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Myeloproliferative Neoplasien
Jakob R PasswegChefarzt Klinik Hämatologie
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Chronische Myeloische Erkrankungen
• Myeloproliferative Neoplasien (MPN)– Polycythämie vera (PV)– Essentielle Thrombozytose
(ET)– Osteo-Myelofibrose (OMF)– Chronische Myeloische
Leukämie (CML)
• MyelodysplastischeSyndrome (MDS)– Refraktäre Anämie (RA)– Refraktäre Cytopenie mit
Multiliniendysplasie (RCMD)– RA mit Ringsideroblasten
(RAS)– Refraktäre Anämie mit
Blastenexzess (RAEB)
• Myeloproliferative /dysplastische OverlapSyndrome• CMMoL (chronische myelomonozytäre
Leukämie)• Nicht klassifizierbare
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Was so dazugehört• Klonale Knochenmarkserkankung• Gestörte Regulation des Wachstums• Ein Zuviel an Proliferation• Transformation von PV und ET in OMF• Transformation in AML (akute myeloische
Leukämie)• 60-70 Jahre m>f• Thrombophilie
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ET PV OMF
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Raynaud SyErythromelalgieAkrale Zyanose, NekroseAtypische Thromboembolische KomplikationenBudd Chiari SyndromPfortaderthrombose
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Myeloproliferative NeoplasienEine Stammzellerkrankung
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Overlaps in clinical presentation and evolution.
Kiladjian J Hematology 2012;2012:561-566
©2012 by American Society of Hematology
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Symptome Myelofibrosefrühe zellreiche Phase, späte Zytopenie
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A Gain-of-Function Mutation of JAK2 in Myeloproliferative Disorders
Robert Kralovics, Ph.D., Francesco Passamonti, M.D., Andreas S. Buser, M.D., Soon-Siong Teo, B.S., Ralph Tiedt, Ph.D., Jakob R. Passweg, M.D., Andre Tichelli, M.D., Mario Cazzola, M.D. and Radek C. Skoda, M.D.
N Engl J MedVolume 352;17:1779-1790 April 28, 2005
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JAK2 Mutation
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Diagnose
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Diagnoseheterogene Präsentation
ETThrombozytose
>450G/L
DD: reaktive Thrombozytose
PVPolyglobulie,
Hämatokrit
Relative / absolute Polyglobulie
OMFFibrose im
Knochenmark
Abgrenzung andere MPN
Zellreiche / zellarmePhasen
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Polyglobulie
Hkt: 43% Hkt: 53% Hkt: 53%
Blutplasma
Erythrozyten-masse
Blutvolumen
relative Polyglobulie
echtePolyglobulie
Wert Werte Referenz EinheitPlasmavolumen 39,2 40 ml/kg KG
Erythrozytenvolumen 27,4 21,5 ml/kg KGBlutvolmen 66,6 61,9 ml/kg KG
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Erythropoetin bei der PV
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Erythropoietinspiegel
Polyzythämia VeraEPO Spiegel < 7.0 U/I
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BlutbildAnisozytose der Tc: ETPolyglobulie: PVTränenfromen: FibroseLeurkorythroblastäres Blutbild: OMF
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Knochenmark Zytologie Histologie
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BildgebungMilzgrösse, andere Organomegalien
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Diagnostische Kriterien
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Therapie
• Ziele der Therapie– Symptome lindern– Transformation in Leukämie verzögern– Thromboembolische Komplikationen verhindern– Hämorrhagische Komplikationen verhindern– Leben verlängern– Blutwerte korrigieren
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Intermediäres Risiko
< 60 Jahre undkeine Vorgeschichte von Thromboembolien
Kardiovaskuläre RisikofaktorenThrombozytenzahl > 1’500 x109/l
Zusätzliche Thrombophilie Risikofaktoren
Hohes Risiko
Alter > 60 Jahreoder
Thromboembolien in der Vorgeschichte
Niedriges Risiko
< 60 JahreKeine Vorgeschichte ThromboembolienKeine kardiovaskuläre Risikofaktoren
Thrombozytenzahl < 1’500 x109/lKeine zusätzlichen Thrombophilie Risikofaktoren
ETWann Zyto-
redutkiveTherapie?
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Bergamo StudieHydroxyurea (Litalir) vermindert das thromboembolie Risiko in Patienten mit hi risk ET
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Art ThrombosenVenöse Thrombosen 55/405 HUBlutung 36/404 AgVakulärer Tod p=0.03
}
ET: Behandlung von Thrombozytose & thromboembolischen KomplikationenThrombozytose: Hydroxyurea = Anagrelidthromboembol Komplikationen: Hydroxyurea besser
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Prognose von jungen good riskET Patienten
• Survival ofyoung patientswith ET compared tohealthy control
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Marchioli R et al. N Engl J Med 2013;368:22-33
45 the numberStudie:
Hämatokrit strikt unter 45%mit Aderlass +- Hydroxureaversus nicht.
Endpoint: Cadiovascular death or major thrombotic event
PV Therapie: Aderlass / Zytoreduktion
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AlleleBurden
Molekulare Response
mit Interferon
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• DIPSS– Age > 65– Hb <100 g/L– Lc > 25 g/L– Blasts > 1%– Constitutional Sy
• DIPSS plus– Karyotype– Plt < 100– Transfusions
Prognostische Einteilung der OMF
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JAK2 Inhibitor: Symptomkontrolle, wenig Einfluss auf Allele burden
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Overall Survival.
Verstovsek S et al. N Engl J Med 2012;366:799-807
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Allogene Stammzell-transplantation als kurative Option
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Zusammenfassung
Chronische Myeloproliferative Erkrankungen-ET / PV / OMFHeterogener VerlaufThromboembolische KomplikationenTransformation in LeukämieRisikokategorie adaptierte Behandlung
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Discussion slidesnicht ins Buch übernehmen
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relative /absolute Polyglobulie
ml/kg
50%
50%
40%
60%
normal relativ
50%
50%
absolut absolut und relativ
40%
60% EV
PV
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ErythrozytenmasseWert Werte Referenz EinheitPlasmavolumen 39,2 40 ml/kg KG
Erythrozytenvolumen 27,4 21,5 ml/kg KGBlutvolmen 66,6 61,9 ml/kg KG
125I-Albumin
125I-AlbuminAktivität/ml
51Cr-RBCAktivität/ml
Blutentnahme:Verdünnungseffekt von
125I-Albumin und51Cr-RBC
Aktivität/ml
51Cr-RBC
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Wert Werte Referenz EinheitHämatokrit 49 36 - 46 %
Hämoglobin 172 120 - 160 g/lRBC 4.5 4.0 - 5.2 x 1012/l
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Entwicklung von JAK2 Inhibitoren
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Changes in Spleen Volume and Spleen Length, According to Treatment Group.
Harrison C et al. N Engl J Med 2012;366:787-798
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