Myeloproliferative disorders.ppt
- 1. MIELOPROLIFERATIVE DISORDERS Dr : Walaa Mamoun ALsafi
- 2. MYELOPROLIFERATIVE DISORDERS (MPD) MPD are clonal diseases originating in pluripotential haematopoietic stem cell. The clonal expansion results in increased and abnormal haematopoiesis and produces a group of interrelated syndromes, classified according to the predominant phenotypic expression of the myeloproliferative clone.
- 3. CHRONIC MYELOPROLIFERATIVE DISORDERS (MPD) Neoplastic (clonal) disorders of hemopoietic stem cells Over-production of all cell lines, with usually one line in particular Fibrosis is a secondary event Acute Myeloid Leukemia may occur
- 4. Rationale for classification Classification is based on the lineage of the predominant proliferation Level of marrow fibrosis Clinical and laboratory data (BPF, BM, cytogenetic & molecular genetic)
- 5. 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
- 6. 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
- 7. Bone marrow stem cell 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%
- 9. 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
- 10. POLYCYTHEMIA VERA (PV) (Polycythaemia rubra vera) Definition of polycythemia Raised packed cell volume (PCV / HCT) Male > 0.52 (52%) Female > 0.48 (48%) Classification Absolute Primary proliferative polycythaemia (polycythaemia vera) Secondary polycythaemia Idiopathic erythrocytosis Apparent Plasma volume reduced but no red cell mass changes
- 11. 11 ERYTHROCYTOSIS (Classification) I. Absolute erythrocytosis (Polycythemia): A. Secondary erythrocytosis (abnormal increase of serum erythropoietin level) 1. Erythrocytosis secondary to decreased tissue oxygenation: a) chronic lung diseases b) cyanotic congenital heart diseases c) high-altitude erythrocytosis d) hypoventilation syndromes - carboxyhemoglobin in „smoker’s polycythemia”
- 12. POLYCYTHEMIA VERA (PV) Clinical features Age – 55-60 years – May occur in young adults and rare in childhood Symptoms common to all erythrocytosis – Headache, mental acuity, weakness Symptoms more specific to P vera and myeloproliferative diseases. – Pruritis after bathing – Erythromelalgia – Hypermetabolic symptoms – Thrombosis (arterial or venous) – Hemorrhage
- 13. POLYCYTHEMIA VERA physical examination 1. Splenomegaly – is present in 75% of patients at the time of diagnosis. 2. Hepatomegaly - is present in approximately 30% of patients at the time of diagnosis. 3. Hypertension 4. On examination of the eye grounds, the vessels may be engorged, tortuous, and irregular in diameter; the veins may be dark purple. Facial plethora
- 14. POLYCYTHEMIA VERA physical examination Hepatosplenomegaly Erythromelalgia – Increased skin temp – Redness Liver 40% Spleen 70% Erythromelalgia
- 15. PRV - DIAGNOSIS exclude secondary polycythemia look for features of primary polycythemia measure erythropoietin JAK-2 mutation analysis
- 16. POLYCYTHEMIA VERA Lab Findings CBC – Hgb/Hct – WBC in 45% – Plts in 65% – Basophilia (seen in all MPDs) Uric acid (can lead to gout) Positive JAK2 V617F mutation in about 97 percent of patient
- 17. JAK2 Mutation JAK2 :is gene in short arm of chromosome 9 that encoded cytoplasmic tyrosine kinase activity which increase cellular proliferation and cell survival Abnormal signalling in PV through JAK2 was first proposed in 2004 a single nucleotide JAK2 somatic mutation (JAK2V617F mutation) in the majority of PV patients
- 20. PV - TREATMENT Phlebotomy Myelosuppressive agents – Hydroxyurea – Alkylating agents Interferon alpha
- 21. 21 POLYCYTHEMIA VERA Antiplatelets agents Aspirin initially 150-300mg/d, maintence therapy 75-100 mg Special Topics 1. Pruritus:antihistaminic agent 2. Hyperuricemia-allopurinol 300mg/day
- 23. THROMBOCYTOSIS Etiology of Thrombocytosis Primary - if the thrombocytosis is caused by a myeloproliferative neoplasm, the platelets are frequently abnormal and the patient may be prone to both bleeding and clotting events. Secondary - if thrombocytosis is secondary to another disorder (reactive), even patients with extremely high platelet counts (e.g., > 1,000,000 cells/μl) are usually asymptomatic. Definition: thrombocytosis is defined as a platelet count > 450,000 cells/μL
- 25. 25 ESSENTIAL THROMBOCYTHEMIA (ET) ET is a clonal myeloproliferative disorder characterized by bone marrow hyperplasia with excessive proliferation of megakaryocytes and sustained elevation of the platelet count.
- 26. ESSENTIAL THROMBOCYTHEMIA (ET) Neoplastic stem cell disorder causing dysregulated production of large numbers of abnormal platelets Abnormal platelets aggregate, causing thrombosis Abnormal platelets also cause bleeding
- 27. 27 ESSENTIAL THROMBOCYTHEMIA clinical picture 1. Thrombotic complications (intermittent or permanent occlusion of small blood vessels) transient cerebral ischemic episodes that may progress to infarction peripheral arterial occlusive disease associated with erythromelalgia” 2. Hemorrhagic complications - bleeding after surgery and spontaneus upper gastrointestinal bleeding 3. Splenomegaly - 20-50% patients 4. Hepatomegaly - rarely
- 28. 28 ESSENTIAL THROMBOCYTHEMIA laboratory findings Thrombocytosis (in most patients patients>1000 G/l) Numerous thrombocyte aggregates in peripheral blood smear Leukocytosis, usually less than 20 Neutrophilia and a mild shift to the left(usually to metamyelocyte) Slight eosinophilia and basophilia Marked hyperplasia of the megakaryocytes in the BM JAC 2 mutain in about 50 of patient
- 30. ET - OUTCOMES Most patients with ET enjoy a normal life expectancy Like PV, the major risks are secondary to thrombosis and disease transformation: ▪ 15-year cumulative risks: ▪ thrombosis - 17% risk ▪ clonal evolution into either myelofibrosis (4%) or AML (2%) High risk for thrombosis: ▪ age ≥ 60 ▪ prior thrombosis ▪ long-term exposure to a plt count of > 1,000,000
- 31. MYELOFIBROSIS
- 32. MYELOFIBROSIS Clonal stem cell disorder affecting megakaryocytes predominantly All myeloproliferative disorders can result in a spent phase which can be difficult to distinguish from primary MF
- 33. MYELOFIBROSIS Myelofibrosis is a chronic myeloproliferative disease with clonal hematopoesis and secondary(non-clonal) hyperproliferation of fibroblasts (stimulated by PDGF, TGF- released from myeloid cells, mainly from neoplastic megakaryocytes) with increased collagen synthesis. It produces bone marrow fibrosis and to extramedullary hematopoesis in the spleen or in multiple organs
- 34. MYELOFIBROSIS Insidious onset in older people – asymptomatic (15% - 30%) – severe fatigue Splenomegaly- massive Hepatomegaly Hypermetabolic symptoms – Loss of weight, fever and night sweats Bleeding problems Bone pain Gout Can transform to acute leukaemia in 10-20% of cases
- 35. MYELOFIBROSIS Anaemia High WBC at presentation Later leucopenia and thrombocytopenia Leucoerythroblastic blood film Tear drops red cells Bone marrow aspiration- Failed due to fibrosis Trephine biopsy- fibrotic hypercellular marrow JAK2+ (V617F) in approximately 50% of cases
- 36. Pathological Features of Peripheral Blood and Bone Marrow in Patients with Myelofibrosis with Myeloid Metaplasia
- 37. MF - OUTCOME As fibrosis progresses, cytopenias worsen leading to a transfusion dependency ▪ symptoms related to extrmedullary hematopoiesis increase (worsening splenomegaly) also frequently identified
- 38. 38 MYELOFIBROSIS - prognosis - a median survival of 3,5 to 5,5 years - the principal causes of death are infections, thrombohemorrhagic events, heart failure, and leukemic transformation - leukemic transformation occurs in approximately 20% of patients during first 10 years