The Leukaemias

The Leukaemias Year 4 · Paediatrics Collection: 4TH YEAR ALL NOTES / PAEDS / PAEDS 4.3 / Munge / ONCOLOGY -- Slide 1 The Leukaemias Dr Rose Munge Slide 2 Outline Definition Classification Pathophysiology Epidemiology Clinical Presentation Management Prognosis Slide 3 Introduction The leukemias are the most common malignant neoplasms in childhood Account for approximately 31% of all malignancies that occur in children younger than 15 yr.\nALL accounts for approximately 77% of cases of childhood leukemia, AML 11%, CML for 2–3%, and JMM for 1–2%.\nThe remaining cases consist of a variety of acute and chronic leukemias that do not fit classic definitions for ALL, AML, CML, or JMML Slide 4 The leukemias may be defined as a group of malignant diseases in which genetic abnormalities in a hematopoietic cell give rise to an unregulated clonal proliferation of cells.\nThe progeny of these cells have a growth advantage over normal cellular elements because of their increased rate of proliferation and a decreased rate of spontaneous apoptosis.\nThe result is a disruption of normal marrow function and marrow failure.\nThe clinical features, laboratory findings, and responses to therapy vary depending on the type of leukemia. Slide 5 Acute lymphoblastic leukemia (ALL ) Epidemiology Acute lymphoblastic leukemia is diagnosed in approximately 3,100 children and adolescents <20 yr old in the United States each year. \nPeak incidence at 2-3 yr of age and occurs more in boys than in girls at all ages. Slide 6 Epidemiology cont. More common in children with certain chromosomal abnormalities -Down syndrome, Bloom syndrome, ataxia-telangiectasia, and Fanconi anemia.\nIn identical twins, the risk to the second twin if one twin develops leukemia is greater than that in the general population. The risk is 70% if ALL is diagnosed in the first twin during the 1st yr of life and the twins shared the same (monochorionic) placenta.\nIf the first twin develops ALL by 5-7 yr of age, the risk to the second twin is at least twice that of the general population, regardless of zygosity. Slide 7 Etiology Is unknown Several genetic and environmental factors are associated with childhood leukemia.\nMost cases of ALL are thought to be caused by postconception somatic mutations in lymphoid cells. Exposure to medical diagnostic radiation both in utero and in childhood is associated with an increased incidence of ALL In certain developing countries, there is an association between B-cell ALL (B-ALL) and Epstein-Barr virus (EBV) infections. Slide 8 Factors predisposing to childhood leukaemia GENETIC CONDITIONS Down syndrome Fanconi anemia Bloom syndrome Diamond-Blackfan anemia Shwachman-Diamond syndrome Kostmann syndrome Neurofibromatosis type 1 Ataxia-telangiectasia Severe combined immune deficiency Paroxysmal nocturnal hemoglobinuria Li-Fraumeni syndrome ENVIRONMENTAL FACTORS Ionizing radiation Drugs Alkylating agents Epipodophyllotoxin Benzene exposure Slide 9 Cellular Classification of ALL Depends on characterizing the malignant cells in the bone marrow to determine the morphology, phenotype and cytogenetic and molecular genetic features. Morphology is usually adequate to establish diagnosis Other studies are essential for disease classification (have a major influence on the prognosis and the choice of appropriate therapy). 85% of cases of ALL are classified as B-lymphoblastic leukemia, 15% are T-lymphoblastic leukemia, 1% are derived from mature B cells. Slide 10 Immunophenotyping ALL cells rearrange their immunoglobulin and T-cell receptor (TCR) genes and express antigen receptor molecules that correspond to such processes in normal developing B and T lymphocytes, so that ALL can be classified as B-lineage or T-lineage ALL. Mature B-cell ALL should be differentiated from other B-lineage ALL and accounts for only 1-3% of childhood ALL. \nThe overall outcome for T-lineage and high risk B-lineage ALL is similar, provided intensive chemotherapy is used. Slide 11 The rare leukemia of mature B cells is termed Burkitt leukemia and is one of the most rapidly growing cancers in humans, requiring a different therapeutic approach than other subtypes of ALL.\n A small percentage of children with leukemia have a disease characterized by surface markers of both lymphoid and myeloid derivation. Slide 12 WHO classification of acute lymphoblastic leukemia B lymphoblastic leukemia/lymphoma: B-lymphoblastic leukemia/lymphoma, not otherwise specified (NOS) B-lymphoblastic leukemia/lymphoma with recurrent genetic abnormalities B-lymphoblastic leukemia/lymphoma with t(9;22)(q34.1;q11.2); BCR-ABL1 B-lymphoblastic leukemia/lymphoma with t(v;11q23.3); KMT2A rearranged B-lymphoblastic leukemia/lymphoma with t(12;21)(p13.2;q22.1); ETV6-RUNX1 B-lymphoblastic leukemia/lymphoma with hyperdiploidy B-lymphoblastic leukemia/lymphoma with hypodiploidy B-lymphoblastic leukemia/lymphoma with t(5;14)(q31.1;q32.3) IL3-IGH B-lymphoblastic leukemia/lymphoma with t(1;19)(q23;p13.3); T