The incidence of ALL appears to be highest in Hispanic children (43 cases per million).[4,5] 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 compared with black children.[4,5]
Childhood ALL originates in the T- and B-lymphocytes in the bone marrow (see 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:
- 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.
- Shwachman syndrome.[9,10]
- Bloom syndrome.
- Ataxia telangiectasia.
- Inherited genetic polymorphisms.
Children with Down syndrome have an increased risk of developing both ALL and acute myeloid leukemia (AML),[13,14] with a cumulative risk of developing leukemia of approximately 2.1% by age 5 years and 2.7% by age 30 years.[13,14]
Approximately one-half to two-thirds of cases of acute leukemia in children with Down syndrome are ALL. 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.[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 lower incidence of T-cell phenotype.[15,16,17,18] Approximately 50% of children with Down syndrome and ALL have a recurring interstitial deletion of the pseudoautosomal region 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 children with B-precursor ALL who do not have Down syndrome.[19,20]
Approximately 20% of ALL cases arising in children with Down syndrome have somatically acquired JAK2 mutations,[21,22,23] 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. Almost all Down syndrome ALL cases with JAK2 mutations also have the pseudoautosomal region deletion and express the P2RY8-CRLF2 fusion gene. Preliminary evidence suggests no correlation between JAK2 mutation status and 5-year event-free survival in children with Down syndrome and ALL.