Acute Leukemia Lecture 4.1 PDF

ACUTE LEUKAEMIA Dr Ncete LECTURE OUTLINE Epidemiology Clinical presentation Types of Acute leukaemia Diagnosis Prognosis Management  INTRODUCTION 13,800 AML and 6000 ALL cases diagnosed in the United States in 2012. Physician-related delays in diagnosis sho...

ACUTE LEUKAEMIA Dr Ncete LECTURE OUTLINE Epidemiology Clinical presentation Types of Acute leukaemia Diagnosis Prognosis Management  INTRODUCTION 13,800 AML and 6000 ALL cases diagnosed in the United States in 2012. Physician-related delays in diagnosis shown to contribute to poor outcomes and higher mortality in low-income nations. Acute leukaemia are extremely aggressive neoplasms. Prior to use of chemotherapy, the average survival of AML patients was 6 weeks.  NORMAL HAEMOPOIESIS All pluripotent cells in the BM proliferate into 2 major cell lineages: - myeloid and lymphoid ( B and T). Myeloid cells proliferate into their mature end cells within BM. Lymphoid precursors migrate to the lymphoid organs (e.g. lymph nodes, spleen, and thymus) to complete maturation. Blood. 2005 May 1;105(9):3397-404. Sharma NS, Choudhary B. Good Cop, Bad Cop: Profiling the Immune Landscape in Multiple Myeloma. Biomolecules. 2023 Nov 7;13(11):1629. PMID: 38002311. ACUTE LEUKAEMIA An uncontrolled proliferation of myeloid or lymphoid blasts. Cells are blocked at an early stage of differentiation and have a proliferative advantage. These can invade BM, blood and extramedullary sites. Often replace normal haematopoietic cells in the BM  life threatening cytopenias.  EPIDEMIOLOGY Acute leukaemia arise from multiple genetic mutations  both unchecked proliferation and abnormal or no maturation. The median age at presentation of AML is 65 years and is the most common type of acute leukaemia in adults. APL patients are often younger. ALL is common in children, with peak incidence between ages of 2 and 5 years. What is the correct order of normal granulocytic maturation? A. Myeloblast, Metamyelocyte, Myelocyte, Promyelocyte, Neutrophil. B. Myelocyte, Promyelocyte, Metamyelocyte, Myeloblast, Neutrophil. C. Myeloblast, Promyelocyte, Myelocyte, Metamyelocyte, Neutrophil. D. Promyelocyte, Myeloblast, Myelocyte, Metamyelocyte, Neutrophil. Name the cell that is not of myeloid origin A. Erythroblast B. Basophil C. Natural killer cell D. Neutrophil GENETIC ABNORMALITIES The pathogenic genomic abnormalities in haematopoietic stem and progenitor cells include: 1. structural cytogenetic abnormalities 2. mutations  leading to abnormal proliferative advantage. Translocation Image from Future Pharmacol. 2023, 3(1), 162-179; https://www.pathologyoutlines.com/topic/ leukemiaAMLwitht821q22q22.html https://www.intechopen.com/chapters/25663 RISK FACTORS Chromosomal abnormalities (e.g., Fanconi anaemia, Down syndrome etc.) Germline predisposition Drugs (i.e. chemotherapy) or benzene Radiation Other myeloid malignancies CLINICAL PRESENTATION Symptoms of bone marrow failure - Anaemia; dyspnoea, palpitations, fatigue, headache etc. - Thrombocytopenia; mucocutaneous bleeding (easy bruising, petechiae, epistaxis, bleeding gums, menorrhagia etc.) - Neutropenia; infections  Infiltration by blasts leads to bone marrow failure Normal bone marrow aspirate and trephine biopsy Images from www.askhematologist.com https://www.quora.com/ https:// www.independent.co.uk/  Tissue infiltration – gingival hyperplasia, lymphadenopathy, hepatomegaly, splenomegaly, CNS, scrotum etc. Joint and bone pain (paediatric Image from www.askhematologist.com population) - limping or refusing to walk.  ACUTE PROMYELOCYTIC LEUKAEMIA Up to 14% of patients diagnosed with APL are dead within 30 days of diagnosis. Many of these are due to haemorrhage and disseminated intravascular coagulation (DIC). Bleeding is a result of a low fibrinogen level and thrombocytopenia. Images from www.askhematologist.com APL CONTINUED…… Accumulation of abnormal promyelocytes. The release of procoagulant granules from the abnormal promyelocytes  DIC  haemorrhage. The translocation t(15;17) is unique to this disease. Involves the PML gene (promyelocytic leukaemia) on chr 15 and the RARa gene (retinoic acid receptor-alpha) on chr 17. A maturation block  myeloid precursors unable to mature beyond the promyelocyte stage. https://www.pathologystudent.com/acute- promyelocytic-leukemia/ HYPERVISCOSITY More common in AML Seen with WBC counts >100 x 109/L Intravascular accumulation of these quickly proliferating cells  increased viscosity of blood  thrombotic complications. A fundoscopic examination is helpful in making a diagnosis. Image from www.askhematologist.com The PML-RARA fusion gene is the same as which translocation? A. t(15;17) B. t(8;21) C. t(9;22) D. t(12;21) ACUTE MYELOID LEUKAEMIA AML has an incidence of ~2-3 per 1000 per annum in children, increasing to 15 per 1000 in older adults. It can occur in all ages but has its peak incidence in the 7 th decade. Survival expectations remain age-dependent, with a 62% estimated 5-year survival in patients diagnosed under the age of 50 years, 37% in 50–64 years, and only 9·4% in ≥ 65 years. Initially classified according to morphology i.e. FAB classification  genetic abnormalities used to classify AML as its linked to prognosis. ACUTE LYMPHOBLASTIC LEUKAEMIA ALL is primarily a disease of childhood, ~75% of cases in children 90% survive without disease in the long term. The outcome of older adults (≥40 years) and patients with relapsed or refractory disease remains poor. B lymphoblastic leukaemia >T lymphoblastic leukaemia. 10% of patients have organ involvement – splenomegaly, hepatomegaly, LAD, testicular swelling, CNS etc. TALL can present with large mediastinal masses  superior vena cava obstruction. DIAGNOSIS Clinical history and examination FBC, differential count and peripheral smear CXR - lymphadenopathy or an enlarged thymus. CEU, LFT’s, PT, PTT, LDH, Uric acid etc. Image from www.askhematologist.com  Auer rod - Full blood count: AML White cell count – low, high or normal Haemoglobin – usually low (anaemia) Platelets – usually low (thrombocytopenia)  typically severe decrease in counts Need to request a differential count, to check WBC composition & neutrophils  pancytopenia = neutropenia, anaemia and thrombocytopenia. Peripheral smear – increase in BLASTS. Acute leukaemia ≥20% blasts in the blood or BM but……… Some acute leukaemia with specific genetic abnormalities can be diagnosed with 50 < 66 chromosomes t(12;21) Bad prognosis t(9;22) KMT2A gene rearrangement –11q23 Slide from Dr P Keene EXAMPLES OF IMPORTANT GENETIC FEATURES IN AML Good prognosis t(8;21) Inversion 16 Bad prognosis Complex karyotype MANAGEMENT Supportive therapy - should be initiated to correct haematologic, metabolic and infectious complications. - transfusions, antibiotics, fluids etc. Specific therapy Chemotherapy – systemic and CNS Allogeneic haemopoietic stem cell transplantation CHEMOTHERAPY Work by impairing mitosis  targeting rapidly dividing cells. They prevent mitosis by various mechanisms including damaging DNA. Familiarity with the agents used is required to prevent or anticipate and treat toxicities timeously. Many side effects are due to damage to normal cells that divide rapidly e.g. BM, digestive tract and hair follicles. CHEMOTHERAPY SIDE EFFECTS Short term; hair loss, immunosuppression, cytopenias, nausea and vomiting, skin rash, mucositis etc. Long term - Infertility – consider fertility preservation prior to chemotherapy. - Secondary malignancies Image from www.askhematologist.com BASIC PRINCIPLES OF TREATMENT Induction – the goal is to completely eradicate blast cells intensive chemotherapy - this is the most risky time during the patient’s treatment; at risk of infections and chemotherapy side effects. Consolidation – for patients in complete remission (CR) to eliminate residual leukaemic blasts and prevent relapse. - better tolerated than induction therapy as the patient has achieved PRINCIPLES OF TREATMENT CONTINUED……. Maintenance – to maintain remission, for up to 2 to 3 years. CNS directed therapy – in ALL, to prevent and treat CNS disease. - given at all the phases of therapy. RESPONSE TO TREATMENT Complete remission – absence of extra-medullary disease (no LAD, hepatomegaly, splenomegaly etc.) - absolute neutrophil count > 1 x 10 9/L - platelet count >100 x 109 /L -