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Acute Lymphoblastic Leukemia

Treatment of acute lymphoblastic leukemia (ALL) is one of the true success stories of modern oncology. During the last 50 years, acute lymphoblastic leukemia has gone from a uniformly fatal disease to an illness with an overall cure rate of acute leukemia

ALL is the most common malignancy in children. It accounts for one fourth of all childhood cancers and approximately 75% of all cases of childhood leukemia. Approximately 2500 to 3000 children are diagnosed with  acute leukemia each year in the United States, with an incidence of

The peak incidence of acute lymphoblastic leukemia occurs at approximately 4 years of age. Among children in the United States, ALL is more common among whites than blacks. This phenomenon may reflect a difference in susceptibility or in exposure to whatever environmental influences may be responsible for the early age peak in acute lymphoblastic leukemia, lymphocytic, lukemia, leukema, lekemia, ALL, lymphobastic. Despite early reports that the outcome for black children with ALL was worse than white children, later reports indicate

The incidence of ALL is higher among boys than girls; the difference is greatest among pubertal children. The male preponderance is particularly evident in cases of T-cell ALL. Despite speculation about a possible role for sex hormones in leukemogenesis, none has been established. There appear to be geographic differences in the frequency and age distribution of ALL. For example, in North Africa and the Middle East, ALL is relatively rare, and non-Hodgkin's lymphoma is the most common childhood malignancy. In India and China, ALL is somewhat more common, but its incidence is still considerably less than in


Genetic factors are presumed to play a significant role in the cause of acute leukemias, including ALL. Evidence is based on several observations, including the association between various constitutional chromosomal abnormalities and childhood ALL, the occurrence of familial leukemia, the high incidence of


In addition to genetics, environmental factors, viral infection, and immunodeficiency may predispose children to leukemia.

Environmental Factors

Exposure to ionizing radiation and certain toxic chemicals can facilitate the development of acute leukemia. The high incidence of leukemia among survivors of the atomic bomb explosions in 

Among survivors of the atomic bomb, there was no increase in the incidence of leukemia in children exposed to radiation in utero. This experience contrasts with other reports of an increased risk of leukemia in children exposed to diagnostic irradiation in utero, particularly during the first trimester. In a study by 

The possibility that exposure to electromagnetic fields (EMF) may be causally related to the development of childhood ALL is also the subject of controversy. Conflicting studies exist in the literature. A case-control evaluation of a population of children in Denver suggested a twofold to threefold higher incidence of childhood cancers, including ALL, among children living in proximity to high-voltage power lines. Similar studies from Sweden have shown increased risk from high-voltage power lines and from electric power lines

Chronic chemical exposure (e.g., benzene) has been associated with the development of ANLL in adults. Direct evidence linking exposure to the development of childhood ALL, however, does not exist. There is substantial evidence that chemotherapy, particularly with alkylating agents, has leukemogenic potential. Exposure to herbicides and pesticides; maternal use of alcohol, contraceptives, diethylstilbestrol, or cigarettes; parental occupational exposures to chemicals and solvents; and chemical contamination of ground water. Definitive links between

Viral Infection

There has been intense interest in the possible role played by viral infection in the pathogenesis of human leukemia. Some reports have suggested an increased risk for ALL in children born to mothers recently infected with influenza, varicella, or other viruses, but no definitive link between prenatal viral exposure and leukemic risk has been confirmed. No association between childhood viral infections and the occurrence of

The Epstein-Barr virus (EBV) has been linked to cases of endemic Burkitt's lymphoma and the L3 subtype of ALL, which is discussed further in the subsequent section on molecular genetics and in


Children with various congenital immunodeficiency diseases, including Wiskott-Aldrich syndrome, congenital hypogammaglobulinemia, and ataxia-telangiectasia, have an increased risk of developing lymphoid malignancies, as do patients receiving chronic treatment with immunosuppressive drugs. These are usually


The signs and symptoms of the child presenting with ALL reflect the degree of bone marrow infiltration with leukemic cells and the extent of extramedullary disease spread. The most common symptoms and clinical findings are usually manifestations of the underlying anemia, thrombocytopenia, and neutropenia, which reflect the failure of normal hematopoiesis. Pallor, fatigue, petechiae, purpura, bleeding, and fever are often present. Lymphadenopathy, hepatomegaly, and splenomegaly are manifestations of extramedullary leukemic spread. Hepatosplen-omegaly occurs in approximately two thirds of the patients and is usually asymptomatic. Lymphadenopathy, usually painless, may be

The duration of symptoms in children presenting with ALL may vary from days to months. Anorexia is common, but significant weight loss is infrequent. Bone pain, particularly affecting the long bones, is common and reflects leukemic involvement of the periosteum and bone. Young children present with a limp or refusal to walk. Bone tenderness is frequently observed. These symptoms and the presence of arthralgias, which

Central Nervous System Leukemia

The potential clinical impact of central nervous system leukemia did not become


The recognition that ALL is a heterogeneous disease and that children can be stratified into various risk groups has profoundly influenced therapy. Although combination chemotherapy remains the primary therapeutic modality, it is no longer considered appropriate, in the context of current biologic knowledge, for all patients with ALL to be treated on a

Induction Therapy

The initial aim of ALL treatment is induction of remission. By definition, patients in remission have no evidence of leukemia when evaluated by physical examination and hematologic assessment of bone marrow and peripheral blood. Peripheral blood values must be within the defined range of normality, and the bone marrow must be of normal cellularity, with fewer than 5% lymphoblasts. Complete remission status also

Although the basic two-drug combination of vincristine and prednisone induces remissions in approximately 85% of children with ALL, the addition of L-asparaginase, an anthracycline, or both improved the remission induction rate to approximately 95%. The addition of a third agent to vincristine and prednisone also significantly prolonged remission duration. Whether the added leukemic cell killing theoretically achieved by including a fourth induction agent leads to improvement in remission duration is controversial. The results of one randomized study indicated that adding daunorubicin (daunomycin) to the three-drug combination of vincristine, prednisone and L-asparaginase did

Consolidation and Maintenance Therapy

After complete remission has been achieved, additional maintenance or continuation therapy is required. Early studies demonstrated that without additional therapy, most patients relapse within a median of 1 to 2 months; the actual time of unmaintained remission varies with the intensity and duration of induction therapy. Patients in complete remission theoretically have a leukemic cell burden in the range of 10. Although

To be effective in preventing relapse, maintenance therapy must suppress leukemic growth and provide continuing leukemic cytoreduction, without permitting the emergence of a drug-resistant clone. In early clinical studies, a variety of single agents were evaluated as maintenance agents. Drugs particularly effective as induction agents were not useful for maintenance therapy. For example, continued treatment with vincristine and prednisone did not prolong remission duration. In contrast, maintenance treatment with methotrexate and 6-mercaptopurine substantially prolonged remission. The combination of methotrexate and 6-mercaptopurine, administered continuously, has been used most widely and constitutes the principle element in most maintenance therapy regimens. The optimal schedule of administration of these


Bone Marrow Relapse

Bone marrow relapse is the principal form of treatment failure in patients with ALL. Depending on the type of chemotherapy employed, complete remissions can be induced in most patients who experience an initial

Bone Marrow Transplantation

The use of bone marrow transplantation as a therapeutic approach for ALL patients who have suffered a bone marrow relapse has increased in recent years. This approach involves the administration of intensive cytoreductive therapy, usually employing total body irradiation and high-dose chemotherapy in doses lethal to normal bone marrow and subsequent hematopoietic "rescue" with intravenously infused bone marrow obtained from a compatible donor. To some degree, the initial interest in bone marrow transplantation was

Continual innovation and technological refinements have given bone marrow transplantation a significant role in the treatment of childhood ALL. Currently, allogeneic marrow transplantation is routinely advocated, particularly for patients in second remission who have an appropriate donor. In this group of patients, overall disease-free survivals range from

Better results are obtained in patients transplanted in remission than in those in relapse or partial remission. In most studies patients transplanted in earlier remissions fare significantly better than patients transplanted after multiple relapses. The length of first remission and high-risk features at diagnosis are predictive factors. Patients with shorter initial remissions and those with high-risk features at diagnosis fare worse when transplanted in second remission. Most studies that have compared the efficacy of allogeneic marrow transplantation with chemotherapy 

A retrospective analysis performed by the International Bone Marrow Transplant Registry (IBMTR) compared marrow transplantation with chemotherapy for children with ALL in second remission and