MYELOPROLIFERATIVE DISEASES By DR. KAMAL E. HIGGY CONSULTANT HAEMATOLOGIST

1. MYELOPROLIFERATIVEDISEASESByDR. KAMAL E. HIGGYCONSULTANT HAEMATOLOGIST

2. Myeloid DisordersUsual Features at Diagnosis

3. WHO Classification Chronic Myeloproliferative Disease --------------------------------------------------------------------------------------------------------------------------- • Chronic Myelogenous Leukaemia [Ph chromosome, t(9;22)(q34;q11) , BCR/ABL- positive ] • Chronic Neutrophilic Leukaemia • Chronic Eosinophilic Leukaemia (and the hypereosinophilic syndrome) • Polycythaemia Vera • Chronic Idiopathic Myelofibrosis (with extramedullary haematopoiesis) • Essential Thrombocythaemia • Chronic Myeloproliferative Disease, Unclassifiable

4. WHO Classification Myelodysplastic / Myeloproliferative Diseases ----------------------------------------------------------------- • Chronic Myelomonocytic Leukaemia • Atypical Chronic Myeloid Leukaemia • Juvenile Myelomonocytic Leukaemia • Myelodysplastic/Myeloproliferative Disease, Unclassifiable

5. Myeloproliferative DiseaseRecurring Genetic Abnormalities and Their Frequency (%)at diagnosis

6. Polycythaemia Vera ---------------------------------------------------------------------------------------------------------------------------------------------------------------------- • Hb : Males >17.5 gm/dl Females > 15.5 gm/dl • RBC : Males > 6.0 X 1012/L Females > 5.5X1012/L • PCV : Males > 51% Females > 48% • TRCV : Males > 36 ml/kg (25-35) Females > 32 ml/kg (22-32) • TPV : 40 – 50 ml/kg

7. Classification of Erythrocytosis Raised PCV (female >0.48; male>0.51) RCM (Interpreted using ICSH reference values) Increased RCMNormal RCM Absolute erythrocytosis Apparent erythrocytosis Abbreviations: PCV = Packed Cell Volume; RCM = red cell mass; ICSH = International Council for Standardization in Haematology;

8. Primary Erythrocytosis Congenital # Truncation of the EPO receptor* Acquired Polycythaemia Vera* Secondary Erythrocytosis Congenital # e.g., high oxygen affinity Hb, autonomous high EPO production Acquired e.g., hypoxemia, renal disease # Sometimes familial * The only condition to be defined in this category at present EPO = erythropoietin

9. Polycythaemia Vera Causes ---------------------------------------------------------------------------------------------------------------------------------------------------------------------- • Primary : Polycythaemia Vera • Secondary: 1. Erythropoietin Compensatory Increase: High Altitude C.V. disease Pulmonary disease High Affinity Hb Heavy smoking Methaemoglobinaemia 2. Abnormal Erythropoietin Production: Renal diseases. Massive uterine fibromatosis Hepatocellular Carcinoma Cerebellar Haemangioblastoma • Relative: Stress, Dehydration, Plasma Loss.

10. Polycythaemia Vera Clinical Features ---------------------------------------------------------------------------------------------------------------------------------------------------------------------- • Headache, Lethargy, Dyspnea • Weight Loss, Night Sweats • Generalized pruritis (Increase after hot bath) • Plethoric Appearance • Haemorrhage & Thrombosis • Hypertension (In about 1/3rd of the patients) • Gout (Increased Uric Acid) • Peptic Ulcers (In 5 – 10% of the patients) • Splenomegaly (In 2/3rd of patients) • Accidental Discovery (On Routine exam)

11. Polycythaemia Vera Laboratory Investigations ---------------------------------------------------------------------------------------------------------------------------------------------------------------------- • C.B.C • Neutrophil Alkaline Phosphatase (N.A.P.) • Serum B12 & B12 binding capacity • Bone Marrow- Blood Viscosity • Uric Acid Level- Hb Electrophoresis • Arterial Oxygen Tension -T.R.C.V. • I.V. Pyelography, CT & US - JAK2:74 – 97 % (PV) • Erythropoietin Assay 33 – 57 % (ET) 35 – 50 % (MF)

18. Polycythaemia Vera Classic Polycythaemia Vera Study Group Diagnostic Criteria -------------------------------------------------------------------------------------------------------------------------------------------------------------------------- A1 ↑ Red Cell MassB1Thrombocytosis Male ≥36 ml/kg Platelet count >400,000/µl Female ≥32ml/kgB2Leukocytosis >12,000/µl (No fever or infection) A2Normal ArterialB3↑ Leukocyte Alkaline O2 Saturation ≥92%Phosphatase score >100 (No fever or infection) A3Splenomegaly ↑ Serum B12 (>900pg/ml) or ↑ Unbound B12 binding capacity (>2200pg/ml) -------------------------------------------------------------------------------------------------------------------------------------------------------------------------- • Diagnosis is acceptable if the following combinations are present: A1 + A2 + A3 or A1 + A2 + any two from Category B.

19. Polycythaemia Vera Proposed diagnostic criteria ------------------------------------------------------------------------------------------------------------------------------- A1 Raised red cell mass B1 Thrombocytosis (>25% above mean normal Platelet count>400X109/1 predicted value) A2 Absence of a cause of B2 Neutrophil leukocytosis Secondary Polycythaemianeutrophil count >10X109/1 A3 Palpable splenomegalyB3 Splenomegaly demonstrated by isotope/ultrasound scanning A4 Clonality marker B4 Characteristic BFU-E growth e.g. - abnormal marrow karyotypeor reduced serum erythropoietin - JAK2 ------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------ A1 + A2 + A3 or A4 establishes PV A1 + A2 + Two of B establishes PV

20. Polycythaemia Vera Treatment -------------------------------------------------------------- • Venesecton • Radioactive Phosphorus (P32) • Chemotherapy: e.g. Hydroxyurea

21. Chronic Idiopathic MyelofibrosisPrefibrotic Stage

22. Chronic Idiopathic MyelofibrosisFibrotic Stage

28. Essential ThrombocythaemiaDiagnostic Criteria Positive Criteria • Sustained platelet count ≥600X109/L • Bone marrow biopsy specimen showing proliferation mainly of the megakaryocytic lineage with increased numbers of enlarged, mature megakaryocytes Criteria of exclusion • No evidence of polycythaemia vera (PV) - Normal red cell mass or Hb <18.5g/dl in men, 16.5g/dl in women - Stainable iron in marrow, normal serum ferritin or normal MCV - If the former condition is not met, failure of iron trial to increase red cell mass or Hgb levels to the PV range • No evidence of CML - No Philadelphia chromosome and no BCR/ABL fusion gene

29. Essential ThrombocythaemiaDiagnostic criteria(Continued) • No evidence of chronic idiopathic myelofibrosis - Collagen fibrosis absent - Reticulin fibrosis minimal or absent 4.No evidence of myelodysplastic syndrome - No del(5q), t(3;3)q21;q26), inv(3)(q21q26) - No significant granulocytic dysplasia, few if any micromegakaryocytes • No evidence that thrombocytosis is reactive due to: - Underlying inflammation or infection -Underlying neoplasm - Prior splenectomy

32. Giant Plat

33. Megakaryocytes in Clusters

34. Chronic Myelogenous Leukaemia Presenting Manifestations Common Anaemia Splenomegaly Less Common Symptoms due to the raised metabolic rate Haemorrhagic Manifestations, especially bruising

35. Chronic Myelogenous Leukaemia Presenting Manifestations (Cont…) Occasional • Acute abdominal pain • Bone or joint pains • Menstrual disturbances • Neurological symptoms • Priapism • Gout • Skin disorder • Disturbances of vision or hearing • Accidental discovery on routine blood examination

36. Chronic Myelogenous Leukaemia Evolution of the disease Chronic Phase Accelerated Phase Blastic Transformation (AML) (ALL)

37. Chronic Myelogenous Leukaemia Laboratory Investigations • CBC

38. Chronic Myelogenous Leukaemia Laboratory Investigations (Cont…) • Neutrophil Alkaline Phosphatase • Bone Marrow Examination. • Serum B12 & B12 binding capacity • Cytogenetic Studies (Ph1) chromosome [ t ( 9 : 22 ) ] • DNA restriction enzyme analysis BCR-ABL (Breakpoint Cluster Region)

43. Chronic Myelogenous LeukaemiaAccelerated Phase • Blasts 10% to 19% of peripheral blood white cells or bone marrow cells • Peripheral blood basophils at least 20% • Persistent thrombocytopenia (<100X109/L) unrelated to therapy or persistent thrombocytosis (> 1000X109L) unresponsive to therapy • Increasing spleen size and increase WBC count unresponsive to therapy

44. Chronic Myelogenous LeukaemiaAccelerated Phase (Cont…) • Cytogenetic evidence of clonal evolution (i.e., the appearance of an additional genetic abnormality that was not present in the initial specimen at the time of diagnosis of chronic phase CML) • Megakaryocytic proliferation in sizable sheets and clusters, associated with marked reticulin or collagen fibrosis, and/or severe granulocytic dysplasia, should be considered as suggestive of CML-AP These findings have not yet been analyzed in large clinical studies, however, so it is not clear if they are independent criteria for accelerated phase. They often occur simultaneously with one or more of the other features listed

45. Chronic Myelogenous LeukaemiaBlastic Phase (BP) Diagnosis is established if one or more of following is present: • Blasts 20% or more of peripheral blood white cells or bone marrow cells • Extramedullary blast proliferation • Large foci or clusters of blasts in bone marrow biopsy

46. Chronic Myelogenous LeukaemiaChronic Phase (BP) Treatment • Hydroxyurea (HU): WBC/ulHU (mg/kg BW/DAY) >50,000 50 15-50,000 30 – 40 <15,000 25 • Busulphan • Alpha – Interferon: 5 MU/DAY 7.5 MU/DAY if WBC > 10,000/mcl 10 MU/DAY if WBC > 20,000/mcl 3 MU/DAY if cytopenia develops • BMT, ABMT & STEM CELL HARVEST • Gleevec