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Myeloproliferative disorders Myeloproliferative disorders Acute Acute Myeloid Leukaemia (AML) Chronic Chronic Myeloid Leukaemia (CML) Polycythaemia rubra vera (PRV) Esential thrombocytosis (ET) Idiopathic Myelofibrosis Acute Myeloid Leukaemia AML ALL 10-15% childhood leukemia 85% of childhood leukemia with increasing age Commonest 2-10 years median age 60 years 20 after 40 years Leukemia: Aetiology • Chemicals/toxins • Radiation • Viruses Chance Etiology Genetic Modifiers MHC/Immune Sx. Carcinogen metabolism DNA Repair Inherited mutated alleles Stem cells Environmental exposures Chance Genotoxic Ionizing Radiation Solvents Proliferative Stress Infection Toxins Diet Transforming viruses Mutations Chance dominant clone Acquired Modifiers Diet Infection Immunosuppression Chance Leukemia Greaves, Lancet Presentation Acute leukemia always serious and life threatening Anemia: Pallor, lethargy, dyspnoea Leucopenia: Infection - mouth, skin, perianal region Thrombocytopenia: -bruising, menorrhagia, gum bleeding Hepatosplenomegaly is common Gum hypertrophy,skin infiltration Investigations FBC: Usually shows HB and platelets (maybe <20) WCC can vary <1.0 - > 200 x 109/l, Abnormal differential Coag. Screening: Maybe abnormal esp. APML Chemistry: LDH reflects tumor burden, renal failure,hyperuricemia Leukaemia diagnosis Morphology Immunophenotype Cytogenetics Molecular genetics Abnormalities seen in at least 50 %of cases Karyotype is of major prognostic significance Used in planning treatment Cytogenetic risk groups in AML Favourable t (8;21), t (15;17) inv(16) Intermediate Normal +8, +21, +22 del (7q), del (9q) Abnormal 11q23 Others Adverse -5, -7, del (5q) Abnormal 3q Complex Grimwade et al, Blood 92 (1998) 100 100 75 75 % Still alive % Still alive Prognostic significance of cytogenetics in AML 50 25 Years from entry 50 25 Years from entry Grimwade et al, Blood 92 (1998) Treatment Supportive Care Red cell transfusion for anaemia Platelets transfusion for thrombocytopenia Vigorous treatment of infection Social and psychological support How does chemotherapy work? Inhibit proliferation Induce apoptosis Treatment Remission induction Consolidation Autologous bone marrow transplantation Allogeneic bone marrow transplantation Outcomes of remission induction treatment by age 100% Remission Induction death Complete remission 50% Resistant disease 0% 0-9 10-19 20-29 30-39 40-49 Age groups 50-59 60-69 70+ Treatment for Younger Adults in First Remission of AML LFS at 5 years Intensive chemotherapy 30-40% Autologous BMT 40-50% Allogeneic BMT (sibling donor) 50-60% Acute leukaemia: Standard of care Lessons from paediatric leukaemia Rigorous diagnostic assessment Population-based registration Clinical trial as first option Agreed protocols for non-trial patients Built-in prospective quality assurance Myeloproliferative disorders Malignant transformation of the multipotential stem cell Essential thrombocytosis (ET) - excess production of platelets Polycythaemia rubra vera (PRV) - excess production of RBC Chronic myeloid leukaemia (CML) - excess production of WBC Myelofibrosis - excess fibrosis Bone marrow stem cell Clonal abnormality Granulocyte precursors Chronic myeloid leukaemia Red cell precursors Polycythaemia rubra vera (PRV) 10% 70% AML Megakaryocytes Reactive fibrosis Essential thrombocytosis (ET) Myelofibrosis 10% 30% Chronic myeloid leukaemia Chronic Myeloid Leukemia (CML) CML Proliferative disorder of hematopoietic stem cells Well-characterized clinical course Philadelphia chromosome Unique chromosome abnormality Bcr-Abl tyrosine kinase Single molecular abnormality causes transformation to a malignant clone The Philadelphia Chromosome: t(9;22) Translocation 9 9+ Philadelphia Ph chromosome 22 bcr bcr-abl abl Fusion protein with tyrosine kinase activity p210Bcr-Abl Fusion Protein Tyrosine Kinase Extracellular space Cytoplasm Y177 BAP-1 SH3 SH2 SH1 GRB2 CBL SHC CRKL Faderl S. N Engl J Med. 1999;341:169. 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 Presentation Insidious onset Anorexia and weight loss Symptoms of anaemia Splenomegaly –maybe massive Pt . maybe asymptomatic Clinical Course: Phases of CML Advanced phases Chronic phase Median 4–6 years stabilization Accelerated phase Blastic phase (blast crisis) Median duration up to 1 year Median survival 3–6 months Terminal phase CML Treatment Chemotherapy to reduce WCC - Hydroxyurea Interferon based treatment Allogeneic bone marrow transplant Molecular therapy -Imatinib 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 Courtesy of BJ Druker, MD Mechanism of Action of STI571 Bcr-Abl Bcr-Abl Substrate Substrate P P P ATP STI571 Y = Tyrosine P = Phosphate P Goldman JM. Lancet. 2000;355:1031-1032. Bone marrow stem cell Clonal abnormality Granulocyte precursors Chronic myeloid leukaemia Red cell precursors Polycythaemia rubra vera (PRV) 10% 70% AML Megakaryocytes Reactive fibrosis Essential thrombocytosis (ET) Myelofibrosis 10% 30% Polycythaemia - Erythrocytosis Absolute 10 Polycythaemia 20 Polycythaemia PRV Tissue hypoxia causing EPO production Lung disease Cardiovascular disease Renal disease Living high altitude Relative Dehydration plasma loss -burns Cigarette smoking “stress polycythaemia” PRV – Clinical Features Disease of older ages. M=F Symptoms develop gradually Headaches , dizziness Generalised pruritus Bleeding episodes Plethoric appearance Splenomegaly in 75% of patients Gout Thrombotic episodes Causes of High platelet count Endogenous Haemorrhage Trauma Chronic iron deficiency Malignancy Chronic infections Post-operative Connective tissue disease Reactive Essential thrombocytosis Other myeloproliferative disorders Myelofibrosis Progressive generalised fibrosis of the bone marrow Development of haematopoiesis in spleen and bone marrow Fatigue Pain 20 massive splenomegaly Hypermetabolic symptoms Anaemia Massive hepatosplenomegaly Classical laboratory findings Leucoerythroblastic blood picture Teardrop poikilocytes Bone marrow stem cell Clonal abnormality Granulocyte precursors Chronic myeloid leukaemia Red cell precursors Polycythaemia rubra vera (PRV) 10% 70% AML Megakaryocytes Reactive fibrosis Essential thrombocytosis (ET) Myelofibrosis 10% 30%
