1. The Chronic Myeloproliferative Disorders (MPD)
S. Sami Kartı, MD, Prof.

2. CHRONIC MYELOPROLIFERATIVE DISORDERS (MPD)
1. Polycythemia vera
2. Chronic myeloid leukaemia
3. Essential thrombocythemia
4. Idiopathic myelofibrosis

3. CHRONIC MYELOPROLIFERATIVE DISORDERS
MPD are clonal diseases originating in pluripotential haematopoietic stem cell.
The clonal expansion results in increased and abnormal haematopoiesis and produces a group of interrelated syndromes, classified according to the predominant phenotypic expression of the myeloproliferative clone.

4. MPD - concepts Neoplastic (clonal) disorders of hemopoietic stem cells
Over-production of all cell lines, with usually one line in particular
Fibrosis is a secondary event
Acute Myeloid Leukemia may occur

5. 1. Myeloproliferative disorders are clonal and the fibrosis is ‘reactive’

6. Essential Thrombocythemia

7. Pathophysiology
Defined by the presence of a markedly elevated platelet count (>600,000/µL) in the absence of any other cause
IL-6 appears to be a primary mediator responsible for an overexpression of thrombopoietin mRNA
The underlying disease mechanism involves a defect in the c-Mpl receptor
Resulting in higher than normal thrombopoietin levels
Increased megacaryocyte proliferation

8. Essential Thrombocythemia (ET)
Neoplastic stem cell disorder causing dysregulated production of large numbers of abnormal platelets
Abnormal platelets aggregate in vivo, causing thrombosis
Abnormal platelets also cause bleeding

11. Clinical features Usually asymptomatic Peripheral Vascular Occlusion
Transient Ischemic Attack (TIA)
Stroke
Bleeding spontaneous or surgical

12. Diagnosis ET is a disease of exclusion
Distinguish from reactive thrombocytosis, and Chronic Myeloid Leukemia
Clinical setting, blood film, bone marrow, and cytogenetics help
50% JAK-2 mutation

13. Causes of reactive thrombocytosis
Acute conditions
Acute bleeding
Postsurgical period
Acute hemolysis
Infections
Tissue damage (acute pancreatitis, myocardial infarction, trauma, burns)
Rebound recovery from chemotherapy

14. Causes of reactive thrombocytosis
Chronic Conditions
Iron deficiency anemia
Surgical or functional asplenia
Metastatic cancers
Lymphomas
Inflammation (rheumatoid arthritis, vasculitis)
Renal failure, nephrotic syndrome

15. Treatment None in low-risk cases Anti-platelet agents (aspirin)
Platelet reduction treatment

16. Treatment Aim is to reduce platelet count <450,000/µL
Hydroxyure 1-4gr/day
Anegralide 1-3mg/day

17. Polycythemia (Rubra) Vera (PRV)

18. Definition
A neoplastic stem cell disorder possessing a JAK-2 mutation, which leads to excessive production of all myeloid cell lines, but predominantly red cells
The increase in whole blood viscosity causes vascular occlusion and ischemia

19. Loss of heterozygosity of chromosome 9; occurs commonly in P vera
normal
LOH

20. Role of JAK2 in Pathway Signaling and Erythropoietin Binding, Stem-Cell Differentiation, and Development of Homozygosity for the V617F Mutation
Campbell P and Green A. N Engl J Med 2006;355:
Figure 2. Role of JAK2 in Pathway Signaling and Erythropoietin Binding, Stem-Cell Differentiation, and Development of Homozygosity for the V617F Mutation. 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 (JAK-STAT), phosphatidylinositol 3 kinase (PI3K), and RAS and mitogen-activated protein kinase (RAS-MAPK). 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.
EPO-dependent signal
EPO-independent signal

21. POLYCYTHEMIA VERA symptoms
Erythrocytosis and hyperviscosity, leading to impaired oxygen delivery:
Poor CNS circulation: headaches, dizziness, vertigo, tinnitus and visual disturbances
Poor coronary circulation: angina pectoris
Peripheral circulation intermittent claudication
Venous thrombosis or thromboembolism
Hemorrhage: epistaxis, gingival bleeding, ecchymoses, gastrointestinal bleeding
Abdominal pain secondary to peptic ulcer
Early satiety due to splenomegaly
Pruritus is secondary to increased histamine release from the basophils and mast cells

22. POLYCYTHEMIA VERA physical examination
Splenomegaly – is present in 75% of patients at the time of diagnosis.
Hepatomegaly - is present in approximately 30% of patients at the time of diagnosis.
Hypertension
On examination of the eye grounds, the vessels may be engorged, tortuous, and irregular in diameter; the veins may be dark purple.
Facial plethora

23. Diagnosis Category A Increased red cell mass
Males, >36 mL/kg
Females, >32mL/kg
Normal arterial oxygen saturation >92%
Splenomegaly

24. Diagnosis Category B Platelets >400,000/µL Leukocytes >12,000/µL
Leukocyte alkaline phosphatase >100
Vitamin B12>900pg/mL

25. Diagnosis
PV is diagnosed when A1+A2+A3 or A1+A2 and any two from category B

26. Diagnosis
Exclude secondary causes of true polycythemia (measure erythropoietin)
JAK-2 mutation analysis if available

27. Treatment Phlebotomy Aim is to reduce hematocrit less than 45%
low-dose aspirin
hydroxyurea
Interferon-
Radioactive phosphorus

28. (Primary) Myelofibrosis (MF)

29. Myelofibrosis=agnogenic myeloid metaplasia (primary myelofibrosis, osteomyelofibrosis, idiopathic myelofibrosis, myelofibrosis with myeloid metaplasia )
Myelofibrosis is a chronic myeloproliferative disease with clonal hematopoesis and secondary(non-clonal) hyperproliferation of fibroblasts (stimulated by PDGF, EGF, TGF- released from myeloid cells, mainly from neoplastic megakaryocytes) with increased collagen synthesis.
It produces bone marrow fibrosis and to extramedullary hematopoesis in the spleen or in multiple organs.

30. The incidence of Myelofibrosis is about 0,5/100.000.
The median age at diagnosis was approximately 65 years.
Common complaints: fatigue, weight loss, night sweats, bone pain, abdominal pain, fever
Physical findings: splenomegaly (often giant), hepatomegaly(in about 50% of patients), symptoms of anemia and thrombocytopenia

31. MYELOFIBROSIS - laboratory findings
Anemia - Hb<10g/dL in 60% of patients
Leukocytosis with counts generally below 50,000/µL(in about 50%), leukopenia (in about 25% at the time of diagnosis)
thrombocytosis in 50% at the time of diagnosis, with disease progression thrombocytopenia becomes common
retikulocytosis
LAP score is usually elevated
Increased level of lactate dehydrogenase
uric acid level is increased in most patients

32. MYELOFIBROSIS- laboratory findings
Peripheral blood smear:anisocytosis and poikilocytosis with the presence of teardrop-shaped and nucleated red cells, immature neutrophils but myeloblasts not always
Aspiration of bone marrow is usually unsuccessful (dry tap).
Smears from successful aspirates usually show neutrophilic and megakaryocytic hyperplasia
Trephine biopsy often shows a hypercellular marrow with increased reticulin fibers and variable collagen deposition . Increased numbers of megakaryocytes are frequently seen.

33. MYELOFIBROSIS - diagnosis (Polycythemia Vera Study Group criteria)
Myelofibrosis involving more than one-third of the sectional area of a bone marrow biopsy
a leukoerythroblaststic blood picture
splenomegaly
absence of the well-established diagnostic criteria for the MPD(i.e absence of increased red cell mass or the Ph chromosome),with systemic disorders excluded

34. MYELOFIBROSIS - therapy
Androgens(oxymetholone 2-4mg/kg) in anemia from decreased red cell production -overall response is about 40%
Corticosteroids(prednisone 1mg/kg) in anemia with shortened red cell life-span-response in 25-50% of patients
Hydroxyurea (15- 20mg/kg) for the control of leukocytosis, thrombocytosis, or organomegaly
Allopurinol-to prevent hyperuricaemia
Vit. D3-analogues(1,25-dihydroxycholecalciferol-1ug/d (?)
Transfusions of packed red cells for anemia or platelets for thrombocytopenia with bleeding

35. MYELOFIBROSIS - therapy
Splenectomy should be considered for: portal hypertension, painful splenomegaly, refractory anemia and thrombocytopenia, or excessive transfusion requirement. However,the procedere is hazardous (an operative mortality is up to 38%).
Splenic irradiation: when there is a contrindication to splenectomy
Allogeneic stem-cell transplantation: for young patients who have a poor prognosis and have a suitable donor identified.
Experimental therapies: Interferon-, antifibrotic and antiangiogenic drugs (anagrelide, suramin, pirfenidone, thalidomide,)

36. MYELOFIBROSIS - prognosis
a median survival of 3,5 to 5,5 years
the principal causes of death are infections, thrombohemorrhagic events, heart failure, and leukemic transformation
leukemic transformation occurs in approximately 20% of patients during first 10 years

38. Tear Drop Cells (or Tear Drop Poikilocytes)