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This information is produced and provided by the National Cancer Institute (NCI). The information in this topic may have changed since it was written. For the most current information, contact the National Cancer Institute via the Internet web site at http://cancer.gov or call 1-800-4-CANCER.
Cancer in children and adolescents is rare, although the overall incidence of childhood cancer, including ALL, has been slowly increasing since 1975. Dramatic improvements in survival have been achieved in children and adolescents with cancer.[1,2,3] Between 1975 and 2010, childhood cancer mortality decreased by more than 50%.[1,2,3] For ALL, the 5-year survival rate has increased over the same time from 60% to approximately 90% for children younger than 15 years and from 28% to more than 75% for adolescents aged 15 to 19 years. Childhood and adolescent cancer survivors require close monitoring because cancer therapy side effects may persist or develop months or years after treatment. (Refer to the PDQ summary on Late Effects of Treatment for Childhood Cancer for specific information about the incidence, type, and monitoring of late effects in childhood and adolescent cancer survivors.)
ALL is the most common cancer diagnosed in children and represents approximately 25% of cancer diagnoses among children younger than 15 years.[2,3] In the United States, ALL occurs at an annual rate of approximately 41 cases per 1 million people aged 0 to 14 years and approximately 17 cases per 1 million people aged 15 to 19 years. There are approximately 3,100 children and adolescents younger than 20 years diagnosed with ALL each year in the United States. Since 1975, there has been a gradual increase in the incidence of ALL.[4,6]
A sharp peak in ALL incidence is observed among children aged 2 to 3 years (>90 cases per 1 million per year), with rates decreasing to fewer than 30 cases per 1 million by age 8 years.[2,3] The incidence of ALL among children aged 2 to 3 years is approximately fourfold greater than that for infants and is likewise fourfold to fivefold greater than that for children aged 10 years and older.[2,3]
The incidence of ALL appears to be highest in Hispanic children (43 cases per 1 million).[2,3,7,8] The incidence is substantially higher in white children than in black children, with a nearly threefold higher incidence of ALL from age 2 to 3 years in white children than in black children.[2,3,7]
Childhood ALL originates in the T and B lymphoblasts in the bone marrow (refer to Figure 1).
Figure 1. Blood cell development. Different blood and immune cell lineages, including T and B lymphocytes, differentiate from a common blood stem cell.
Marrow involvement of acute leukemia as seen by light microscopy is defined as follows:
Almost all patients with ALL present with an M3 marrow.
Risk Factors for Developing ALL
Few factors associated with an increased risk of ALL have been identified. The primary accepted risk factors for ALL and associated genes (when relevant) include the following:
Children with Down syndrome have an increased risk of developing both ALL and AML,[20,21] with a cumulative risk of developing leukemia of approximately 2.1% by age 5 years and 2.7% by age 30 years.[20,21]
Approximately one-half to two-thirds of cases of acute leukemia in children with Down syndrome are ALL, and about 2% to 3% of childhood ALL cases occur in children with Down syndrome.[22,23,24] While the vast majority of cases of AML in children with Down syndrome occur before the age of 4 years (median age, 1 year), ALL in children with Down syndrome has an age distribution similar to that of ALL in non-Down syndrome children, with a median age of 3 to 4 years.[22,23]
Patients with ALL and Down syndrome have a lower incidence of both favorable (t(12;21)(p13;q22)/ETV6-RUNX1 [TEL-AML1]) and hyperdiploidy [51-65 chromosomes]) and unfavorable (t(9;22)(q34;q11.2)) or t(4;11)(q21;q23) and hypodiploidy [<44 chromosomes]) cytogenetic findings and a near absence of T-cell phenotype.[22,23,24,25,26]
Approximately 50% to 60% of cases of ALL in children with Down syndrome have genomic alterations affecting CRLF2 that generally result in overexpression of the protein produced by this gene, which dimerizes with the interleukin-7 receptor alpha to form the receptor for the cytokine thymic stromal lymphopoietin.[27,28,29]CRLF2 genomic alterations are observed at a much lower frequency (<10%) in children with precursor B-cell ALL who do not have Down syndrome.[29,30,31] Based on the relatively small number of published series, it does not appear that genomic CRLF2 aberrations in patients with Down syndrome and ALL have prognostic relevance.[26,28] However, IKZF1 gene deletions, observed in up to 35% of patients with Down syndrome and ALL, have been associated with a significantly worse outcome in this group of patients.[28,32]
Approximately 20% of ALL cases arising in children with Down syndrome have somatically acquired JAK2 mutations,[27,28,33,34,35] a finding that is uncommon among younger children with ALL but that is observed in a subset of primarily older children and adolescents with high-risk precursor B-cell ALL. Almost all Down syndrome ALL cases with JAK2 mutations also have CRLF2 genomic alterations.[27,28,29] Preliminary evidence suggests no correlation between JAK2 mutation status and 5-year event-free survival in children with Down syndrome and ALL,[28,34] but more study is needed to address this issue, as well as the prognostic significance of CRLF2 alterations and IKZF1 gene deletions in this patient population.
Low- and high-penetrance inherited genetic variants
Genetic predisposition to ALL can be divided into the following several broad categories:
Prenatal origin of childhood ALL
Development of ALL is in most cases a multistep process, with more than one genomic alteration required for frank leukemia to develop. In at least some cases of childhood ALL, the initial genomic alteration appears to occur in utero. Evidence to support this comes from the observation that the immunoglobulin or T-cell receptor antigen rearrangements that are unique to each patient's leukemia cells can be detected in blood samples obtained at birth.[49,50] Similarly, in ALL characterized by specific chromosomal abnormalities, some patients have blood cells that carry at least one leukemic genomic abnormality at the time of birth, with additional cooperative genomic changes acquired postnatally.[49,50,51] Genomic studies of identical twins with concordant leukemia further support the prenatal origin of some leukemias.[49,52]
Evidence also exists that some children who never develop ALL are born with very rare blood cells carrying a genomic alteration associated with ALL. For example, in one study, 1% of neonatal blood spots (Guthrie cards) tested positive for the ETV6-RUNX1 translocation, far exceeding the number of cases of ETV6-RUNX1 ALL in children. Other reports confirm  or do not confirm [55,56] this finding, and methodological issues related to fluorescence in situ hybridization testing complicate interpretation of the initial 1% estimate.
The typical and atypical symptoms and clinical findings of childhood ALL have been published.[58,59,60]
The diagnostic evaluation needed to definitively diagnose childhood ALL has been published.[58,59,60,61]
The 2016 revision to the World Health Organization classification of tumors of the hematopoietic and lymphoid tissues lists the following entities for acute lymphoid leukemias:
Key clinical and biological characteristics, as well as the prognostic significance for these entities, are discussed in the Cytogenetics/genomics alterations section of this summary.
Overall Outcome for ALL
Among children with ALL, approximately 98% attain remission, and approximately 85% of patients aged 1 to 18 years with newly diagnosed ALL treated on current regimens are expected to be long-term event-free survivors, with over 90% surviving at 5 years.[63,64,65,66]
Despite the treatment advances in childhood ALL, numerous important biologic and therapeutic questions remain to be answered before the goal of curing every child with ALL with the least associated toxicity can be achieved. The systematic investigation of these issues requires large clinical trials, and the opportunity to participate in these trials is offered to most patients and families.
Clinical trials for children and adolescents with ALL are generally designed to compare therapy that is currently accepted as standard with investigational regimens that seek to improve cure rates and/or decrease toxicity. In certain trials in which the cure rate for the patient group is very high, therapy reduction questions may be asked. Much of the progress made in identifying curative therapies for childhood ALL and other childhood cancers has been achieved through investigator-driven discovery and tested in carefully randomized, controlled, multi-institutional clinical trials. Information about ongoing clinical trials is available from the NCI website.
Current Clinical Trials
Check the list of NCI-supported cancer clinical trials that are now accepting patients with childhood acute lymphoblastic leukemia. The list of clinical trials can be further narrowed by location, drug, intervention, and other criteria.
General information about clinical trials is also available from the NCI website.