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Childhood Acute Lymphoblastic Leukemia Treatment (PDQ®)

Health Professional Version
Last Modified: 05/02/2014

General Information About Childhood Acute Lymphoblastic Leukemia (ALL)

Incidence and Epidemiology
Anatomy
Risk Factors for Developing ALL
        Down syndrome
        Inherited genetic polymorphisms
        Prenatal origin of childhood ALL
Clinical Presentation
Diagnosis
Overall Outcome for ALL
Current Clinical Trials

Fortunately, cancer in children and adolescents is rare, although the overall incidence of childhood cancer, including ALL, 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 following health care professionals and others to ensure that children receive treatment, supportive care, and rehabilitation that will achieve optimal survival and quality of life:

  • Primary care physician.
  • Pediatric surgical subspecialists.
  • Radiation oncologists.
  • Pediatric medical oncologists/hematologists.
  • Rehabilitation specialists.
  • Pediatric nurse specialists.
  • Social workers.
  • Child life professionals.
  • Psychologists.

(Refer to the PDQ Supportive and Palliative Care summaries for specific information about supportive care for children and adolescents with cancer.)

Guidelines for 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 ALL entails complicated risk assignment and therapies and the need for intensive supportive care (e.g., transfusions; management of infectious complications; and emotional, financial, and developmental support), evaluation and treatment are best coordinated by pediatric oncologists 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.[1,3,4] Between 1975 and 2010, childhood cancer mortality decreased by more than 50%.[3,4] 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 approximately 70% for adolescents aged 15 to 19 years.[1,3-5] 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.)

Incidence and Epidemiology

ALL is the most common cancer diagnosed in children and represents approximately 25% of cancer diagnoses among children younger than 15 years.[3,4] ALL occurs at an annual rate of 35 to 40 cases per 1 million people in the United States.[3,4,6] There are approximately 2,900 children and adolescents younger than 20 years diagnosed with ALL each year in the United States.[6,7] Over the past 25 years, there has been a gradual increase in the incidence of ALL.[3,4,8]

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.[3,4] 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.[3,4]

The incidence of ALL appears to be highest in Hispanic children (43 cases per 1 million).[3,4,6] 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.[3,4,6]

Anatomy

Childhood ALL originates in the T- and B-lymphoblasts in the bone marrow (see Figure 1).

Enlarge
Blood cell development; drawing shows the steps a blood stem cell goes through to become a red blood cell, platelet, or white blood cell. A myeloid stem cell becomes a red blood cell, a platelet, or a myeloblast, which then becomes a granulocyte (the types of granulocytes are eosinophils, basophils, and neutrophils). A lymphoid stem cell becomes a lymphoblast and then becomes a B-lymphocyte, T-lymphocyte, or natural killer cell.
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:

  • M1: Fewer than 5% blast cells.
  • M2: 5% to 25% blast cells.
  • M3: Greater than 25% blast cells.

Most patients with acute leukemia 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 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).

  • Genetic conditions that include the following:
    • Down syndrome.
    • Neurofibromatosis.[9]
    • Shwachman syndrome.[10,11]
    • Bloom syndrome.[12]
    • Ataxia telangiectasia.[13]

  • Inherited genetic polymorphisms.

Down syndrome

Children with Down syndrome have an increased risk of developing both ALL and acute myeloid leukemia (AML),[14,15] with a cumulative risk of developing leukemia of approximately 2.1% by age 5 years and 2.7% by age 30 years.[14,15]

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.[16-18] While the vast majority of cases of AML in children with Down syndrome occur before the age of 4 years (median age, 1 year),[19] 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.[16,17]

Patients with ALL and Down syndrome have a lower incidence of both favorable (t(12;21) and hyperdiploidy) and unfavorable (t(9;22) or t(4;11) and hypodiploidy) cytogenetic findings and a near absence of T-cell phenotype.[16-19] Approximately 50% to 60% of cases of ALL in children with Down syndrome have genomic alterations affecting CRLF2 that generally result in overexpression of this gene.[20-22] CRLF2 genomic alterations are observed at a much lower frequency (<10%) in children with B-precursor ALL who do not have Down syndrome.[22-24] It does not appear that genomic CRLF2 aberrations in patients with Down syndrome and ALL have prognostic relevance.[21] 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.[21]

Approximately 20% of ALL cases arising in children with Down syndrome have somatically acquired JAK2 mutations,[20,21,25-27] 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.[28] Almost all Down syndrome ALL cases with JAK2 mutations also have CRLF2 genomic alterations.[20-22] Preliminary evidence suggests no correlation between JAK2 mutation status and 5-year event-free survival in children with Down syndrome and ALL,[21,26] but more study is needed to address this issue and the prognostic significance of IKZF1 gene deletions.

Inherited genetic polymorphisms

Genome-wide association studies show that some germline (inherited) genetic polymorphisms are associated with the development of childhood ALL.[29] For example, the risk alleles of ARID5B are strongly associated with the development of hyperdiploid B-precursor ALL. ARID5B is a gene that encodes a transcriptional factor important in embryonic development, cell type–specific gene expression, and cell growth regulation.[30,31]

Prenatal origin of childhood ALL

Development of ALL is in most cases a multi-step 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 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.[32,33] Similarly, in ALL characterized by specific chromosomal abnormalities, some patients appear to have blood cells carrying at least one leukemic genomic abnormality at the time of birth, with additional cooperative genomic changes acquired postnatally.[32-34] Genomic studies of identical twins with concordant leukemia further support the prenatal origin of some leukemias.[32,35]

There is also evidence 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.[36] Other reports confirm [37] or do not confirm [38] this finding. Nonetheless, if confirmed, it would support the hypothesis that additional postnatal genomic changes are needed for the development of this type of ALL and that in most cases in which a leukemia-associated alteration is present at birth, the additional leukemogenic genomic changes do not occur and no leukemia develops.

Clinical Presentation

The typical and atypical symptoms and clinical findings of childhood ALL have been published.[39-41]

Diagnosis

The diagnostic evaluation needed to definitively diagnose childhood ALL has been published.[39-42]

Overall Outcome for ALL

Among children with ALL, more than 95% attain remission, and approximately 80% of patients aged 1 to 18 years with newly diagnosed ALL treated on current regimens are expected to be long-term event-free survivors.[43-48]

Despite the treatment advances noted 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/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 Web site.

Current Clinical Trials

Check for U.S. clinical trials from NCI's list of 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 Web site.

References
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