Acute

Myeloid Dysplasia

Malignant transformation of a myeloid precursor cell Usually at the early stages of development. Promyeolocytic leukaemia proliferation of a more mature cell. Clinical features Little uniformity Triad Infection Anaemia Thrombocytopenia Acute promyeolocytic leukaemia t(15;17) Considered a medical emergency High risk of DIC and bleeding into organs Diagnosis Blood film count WCC Anaemia Thrombocytopenia Bone marrow aspirate and trephine Leukaemic blast celss Cytochemistry Sudan black +ve Myeloperoxidase +ve (both ve in ALL) Immunophenotyping CD13, CD33;CD34 - all indicative of immature cell origin Cytogenetics Chromosomal abnormalities Molecular biology E.g. mutation of the tyrosine kinase receptor gene FLT3 poor prognosis Management Supportive care Red cell transfusion - anaemia Platelet concentrates - thrombocyopenia Broad spectrum Abx infection (2y to neutropenia) Indwelling IV catheter facilitates chemotherapy administration Chemotherapy and Stem cell transplantation Goal completete remission defined as blasts < 5% Initial stage induction Second sequence consolidation These two stages my last several months Longer-term treatment maintenance Treatment PML: use od all-trans-retinoic acid improves survival, reduces death from bleeding New potential targets: CD33, FLT3 and the RAS familiy proto-oncogenes. Stem cell transplantation can be used in conjunction to intensify chemotherapy.

Chronic myeloid leukamia

Acquire geneyic change in a pluripotential stem cell Characteristic gross over production of neutrophils and their precursors Three clinical phases Chronic phase Accelerated phase Blast crisis Pathogenesis Hallmark Philedelphia chromosome t(9;22) 95% +ve fusion of the ABL proto-oncogene to the interrupted end of the breakpoint bluster region of chromosome 22 result encodes a protein with a considerably higher TK activity in the progenitor pool myeloproliferative syndrome differentiation and cell death remain unchanged Blast crisis increased proliferation and self-renewal capacity, block in differentiation, avoidance of cell death. Clinical features Symptoms Anaemia Weight loss Anorexia Splenomegaly Causes pain, bloating and satiety May develop gout and hyperviscosity due to increase in WCC Diagnosis Blood film Normal myeloid cells at all levels of differentiation Increase in number of myelocytes and neutrophils Absolute basophilia May have thrmobocytosis and nucleated RBCs Bone marrow Less apparent changes Cytogenetics Philedelphia translocation Although a small percentage are Ph translocation negative these pts may present with an atypical myeloproliferative disease. Accelerated and blast crisis Increased appearance of immature cell in the peripheral blood in the accelerated phase. Blast crisis presence of myeloblasts in the peripheral blood. Management Chronic phase Hyperviscosity leucapheresis

 Cryopreservation of stem cells in younger patients. Drug therapy Hydroxycarbamide rapid reduction in high WCC count Imatinib TK inhibitor Stem cell transplantation Allogenic SCT currently the only surative treatment Important to do SCT as close as possible to diagnosis. Advanced disease Worse prognosis requires more aggressive therapies.

Polycythaemia Vera

Due to a mutated pluripotent stem cell Associated with the JAK2 mutation Clinical feature Raised rbc mass Increased total blood volume Associated hyperviscosity that causes thte signs and symptoms Symptoms Dizziness Lethargy Sweating Pruritis (particularly after hot baths Signs Plethoric and rosacea splenomegaly Complications Increased risk of arterial and venous thrombosis particulary strokes Combination of hyperviscosity and platelet dysfunction - paradoxical bleeding Increased cell turnover gout Diagnosis Differentiated PV from 2y polycythaemia Splenomegaly, WCC , platelet count BM aspirate and trephin Increased cellularity Genetics 90% have JAK2 mutation Management Relieve symptoms and reduce the risk of complications Aspirin Reduction of the packed cell volume by venesection Suppression of erythropoesis hydroxycarbamine Relatively begnign disease Limit exposre to carcinogenic treatments in elderly pts - risk of second malignancy May progress to myeolofibrosis or acute leukaemia. Essential thrombocythaemia Chronic myeoloproliferative disorder

Pts may not present with a clinical syndrome May present with thrombotic or haemorrhagic complications Clinical feature Often detected on routine checking of blood numbers Symptoms Buring sensation on the soles of their feet and palms Cold peripheries Varied neurological symptoms headache and dizziness Complications Thromobosis in large arteries Haemorrhage Ecchymoses (large areas of purpura) Epistaxis Menorrhagia Bleeding into the gut or mouth Splenomegly - uncommon due to splenic infarct - painful Diagnosis Often a process of exclusion Lack of acute phase response Normal ESR, plasma viscosity, fibrinogen ~ 50% have the JAK2 mutation Management Descision to treat will depend upon the age of the pt. Careful weighing up - clinical benefit v. adverse effects/toxicity of the drug Goal maintain the platelet count within the normal range but risk of haemorrhagic and thrombotic events

Myelofibrosis

Characterized by BM fibrosis and splenomegaly May develop following PV or thrombocythaemia or de novo Neoplastic clonal disorder with high numbers of abnormal megakaryocytes Produce PDGF and TGF stimulate fibroblast proliferation Reduced haematopoeitic capabilities of the scarred marrow extramedullary haematopoeisis in spleen, liver and other bones e.g. skull) Clinical features Insidious onset Symptoms Fatigue, weight loss Signs Splenomegaly splenic pain, and mass may result in portal HT. Hepatomegaly in 2/3 cases Diagnosis Blood film Teardrop poikilocytes Leucoerythrobalstic syndrome Thrmobocytosis, neutrophilia initially not seen later.

Trephine Dense reticulin fibres, fibrosis, osteosclerosis Degree of BM fibrosis differentiates from other myeloproliferative disorders. Genetics JAK2 mutation in ~40% of cases X-ray Bone sclerosis Prognosis and management Leukaemic transformation in 15% of the cases Chemotherapeutic agents To splenic pain splenic irradiation ** must not remove the spleen as it is associated with considerable mortality.** Allogenic SCT is the only potentially curative therapy often limited to the younger pt with matched donor.