1. cough, dyspnoea, orthopnoea, dysphagia, stridor
2. Classification
   1. Acute Myeloid Leukaemia
      1. Acute promyelocytic leukaemia
   2. Acute Lymphoblastic leukaemia
3. Presentation
   1. Onset
      1. Sudden
      2. Sudden
   2. Recurrent Infections
      1. deficient in working leukocytes
      2. "
   3. Bleeding
      1. Thrombocytopenia
      2. "
   4. Anaemia
      1. "
      2. "
   5. DIC
      1. Esp APL
   6. Gum hypertrophy
      1. Esp AML
4. Epidemiology
   1. ALL
      1. 80% of childhood AL
      2. Peak incidence: 3-7 yoa
      3. 20% of adult ALs
      4. Aetiology: Most cases idiopathic some cases ionizing radiation implicated (in utero Dx X-rays)?
      5. 5% of cases associated with inherited, predisposing genetic syndromes
      6. Children with Down S: 10-30 ×risk (heterogenous)
      7. High birth weight - ↑risk (marker for endogenous factor: IGF)
   2. AML
      1. Adult disease
      2. median age: 60
      3. increasing incidence with advanced age
      4. Most patients: idiopathic
      5. Risk factors
         1. Exposure to radiation
         2. Chronic exposure to high doses of benzene
         3. Tobacco smoke
         4. Chemotherapy for lymphomas: alkylating agents/topoisomerase II inhibitors
5. Pathogenesis
   1. ALL
      1. 85% of pre-B-Cell origin
      2. Cellular fx altered: ↑ability for self-renewal, subversion of control of normal proliferation, block in differentiation, ↑resistance to apoptotic signals.
      3. Genetic abnormalities
         1. Chromosomal abnormalities (ploidy & structure)
         2. Two cooperative mutations needed for leukaemic transformation.
         3. Most common mutations: disruption of genes encoding regulators of normal lymphoid development
            1. Most B-Cell ALL: Philadelphia chromosome t(9;22) with BCR/ABL fusion protein
            2. 25% of paediatric B-cell ALL: TEL-AML1 t(12;21)
            3. Most T-cell ALL: NOTCH translocations
   2. AML
      1. Evolution from chronic clonal haemopathy
         1. May develop from other clonal disorders: CML, polycythemia vera, 1° myelofibrosis, essential thrombocythemia
      2. Predisposing diseases
         1. aplastic anaemia
         2. myeloma
         3. rarely AIDS
      3. Molecular Pathogenesis
         1. Chromosomal translocation: rearrangement of protooncogene with formation of fusion protein that disrupts normal cell control - Uncontrolled proliferation
         2. Translocations that affect differentiation
         3. Acute Promyelocytic leukaemia
            1. chromosomal translocation t(15;17) produces fusion gene PML-RARα which interacts with the retinoic acid receptor to produce a block in differentiation
         4. Acute Myelocytic Leukaemia with Differentiation
            1. t(8;21)
6. Pathology
   1. Laboratory findings - Microscopy
      1. Pancytopenia with circulating blasts
      2. Bone marrow hypercellular, dominated by blasts. Dx>20% blasts
         1. AML with inv16
            1. Acute megakaryoblastic leukaemia
      3. AML
         1. Auer rod is Dx (esp in APL)
   2. Laboratory findings - Cytogenetic and genic
      1. ALL
         1. Immunologic subtyping - by checking for CD markers on cells
            1. B-cell precursors (Pro-B to pre-B) - CD19+, CD22+, CD79a+, with CD10+
            2. Mature B-cell - CD19+, CD22+, CD79a+
            3. T-cell lineages: CD7+, CD3+, CD2+, CD1+, CD8±
         2. Genetic (flow cytometry)
            1. Hyper & Hypoploidy
            2. Philadelphia chr: t(9;22) - BCR-ABL1 protein
            3. t(12;21) ETV6-RUNX1 or TEL-AML1
            4. NOTCH1 translocations: most T-cell phenotypes
      2. AML
         1. Aneuploidies
            1. Trisomy 8 & 21
            2. Monosomy 7 & 21
            3. Loss of X or Y
         2. Translocations & inversions
            1. t(8;21) RUNX1(AML1)-RUNX1T1(ETO
            2. t(16;16) - M4
            3. t(15;17) PML-RARα
7. Complications
   1. ALL
      1. Ecchymosis in skin & mucous membranes
      2. Bone tenderness: leukaemic infiltration or haemorrhage
      3. Organomegaly: liver, spleen & lymph nodes freq sites of extramedullary involvement
      4. Anterior thymic mass (8-10% of children, 15% of adults)
         1. Superior mediastinal syndrome
         2. Superior vena cava syndrome
      5. Lymphatic obstruction
   2. AML
      1. Disseminated intravascular coagulopathy can occur, esp in APL
      2. Bleeding
      3. Pustules & other pyogenic infections of skin
      4. Myeloid (granulocytic) Sarcoma
      5. Leukemic blasts may infiltrate any tissue and cause functional disturbances
8. Management
   1. Supportive
      1. Psychosocial
      2. Metabolic + infectious complications
      3. Rational use of blood products
   2. Specific
      1. ALL
         1. Chemotherapeutic agents
            1. Cyclophosphamine
            2. Vincristine
         2. CNS prophylaxis
         3. Pt with Philadelphia Chromosome
            1. Imatinib
      2. AML
         1. Anthracycline
         2. cytarabine
         3. APL
            1. Atrhracycline PLUS All-trans-retinoic acid
9. Prognosis
   1. Age
      1. Small children worse
      2. Elderly worse
      3. 2-9 better
         1. Cure rate 80% in children
   2. Chromosomal abnormalities
      1. ALL
         1. Cytogenetics can be used as a prognostic factor
      2. AML
         1. Translocations known as Core Binding Factor translocations have a better prognosis