Pediatric Acute Lymphoblastic Leukemia 

Acute lymphoblastic leukemia (ALL) is the most common malignancy diagnosed in children, representing nearly one third of all pediatric cancers. The annual incidence of acute lymphoblastic leukemia within the United States is 3.7-4.9 cases per 100,000 children age 0-14 years,^[1] with a peak incidence in children aged 2-5 years.

Although a few cases are associated with inherited genetic syndromes (eg, Down syndrome) or congenital immunodeficiencies (eg, Wiskott-Aldrich syndrome, ataxia-telangiectasia), the cause remains largely unknown.^[2]

With improvements in diagnosis and treatment, overall cure rates for children with acute lymphoblastic leukemia have reached 90%.^[3] The use of risk-adapted treatment protocols has improved cure rates while limiting the toxicity of therapy. This article summarizes the current diagnosis and treatment of childhood acute lymphoblastic leukemia.

In acute lymphoblastic leukemia (ALL), a lymphoid progenitor cell becomes genetically altered and subsequently undergoes dysregulated proliferation, with clonal expansion. In ALL, the transformed lymphoid cells reflect the altered expression of genes usually involved in the normal development of B cells and T cells. Several studies indicate that leukemic stem cells are present in certain types of acute lymphoblastic leukemia.

Annually, around 3000 children in the United States are diagnosed with ALL. The annual incidence of ALL within the United States is 3.7-4.9 cases per 100,000 children 0-14 years of age.^[1] with a similar estimated worldwide incidence, although it has been questioned whether the incidence may be less in low-income countries.^[4] White children are more frequently affected than black children, and there is a slight male preponderance, which is most pronounced for T-cell acute lymphoblastic leukemia. The incidence of acute lymphoblastic leukemia peaks in children aged 2-5 years and subsequently decreases with age.

Although a few cases are associated with inherited genetic syndromes (eg, Down syndrome) or congenital immunodeficiencies (eg, Wiskott-Aldrich syndrome, ataxia-telangiectasia), the cause remains largely unknown.^[2] Environmental risk factors such as exposure to ionizing radiation and electromagnetic fields and parental use of alcohol and tobacco have not been shown to cause pediatric acute lymphoblastic leukemia. In addition, no direct link has been established between viral exposure and the development of childhood leukemia.

The likelihood of long-term cure in ALL depends on the clinical and laboratory features and the treatment. Prognostic risk assessment includes clinical features (age and white blood cell [WBC] count at diagnosis), biologic characteristics of the leukemic blasts, response to the induction chemotherapy, and minimal residual disease (MRD) burden. Based on these criteria, patients can be effectively stratified into low risk, average or standard risk, high risk, and very high risk.^[5]

Standard-risk patients are aged 1-9.9 years with WBC of less than 50,000 at presentation, lack unfavorable cytogenetic features, and show a good response to initial chemotherapy, with less than 5% bone marrow blasts by 14 days and less than 0.01% blasts by 28 days (rapid early response). Low-risk patients meet all these criteria and have favorable cytogenetics (eg, trisomy 4, 10, 17). High-risk patients do not meet these criteria or have extramedullary involvement that makes it inappropriate for them to be treated as standard risk. Very-high-risk patients have unfavorable cytogenetic features (Philadelphia chromosome, hypodiploidy (n < 44, MLL gene rearrangement) or very poor response to initial chemotherapy (induction failure with MRD >1%).

Patients younger than 1 year with acute leukemia have disease that is biologically distinct with a poor outcome.^[6]

The 5-year event-free survival (EFS) varies considerably depending on risk category, from 95% (low risk) to 30% (very high risk), with infant leukemia having the worst outcomes: 20% for patients younger than 90 days. Overall, the cure rate for childhood acute lymphoblastic leukemia (ALL) is more than 80%.

Five-year survival rates for children diagnosed with acute lymphoblastic leukemia, the most common type in this group, rose to 90% from 2000-2005, which was up from 84% in 1990-1994.^[3] Improvement in survival was observed for all age groups of children, except for infants younger than 1 year. In low-income countries (LIC), therapy results for pediatric ALL have been less encouraging due to delayed diagnosis, abandonment of therapy, and death from toxicity due to suboptimal supportive care. Nevertheless, improved supportive care with intensive therapy protocols has increased current 4-year event-free survival rates to 61% in India^[7] , and over 78% in Lebanon^[8] , demonstrating that pediatric ALL is potentially highly curable in LIC.

An analysis of long-term survival among 21,626 people who were treated for leukemia as children in Clinical Oncology Group trials from 1990-2005 found that 10-year survival rose to almost 84% in 1995-1999 from 80% in 1990-1994. The analysis also found that survival improved for almost all groups, including older children and black children.^[3]

Acute complications may involve all organ systems and include the following:

• Tumor lysis syndrome
• Renal failure
• Sepsis
• Bleeding
• Thrombosis
• Typhlitis
• Neuropathy
• Encephalopathy
• Seizures

In addition, lifelong follow-up is necessary,^[9] because survivors may experience late effects from treatment for this condition, such as the following:

• Secondary malignancy
• Short stature (if craniospinal radiation)
• Growth hormone deficiency
• Learning disability
• Cognitive defects

Ensure that the patient's parents and guardians understand that ALL usually does not have a known cause, that accurate stratification helps guide therapy, and that participating in institutional or consortium-based protocol therapy may help lead to better outcomes in the future. In addition, parents and guardians must know the expected adverse effects of each medication and be able to recognize signs and symptoms that require immediate medical attention, such as those for anemia, thrombocytopenia, and infection. Furthermore, parents and patients must know how to quickly access medical help from the oncology team.

For patient education information, see Cancer and Tumors Center, as well as Leukemia.