dominique C Valla, Jean-Jacques Kiladjian, Harry L A Janssen, Frank W G Leebeek
雑誌名: Blood. 2012 Dec 13;120(25):4921-8. doi: 10.1182/blood-2011-09-376517. Epub 2012 Oct 4.
Abstract/Text Myeloproliferative neoplasms (MPNs) are the most common cause of Budd-Chiari syndrome (BCS) and nonmalignant, noncirrhotic portal vein thrombosis (PVT). In this meta-analysis, we determined the prevalence of MPNs and their subtypes as well as JAK2V617F and its diagnostic role in these uncommon disorders. MEDLINE and EMBASE databases were searched. Prevalence of MPNs, JAK2V617F, and MPN subtypes were calculated using a random-effects model. A total of 1062 BCS and 855 PVT patients were included. In BCS, mean prevalence of MPNs and JAK2V617F was 40.9% (95% CI, 32.9%-49.5%) and 41.1% (95% CI, 32.3%-50.6%), respectively. In PVT, mean prevalence of MPNs and JAK2V617F was 31.5% (95% CI, 25.1%-38.8%) and 27.7% (95% CI, 20.8%-35.8%), respectively. JAK2V617F and MPNs were more frequent in BCS compared with PVT (P = .03 and P = .09, respectively). Polycythemia vera was more prevalent in BCS than in PVT (P = .001). JAK2V617F screening in splanchnic vein thrombosis (SVT) patients without typical hematologic MPN features identified MPN in 17.1% and 15.4% of screened BCS and PVT patients, respectively. These results demonstrate a high prevalence of MPNs and JAK2V617F in SVT patients and show differences in underlying etiology between these disorders. Furthermore, these results validate routine inclusion of JAK2V617F in the diagnostic workup of SVT patients.

PMID 23043069  Blood. 2012 Dec 13;120(25):4921-8. doi: 10.1182/blood-2・・・
著者: Pascal Mossuz, François Girodon, Magali Donnard, Véronique Latger-Cannard, Irène Dobo, Nathalie Boiret, Jean Claude Lecron, Christine Binquet, Claire Barro, Sylvie Hermouet, Vincent Praloran
雑誌名: Haematologica. 2004 Oct;89(10):1194-8.
Abstract/Text BACKGROUND AND OBJECTIVES: The diagnosis of polycythemia vera (PV) is based on clinical and biological criteria defined by either the Polycythemia Vera Study Group (PVSG) or the World Health Organization (WHO). Both the PVSG and WHO PV criteria have proved helpful and are extensively used, yet diagnostic strategies and scheduling of biological investigations vary. We assessed the value of measuring serum erythropoietin (Epo) as a first intention diagnostic test in patients with absolute erythrocytosis (AE).
DESIGN AND METHODS: Serum and bone marrow (BM) samples of 241 patients with a suspicion of erythrocytosis were collected in 8 hospital centers. One hundred and ninety had an absolute erythrocytosis (116 had PV, 66 had secondary erythrocytosis and 4 had idiopathic erythrocytosis). Serum Epo was assayed (ELISA) in 186. Statistical analysis (ROC curves) was used to define serum Epo thresholds that were specific for PV and secondary erythrocytosis and to analyze the diagnostic value of a low or high serum Epo level.
RESULTS: A large majority of PV patients (87% or 101/116) had a serum Epo level below the normal range in healthy patients (3.3 IU/L), giving this value a specificity of 97% with a 97.8% positive predictive value for the diagnosis of PV. Statistical analysis (ROC curves) defined two thresholds allowing a specific and direct diagnosis of 65.6% (65/99) of untreated PV (Epo < 1.4 IU/L) and 19.7% (13/66) of those with secondary erythrocytosis (Epo > 13.7 IU/L).
INTERPRETATION AND CONCLUSIONS: Based on these data, we propose that measurement of serum Epo level, a simple, reliable and inexpensive test, should be considered as a first intention diagnostic test for patients with absolute erythrocytosis.

PMID 15477203  Haematologica. 2004 Oct;89(10):1194-8.
著者: Gilles Bonicelli, Khadija Abdulkarim, Morgane Mounier, Peter Johansson, Cédric Rossi, Valérie Jooste, Björn Andreasson, Marc Maynadié, François Girodon
雑誌名: Br J Haematol. 2013 Jan;160(2):251-4. doi: 10.1111/bjh.12117. Epub 2012 Nov 15.
Abstract/Text Three hundred and twenty-seven patients from two population-based cohorts with an established diagnosis of polycythaemia vera were studied for prognostic risk factors for survival and leukaemia in a long-term survey. The relative survival (RS) was 72% and 46% at 10 and 20 years respectively, from the time of diagnosis. Multivariate analysis identified age >70 years, white blood cell count >13 × 10(9) /l and thrombo-embolism at diagnosis as independent risk factors. Patients with two or three of these factors had a 10 year RS of 26%, compared with 59% and 84% in patients with one and no risk factors, respectively. Age and leucocyte count are the main predicting factors for survival in polycythaemia vera.

© 2012 Blackwell Publishing Ltd.
PMID 23151052  Br J Haematol. 2013 Jan;160(2):251-4. doi: 10.1111/bjh.・・・
著者: A Tefferi, E Rumi, G Finazzi, H Gisslinger, A M Vannucchi, F Rodeghiero, M L Randi, R Vaidya, M Cazzola, A Rambaldi, B Gisslinger, L Pieri, M Ruggeri, I Bertozzi, N H Sulai, I Casetti, A Carobbio, G Jeryczynski, D R Larson, L Müllauer, A Pardanani, J Thiele, F Passamonti, T Barbui
雑誌名: Leukemia. 2013 Sep;27(9):1874-81. doi: 10.1038/leu.2013.163. Epub 2013 Jun 6.
Abstract/Text Under the auspices of an International Working Group, seven centers submitted diagnostic and follow-up information on 1545 patients with World Health Organization-defined polycythemia vera (PV). At diagnosis, median age was 61 years (51% females); thrombocytosis and venous thrombosis were more frequent in women and arterial thrombosis and abnormal karyotype in men. Considering patients from the center with the most mature follow-up information (n=337 with 44% of patients followed to death), median survival (14.1 years) was significantly worse than that of the age- and sex-matched US population (P<0.001). In multivariable analysis, survival for the entire study cohort (n=1545) was adversely affected by older age, leukocytosis, venous thrombosis and abnormal karyotype; a prognostic model that included the first three parameters delineated risk groups with median survivals of 10.9-27.8 years (hazard ratio (HR), 10.7; 95% confidence interval (CI): 7.7-15.0). Pruritus was identified as a favorable risk factor for survival. Cumulative hazard of leukemic transformation, with death as a competing risk, was 2.3% at 10 years and 5.5% at 15 years; risk factors included older age, abnormal karyotype and leukocytes ≥15 × 10(9)/l. Leukemic transformation was associated with treatment exposure to pipobroman or P32/chlorambucil. We found no association between leukemic transformation and hydroxyurea or busulfan use.

PMID 23739289  Leukemia. 2013 Sep;27(9):1874-81. doi: 10.1038/leu.2013・・・
著者: Roberto Marchioli, Guido Finazzi, Raffaele Landolfi, Jack Kutti, Heinz Gisslinger, Carlo Patrono, Raphael Marilus, Ana Villegas, Gianni Tognoni, Tiziano Barbui
雑誌名: J Clin Oncol. 2005 Apr 1;23(10):2224-32. doi: 10.1200/JCO.2005.07.062. Epub 2005 Feb 14.
Abstract/Text PURPOSE: The clinical course of polycythemia vera is often complicated by thrombosis as well as by the possible transition to myeloid metaplasia with myelofibrosis or acute myeloid leukemia. The aim of this study was to assess the rate of these complications in subjects receiving currently recommended treatments.
PATIENTS AND METHODS: Overall, 1,638 patients from 12 countries were enrolled onto a large, prospective multicenter project aimed at describing the clinical history of polycythemia vera for the following outcomes: survival, the cumulative rate of cardiovascular death and thrombosis, the cumulative rate of leukemia, myelodysplasia, and myelofibrosis. The mean duration of the disease at entry and the duration of the follow-up were 4.9 and 2.7 years, respectively.
RESULTS: The overall mortality rate of 3.7 deaths per 100 persons per year resulted from a moderate risk of cardiovascular death and a high risk of death from noncardiovascular causes (mainly hematologic transformations). Age older than 65 years and a positive history of thrombosis were the most important predictors of cardiovascular events. Antiplatelet therapy, but not cytoreductive treatment, was significantly associated with a lower risk of cardiovascular events. We found a consistent association between age and risk of leukemia, and between duration of the disease with risk of myelofibrosis.
CONCLUSION: The European Collaboration on Low-Dose Aspirin in Polycythemia Vera study documents that large international collaborative studies are feasible in this field, in which few epidemiologic data are available. The persistently high mortality rate from hematologic malignancies characterizes the unmet therapeutic need of polycythemic patients and suggests a priority for future studies in this disease.

PMID 15710945  J Clin Oncol. 2005 Apr 1;23(10):2224-32. doi: 10.1200/J・・・
著者: Ayalew Tefferi, William Vainchenker
雑誌名: J Clin Oncol. 2011 Feb 10;29(5):573-82. doi: 10.1200/JCO.2010.29.8711. Epub 2011 Jan 10.
Abstract/Text To update oncologists on pathogenesis, contemporary diagnosis, risk stratification, and treatment strategies in BCR-ABL1-negative myeloproliferative neoplasms, including polycythemia vera (PV), essential thrombocythemia (ET), and primary myelofibrosis (PMF). Recent literature was reviewed and interpreted in the context of the authors' own experience and expertise. Pathogenetic mechanisms in PV, ET, and PMF include stem cell-derived clonal myeloproliferation and secondary stromal changes in the bone marrow and spleen. Most patients carry an activating JAK2 or MPL mutation and a smaller subset also harbors LNK, CBL, TET2, ASXL1, IDH, IKZF1, or EZH2 mutations; the precise pathogenetic contribution of these mutations is under investigation. JAK2 mutation analysis is now a formal component of diagnostic criteria for PV, ET, and PMF, but its prognostic utility is limited. Life expectancy in the majority of patients with PV or ET is near-normal and disease complications are effectively (and safely) managed by treatment with low-dose aspirin, phlebotomy, or hydroxyurea. In PMF, survival and quality of life are significantly worse and current therapy is inadequate. In ET and PV, controlled studies are needed to show added value and justify the risk of unknown long-term health effects associated with nonconventional therapeutic approaches (eg, interferon-alfa). The unmet need for treatment in PMF dictates a different approach for assessing the therapeutic value of new drugs (eg, JAK inhibitors, pomalidomide) or allogeneic stem-cell transplantation.

PMID 21220604  J Clin Oncol. 2011 Feb 10;29(5):573-82. doi: 10.1200/JC・・・
著者: Tiziano Barbui, Giovanni Barosi, Gunnar Birgegard, Francisco Cervantes, Guido Finazzi, Martin Griesshammer, Claire Harrison, Hans Carl Hasselbalch, Rudiger Hehlmann, Ronald Hoffman, Jean-Jacques Kiladjian, Nicolaus Kröger, Ruben Mesa, Mary F McMullin, Animesh Pardanani, Francesco Passamonti, Alessandro M Vannucchi, Andreas Reiter, Richard T Silver, Srdan Verstovsek, Ayalew Tefferi, European LeukemiaNet
雑誌名: J Clin Oncol. 2011 Feb 20;29(6):761-70. doi: 10.1200/JCO.2010.31.8436. Epub 2011 Jan 4.
Abstract/Text We present a review of critical concepts and produce recommendations on the management of Philadelphia-negative classical myeloproliferative neoplasms, including monitoring, response definition, first- and second-line therapy, and therapy for special issues. Key questions were selected according the criterion of clinical relevance. Statements were produced using a Delphi process, and two consensus conferences involving a panel of 21 experts appointed by the European LeukemiaNet (ELN) were convened. Patients with polycythemia vera (PV) and essential thrombocythemia (ET) should be defined as high risk if age is greater than 60 years or there is a history of previous thrombosis. Risk stratification in primary myelofibrosis (PMF) should start with the International Prognostic Scoring System (IPSS) for newly diagnosed patients and dynamic IPSS for patients being seen during their disease course, with the addition of cytogenetics evaluation and transfusion status. High-risk patients with PV should be managed with phlebotomy, low-dose aspirin, and cytoreduction, with either hydroxyurea or interferon at any age. High-risk patients with ET should be managed with cytoreduction, using hydroxyurea at any age. Monitoring response in PV and ET should use the ELN clinicohematologic criteria. Corticosteroids, androgens, erythropoiesis-stimulating agents, and immunomodulators are recommended to treat anemia of PMF, whereas hydroxyurea is the first-line treatment of PMF-associated splenomegaly. Indications for splenectomy include symptomatic portal hypertension, drug-refractory painful splenomegaly, and frequent RBC transfusions. The risk of allogeneic stem-cell transplantation-related complications is justified in transplantation-eligible patients whose median survival time is expected to be less than 5 years.

PMID 21205761  J Clin Oncol. 2011 Feb 20;29(6):761-70. doi: 10.1200/JC・・・
著者: Raffaele Landolfi, Leonardo Di Gennaro, Tiziano Barbui, Valerio De Stefano, Guido Finazzi, Rosamaria Marfisi, Gianni Tognoni, Roberto Marchioli, European Collaboration on Low-Dose Aspirin in Polycythemia Vera (ECLAP)
雑誌名: Blood. 2007 Mar 15;109(6):2446-52. doi: 10.1182/blood-2006-08-042515. Epub 2006 Nov 14.
Abstract/Text In polycythemia vera, vascular risk assessment is based on age and thrombotic history, while the role of other potential predictors of this risk is still uncertain. Thus, we exploited the large database collected by the observational study of the European Collaboration on Low-Dose Aspirin in Polycythemia Vera (ECLAP) to investigate the association of hematologic variables and cardiovascular risk factors with the thrombotic risk. Among 1638 polycythemic patients followed for 2.7 +/- 1.3 years, there were 205 thromboses. Subjects with hypertension had a mild nonsignificant increase in the risk of arterial thrombosis, while this risk was significantly increased by smoking (hazard ratio [HR], 1.90; 95% confidence interval [CI], 1.15-3.14; P = .012). The time-dependent analysis adjusted for potential confounders showed that patients with a white blood cell count above 15 x 10(9)/L, compared with those with a white blood cell count below 10 x 10(9)/L, had a significant increase in the risk of thrombosis (HR, 1.71; 95% CI, 1.10-2.65; P = .017), mainly deriving from an increased risk of myocardial infarction (HR, 2.84; 95% CI, 1.25-6.46; P = .013). Thus, leukocyte count may help in defining the vascular risk of polycythemic subjects.

PMID 17105814  Blood. 2007 Mar 15;109(6):2446-52. doi: 10.1182/blood-2・・・
著者: Tiziano Barbui, Alessandra Carobbio, Alessandro Rambaldi, Guido Finazzi
雑誌名: Blood. 2009 Jul 23;114(4):759-63. doi: 10.1182/blood-2009-02-206797. Epub 2009 Apr 16.
Abstract/Text Leukocyte (WBC) count has been recently identified as an independent predictor of major thrombosis in both essential thrombocythemia (ET) and polycythemia vera (PV). However, whether leukocytosis should be simply considered a marker for vascular disease or whether elevated WBC levels actually contribute directly to causing such disorders is presently matter of many studies. By adopting epidemiologic criteria for causation, we have examined the characteristics to support this association such as (1) strength, (2) consistency, (3) specificity, (4) temporality, (5) biologic gradient, (6) plausibility, (7) experimental evidence, and (8) analogy. Our conclusion supports the notion that baseline leukocytosis in ET and PV patients adds prognostic significance to existing risk factors and that may be considered causative of vascular events. These developments could induce clinicians to incorporate WBC count into standard clinical practice. However, we need prospective clinical studies with stratification of patients according to their baseline leukocyte counts. Until such evidence is available, the decision on how to manage these patients should continue to follow conventional criteria.

PMID 19372254  Blood. 2009 Jul 23;114(4):759-63. doi: 10.1182/blood-20・・・
著者: F Passamonti, E Rumi, D Pietra, C Elena, E Boveri, L Arcaini, E Roncoroni, C Astori, M Merli, S Boggi, C Pascutto, M Lazzarino, M Cazzola
雑誌名: Leukemia. 2010 Sep;24(9):1574-9. doi: 10.1038/leu.2010.148. Epub 2010 Jul 15.
Abstract/Text We studied the relationship between JAK2 (V617F) mutant allele burden and clinical phenotype, disease progression and survival in patients with polycythemia vera (PV). The percentage of granulocyte mutant alleles was evaluated using a quantitative real-time polymerase chain reaction-based allelic discrimination assay. Of the 338 patients enrolled in this prospective study, 320 (94.7%) carried the JAK2 (V617F) mutation. Direct relationships were found between mutant allele burden and hemoglobin concentration (P=0.001), white blood cell count (P=0.001), spleen size (P=0.001) and age-adjusted bone marrow cellularity (P=0.002), while an inverse relationship was found with platelet count (P<0.001). During the study period, eight patients progressed to post-PV myelofibrosis (MF) (all carrying >50% mutant alleles), while 10 patients developed acute myeloid leukemia (AML). The mutant allele burden was significantly related to the risk of developing myelofibrosis (P=0.029) and retained its significant effect also in multivariable analysis (P=0.03). By contrast, the risk of developing AML as well as that of thrombosis was not significantly related to mutant allele burden. Leukocytosis did not affect thrombosis, MF, leukemia or survival. In conclusion, a JAK2 (V617F) allele burden >50% represents a risk factor for progression to MF in PV.

PMID 20631743  Leukemia. 2010 Sep;24(9):1574-9. doi: 10.1038/leu.2010.・・・
著者: Magnus Björkholm, Asa R Derolf, Malin Hultcrantz, Sigurdur Y Kristinsson, Charlotta Ekstrand, Lynn R Goldin, Björn Andreasson, Gunnar Birgegård, Olle Linder, Claes Malm, Berit Markevärn, Lars Nilsson, Jan Samuelsson, Fredrik Granath, Ola Landgren
雑誌名: J Clin Oncol. 2011 Jun 10;29(17):2410-5. doi: 10.1200/JCO.2011.34.7542. Epub 2011 May 2.
Abstract/Text PURPOSE: Patients with myeloproliferative neoplasms (MPNs), including polycythemia vera, essential thrombocythemia, and primary myelofibrosis, have a propensity to develop acute myeloid leukemia (AML) and myelodysplastic syndromes (MDSs). Using population-based data from Sweden, we assessed the role of MPN treatment and subsequent AML/MDS risk with special focus on the leukemogenic potential of hydroxyurea (HU).
METHODS: On the basis of a nationwide MPN cohort (N = 11,039), we conducted a nested case-control study, including 162 patients (153 and nine with subsequent AML and MDS diagnosis, respectively) and 242 matched controls. We obtained clinical and MPN treatment data for all patients. Using logistic regression, we calculated odds ratios (ORs) as measures of AML/MDS risk.
RESULTS: Forty-one (25%) of 162 patients with MPNs with AML/MDS development were never exposed to alkylating agents, radioactive phosphorous (P(32)), or HU. Compared with patients with who were not exposed to HU, the ORs for 1 to 499 g, 500 to 999 g, more than 1,000 g of HU were 1.5 (95% CI, 0.6 to 2.4), 1.4 (95% CI, 0.6 to 3.4), and 1.3 (95% CI, 0.5 to 3.3), respectively, for AML/MDS development (not significant). Patients with MPNs who received P(32) greater than 1,000 MBq and alkylators greater than 1 g had a 4.6-fold (95% CI, 2.1 to 9.8; P = .002) and 3.4-fold (95% CI, 1.1 to 10.6; P = .015) increased risk of AML/MDS, respectively. Patients receiving two or more cytoreductive treatments had a 2.9-fold (95% CI, 1.4 to 5.9) increased risk of transformation.
CONCLUSION: The risk of AML/MDS development after MPN diagnosis was significantly associated with high exposures of P(32) and alkylators but not with HU treatment. Twenty-five percent of patients with MPNs who developed AML/MDS were not exposed to cytotoxic therapy, supporting a major role for nontreatment-related factors.

PMID 21537037  J Clin Oncol. 2011 Jun 10;29(17):2410-5. doi: 10.1200/J・・・
著者: A M Vannucchi, E Antonioli, P Guglielmelli, G Longo, A Pancrazzi, V Ponziani, C Bogani, P R Ferrini, A Rambaldi, V Guerini, A Bosi, T Barbui, MPD Research Consortium
雑誌名: Leukemia. 2007 Sep;21(9):1952-9. doi: 10.1038/sj.leu.2404854. Epub 2007 Jul 12.
Abstract/Text The aim of this study was to determine whether the burden of JAK2(V617F) allele correlated with major clinical outcomes in patients with polycythemia vera (PV). To this end, we determined JAK2 mutant allele levels in granulocytes of 173 PV patients at diagnosis. The mean (+/-s.d.) mutant allele burden was 52% (+/-29); 32 patients (18%) had greater than 75% mutant allele. The burden of JAK2(V617F) allele correlated with measurements of stimulated erythropoiesis (higher hematocrit, lower mean cell volume, serum ferritin and erythropoietin levels) and myelopoiesis (higher white cell count, neutrophil count and serum lactate dehydrogenase) and with markers of neutrophil activation (elevated leukocyte alkaline phosphatase and PRV-1 expression). As compared to those with less than 25% mutant allele, patients harboring greater than 75% JAK2(V617F) allele were at higher relative risk (RR) of presenting larger spleen (RR 4.7; P<0.001) or suffering from pruritus (RR 3.1; P<0.001). In these patients, the risk of requiring chemotherapy (RR 1.8; P=0.001) or developing major cardiovascular events (RR 7.1; P=0.003) during follow up were significantly increased. We conclude that a burden of JAK2(V617F) allele greater than 75% at diagnosis points to PV patients with high-risk disease.

PMID 17625606  Leukemia. 2007 Sep;21(9):1952-9. doi: 10.1038/sj.leu.24・・・
著者: Ayalew Tefferi, Terra L Lasho, Susan M Schwager, Jacob S Strand, Michelle Elliott, Ruben Mesa, Chin-Yang Li, Martha Wadleigh, Stephanie J Lee, D Gary Gilliland
雑誌名: Cancer. 2006 Feb 1;106(3):631-5. doi: 10.1002/cncr.21645.
Abstract/Text BACKGROUND: Several studies have recently reported on the occurrence of a JAK2(V617F) mutation in myeloid cells from the majority of patients with polycythemia vera (PV). The clinical relevance of this novel observation currently is under study.
METHODS: In a single institutional study, mutation screening for JAK2(V617F) was performed in DNA derived from archived blood granulocytes from 63 consecutive patients with PV in whom current diagnostic criteria were strictly applied and the diagnosis confirmed by bone marrow histology.
RESULTS: The JAK2(V617F) mutant allele was detected in 58 of the 63 patients (92%) with 21% homozygosity. The clinical phenotype of the five patients with the wild-type allele was otherwise typical for the disease. A statistical comparison between JAK2(V617F) heterozygotes (n=45 patients) and homozygotes (n=13 patients) did not reveal any significant associations with regard to age, gender, leukocyte or platelet count at the time of diagnosis, duration of disease, or the incidences of thrombosis or bleeding. However, compared with their heterozygote counterparts, JAK2(V617F) homozygote patients displayed a significantly higher hemoglobin level at the time of diagnosis (P=0.001), an increased incidence of pruritus (69% vs. 38%; P=0.04), a higher rate of fibrotic transformation (23% vs. 2%; P=0.009), and higher PRV-1 transcript levels in their blood granulocytes (P=0.07).
CONCLUSIONS: The results of the current clinical study support previous laboratory observations that link JAK2(V617F) with the PV phenotype by demonstrating a mutant allele dose effect on erythrocytosis and clinical and laboratory features characteristic of PV.

Copyright (c) 2005 American Cancer Society.
PMID 16369984  Cancer. 2006 Feb 1;106(3):631-5. doi: 10.1002/cncr.2164・・・
著者: T C Pearson, G Wetherley-Mein
雑誌名: Lancet. 1978 Dec 9;2(8102):1219-22.
Abstract/Text The relations between the incidence of vascular occlusive episodes and packed-cell volume (P.C.V) and platelet-count in patients with primary proliferative polycythaemia were determined retrospectively in patients treated by venesection with or without chemotherapy. The incidence of occlusive episodes correlated positively with P.C.V. level. The risk of vascular occlusive episodes was increased at moderately increased P.C.V. levels and the optimum P.C.V. level was rather lower than is often assumed. There was no statistically significant association between platelet-count, either alone or in combination with raised P.C.V., and incidence of vascular occlusion, though, episodes of occlusion were 1.5 times more common with platelet-counts above 400 x 10(9)/l. The results of this study indicate that P.C.V. should be maintained at less than 0.45 and the platelet-count at less than 400 x 10(9)/l in primary proliferative polycythaemia.

PMID 82733  Lancet. 1978 Dec 9;2(8102):1219-22.
著者: Marcello Di Nisio, Tiziano Barbui, Leonardo Di Gennaro, Giovanna Borrelli, Guido Finazzi, Raffaele Landolfi, Giuseppe Leone, Rosamaria Marfisi, Ettore Porreca, Marco Ruggeri, Anne W S Rutjes, Gianni Tognoni, Alessandro M Vannucchi, Roberto Marchioli, European Collaboration on Low-dose Aspirin in Polycythemia Vera (ECLAP) Investigators
雑誌名: Br J Haematol. 2007 Jan;136(2):249-59. doi: 10.1111/j.1365-2141.2006.06430.x. Epub 2006 Dec 8.
Abstract/Text Polycythemia vera (PV) is a chronic myeloproliferative disorder whose major morbidity and mortality are thrombohaemorragic events and progression to acute leukaemia or myelofibrosis. Whether the haematocrit and platelet count predict such complications remains unclear. The European Collaboration on Low-dose Aspirin in Polycythemia Vera prospective study included 1638 PV patients. A total of 164 deaths (10%), 145 (8.85%) major thrombosis and 226 (13.8%) total thrombosis were encountered during 4393 person-years follow-up (median 2.8 years). In time-dependent multivariable analysis, a haematocrit in the evaluable range of 40-55% was neither associated with the occurrence of thrombotic events, mortality nor with haematological progression in the studied population. The haematocrit of patients in the highest and lowest deciles at baseline was maintained within a narrow interval of haematocrit values ranging from 40% to 47% throughout follow-up. High platelet count was associated with a lower progression rate to acute leukaemia/myelofibrosis, whereas it had no significant relationship with thrombotic events or mortality. Our findings do not suggest that the range of haematocrit (<55%) and platelet counts (<600 x 10(9)/l) we encountered in our population had an impact on the outcome of PV patients treated by current therapeutic strategies.

PMID 17156406  Br J Haematol. 2007 Jan;136(2):249-59. doi: 10.1111/j.1・・・
著者: Roberto Marchioli, Guido Finazzi, Giorgina Specchia, Rossella Cacciola, Riccardo Cavazzina, Daniela Cilloni, Valerio De Stefano, Elena Elli, Alessandra Iurlo, Roberto Latagliata, Francesca Lunghi, Monia Lunghi, Rosa Maria Marfisi, Pellegrino Musto, Arianna Masciulli, Caterina Musolino, Nicola Cascavilla, Giovanni Quarta, Maria Luigia Randi, Davide Rapezzi, Marco Ruggeri, Elisa Rumi, Anna Rita Scortechini, Simone Santini, Marco Scarano, Sergio Siragusa, Antonio Spadea, Alessia Tieghi, Emanuele Angelucci, Giuseppe Visani, Alessandro Maria Vannucchi, Tiziano Barbui, CYTO-PV Collaborative Group
雑誌名: N Engl J Med. 2013 Jan 3;368(1):22-33. doi: 10.1056/NEJMoa1208500. Epub 2012 Dec 8.
Abstract/Text BACKGROUND: Current treatment recommendations for patients with polycythemia vera call for maintaining a hematocrit of less than 45%, but this therapeutic strategy has not been tested in a randomized clinical trial.
METHODS: We randomly assigned 365 adults with JAK2-positive polycythemia vera who were being treated with phlebotomy, hydroxyurea, or both to receive either more intensive treatment (target hematocrit, <45%) (low-hematocrit group) or less intensive treatment (target hematocrit, 45 to 50%) (high-hematocrit group). The primary composite end point was the time until death from cardiovascular causes or major thrombotic events. The secondary end points were cardiovascular events, cardiovascular hospitalizations, incidence of cancer, progression to myelofibrosis, myelodysplasia or leukemic transformation, and hemorrhage. An intention-to-treat analysis was performed.
RESULTS: After a median follow-up of 31 months, the primary end point was recorded in 5 of 182 patients in the low-hematocrit group (2.7%) and 18 of 183 patients in the high-hematocrit group (9.8%) (hazard ratio in the high-hematocrit group, 3.91; 95% confidence interval [CI], 1.45 to 10.53; P=0.007). The primary end point plus superficial-vein thrombosis occurred in 4.4% of patients in the low-hematocrit group, as compared with 10.9% in the high-hematocrit group (hazard ratio, 2.69; 95% CI, 1.19 to 6.12; P=0.02). Progression to myelofibrosis, myelodysplasia or leukemic transformation, and bleeding were observed in 6, 2, and 2 patients, respectively, in the low-hematocrit group, as compared with 2, 1, and 5 patients, respectively, in the high-hematocrit group. There was no significant between-group difference in the rate of adverse events.
CONCLUSIONS: In patients with polycythemia vera, those with a hematocrit target of less than 45% had a significantly lower rate of cardiovascular death and major thrombosis than did those with a hematocrit target of 45 to 50%. (Funded by the Italian Medicines Agency and others; ClinicalTrials.gov number, NCT01645124, and EudraCT number, 2007-006694-91.).

PMID 23216616  N Engl J Med. 2013 Jan 3;368(1):22-33. doi: 10.1056/NEJ・・・
著者: Raffaele Landolfi, Roberto Marchioli, Jack Kutti, Heinz Gisslinger, Gianni Tognoni, Carlo Patrono, Tiziano Barbui, European Collaboration on Low-Dose Aspirin in Polycythemia Vera Investigators
雑誌名: N Engl J Med. 2004 Jan 8;350(2):114-24. doi: 10.1056/NEJMoa035572.
Abstract/Text BACKGROUND: The use of aspirin for the prevention of thrombotic complications in polycythemia vera is controversial.
METHODS: We enrolled 518 patients with polycythemia vera, no clear indication for aspirin treatment, and no contraindication to such treatment in a double-blind, placebo-controlled, randomized trial to assess the safety and efficacy of prophylaxis with low-dose aspirin (100 mg daily). The two primary end points were the cumulative rate of nonfatal myocardial infarction, nonfatal stroke, or death from cardiovascular causes and the cumulative rate of nonfatal myocardial infarction, nonfatal stroke, pulmonary embolism, major venous thrombosis, or death from cardiovascular causes. The mean duration of follow-up was about three years.
RESULTS: Treatment with aspirin, as compared with placebo, reduced the risk of the combined end point of nonfatal myocardial infarction, nonfatal stroke, or death from cardiovascular causes (relative risk, 0.41; 95 percent confidence interval, 0.15 to 1.15; P=0.09) and the risk of the combined end point of nonfatal myocardial infarction, nonfatal stroke, pulmonary embolism, major venous thrombosis, or death from cardiovascular causes (relative risk, 0.40; 95 percent confidence interval, 0.18 to 0.91; P=0.03). Overall mortality and cardiovascular mortality were not reduced significantly. The incidence of major bleeding episodes was not significantly increased in the aspirin group (relative risk, 1.62; 95 percent confidence interval, 0.27 to 9.71).
CONCLUSIONS: Low-dose aspirin can safely prevent thrombotic complications in patients with polycythemia vera who have no contraindications to such treatment.

Copyright 2004 Massachusetts Medical Society
PMID 14711910  N Engl J Med. 2004 Jan 8;350(2):114-24. doi: 10.1056/NE・・・
著者: Andreas Tiede, Jacob H Rand, Ulrich Budde, Arnold Ganser, Augusto B Federici
雑誌名: Blood. 2011 Jun 23;117(25):6777-85. doi: 10.1182/blood-2010-11-297580. Epub 2011 May 3.
Abstract/Text The acquired von Willebrand syndrome (AVWS) is a bleeding disorder that is frequently unrecognized or is misdiagnosed as von Willebrand disease. AVWS is characterized by structural or functional defects of von Willebrand factor (VWF) that are secondary to autoimmune, lymphoproliferative or myeloproliferative, malignant, cardiovascular, or other disorders. VWF abnormalities in these disorders can result from (1) antibody-mediated clearance or functional interference, (2) adsorption to surfaces of transformed cells or platelets, or (3) increased shear stress and subsequent proteolysis. Diagnosis can be challenging as no single test is usually sufficient to prove or exclude AVWS. Furthermore, there are no evidence-based guidelines for management. Treatments of the underlying medical condition, including chemo/radiotherapy, surgery, or immunosuppressants can result in remission of AVWS, but is not always feasible and successful. Because of the heterogeneous mechanisms of AVWS, more than one therapeutic approach is often required to treat acute bleeds and for prophylaxis during invasive procedures; the treatment options include, but are not limited to, desmopressin, VWF-containing concentrates, intravenous immunoglobulin, plasmapheresis or recombinant factor VIIa. Here, we review the management of AVWS with an overview on the currently available evidence and additional considerations for typical treatment situations.

PMID 21540459  Blood. 2011 Jun 23;117(25):6777-85. doi: 10.1182/blood-・・・
著者: Giovanni Barosi, Gunnar Birgegard, Guido Finazzi, Martin Griesshammer, Claire Harrison, Hans Carl Hasselbalch, Jean-Jacques Kiladjian, Eva Lengfelder, Mary Frances McMullin, Francesco Passamonti, John T Reilly, Alessandro M Vannucchi, Tiziano Barbui
雑誌名: Blood. 2009 May 14;113(20):4829-33. doi: 10.1182/blood-2008-09-176818. Epub 2009 Mar 10.
Abstract/Text European experts were convened to develop a definition of response to treatment in polycythemia vera (PV) and essential thrombocythemia (ET). Clinicohematologic (CH), molecular, and histologic response categories were selected. In ET, CH complete response (CR) was: platelet count less than or equal to 400 x 10(9)/L, no disease-related symptoms, normal spleen size, and white blood cell count less than or equal to 10 x 10(9)/L. Platelet count less than or equal to 600 x 10(9)/L or a decrease greater than 50% was partial response (PR). In PV, CH-CR was: hematocrit less than 45% without phlebotomy, platelet count less than or equal to 400 x 10(9)/L, white blood cell count less than or equal to 10 x 10(9)/L, and no disease-related symptoms. A hematocrit less than 45% without phlebotomy or response in 3 or more of the other criteria was defined as PR. In both ET and in PV, molecular CR was a reduction of any molecular abnormality to undetectable levels. Molecular PR was defined as a reduction more than or equal to 50% in patients with less than 50% mutant allele burden, or a reduction more than or equal to 25% in patients with more than 50% mutant allele burden. Bone marrow histologic response in ET was judged on megakaryocyte hyperplasia while on cellularity and reticulin fibrosis in PV. The combined use of these response definitions should help standardize the design and reporting of clinical studies.

PMID 19278953  Blood. 2009 May 14;113(20):4829-33. doi: 10.1182/blood-・・・
著者: Susan Robinson, Susan Bewley, Beverley J Hunt, Deepti H Radia, Claire N Harrison
雑誌名: Haematologica. 2005 Nov;90(11):1477-83.
Abstract/Text BACKGROUND AND OBJECTIVES: Polycythemia vera (PV) is rare in women of childbearing age with only 20 previous pregnancies reported.
DESIGN AND METHODS: We report a series of 18 pregnancies (19 fetuses) in eight women with PV managed prior to or following implementation of management guidelines tailored to PV in pregnancy, and review the literature.
RESULTS: Seven of these pregnancies were managed by standard antenatal care (group A) without specific attention to the women's PV. All remaining 11 pregnancies (group B) were managed following a formal protocol and received tailored management principally comprising tight control of the hematocrit by venesection, and the use of interferon ? in three patients, in addition to aspirin 75 mg, and prophylactic low molecular weight heparin (LMWH). Each pregnancy was monitored with uterine artery Doppler examinations and regular fetal scanning. In group A (n=7) there was one live birth, which required delivery at 34 weeks due to placental insufficiency, three first trimester miscarriages, two stillbirths and one combined stillbirth and neonatal death (twins) associated with placental dysfunction. All 11 patients in group B received aspirin and post-partum LMWH; four also received venesection (during pregnancy), three interferon-a and three antenatal LMWH. There were ten live births, nine at term, one first trimester miscarriage and no intrauterine growth retardation.
INTERPRETATION AND CONCLUSIONS: Pregnancy in PV without meticulous attention to hematocrit is associated with poor fetal outcome. Aggressive intervention with control of hematocrit, aspirin and some LMWH appears to be associated with significantly better outcome (p=0.0017).

PMID 16266894  Haematologica. 2005 Nov;90(11):1477-83.
著者: Alessandro M Vannucchi, Jean Jacques Kiladjian, Martin Griesshammer, Tamas Masszi, Simon Durrant, Francesco Passamonti, Claire N Harrison, Fabrizio Pane, Pierre Zachee, Ruben Mesa, Shui He, Mark M Jones, William Garrett, Jingjin Li, Ulrich Pirron, Dany Habr, Srdan Verstovsek
雑誌名: N Engl J Med. 2015 Jan 29;372(5):426-35. doi: 10.1056/NEJMoa1409002.
Abstract/Text BACKGROUND: Ruxolitinib, a Janus kinase (JAK) 1 and 2 inhibitor, was shown to have a clinical benefit in patients with polycythemia vera in a phase 2 study. We conducted a phase 3 open-label study to evaluate the efficacy and safety of ruxolitinib versus standard therapy in patients with polycythemia vera who had an inadequate response to or had unacceptable side effects from hydroxyurea.
METHODS: We randomly assigned phlebotomy-dependent patients with splenomegaly, in a 1:1 ratio, to receive ruxolitinib (110 patients) or standard therapy (112 patients). The primary end point was both hematocrit control through week 32 and at least a 35% reduction in spleen volume at week 32, as assessed by means of imaging.
RESULTS: The primary end point was achieved in 21% of the patients in the ruxolitinib group versus 1% of those in the standard-therapy group (P<0.001). Hematocrit control was achieved in 60% of patients receiving ruxolitinib and 20% of those receiving standard therapy; 38% and 1% of patients in the two groups, respectively, had at least a 35% reduction in spleen volume. A complete hematologic remission was achieved in 24% of patients in the ruxolitinib group and 9% of those in the standard-therapy group (P=0.003); 49% versus 5% had at least a 50% reduction in the total symptom score at week 32. In the ruxolitinib group, grade 3 or 4 anemia occurred in 2% of patients, and grade 3 or 4 thrombocytopenia occurred in 5%; the corresponding percentages in the standard-therapy group were 0% and 4%. Herpes zoster infection was reported in 6% of patients in the ruxolitinib group and 0% of those in the standard-therapy group (grade 1 or 2 in all cases). Thromboembolic events occurred in one patient receiving ruxolitinib and in six patients receiving standard therapy.
CONCLUSIONS: In patients who had an inadequate response to or had unacceptable side effects from hydroxyurea, ruxolitinib was superior to standard therapy in controlling the hematocrit, reducing the spleen volume, and improving symptoms associated with polycythemia vera. (Funded by Incyte and others; RESPONSE ClinicalTrials.gov number, NCT01243944.).

PMID 25629741  N Engl J Med. 2015 Jan 29;372(5):426-35. doi: 10.1056/N・・・
著者: Jean-Jacques Kiladjian, Pierre Zachee, Masayuki Hino, Fabrizio Pane, Tamas Masszi, Claire N Harrison, Ruben Mesa, Carole B Miller, Francesco Passamonti, Simon Durrant, Martin Griesshammer, Keita Kirito, Carlos Besses, Beatriz Moiraghi, Elisa Rumi, Vittorio Rosti, Igor Wolfgang Blau, Nathalie Francillard, Tuochuan Dong, Monika Wroclawska, Alessandro M Vannucchi, Srdan Verstovsek
雑誌名: Lancet Haematol. 2020 Jan 23;. doi: 10.1016/S2352-3026(19)30207-8. Epub 2020 Jan 23.
Abstract/Text BACKGROUND: Polycythaemia vera is a myeloproliferative neoplasm characterised by excessive proliferation of erythroid, myeloid, and megakaryocytic components in the bone marrow due to mutations in the Janus kinase 2 (JAK2) gene. Ruxolitinib, a JAK 1 and JAK 2 inhibitor, showed superiority over best available therapy in a phase 2 study in patients with polycythaemia vera who were resistant to or intolerant of hydroxyurea. We aimed to compare the long-term safety and efficacy of ruxolitinib with best available therapy in patients with polycythaemia vera who were resistant to or intolerant of hydroxyurea.
METHODS: We report the 5-year results for a randomised, open-label, phase 3 study (RESPONSE) that enrolled patients at 109 sites across North America, South America, Europe, and the Asia-Pacific region. Patients (18 years or older) with polycythaemia vera who were resistant to or intolerant of hydroxyurea were randomly assigned 1:1 to receive either ruxolitinib or best available therapy. Patients randomly assigned to the ruxolitinib group received the drug orally at a starting dose of 10 mg twice a day. Single-agent best available therapy comprised hydroxyurea, interferon or pegylated interferon, pipobroman, anagrelide, approved immunomodulators, or observation without pharmacological treatment. The primary endpoint, composite response (patients who achieved both haematocrit control without phlebotomy and 35% or more reduction from baseline in spleen volume) at 32 weeeks was previously reported. Patients receiving best available therapy could cross over to ruxolitinib after week 32. We assessed the durability of primary composite response, complete haematological remission, overall clinicohaematological response, overall survival, patient-reported outcomes, and safety after 5-years of follow-up. This study is registered with ClinicalTrials.gov, NCT01243944.
FINDINGS: We enrolled patients between Oct 27, 2010, and Feb 13, 2013, and the study concluded on Feb 9, 2018. Of 342 individuals screened for eligibility, 222 patients were randomly assigned to receive ruxolitinib (n=110, 50%) or best available therapy (n=112, 50%). The median time since polycythaemia vera diagnosis was 8·2 years (IQR 3·9-12·3) in the ruxolitinib group and 9·3 years (4·9-13·8) in the best available therapy group. 98 (88%) of 112 patients initially randomly assigned to best available therapy crossed over to receive ruxolitinib and no patient remained on best available therapy after 80 weeks of study. Among 25 primary responders in the ruxolitinib group, six had progressed at the time of final analysis. At 5 years, the probability of maintaining primary composite response was 74% (95% CI 51-88). The probability of maintaining complete haematological remission was 55% (95% CI 32-73) and the probability of maintaining overall clinicohaematological responses was 67% (54-77). In the intention-to-treat analysis not accounting for crossover, the probability of survival at 5 years was 91·9% (84·4-95·9) with ruxolitinib therapy and 91·0% (82·8-95·4) with best available therapy. Anaemia was the most common adverse event in patients receiving ruxolitinib (rates per 100 patient-years of exposure were 8·9 for ruxolitinib and 8·8 for the crossover population), though most anaemia events were mild to moderate in severity (grade 1 or 2 anaemia rates per 100 patient-years of exposure were 8·0 for ruxolitinib and 8·2 for the crossover population). Non-haematological adverse events were generally lower with long-term ruxolitinib treatment than with best available therapy. Thromboembolic events were lower in the ruxolitinib group than the best available therapy group. There were two on-treatment deaths in the ruxolitinib group. One of these deaths was due to gastric adenocarcinoma, which was assessed by the investigator as related to ruxolitinib treatment.
INTERPRETATION: We showed that ruxolitinib is a safe and effective long-term treatment option for patients with polycythaemia vera who are resistant to or intolerant of hydroxyurea. Taken together, ruxolitinib treatment offers the first widely approved therapeutic alternative for this post-hydroxyurea patient population.
FUNDING: Novartis Pharmaceuticals Corporation.

Copyright © 2020 Elsevier Ltd. All rights reserved.
PMID 31982039  Lancet Haematol. 2020 Jan 23;. doi: 10.1016/S2352-3026(・・・
著者: Annkristin Heine, Peter Brossart, Dominik Wolf
雑誌名: Blood. 2013 Nov 28;122(23):3843-4. doi: 10.1182/blood-2013-10-531103.
Abstract/Text
PMID 24288410  Blood. 2013 Nov 28;122(23):3843-4. doi: 10.1182/blood-2・・・
著者: G Caocci, F Murgia, L Podda, A Solinas, S Atzeni, G La Nasa
雑誌名: Leukemia. 2014 Jan;28(1):225-7. doi: 10.1038/leu.2013.235. Epub 2013 Aug 9.
Abstract/Text
PMID 23929216  Leukemia. 2014 Jan;28(1):225-7. doi: 10.1038/leu.2013.2・・・
著者: Nicholas G Wysham, Donald R Sullivan, Gopal Allada
雑誌名: Chest. 2013 May;143(5):1478-9. doi: 10.1378/chest.12-1604.
Abstract/Text We report a case of Cryptococcus neoformans pneumonia in a patient taking ruxolitinib, a janus kinase 1,2 inhibitor approved for the treatment of myelofibrosis. We hypothesize that ruxolitinib contributed to this infection through its effects on cell-mediated immunity. Clinicians should be aware of the potential for intracellular or opportunistic infections associated with this novel drug class.

PMID 23648912  Chest. 2013 May;143(5):1478-9. doi: 10.1378/chest.12-16・・・

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