immunologic-- immunophenotypes are found by monoclonal antibodies - B-progenitor cells T-progenitor cells, mature B cells

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1 Acute Lymphoblastic Leukemia and Acute Myeloid Leukemia Acute Lymphoblastic Leukemia Childhood ALL was the first form of cancer shown to be curable with chemotherapy and irradiation. Lymphoid leukemias occur more in patients with Down and Bloom's syndromes and in immunodeficiency diseases (e.g., congenital hypogammaglobulinemia, ataxiatelangiectasia). Epstein-Barr virus has been implicated in the pathogenesis of some cases of B-cell leukemia. PATHOLOGY. Classification of ALL depends on a combination of cytologic immunologic karyotypic features cytologic-- The French-American-British (FAB) system = three morphologic subtypes, L1 to L3. L1 lymphoblasts are small, with little cytoplasm L2 cells are larger increased cytoplasm, irregular nuclear shape, and prominent nucleoli L3 cells have homogeneous nuclear chromatin, prominent nucleoli, and deep blue cytoplasm with prominent vacuolation immunologic-- immunophenotypes are found by monoclonal antibodies - B-progenitor cells T-progenitor cells, mature B cells karyotypic-- karyotypes of leukemic cells have diagnostic, prognostic, and therapeutic significance. Childhood ALL can be classified by the number of chromosomes per leukemic cell (ploidy) and by structural chromosomal rearrangements such as translocations. Another biologic marker = terminal deoxynucleotidyltransferase (TdT) activity, is present in B-progenitor-cell and T-cell ALL. Because this enzyme is absent in normal lymphocytes, TdT activity in cells from cerebrospinal fluid (CSF) may help to distinguish early CNS relapse There is no anatomic staging system for ALL because at the time of presentation all organs are affected. CLINICAL MANIFESTATIONS. Onset of signs and symptoms -less than 4 wk at the time of diagnosis. nonspecific - anorexia, irritability, and lethargy. history of viral respiratory infection or exanthem - not recovering fully.

Epstein-Barr virus has been implicated in the pathogenesis of some cases of B-cell leukemia. PATHOLOGY.

2 Bone marrow failure leads to pallor, bleeding, petechiae, and fever On examination pale petechiae mucous membrane bleeding. fever, which may be falsely ascribed to an upper respiratory infection or otitis media. Lymphadenopathy splenomegaly hepatomegaly bone pain and arthralgias caused by leukemic infiltration of the perichondral bone or joint or by leukemic expansion of the marrow cavity. increased intracranial pressure =headache and vomiting, - leukemic meningeal involvement. anterior mediastinal mass in -- T-cell ALL DIAGNOSIS. CBC - hemoglobin levels below 6 g/dl. thrombocytopenia, white blood cell (WBC) counts may be normal or increased Blast cells on a peripheral blood smear Confirmed by examination of bone marrow - aspiration, biopsy marrow is initially hypocellular. Cytogenetic studies - useful in identifying - preleukemic syndromes. Cytogenetic studies can be performed on biopsy specimens if they are placed in tissue culture medium. Chest X ray PA view erect for mediastinal mass. Bone X ray - altered medullary trabeculae, cortical defects, or subepiphyseal bone resorption. CSF should be examined for leukemic cells, as early involvement of the CNS has important prognostic and therapeutic implications. Uric acid level and renal function should be determined before treatment is started DIFFERENTIAL DIAGNOSIS. bone marrow failure due to Aplastic anemia and myelofibrosis. Infectious mononucleosis rheumatoid arthritis Pertussis Infiltration of the marrow by other types of malignant cells (Neuroblastoma, rhabdomyosarcoma, Ewing's sarcoma, and retinoblastoma) can produce pancytopenia. TREATMENT. Factors of risk of relapse are ages nelow 1 and above 10 yr

Lymphadenopathy splenomegaly hepatomegaly bone pain and arthralgias caused by leukemic infiltration of the perichondral bone or joint or by leukemic expansion of the marrow cavity.

3 WBC count under 100,000/mm3, lack evidence of a mediastinal mass or CNS leukemia, B-progenitor cell immunophenotype. presence of certain specific chromosomal translocations Steps - induction chemotherapy --prednisone, vincristine, and L-asparaginase for 4 wk 5% of patients require another 2 wk of induction therapy prophylactic treatment of the CNS continuation chemotherapy includes - methotrexate and 6-mercaptopurine plus vincristine and prednisone for 2 to 3 yr. Leukemic cells are usually present in the meninges at diagnosis even if they are not identifiable in the CSF. We give intrathecal chemotherapy with Methotrexate, Hydrocortisone & Cytosar to prevent clinical CNS involvement. RELAPSE. The bone marrow is the most common site of relapse, If bone marrow relapse is detected, intensive therapy that includes drugs not used previously patients who experience bone marrow relapse during treatment, intensive chemotherapy followed by bone marrow transplantation from a matched sibling or related donor Autologous, haploidentical, or matched unrelated donor transplants are options for those without histocompatible sibling donors The most important extramedullary sites of relapse are - CNS and testes. manifestations of CNS leukemia - increased intracranial pressure and include vomiting, headache, Papilloedema, and lethargy. Chemical meningitis secondary to intrathecal therapy can produce the same symptoms Convulsions and isolated cranial nerve palsies Hypothalamic involvement - excessive weight gain or behavioral disturbances. CNS relapse = give intrathecal chemotherapy weekly for 4 to 6 wk until lymphoblasts have disappeared from the CSF. Cranial irradiation is the only treatment that completely eradicates CNS leukemia and is given after intrathecal therapy. Systemic treatment should also be intensified, preventive CNS therapy should be repeated Testicular relapse = produces painless swelling of one or both testicles. Look for testicular size at diagnosis and during follow-up. The diagnosis is confirmed by biopsy. Treatment should include irradiation of the gonads. testicular relapse usually means - bone marrow relapse PROGNOSIS. The overall cure rate for childhood ALL is estimated at about 80%. poor prognosis for -

prophylactic treatment of the CNS continuation chemotherapy includes - methotrexate and 6-mercaptopurine plus vincristine and prednisone for 2 to 3 yr.

4 1. Age older than 10 yr 2. Younger than 1 year 3. B-cell cases with L3 morphology and surface immunoglobulin 4. Chromosomal rearrangement involving the 11q23 region 5. Two chromosomal translocations the t(9;22), or Philadelphia chromosome, and the t(4;11) Favorable prognosis for Hyperdiploidy with more than 50 chromosomes Acute Myeloid Leukemia Trisomy 21, Diamond-Blackfan syndrome, Fanconi's aplastic anemia, Bloom's syndrome, Kostmann's syndrome, paroxysmal nocturnal hemoglobinuria, Li-Fraumeni syndrome, and neurofibromatosis are associated with a predisposition to development of AML. Exposure to drugs such as alkylating agents, epipodophyllotoxins, and nitrosoureas and to ionizing radiation are also associated with an increased risk of developing AML. CLINICAL MANIFESTATIONS. anemia, thrombocytopenia, neutropenia fatigue and pallor or heart failure secondary to anemia. Bruising, petechiae, epistaxis, or gum bleeding secondary to thrombocytopenia fever secondary to infection associated with neutropenia. hepatic or splenic enlargement, lymphadenopathy, gum hypertrophy. A localized mass of leukemic cells, known as a chloroma, may herald the onset of AML. Orbital or epidural locations are common sites of chloromas. Investigations - anemia thrombocytopenia WBC may be normal, high, or low. With extremely high WBC count (>100,000/mm3 ), sludging of blood due to increased viscosity and stickiness of the WBCs may occur, resulting in cerebrovascular symptoms DIAGNOSIS. demonstration of greater than 25% myeloblasts in the bone marrow. Characterization of the blasts morphologically, immunophenotypically, and immunohistochemically distinguishes ALL from AML. Within AML, the most commonly used classification system is the FAB, seven subtypes M1 to M7 Certain karyotypic abnormalities are associated with specific subtypes of AML. For example,

Diamond-Blackfan syndrome, Fanconi's aplastic anemia, Bloom's syndrome, Kostmann's syndrome, paroxysmal nocturnal hemoglobinuria, Li-Fraumeni syndrome, and neurofibromatosis are associated with a

5 t(15;17) is found in cases of acute promyelocytic leukemia (APL). APL is often associated with a life-threatening form of disseminated intravascular coagulation at presentation owing to release of procoagulant substances from the leukemic blast cells. Inversion of chromosome 16 is often associated with eosinophilia and the FAB M4 subtype. Secondary leukemia is associated with chromosomal abnormalities, which affect 11q23 or with monosomy 7. Myelodysplastic syndrome, which often evolves into AML, may have associated chromosomal changes such as trisomy 8 or deletion of chromosome 5 or 7 (monosomy). TREATMENT. Anthracycline and cytosine arabinoside supportive care with broad-spectrum antibiotics, antifungals, blood products nutritional CNS prophylaxis with intrathecal chemotherapy After initial induction of remission, -stem cell transplantation. Either bone marrow or peripheral blood stem cells can be used. The use of interleukin 2 to produce immune modulation with an antileukemic effect is under study during remission after completion of chemotherapy. Patients with APL benefit from retinoic acid. Such patients should not receive marrow transplants in first remission. Children with Down syndrome and AML have a particularly good cure rate PROGNOSIS. Cure rate is about 70% using chemotherapy followed by bone marrow transplantation. Myelodysplastic syndrome or secondary AML do not respond to chemotherapy. Children with AML who relapse have an extremely poor prognosis Compiled by Dr.N.S.Mani

Inversion of chromosome 16 is often associated with eosinophilia and the FAB M4 subtype. Secondary leukemia is associated with chromosomal abnormalities, which affect 11q23 or with monosomy 7.

Acute myeloid leukemia (AML)

Acute myeloid leukemia (AML) Adult acute myeloid leukemia (AML) is a type of cancer in which the bone marrow makes abnormal myeloblasts (a type of white blood cell), red blood cells, or platelets. Adult