Chronic Myeloproliferative Disorders

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2 Chronic Myeloproliferative Disorders 15th 9 April2015 Polycythemia vera Essential thrombocythemia Idiopathic primary myelofibrosis 2

3 Learning objectives To appreciate types of polycythaemia (erythrocytosis) To define criteria for diagnosis of PV. To understand causes of thrombocytosis. To be familiar with presentation of ET. To know pathogenesis, manifestation & treatment of MF 3

4 Polycythaemia An elevation in packed cell volume (PCV), (>52% in males, >48% in females) types of polycythaemia True polycythaemia: Absolute erythrocytosis an absolute increase in total red cell mass. Apparent (or relative) polycythaemia. a reduction in plasma volume will give a raised PCV also but without an increase in total red cell mass 4

5 Polycythaemia True polycythaemia: 1. primary polycythaemia (PRV) MPN (erythropoietin independent) 2. secondary polycythaemia Response to an increased erythropoietin Increased Red cell mass more than 25% : true polycythaemia. 5

6 Classification of true polycythaemias Primary: PRV ( Secondary: ( EPO) EPO) appropriate erythropoietin response :Hypoxia living at high altitude Pulmonary cardiac ectopic erythropoietin secretion: renal disease: cyst, RAS renal cell carcinomas, hepatocellular carcinomas, and cerebellar hemangioblastomas, bronchogenic CA, Phaeochromocytoma Uterine fibroid or leiomyoma exogenous androgens 6

7 Polycythaemia vera :pathogenesis a neoplastic disorder (MPN) characterized by hyperplasia of myeloid cell lineages, predominantly erythrocyte autonomous Erythropoiesis not controlled by erythropoietin. Plasma level of erythropoietin is reduced JAK2 tyrosine kinase : acquired mutation in myeloid cells leads to stimulation of erythropoiesis in about 97% of PV patients. 7

8 Polycythaemia vera:epidemiology male to female ratio of 1.2 : 1. The median age at onset is years 8

9 Polycythaemia vera:presentation 1. incidental (Palpable splenomegaly is present in 50%) 2.Thrombosis is the most common serious complication: 1. Venous thromboses more common deep venous thrombosis, pulmonary embolism 2. Arterial thrombosis myocardial infarcts, strokes, transient ischaemic attacks and mesenteric and limb ischaemia. 3. Neurological like headaches, drowsiness, tinnitus, vertigo Transient visual disturbances 9

10 Polycythaemia vera:presentation 4. Pruritus In 25% ( severe). precipitated by warm baths, and can be associated with erythema, swelling or even pain. relieved by controlling the PCV, 5. Skin Plethora 6. Hypertension 7. hyperuricaemia, with gout in 5% 8. Acute leukemia 5%, MF 10% 10

11 Polycythaemia vera:investigation 1) High PCV>60% in men and >55% in women 2) Hb>18.5 gm/dl in men and >16.5 gm/dl in women. 3) Leucocytosis &/ or thrmbocytosis 4) Low ESR 5) High Red cell mass 6) low serum erythropoietin level 7) JAK2 mutation is estimated at over 95% 8) Bone marrow 9) U/S 10) Exclusion: a. Room air arterial blood gas (PaO2 and SaO2) b. Chest radiograph 11

12 Polycythaemia vera:diagnosis Major criteria PRV Hb > 18.5 g/dl (men) or > 16.5 g/dl (women) >60% male or >55% female elevated red cell mass > 25% above mean normal Presence of JAK2 mutation Minor criteria Bone marrow biopsy: hyper cellular (3 lineage) Serum erythropoietin level below normal For diagnosis: Both major criteria plus one minor criterion first major criterion plus two minor criteria No secondary cause 12

13 Polycythaemia vera:treatment 1. Repeated venesection: (Phlebotomy) the mainstay of treatment. to keep PCV at 45% Reduce risk of thrombosis. regimen starts with phlebotomy every 2 3 weeks until the PCV is controlled 13

14 Polycythaemia vera:treatment 2. chemotherapy for : 1. patients unable to undergo venesection. 2. those with thrombocytosis & leucocytosis. Hydroxyurea ( g daily) Interferon alfa. (3 5 million units x3 per week). in pregnancy in patients with intractable pruritus. Low- dose aspirin ( mg daily) Pruritus often improves with control of the PCV but paroxetine, antihistamines and aspirin radioactive phosphorus. 14

15 Secondary polycythaemia 1. the commonest being hypoxaemia (arterial saturation< 92%) 2. renal diseases. 3. drugs such as erythropoietin and anabolic steroids Treatment aimed to remove the underlying cause when possible. venesection to keep PCV 50-52%. Gaisbock s disease(relative polycythemia): middle-aged, overweight, hypertensive and anxious ( stressed ) individuals with smoking, alcohol excess, diuretics, and hypertension 15

16 Idiopathic primary myelofibrosis agnogenic myeloid metaplasia clonal MPN characterized by a proliferation of predominantly megakaryocytes and granulocytes in the bone marrow: Progressive bone marrow fibrosis extramedullary haemopoiesis (production of blood cells within organs other than the bone marrow) splenomegaly, and leucoerythroblastic blood picture 16

17 Idiopathic myelofibrosis: pathogenesis JAK2 mutation : 50% increased expression of cytokines such as transforming growth factor (TGF) - β 1, platelet- derived growth factor (PDGF) and vascular endothelial growth factor(vegf) in the bone marrow 17

18 Idiopathic myelofibrosis: epidemiology most patients diagnosed in the sixth decade equal involvement of the two genders. Up to one - third of patients are asymptomatic at diagnosis 18

19 MF: presentation Splenomegaly ; almost all at presentation (massive) Painful splenic infarcts. portal hypertension with oesophageal varices and ascites. Extramedullary haemopoiesis in spleen & liver or lymph nodes,cns,etc Hypermetabolic state: (= a worse outcome) weight loss, fatigue Fevers and night sweats Anemia Thrombocytosis in 50% of the cases Thrombosis or bleeding Transformation to AML occurs in 20 30% and is usually rapidly fatal 19

20 M F: investigation A leucoerythroblastic blood picture is characteristic for idiopathic myelofibrosis Teardrop poikilocytes (dacryocytes), Nucleated RBC,macrocytosis Left shift & Neutrophilia is common. The blood count is variable. In the initial proliferative phase : the classic cytopenic phase : bone marrow becomes more fibrotic, As the disease progresses, pancytopenia 20

21 M F: investigation bone marrow aspiration :a dry tap Bone marrow trephine biopsy is essential to make a diagnosis of PMF. Initial stages are characterized by an increase in bone marrow cellularity in and the presence of abnormal large megakaryocytes in clusters & increasing collagen fibers 21

22 M F: treatment Allo-BMT is the only curative treatment modality not feasible in the majority of patients, who are over 50 years old at diagnosis. Supportive blood transfusion. Androgenic steroids (danazol & oxymethalone) can improve the haemoglobin. Cytotoxic agents : in the proliferative phase. antifibrotic and antiangiogenic agents (thalidomide) to inhibit progression Splenectomy. Splenic irradiation if surgery not done due to complication of large spleen JAK2 Inhibitor 22

23 M F: prognosis The median survival of 2-4 years. Death can be due to haemorrhage, infection or transformation to acute leukaemia 23

24 Essential thrombocythaemia MPN : A persisting platelet count >450 x10^9/l After exclusion of reactive thrombocytosis. The lack of pathognomonic features and the existence of many other causes of a raised platelet count makes diagnosis by exclusion 24

25 E T: Epidemiology The annual incidence is similar to that of PV The median age at onset is years 25

26 Causes of a raised platelet count Reactive thrombocytosis Infection Malignancy Inflammatory diseases Haemorrhage Post-surgery Post-splenectomy Myeloproliferative disorders 26

27 E T: Presentation 1. thrombosis: the main cause of morbidity and mortality, (20%), may be arterial or venous ( microvascular) : burning pain in extremities (erythromelalgia) digital ischaemia, major vascular occlusive events, (cerebrovascular accident, myocardial infarction) 27

28 E T: Presentation 2. haemorrhage : bleeding is more common in patients with platelet counts above ^9 /L 3.Mild Splenomegaly in about 5% 4.Transformation to myelofibrosis or acute leukaemia may occur in a minority of patients. 28

29 E T: Treatment All patients should receive daily low dose aspirin, unless contraindicated. reduction of the platelet count by cytotoxic agents (hydroxyurea) anagrelide ; it selectively inhibits megakaryocyte differentiation IFN; pregnancy 29