General Information About Childhood Acute Lymphoblastic Leukemia (ALL)

Incidence and Epidemiology
Risk Factors for Developing ALL
Overall Outcome for ALL

Fortunately, cancer in children and adolescents is rare, although the overall incidence of childhood cancer has been slowly increasing since 1975.[1] Children and adolescents with cancer should be referred to medical centers that have a multidisciplinary team of cancer specialists with experience treating the cancers that occur during childhood and adolescence. This multidisciplinary team approach incorporates the skills of the primary care physician, pediatric surgical subspecialists, radiation oncologists, pediatric medical oncologists/hematologists, rehabilitation specialists, pediatric nurse specialists, social workers, and others to ensure that children receive treatment, supportive care, and rehabilitation that will achieve optimal survival and quality of life. (Refer to the PDQ Supportive and Palliative Care summaries for specific information about supportive care for children and adolescents with cancer.)

Guidelines for pediatric cancer centers and their role in the treatment of pediatric patients with cancer have been outlined by the American Academy of Pediatrics.[2] Because treatment of children with acute lymphoblastic leukemia (ALL) entails many potential complications and requires intensive supportive care (e.g., transfusions; management of infectious complications; and emotional, financial, and developmental support), this treatment is best coordinated by pediatric oncologists and performed in cancer centers or hospitals with all of the necessary pediatric supportive care facilities. It is important that the clinical centers and the specialists directing the patient’s care maintain contact with the referring physician in the community. Strong lines of communication optimize any urgent or interim care required when the child is at home.

Dramatic improvements in survival have been achieved in children and adolescents with cancer.[1] Between 1975 and 2002, childhood cancer mortality has decreased by more than 50%. For ALL, the 5-year survival rate has increased over the same time from 60% to 89% for children younger than 15 years and from 28% to 50% for adolescents aged 15 to 19 years.[1] Childhood and adolescent cancer survivors require close follow-up 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 23% of cancer diagnoses among children younger than 15 years. ALL occurs at an annual rate of approximately 30 to 40 per million.[3,4] There are approximately 2,900 children and adolescents younger than 20 years diagnosed with ALL each year in the United States,[4,5] and there has been a gradual increase in the incidence of ALL in the past 25 years.[6] A sharp peak in ALL incidence is observed among children aged 2 to 3 years (>80 per million per year), with rates decreasing to 20 per million for ages 8 to 10 years. The incidence of ALL among children aged 2 to 3 years is approximately fourfold greater than that for infants and is nearly tenfold greater than that for adolescents aged 16 to 21 years.

For unexplained reasons, the incidence of ALL is substantially higher in white children than in black children, with a nearly threefold higher incidence from age 2 to 3 years in white children compared with black children.[3,4] The incidence of ALL appears to be highest in Hispanic children (43 per million).[3,4]

Few factors associated with an increased risk of ALL have been identified. The primary accepted risk factors for ALL include the following:

• Prenatal exposure to x-rays.
• Postnatal exposure to high doses of radiation (e.g., therapeutic radiation as previously used for conditions such as tinea capitis and thymus enlargement).
• Down syndrome and other genetic conditions.
• Inherited genetic polymorphisms.

Children with Down syndrome have an increased risk of developing both ALL and acute myeloid leukemia (AML),[7,8] with a cumulative risk of developing leukemia of approximately 2.1% by age 5 years and 2.7% by age 30 years.[7,8] Approximately one-half to two-thirds of cases of acute leukemia in children with Down syndrome are ALL. Patients with ALL and Down syndrome have a lower incidence of both favorable (t(12;21) and hyperdiploidy) and unfavorable (t(9;22), t(4;11), and hypodiploidy) cytogenetic findings and a lower incidence of T-cell phenotype.[9-12] Approximately 50% of children with Down syndrome and ALL have a recurring interstitial deletion of the pseudoautosomal region (PAR) of chromosomes X and Y that juxtaposes the first, noncoding exon of P2RY8 with the coding region of CRLF2. The resulting P2RY8-CRLF2 fusion gene is observed at a much lower frequency (<10%) in non-Down children with B-precursor ALL.[13,14] Approximately 20% of ALL cases arising in children with Down syndrome have somatically acquired JAK2 mutations,[15-17] 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 B-precursor ALL.[18] Almost all Down syndrome ALL cases with JAK2 mutations also have the PAR deletion and express the P2RY8-CRLF2 fusion gene.[13] Preliminary evidence suggests no correlation between JAK2 mutation status and 5-year event-free survival in children with Down syndrome and ALL.[16]

While the vast majority of cases of AML in children with Down syndrome occur before the age of 4 years (median age, 1 year),[9] 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.[10,11] Increased occurrence of ALL is also associated with other genetic conditions, including neurofibromatosis,[19] Shwachman syndrome,[20,21] Bloom syndrome,[22] and ataxia telangiectasia.[23]

Genome-wide association studies show that germline (inherited) genetic polymorphisms are associated with the development of childhood ALL.[24] For example, the risk alleles of ARID5B, a gene that encodes a transcriptional factor important in embryonic development, cell type–specific gene expression, and cell growth regulation, are strongly associated with the development of hyperdiploid B-precursor ALL.[25,26]

Some cases of ALL have a prenatal origin. Evidence in support of 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.[27,28] Similarly, in ALL characterized by specific chromosomal abnormalities, data exist to support that patients had blood cells carrying the abnormalities at the time of birth with additional cooperative genetic changes acquired postnatally.[27-29] In one study, 1% of neonatal blood spots (Guthrie cards) tested positive for the TEL-AML1 translocation, far exceeding the number of cases of TEL-AML ALL in children.[30] Other reports confirm [31] and do not confirm [32] this finding; nonetheless, this may support the hypothesis that additional genetic changes are needed for the development of this type of ALL. Genetic studies of identical twins with concordant leukemia further support the prenatal origin of some leukemias.[33]

Among children with ALL, more than 95% attain remission and 75% to 90% survive free of leukemia recurrence at least 5 years from diagnosis with current treatments that incorporate systemic therapy (e.g., combination chemotherapy) and specific central nervous system preventive therapy (e.g., intrathecal chemotherapy with or without cranial radiation).[34-39]

Despite the treatment advances noted in childhood ALL, numerous important biologic and therapeutic questions remain to be answered to achieve the goal of curing every child with ALL with the least associated toxicity. The systematic investigation of these issues requires large clinical trials, and the opportunity to participate in these trials is offered to most patients/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 clinical trials. Information about ongoing clinical trials is available from the NCI Web site.

References

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