Chronisch

myeloproliferative

Erkrankungen

Dr. Sormann Siegfried

Polycythemia rubra vera

Die Ursache der PRV liegt in einer vermehrten Proliferation aller hämatopoetischen Zellreihen. In nahezu 100% verursacht durch die JAK2-Mutationen V617F zu 96% oder Exon 12 in 4% der Fälle.

JAK2(V617F)homozygous subclones are found both in ET and PV patients, the expansion of a dominant homozygous subclone occurs almost exclusively in PV.
Das verursacht auch die Transformation einer JAK2 positiven ETH in einer PRV.

pruritus after bathing, erythromelalgia, gout, arterial or venous thromboses, hemorrhage, and early satiety due to the presence of splenomegaly

Definition

Erythrocytosis is a major diagnostic criterion for PV

Vorgangsweise

  • Anamnese mit Erfassung der cardivaskulären Risikofaktoren - Thrombose
  • CRP - Eisenstatus im Labor
  • sek vWJ Syndrom bei hoher Thrombozytenzahl
  • Oberbauchsono - Milzgröße - PMF - Jamshidi
  • bcr-abl Kombinationen kommen vor
  • Treibermutationen - JAK2,wenn negativ: Calreticulin,MPL
  • Risikoscore
  • Knochenmarkpunktion bei jungen Patienten, fortgeschrittener Erkrankung,Splenomegalie (PMF), NGS zur Erfassung modifizierender Mutationen


Pathophysiologie


JAK2 Mutation

JAK2 ist an der Signaltransduktion von homodimerischen Rezeptoren beteiligt, und Bestandteil von Rezeptoren unterschiedlicher Spezifität.

JAK2V617F activates signaling through the 3 main homodimeric receptors EPOR,MPL, and G-CSFR, which are involved in erythrocytosis, thrombocytosis, and neutrophilia.

the association of JAKs with receptors is important for their proper trafficking to the cell surface.
Heteromeric receptors use JAK1 and JAK2/tyrosine kinase 2 (TYK2) or JAK3

The activated JAKs will phosphorylate the receptors, which are subsequently used as a docking site for other signaling molecules,more particularly the STATs

JAK2V617F induces constitutive activation of STATs, and of the phosphatidy-linositol 3-kinase (PI3K) and MAPK pathways. This cytokine hypersensitivity or independence induced by JAK2V617F in cell lines

Übersicht der Risiken


Score

Alter >70 1 Punkt 84% OAS 0 Punkt
Thrombose 1 Punkt 59% OAS 1 Punkt
Leuko >13000 1 Punkt 26% OAS 2,3 Punkte

Score 2

Alter >67 5 Punkt low risk 0 Punkt
Alter 57-67 2 Punkt
Thrombose 1 Punkt intermediate risk 1,2 Punkte
Leuko >15000 1 Punkt high risk 3 Punkte


OAS

OAS Todesursachen
93% 5 Jahre 29% Thrombose
72% 10 Jahre 23% AML,MDS,NHL
46% 20 Jahre 16% solide Tumore
   7% Blutungen
  3% post-PV Myelofiborse


Therapie

Ziele:

  • OAS
  • Symptome
  • Vorbeugung Thrombose
  • Vorbeugung Blutung

Hämatokrit

CYTO-PV trial
As a result of the above studies, we and various authors have suggested that the hematocrit be maintained at less than 45 percent , or at less than 45 percent in men and less than 42 percent in women.

Ziel:  Hkt < 45% Männer;  <42% Frauen; Thrombo < 400 000

Vorgangsweise

low risk - Phlebotomie + Aspirin

high risk - Phlebotomie + zytoreduktive Therapie + Aspirin


Phlebotomie

A standard one unit phlebotomy (500 mL) should reduce the hematocrit by 3 percentage points in a normal-sized adult (eg, from 46 to 43 percent).
Optimal control is to keep the hematocrit continuously below 45 percent in men and 42 percent in women
Since phlebotomy is effective in controlling PV by producing a state of relative or absolute iron deficiency, iron supplementation should not be given


Aspirin

If not otherwise contraindicated because of a history of major bleeding or intolerance, we suggest that aspirin be given to all patients (Grade 2C). The appropriate dose is 75 to 100 mg/day. Treatment with higher doses should be avoided
A 2013 Cochrane analysis of these two reports [87,90], covering 630 PV patients, concluded that the use of low-dose aspirin (compared with placebo) was associated with a non-significant lower risk of fatal thrombotic events (OR 0.20; 95% CI 0.03-1.14), a non-significant benefit for all-cause mortality (OR 0.46; 95% CI 0.21-1.01), a non-significant increase in minor bleeding (OR 1.85; 95% CI 0.90-3.79), and no significant increase in the risk of major bleeding


Hydroxyurea

primäre Therapie bei älteren Patienten - zytoreduktiv - auch CHR; gute Kontrolle, keine Wirkung auf mutierte HSC; erhöhtes Leukämierisiko nicht sicher; Erstlinie
weiter...

Pegasys

genetisches Ansprechen, Stammzellwirkung,JAK2-VAF Reduktion; LPS; grippale NW; Erstlinie
weiter...

Besemri

genetisches Ansprechen, Stammzellwirkung,JAK2-VAF Reduktion; LPS; grippale NW; pegINF Gabe alle 14 Tage; Erstlinie
weiter...

Jakavi

häufig komplette Remission; JAK2verminderung; Infektneigung; Absetzreaktion; Zweitlinie
weiter...

Thromboreductin

weiter...

Responsekriterien ELN

Leukämie-Risiko der Therapien

Literatur: