Diagnose und Therapie der Polycythaemia vera in der Ära von JAK2

Zusammenfassung

Das Review behandelt relevante Gesichtspunkte zur Pathogenese und Diagnostik der Polycythaemia vera (PV), die seit der Entdeckung der JAK2V617-Mutation im Jahre 2005 zunehmend in den Vordergrund gerückt sind. Die aktuellen Therapiemöglichkeiten der PV werden diskutiert und praktische Empfehlungen zur Behandlung dieser Erkrankung gegeben.

Mit der JAK2V617-Mutation, einer Punktmutation im Janus-Kinase 2-Gen (JAK2), liegt ein spezifischer diagnostischer Marker vor, der die klonale myeloproliferative Neoplasie (MPN) beweist. Die intensive Beforschung der molekularen Grundlagen der MPN hat die wichtige Rolle der Mutation bestätigt, hat aber auch gezeigt, dass die Pathogenese komplex ist und dass weitere Schritte zur Entstehung einer MPN beitragen.

Im Jahre 2008 wurde die Mutation JAK2V617F als eines von zwei Hauptkriterien der PV in die neu abgefassten Diagnosekriterien aufgenommen. Dadurch konnte die Diagnosesicherung insbesondere von frühen Formen und die Abgrenzung gegenüber reaktiver Polyglobulie verbessert werden.

Primäre Therapieziele bei der PV sind die Reduktion bzw. Prophylaxe von Thromboembolien und die Minimierung des Risikos von Myelofibrose und akuter Leukämie. Patienten mit niedrigem Thromboserisiko sollten primär mit Aderlässen und niedrig dosierter Acetylsalicylsäure behandelt werden. Bei Patienten mit hohem Risiko wird die Einleitung einer zytoreduktiven Therapie mit Hydroxyurea bzw. Interferon alpha empfohlen. JAK-Inhibitoren werden derzeit in klinischen Studien geprüft.

Abstract

This review gives an overview on relevant topics of pathogenesis and diagnosis of polycythemia vera (PV). The presently available treatment options in PV are discussed and recommendations for the clinical management are given.

The JAK2V617F mutation, a point mutation in the tyrosine kinase gene JAK2 (Janus Kinase 2), has emerged as a central feature in the pathogenesis of the myeloproliferative neoplasms (MPN). Subsequently, the identification of several other mutated genes in MPN has shown that the pathogenesis is complex and that the JAK2V617F mutation is a critical, but not the only step leading to the uncontrolled proliferation in MPN including PV.

The diagnostic criteria of PV have been revised in 2008 and include the JAK2V617F mutation as one of the two major criteria of the disease. This molecular diagnostic marker proves the clonality and facilitates the diagnosis of early and uncertain cases which remained sometimes undiagnosed in the past.

Main treatment aims are the reduction of thromboembolic events and the minimization of the risk of myelofibrosis and of acute leukemia. PV patients with low risk of vascular complications should be treated with phlebotomy and low dose acetylsalicylic acid. High risk patients should receive cytoreductive therapy with hydroxyurea or interferon alpha. Studies with JAK inhibitors are presently ongoing.

Schlüsselwörter

Polycythaemia vera - JAK2V617F-Mutation

Keywords

Polycythemia vera - JAK2V617F mutation

• Literatur

• 1 Anagrelide study group. Anagrelide, a therapy for thrombocythemic states: Experience in 577 patients. Am J Med 1992; 92: 69-76
• 2 Barbui T, Barosi G, Birgegard G et al. Philadelphia-negative classical myeloproliferative neoplasms: critical concepts and management recommendations from European LeukemiaNet. J Clin Oncol 2011; 29: 761-770
• 3 Barosi G, Birgegard G, Finazzi G et al. Response criteria for essential thrombocythemia and polycythemia vera: result of a European LeukemiaNet consensus conference. Blood 2009; 113: 4829-4833
• 4 Barosi G, Birgegard G, Finazzi G et al. A unified definition of clinical resistance and intolerance to hydroxycarbamide in polycythaemia vera and primary myelofibrosis: results of a European LeukemiaNet (ELN) consensus process. Br J Haematol 2010; 148: 961-963
• 5 Berk PD, Goldberg JD, Silverstein MN et al. Increased incidence of acute leukemia in polycythemia vera associated with chlorambucil therapy. N Engl J Med 1981; 304: 441-447
• 6 Björkholm M, Derolf AR, Hultcrantz M et al. Treatment-related risk factors for transformation to acute myeloid leukemia and myelodysplastic syndromes in myeloproliferative neoplasms. J Clin Oncol 2011; 29: 2410-2415
• 7 Campbell PJ, Green AR. The myeloproliferative disorders. N Engl J Med 2006; 355: 2452-2466
• 8 Cross N. Genetic and epigenetic complexity in myeloproliferative disorders. American Society of Hematology. Education Book 2011; 208-214
• 9 De Stefano V, Fiorini A, Rossi E et al. Incidence of the JAK2 V617F mutation among patients with splanchnic or cerebral venous thrombosis and without overt chronic myeloproliferative disorders. J Thromb Haemost 2007; 5: 708-714
• 10 Dentali F, Squizzato A, Brivio L. JAK2V617F mutation for the early diagnosis of Ph- myeloproliferative neoplasms in patients with venous thromboembolism: a meta-analysis. Blood 2009; 113: 5617-5623
• 11 Fruchtman SM, Mack K, Kaplan ME et al. From efficacy to safety: A polycythemia vera study group report on hydroxyurea in patients with polycythemia vera. Semin Hematol 1997; 34: 17-23
• 12 Gruppo Italiano Studio Polycythemia vera. The natural history of 1213 patients followed for 20 years. Ann Intern Med 1995; 123: 656-664
• 13 Haanen C, Mathe G, Hayat M. Treatment of polycythemia vera by radiophosphorus or busulfan: a randomized trial. Br J Cancer 1981; 44: 75-80
• 14 James C, Ugo V, Couédic J et al. A unique clonal JAK2 mutation leading to constitutive signaling causes polycythaemia vera. Nature 2005; 434: 1144-1148
• 15 Jones A, Kreil S, Zoi K et al. Widespread occurrence of the JAK2V617F mutation in chronic myeloproliferative disorders. Blood 2005; 106: 2162-2168
• 16 Jones AV, Chase A, Silver RT et al. JAK2 haplotype is a major risk factor for the development of myeloproliferative neoplasms. Nat Genet 2009; 41: 446-449
• 17 Kiladjian JJ, Cervantes F, Leebeek FW et al. The impact of JAK2 and MPL mutations on diagnosis and prognosis of splanchnic vein thrombosis: a report on 241 cases. Blood 2008; 111: 4922-4929
• 18 Kiladjian JJ, Cassinat B, Chevret S et al. Pegylated interferon-alfa-2a induces complete hematologic and molecular responses with low toxicity in polycythemia vera. Blood 2008; 112: 3065-3072
• 19 Landolfi R, Marchioli R, Kutti J et al. Efficacy and safety of low-dose aspirin in polycythemia vera. N Engl J Med 2004; 350: 114-124
• 20 Lengfelder E, Berger U, Hehlmann R. Interferon alpha in the treatment of polycythemia vera. Ann Hematol 2000; 79: 103-109
• 21 Lengfelder E, Petrides PE, Grießhammer M. Polycythaemia vera. Empfehlungen der Fachgesellschaft zur Diagnostik und Therapie hämatologischer und onkologischer Erkrankungen. www.dgho-onkopedia.de
• 22 Marchioli R, Finazzi G, Landolfi R et al. Vascular and neoplastic risk in a large cohort of patients with polycythemia vera. J Clin Oncol 2005; 23: 2224-2232
• 23 Najean Y, Dresch C, Rain JD. The very-long-term course of polycythemia: a complement to the previously published data of the polycythemia vera study group. Br J Haematol 1993; 86: 233-235
• 24 Najean Y, Rain JD. for the French Polycythemia Study Group. Treatment of polycythemia vera: Use of ³²P alone or in combination with maintenance therapy using hydroxyurea in 461 patients greater than 65 years of age. Blood 1997; 89: 2319-2327
• 25 Ricksten A, Palmqvist L, Johansson P et al. Rapid decline of JAK2V617F levels during hydroxyurea treatment in patients with polycythemia vera and essential thrombocythemia. Haematologica 2008; 93: 1260-1261
• 26 Scott L, Tong W, Levine R et al. Jak2 exon12 mutations in polycythemia vera and idiopathic myelofibrosis. N Engl J Med 2007; 356: 459-468
• 27 Silver RT, Bourla MH, Vandris K et al. Treatment of polycythemia vera with imatinib mesylate. Leuk Res 2012; 36: 156-162
• 28 Tefferi A. JAK inhibitors for myeloproliferative neoplasms: clarifying facts from myths. Blood 2012; 119: 2721-2730
• 29 Vannucchi A, Antonioli E, Guglielmelli P et al. Clinical profile of homozygous JAK2V617V>F mutation in patients with polycythemia vera or essential thrombocythemia. Blood 2007; 110: 840-846
• 30 Vannucchi AM, Antonioli E, Guglielmelli P et al. Clinical correlates of JAK2V617F presence or allele burden in myeloproliferative neoplasms: a critical reappraisal. Leukemia 2008; 22: 1299-1307
• 31 Verstovsek S, Francesco Passamonti F, Rambaldi A et al. Durable responses with the JAK1/JAK2 inhibitor, INCB018424, in patients with polycythemia vera and essential thrombocythemia refractory or intolerant to hydroxyurea. Blood (ASH Annual Meeting Abstracts) 11/2010; 116: 313
• 32 World Health Organization. WHO classification of tumours of haemopoietic and lymphoid tissues. WHO Press; 2008: 40-43
• 33 Marchioli R, Finazzi G, Specchia G et al. Cardiovascular events and intensity of treatment in polycythemia vera. N Engl J Med 2013; 368: 22-33