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Myeloproliferative disorders

Myeloproliferative disorders. Clonal haematopoeitic disorders Proliferation of one of myeloid lineages Granulocytic Erythroid Megakaryocytic Relatively normal maturation. Myeloproliferative disorders. WHO Classification of CMPD Ch Myeloid leukemia Ch Neutrophillic leukemia

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Myeloproliferative disorders

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  1. Myeloproliferative disorders • Clonal haematopoeitic disorders • Proliferation of one of myeloid lineages • Granulocytic • Erythroid • Megakaryocytic • Relatively normal maturation

  2. Myeloproliferative disorders WHO Classification of CMPD • Ch Myeloid leukemia • Ch Neutrophillic leukemia • Ch Eosinophillic leukemia / Hyper Eo Synd • Polycythemia Vera • Essential Thrombocythemia • Myelofibrosis • CMPD unclassifiable

  3. MPD • PRV • ET • MF AML CML CMML • MDS • RA • RARS • RAEB I • RAEB II Myeloproliferative disorders

  4. Myeloproliferative disorders • Ch Myeloid leukemia (BCR-ABL positive) • Polycythemia Vera • Essential Thrombocythemia • Myelofibrosis • Specific clincopathologic criteria for diagnosis and distinct diseases, have common features • Increased number of one or more myeloid cells • Hepatosplenomegaly • Hypercatabolism • Clonal marrow hyperplasia without dysplasia • Predisposition to evolve

  5. Granulocyte precursors Red cell precursors Megakaryocytes Reactive fibrosis Bone marrow stem cell Clonal abnormality Chronic myeloid leukemia Polycythaemia rubra vera (PRV) Essential thrombocytosis (ET) Myelofibrosis 10% 10% 70% AML 30%

  6. Epidemiology of CML • Median age range at presentation: 45 to 55 years • Incidence increases with age • 12% - 30% of patients are >60 years old • At presentation • 50% diagnosed by routine laboratory tests • 85% diagnosed during chronic phase

  7. Epidemiology of CML Ionizing radiationLatent Period Atomic bomb survivors 11 years ( 2-25) Ankylosing spondylitis pts 3.6 years (1-6) No evidence of other genetic factors Chemical have not been associated with CML Incidence 1-1.5/100,000 population Male predominance

  8. Presentation Insidious onset Anorexia and weight loss Symptoms of anaemia Splenomegaly –maybe massive Pt . maybe asymptomatic

  9. 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 X Y The Philadelphia Chromosome

  10. The Philadelphia Chromosome: t(9;22) Translocation 9 9+ Philadelphia chromosome 22 Ph bcr bcr-abl abl Fusion proteinwith tyrosinekinase activity

  11. Clinical Course: Phases of CML Advanced phases Chronic phase Median 4–6 yearsstabilization Accelerated phase Median durationup to 1 year Blastic phase (blast crisis) Median survival3–6 monthsTerminal phase

  12. Treatment of Chronic Myeloid leukemia Arsenic Lissauer, 1865 Radiotherapy Pusey, 1902 Busulfan Galton, 1953 Hydroxyurea Fishbein et al, 1964 Autografting Buckner et al, 1974 Allogeneic BMT (SD) Doney et al, 1978 Interferon Talpaz et al, 1983 Allogeneic BMT (UD) Beatty et al, 1989 Donor Leukocytes Kolb et al, 1990 Imatinib Druker et al, 1998 Imatinib/Combination therapy O’Brien et al, 200……

  13. CML Treatment • Chemotherapy to reduce WCC - Hydroxyurea • Interferon based treatment • Allogeneic bone marrow transplant • Molecular therapy - Imatinib

  14. CML-CP survival post BMT (IBMTR 1994-1999) Probability % Years

  15. Issues related to BMT • 70% long term cure rate • Donor Availability • Age of patient • Length/stage of disease • Treatment related mortality • Long term sequalae – infertility, cGVHD

  16. The Ideal Target for Molecular Therapy • Present in the majority of patients with a specific disease • Determined to be the causative abnormality • Has unique activity that is - Required for disease induction - Dispensable for normal cellular function

  17. Bcr-Abl Bcr-Abl Substrate Substrate Imatinib P ATP P P Y = Tyrosine P = Phosphate P Mechanism of Action of Imatinib Goldman JM. Lancet. 2000;355:1031-1032.

  18. Imatinib compared with interferon and low dose Cytarabine for newly diagnosed chronic-phase Chronic Myeloid leukemia S.G. O’Brien et al New England Journal of Medicine Vol. 348 March 2003

  19. Imatinib vs Interferon in newly diagnosed CP Chronic Myeloid leukemia (18 months) Imatinib 400mg Interferon and Ara-C CHR 96% 67% MCR 83% 20% CCR 68% 7% Intolerance 0.7% 23% Progressive 1.5% 7% disease

  20. Evolution of treatment goals HR MCR CCR PCR- HU IFN Imatinib BMT

  21. Issues related to Imatinib • Very few molecular responses (5-10%) • Resistance in some patients • Lack of response in some patients • Expensive • Long term toxicity/side effects unknown

  22. CML

  23. Polycythemia • True / Absolute • Primary Polycythemia • Secondary Polycythemia • Epo dependent • Hypoxia dependent • Hypoxia independent • Epo independent • Apparent / Relative • Reduction in plasma volume

  24. Causes of secondary polycythemia • ERYTHROPOIETIN (EPO)-MEDIATED • Hypoxia-Driven • Chronic lung disease • Right-to-left cardiopulmonary vascular shunts • High-altitude habitat • Chronic carbon monoxide exposure (e.g., smoking) • Hypoventilation syndromes including sleep apnea • Renal artery stenosis or an equivalent renal pathology • Hypoxia-Independent (Pathologic EPO Production) • Malignant tumors • Hepatocellular carcinoma • Renal cell cancer • Cerebellar hemangioblastoma • Nonmalignant conditions • Uterine leiomyomas • Renal cysts • Postrenal transplantation • Adrenal tumors • EPO RECEPTOR–MEDIATED • Activating mutation of the erythropoietin receptor • DRUG-ASSOCIATED • EPO Doping • Treatment with Androgen Preparations

  25. POLYCYTHEMIA VERA • Chronic, clonal myeloproliferative disorder characterized by an absolute increase in number of RBCs • 2-3 / 100000 • Median age at presentation: 55-60 • M/F: 0.8:1.2

  26. POLYCYTHEMIA VERA JAK2 Mutation • JAK/STAT: cellular proliferation and cell survival • deficiency in mice at embryonic stage is lethal due to the absence of definitive erythropoiesis • Abnormal signaling in PV through JAK2 was first proposed in 2004 • a single nucleotide JAK2 somatic mutation (JAK2V617F mutation) in the majority of PV patients

  27. Clinical features • Plethora • Persistent leukocytosis • Persistent thrombocytosis • Microcytosis secondary to iron deficiency • Splenomegaly • Generalized pruritus (after bathing) • Unusual thrombosis (e.g., Budd-Chiari syndrome) • Erythromelalgia (acral dysesthesia and erythema)

  28. Clinical features • Hypertention • Gout • Leukaemic transformation • Myelofibrosis

  29. Diagnostic Criteria A1 Raised red cell mass A2 Normal O2 sats and EPO A3 Palpable spleen A4 No BCR-ABL fusion B1 Thrombocytosis >400 x 109/L B2 Neutrophilia >10 x 109/L B3 Radiological splenomegaly B4 Endogenous erythroid colonies A1+A2+either another A or two B establishes PV

  30. Treatment • The mainstay of therapy in PV remains phlebotomy to keep the hematocrit below 45 percent in men and 42 percent in women • Additional hydroxyurea in high-risk pts for thrombosis (age over 70, prior thrombosis, platelet count >1,500,000/microL, presence of cardiovascular risk factors) • Aspirin (75-100 mg/d) if no CI • IFNa (3mu three times per week) in patients with refractory pruritus, pregnancy • Anagrelide (0.5 mg qds/d) is used mainly to manage thrombocytosis in patients refractory to other treatments. • Allopurinol

  31. Essential Thrombocythaemia (ET) • Clonal MPD • Persistent elevation of Plt>600 x109/l • Poorly understood • Lack of positive diagnostic criteria • 2.5 cases/100000 • M:F 2:1 • Median age at diagnosis: 60, however 20% cases <40yrs

  32. Clinical Features • Vasomotor • Headache • Lightheadedness • Syncope • Erythromelalgia (burning pain of the hands or feet associated with erythema and warmth) • Transient visual disturbances (eg, amaurosis fujax, scintillating scotomata, ocular migraine) • Thrombosis and Haemorrhage • Transformation

  33. Investigations ET is a diagnosis of exclusion • Rule out other causes of elevated platelet count

  34. Diagnostic criteria for ET • Platelet count >600 x 109/L for at least 2 months • Megakaryocytic hyperplasia on bone marrow aspiration and biopsy • No cause for reactive thrombocytosis • Absence of the Philadelphia chromosome • Normal red blood cell (RBC) mass or a HCT <0.48 • Presence of stainable iron in a bone marrow aspiration • No evidence of myelofibrosis • No evidence of MDS

  35. Therapy of ET based on the risk of thrombosis

  36. Thrombophilia Barry White National Haemophilia Director Director, National Centre for Hereditary Coagulation Disorders, St James’s Hospital

  37. Virchow’s Triad • Disorder of blood vessel wall • Disordered blood flow (stasis) • Abnormality of blood constituents

  38. Venous thrombosis - a multifactorial disease • Acquired risk factors pregnancy, surgery, hormonal therapy, malignancy • Inherited risk factors single gene defects e.g. antithrombin multigenic defects e.g. antithrombin + FV leiden

  39. Thrombophilia • Inherited or acquired predisposition to venous thrombosis • Laboratory abnormalities

  40. Increased procoagulants • FVIII • FIX • FXI • Prothrombin 20210A • Fibrinogen • Thrombin activator fibrinolysis inhibitor (TAFI)

  41. Decreased anticoagulants • Antithrombin deficiency • Protein C deficiency • Protein S deficiency • Activated PC resistance (FV Leiden)

  42. Unknown mechanism • Antiphospholipid syndrome • Hyperhomocysteinemia

  43. Activated protein C resistance • Activated protein C resistance • Factor V leiden (R506Q) in 90% of cases • Coagulation based assay (+/-FV def plasma) • PCR based assay • 2%-15% • 2.0 –2.3% of Irish population are heterozygous FVL Livingstone et al 2000 • 20% of unselected VTE • Relative risk 3-8 fold for heterozygotes

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