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myeloproliferative disorders in hematology for students
- 1. Myeloproliferative disorders • Clonalhaematopoeitic disorders • Proliferation of one of myeloid lineages – Granulocytic – Erythroid – Megakaryocytic • Relatively normal maturation
- 2. Myeloproliferative disorders WHO Classificationof CMPD • Ch Myeloid leukemia • Ch Neutrophillic leukemia • Ch Eosinophillic leukemia / Hyper Eo Synd • Polycythemia Vera • Essential Thrombocythemia • Myelofibrosis • CMPD unclassifiable
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- 4. Myeloproliferative disorders • ChMyeloid 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. Bone marrow stemcell Clonal abnormality Granulocyte precursors Red cell precursors Megakaryocytes Reactive fibrosis Essential thrombocytosis (ET) Polycythaemia rubra vera (PRV) Myelofibrosis AML Chronic myeloid leukemia 70% 10% 10% 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. Ionizing radiation LatentPeriod 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 Epidemiology of CML
- 8. Presentation Insidious onset Anorexia andweight loss Symptoms of anaemia Splenomegaly –maybe massive Pt . maybe asymptomatic
- 10. The Philadelphia Chromosome 23 4 5 1 7 8 9 10 11 12 6 13 14 15 16 17 18 20 21 22 X Y 19
- 11. The Philadelphia Chromosome:t(9;22) Translocation bcr-abl Fusion protein with tyrosine kinase activity 22 bcr abl Ph 9 9+ Philadelphia chromosome
- 12. Clinical Course: Phasesof CML Chronic phase Median 4–6 years stabilization Accelerated phase Median duration up to 1 year Blastic phase (blast crisis) Median survival 3–6 months Terminal phase Advanced phases
- 13. Treatment of ChronicMyeloid 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……
- 14. CML Treatment •Chemotherapy toreduce WCC - Hydroxyurea •Interferon based treatment •Allogeneic bone marrow transplant •Molecular therapy - Imatinib
- 15. CML- CP survivalpost BMT (IBMTR 1994-1999) Years Probability %
- 16. Issues related toBMT • 70% long term cure rate • Donor Availability • Age of patient • Length/stage of disease • Treatment related mortality • Long term sequalae – infertility, cGVHD
- 17. The Ideal Targetfor 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
- 18. Mechanism of Actionof Imatinib Goldman JM. Lancet. 2000;355:1031-1032. Bcr-Abl ATP Substrate Imatinib Y = Tyrosine P = Phosphate Bcr-Abl Substrate P P P P
- 19. Imatinib compared withinterferon 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
- 20. Imatinib vs Interferonin newly diagnosed CP Chronic Myeloid leukemia (18 months) CHR 96% 67% MCR 83% 20% CCR 68% 7% Intolerance 0.7% 23% Progressive 1.5% 7% disease Imatinib 400mg Interferon and Ara-C
- 21. Evolution of treatmentgoals HR MCR CCR PCR - HU IFN Imatinib BMT
- 22. Issues related toImatinib • Very few molecular responses (5-10%) • Resistance in some patients • Lack of response in some patients • Expensive • Long term toxicity/side effects unknown
- 23. CML Diagnosis Young with a well-matcheddonor Start Imatinib at 400mg/day Cosider for Allograft Allo SCT Poor response or Initial response Followed by Loss of response Add or substitute Other agents Allo-SCT Auto Good response maintained Continue Imatinib indefinitely
- 24. Polycythemia • True /Absolute – Primary Polycythemia – Secondary Polycythemia • Epo dependent – Hypoxia dependent – Hypoxia independent • Epo independent • Apparent / Relative – Reduction in plasma volume
- 25. Causes of secondarypolycythemia • 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
- 26. 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
- 27. 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
- 28. 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)
- 29. Clinical features • Hypertention •Gout • Leukaemic transformation • Myelofibrosis
- 30. Diagnostic Criteria A1 Raisedred 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
- 32. Treatment • The mainstayof 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
- 33. 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
- 34. 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
- 35. Investigations ET is adiagnosis of exclusion • Rule out other causes of elevated platelet count
- 36. Diagnostic criteria forET • 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
- 40. Therapy of ETbased on the risk of thrombosis
- 41. Thrombophilia Barry White National HaemophiliaDirector Director, National Centre for Hereditary Coagulation Disorders, St James’s Hospital
- 42. Virchow’s Triad • Disorderof blood vessel wall • Disordered blood flow (stasis) • Abnormality of blood constituents
- 43. 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
- 44. Thrombophilia • Inherited oracquired predisposition to venous thrombosis • Laboratory abnormalities
- 47. Increased procoagulants • FVIII •FIX • FXI • Prothrombin 20210A • Fibrinogen • Thrombin activator fibrinolysis inhibitor (TAFI)
- 48. Decreased anticoagulants • Antithrombindeficiency • Protein C deficiency • Protein S deficiency • Activated PC resistance (FV Leiden)
- 49. Unknown mechanism • Antiphospholipidsyndrome • Hyperhomocysteinemia
- 50. Activated protein Cresistance • 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
- 51. APC Factor V (normal) APCFactor V Leiden
- 52. Prothrombin G20210A • Poort1996 • Mutation in 3’ UTR associated with increased prothrombin levels • 1.3% of Irish population heterozygous (Keenan et al 2000) • 6-8% of unselected VTE • 16% of familial VTE
- 53. Hyperhomocysteinemia • Definite riskfactor for arterial vascular disease • >18.5 mol/l in 5% of normal population • >18.5 mol/l in 10% of VTE • Homozygous MTHFR (C677T) - 10% Irish population • Acquired B12, folate, B6 deficiency
- 54. Antiphospholipid syndrome • Venous,arterial or small vessel except superficial venous thrombosis • 3 consecutive unexplained fetal loss • Severe pre-eclampsia or placental insufficiency leading to prematurity (<34w) • Unexplained single fetal loss >10 wks with normal morphology
- 55. APLS - laboratorydiagnosis • ACL IgG or IgM (> 3SD above normal) • Lupus anticoagulant • Need 2 positive tests (either test will do) at least 6 weeks apart • Anti B2-Glycoprotein I
- 56. Hormonal therapy • OCPrisk of VTE increased x 2-3 fold (baseline risk 1:10,000) • FVL risk of VTE increased x 3-7 fold • OCP + FVL risk of VTE increased x 33 fold (30:10,000 = 0.3%) • Need to screen 2 million to save one life • Similar synergistic interaction with other thrombophilic defects • HRT likely to be similar
- 57. Pregnancy and Virchow’striad • Venous stasis - changes in tone and obstruction • Vascular damage at time of delivery APTT, PS (free and total), APCr FVIII:C, VWF, Fibrinogen PAI-1 and PAI-2
- 58. Pregnancy and venous thromboembolicdisease • Pregnancy increases risk x 5-10 fold • 0.86/1000 deliveries • 0.71/1000 (DVT) : 0.15/1000 (PE) • Left leg >80% • Ileofemoral more common than calf vein (72% versus 9%) • Increased with age, caesarian section, bed rest and prior history of DVT/PE
- 59. Clinical practice –DVT/PE • Diagnosis DVT – doppler ultrasound primarily (venogram gold standard) PE – ventilation perfusions scan primarily (pulmonary angiogram is gold standard) • Treatment Heparin x 5-10 days until at least 5 days of warfarin Warfarin x 6 months ( indefinite for second thrombosis)