DEFINITION

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DEFINITION
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Myeloproliferative disorders

• Clonal hematopoiesis (stem cell disorder)
• Marrow hypercellularity
• Overproduction of one or more cell lines
  (effective hematopoiesis)
• Exception myelofibrosis
• Differentiation nearly normal

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CLASSIFICATION
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The common bcr-abl negative myeloproliferative
disorders

• Polycythemia vera
• Essential thrombocythemia
• Myelofibrosis/myeloid metaplasia

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Less common conditions

• Undifferentiated myeloproliferative disorder
• Mast cell disease
• Hypereosinophilic syndrome
• Chronic neutrophilic leukemia
• Myelodysplastic/myeloproliferative disorders
• CMML
• Atypical CML (BCR-ABL negative)
• Juvenile CML
• Unclassifiable MDS/MPD

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Molecular biology
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JAK-2

• Tyrosine kinase involved in signaling pathways
  initiated by EPO, TPO, G-CSF and other growth
  factors
• V617F mutations in most cases of PV, ET, MF
• Other JAK-2 mutations (exon 12, etc) in a
  minority of PV cases (almost all cases of PV have
  a JAK-2 mutation of some type)
• Some cases of ET, MF lack JAK-2 mutation
• Mutation increases sensitivity of precursors to
  EPO, other growth factors
• Homozygosity for mutation seen mainly in P vera,
  associated with disease progression
• Specific inhibitors of the kinase now in clinical
  trials

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In Panel A, in the absence of ligand, the
erythropoietin receptor (EPOR) binds JAK2 as an
inactive dimer. In cells with wild-type JAK2
protein, the binding of erythropoietin (Epo) to
its receptor induces conformational changes in
the receptor, resulting in phosphorylation (P) of
JAK2 and the cytoplasmic tail of the receptor.
This leads to signaling through pathways made up
of Janus kinases and signal transducers and
activators of transcription (JAKSTAT),
phosphatidylinositol 3 kinase (PI3K), and RAS and
mitogen-activated protein kinase (RASMAPK). In
cells with the V617F mutation, the signaling is
constitutively increased, even in the absence of
erythropoietin. In Panel B, the JAK2 protein
binds to multiple cytokine receptors EPOR,
thrombopoietin receptor (MPL), granulocyte
colony-stimulating factor receptor (G-CSFR), and
probably others that are important for
hematopoietic stem-cell biology and
differentiation. Therefore, the JAK2 protein with
the V617F mutation exerts its effects at various
stages of differentiation and in various
lineages. In Panel C, the development of
homozygosity for the V617F mutation is a two-step
process, with the initial point mutation followed
by mitotic recombination of chromosome 9p between
the JAK2 locus and the centromere. This results
in the loss of heterozygosity but a diploid DNA
copy number. NEJM 2006 3552452
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NEJM 2006 3552452
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Polycythemia vera

• Elevated RBC mass, typically high platelets and
  WBC
• Some patients present with thrombocytosis and
  develop erythrocytosis subsequently
• Hypercellular marrow with variable degree of
  reticulin fibrosis
• Morphology fairly normal, some clustering and
  dysmorphism of megas
• Splenomegaly in 70, constitutional sx, increased
  risk of arterial venous thrombosis (esp portal
  vein), microvascular disease (erythromelalgia,
  pruritus, headache, etc), hypermetabolic sx gout

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Differential diagnosis of erythrocytosis

• HP
• COPD or other possible causes of hypoxemia?
• Smoker?
• Splenomegaly, pruritus, erythromelalgia?
• Concomitant thrombocytosis and/or leukocytosis?
• Serum EPO
• JAK-2 mutation testing

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Diagnostic algorithm for polycythemia vera
Mayo Clin Proc 200580947
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POLYCYTHEMIA VERANatural History

• Life expectancy decreased
• 3 deaths/100 pts/yr
• Cardiovascular mortality increased 1.4x
• Incidence of major thrombosis 3/100pts/yr
• Risk of death from leukemia increased 36-fold
• Progressive myelofibrosis

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NEJM 2004 35099
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NEJM 2004 35099
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Oxygen delivery vs Hematocrit
J Clin Invest 1963421150
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VASO-OCCUSION IN POLYCYTHEMIA VERA
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Hematology 2005201
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Aspirin vs placebo in P vera
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Essential thrombocytosis

• Thrombocytosis (typically gt 600K) with variable
  leukocytosis, normal RBC count
• About 50 have JAK2 mutation
• Normal to mildly hypercellular marrow with marked
  increase in megakaryocytes, often with clustering
• Minimal reticulin fibrosis
• Splenomegaly in about 50
• Many patients asymptomatic at diagnosis
• Increased risk of arterial and venous thrombosis
  as well as hemorrhage

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THROMBOCYTOSISDifferential diagnosis

• Essential thrombocythemia
• Other MPD
• P vera
• Myelofibrosis
• CML
• Myelodysplasia (5q- et al)
• Reactive
• Inflammation
• Surgery/trauma
• Non-myeloid malignancy
• Iron deficiency
• Hemolysis
• Acute blood loss
• Absence of spleen
• Rebound following thrombocytopenia

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Hematology 2005201
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ESSENTIAL THROMBOCYTOSISNatural History

• 1-2 cases/100,000/yr
• Most patients gt50, but occurs in young adults
• Woman more often affected than men
• Life expectancy normal to slightly decreased
• Patients gt 60, or with prior thrombosis, at
  increased risk for thrombotic events
• Very high platelet counts (gt1.5 million) increase
  risk of bleeding
• Risk of myelofibrosis about 8 at 10 years
• Risk of AML about 1 overall

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ESSENTIAL THROMBOCYTOSISTreatment

• Low-risk patients (young, no vascular risk
  factors) may not require treatment
• Aspirin decreases thrombotic events
• Hydroxyurea
• Anagrelide
• Interferon
• Other P32, busulfan (leukemogenic)

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Hematology 2005201
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(No Transcript)
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MYELOFIBROSIS

• 0.5-1.5 cases/100,000/yr
• Most patients gt60
• Marrow fibrosis with extramedullary hematopoiesis
  in spleen, liver, many other tissues
• Prefibrotic stage with hypercellular marrow
  abnormal megakaryocytes
• Peripheral leukoerythroblastosis, teardrop cells,
  often with anemia. WBC and platelet counts may
  be high, normal or low
• Splenomegaly, constitutional symptoms
• Poor prognosis marrow failure, AML in 5-30

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MARROW FIBROSISDifferential diagnosis

• Myeloproliferative disorders
• MF gt gt P vera, ET, CML
• Other heme neoplasm
• Megakaryocytic leukemia
• Hodgkins
• Hairy cell leukemia
• Non-heme cancer
• Non-malignant conditions
• Renal osteodystrophy
• Autoimmune disease
• Vitamin D deficiency

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MYELOFIBROSISTreatment

• Supportive care
• Transfusions
• Splenectomy
• Thalidomide/lenalidomide (low dose)
• Reduce transfusion requirements, reduce spleen
  size
• Chemotherapy (limited data myelosuppression
  often dose-limiting)
• Cladribine
• Azacytidine/decitabine
• Low dose cytarabine
• Marrow transplant in selected patients

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SPLENOMEGALY IN MYELOFIBROSIS