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Myeloproliferative disorders

Myeloproliferative disorders. Introduction. Hemopoietic stem cell disorder Clonal Characterized by proliferation Granulocytic Erythroid Megakaryocytic Interrelationship between Polycythaemia Essential thrombocythaemia myelofibrosis. Introduction / haemopoiesis. Introduction.

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Myeloproliferative disorders

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  1. Myeloproliferative disorders

  2. Introduction • Hemopoietic stem cell disorder • Clonal • Characterized by proliferation • Granulocytic • Erythroid • Megakaryocytic • Interrelationship between • Polycythaemia • Essential thrombocythaemia • myelofibrosis

  3. Introduction / haemopoiesis

  4. Introduction • Normal maturation (effective) • Increased number of • Red cells • Granulocytes • Platelets (Note: myeloproliferation in myelodysplastic syndrome is ineffective) • Frequent overlap of the clinical, laboratory & morphologic findings • Leucocytosis, thrombocytosis, increased megakaeryocytes, fibrosis & organomegaly blurs the boundaries • Hepatosplenomegaly • Sequestration of excess blood • Extramedullary haematopoiesis • Leukaemic infiltration

  5. Rationale for classification • Classification is based on the lineage of the predominant proliferation • Level of marrow fibrosis • Clinical and laboratory data (FBP, BM, cytogenetic & molecular genetic)

  6. Differential diagnosisFeatures distinguishing MPD from MDS, MDS/MPD & AML

  7. Clonal evolutionClonal evolution & stepwise progression to fibrosis, marrow failure or acute blast phase

  8. Incidence and epidemiology • Disease of adult • Peak incidence in 7th decade • 6-9/100,000

  9. Pathogenesis • Dysregulated proliferation • No specific genetic abnormality • CML (Ph chromosome t(9;22) BCR/ABL) • Growth-factor independent proliferation • PV, hypersensitiviy to IGF-1 • Bone marrow fibrosis in all MPD • Fibrosis is secondary phenomena • Fibroblasts are not from malignant clone • TGF-β & Platelet like growth factor

  10. Prognosis • Depends on the proper diagnosis and early treatment • Role of • IFN • BMT • Tyrosine kinase inhibitors

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

  12. 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

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

  14. 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

  15. 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%

  16. 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

  17. 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

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

  19. 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

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

  21. 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

  22. 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……

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

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

  25. 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

  26. 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

  27. 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.

  28. 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

  29. 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

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

  31. 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

  32. CML

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

  34. 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

  35. 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

  36. Polycythaemia vera(Polycythaemia rubra vera) • Definition of polycythemia • Raised packed cell volume (PCV / HCT) • Male > 0.51 (50%) • Female > 0.48 (48%) • Classification • Absolute • Primary proliferative polycythaemia (polycythaemia vera) • Secondary polycythaemia • Idiopathic erythrocytosis • Apparent • Plasma volume or red cell mass changes

  37. Polycythaemia vera(Polycythaemia rubra vera) • Polycythaemia vera is a clonal stem cell disorder characterised by increased red cell production • Abnormal clones behave autonomous • Same abnormal stem cell give rise to granulocytes and platelets • Disease phase • Proliferative phase • “Spent” post-polycythaemic phase • Rarely transformed into acute leukemia

  38. Polycythaemia vera(Polycythaemia rubra vera) • Clinical features • Age • 55-60 years • May occur in young adults and rare in childhood • Majority patients present due to vascular complications • Thrombosis (including portal and splenic vein) • DVT • Hypertension • Headache, poor vision and dizziness • Skin complications (pruritus, erythromelalgia) • Haemorrhage (GIT) due to platelet defect

  39. Polycythaemia vera(Polycythaemia rubra vera) Erythromelalgia • Hepatosplenomegaly • Erythromelalgia • Increased skin temp • Burning sensation • Redness Liver 40% Spleen 70%

  40. Polycythaemia vera(Polycythaemia rubra vera) Bone marrow in PV • Laboratory features and morphology • Hb, PCV (HCT), and Red cell mass increased • Increased neutrophils and platelets • Normal NAP • Plasma urate high • Circulation erythroid precursors • Hypercellular bone marrow • Low serum erythropoietin

  41. Polycythaemia vera(Polycythaemia rubra vera) • Treatment • To decrease PVC (HCT) • Venesection • Chemotherapy • Treatment of complications

  42. 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)

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

  44. 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

  45. 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

  46. 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

  47. Causes of secondary polycythemia • EPO RECEPTOR–MEDIATED • Activating mutation of the erythropoietin receptor • DRUG-ASSOCIATED • EPO Doping • Treatment with Androgen Preparations

  48. Secondary polycythaemia • Polycythaemia due to known causes • Compensatory increased in EPO • High altitude • Hulmonary diseases • Heart dzs eg- cyanotic heart disease • Abnormal hemoglobin- High affinity Hb • Heavy cigarette smoker • Inappropriate EPO production • Renal disease-carcinoma, hydronephrosis • Tumors-fibromyoma and liver carcinoma

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