Risk-based treatment assignment is an important therapeutic strategy utilized for children with acute lymphoblastic leukemia (ALL). This approach allows children who historically have a very good outcome to be treated with modest therapy and to be spared more intensive and toxic treatment, while allowing children with a historically lower probability of long-term survival to receive more intensive therapy that may increase their chance of cure. As discussed in the Cellular Classification and Prognostic Variables section of this summary, a number of clinical and laboratory features have demonstrated prognostic value. A subset of the known prognostic factors (e.g., age, white blood cell [WBC] count at diagnosis, presence of specific cytogenetic abnormalities) are used for the initial stratification of children with ALL into treatment groups with varying degrees of risk of treatment failure. Event-free survival (EFS) rates exceed 80% in children meeting good-risk criteria for age and WBC count; in children meeting high-risk criteria, EFS rates are approximately 70%.[1-4] Application of biological factors (e.g., specific chromosomal translocations and hypodiploidy) can identify patient groups with expected outcome survival rates ranging from less than 40% to more than 95%.[5,6]

Nationwide clinical trials are generally available for children with ALL, with specific protocols designed for children at standard (low) risk of treatment failure and for children at higher risk of treatment failure. Clinical trials for children with ALL are generally designed to compare therapy that is currently accepted as standard for a particular risk group with a potentially better treatment approach that may improve survival outcome and/or diminish toxicities associated with the standard treatment regimen. Many of the improvements in therapy that have led to increased survival rates in children with ALL have been made through nationwide clinical trials,[7,8] and it is appropriate for children and adolescents with ALL to be offered participation in a clinical trial. In addition, treatment planning by a multidisciplinary team of pediatric cancer specialists with experience and expertise in treating leukemias of childhood is required to determine and implement optimum treatment. This treatment is best accomplished in a center with specialized expertise in pediatric cancer.[9]

Older children and adolescents (≥10 years) and infants (<12 months) have a less favorable outcome than children aged 1 to 9 years at diagnosis, and more aggressive treatments are generally employed for these patients.[10] Increasing evidence demonstrates a significant advantage for adolescents with ALL being treated on pediatric-based treatment protocols.[11] A report from France of 15- to 20-year-old patients diagnosed between 1993 and 1999 showed superior outcome in patients treated on a pediatric trial (67% 5-year EFS) compared with patients treated on an adult trial (41% 5-year EFS).[12] The reason for these differences is not known, though possible explanations include treatment setting (i.e., site experience in treating ALL), adherence to protocol therapy, and components of protocol therapy itself.

Successful treatment of children with ALL requires the control of systemic disease (e.g., marrow, liver and spleen, lymph nodes) as well as the prevention or treatment of extramedullary disease, particularly in the central nervous system (CNS). Only 3% of patients have detectable CNS involvement by conventional criteria at diagnosis (≥5 WBC/μL with lymphoblast cells present). Unless specific therapy is directed toward the CNS, however, 50% to 70% or more of children will eventually develop overt CNS leukemia. Therefore, all children with ALL should receive systemic combination chemotherapy together with some form of CNS prophylaxis. At present, most groups treat patients with documented CNS leukemia at diagnosis (>5 WBC/μl with blasts; CNS3), and those with T-cell phenotype and high WBC count at diagnosis, with intrathecal therapy and subsequent cranial radiation.

Treatment for children with ALL is divided into stages: remission induction, consolidation or intensification, and maintenance (continuation) therapy, with CNS sanctuary therapy generally provided in each stage. An intensification phase of therapy following remission induction is used for all patients. The intensity of both induction therapy and postinduction therapy is determined by the clinical and biologic prognostic factors utilized for risk-based treatment assignment and some type of early response assessment. This assessment may include day 7 and/or day 14 marrow blast percentage, day 8 peripheral blood blast count, and minimal residual disease determinations in bone marrow and/or peripheral blood during or at the end of induction.[5,13-15] The duration of therapy for children with ALL ranges between 2 and 3 years.

Overt testicular involvement at the time of diagnosis occurs in approximately 2% of males. In early ALL trials, testicular involvement at diagnosis was an adverse prognostic factor. With more aggressive initial therapy, however, the prognostic significance of initial testicular involvement is unclear.[16,17] The role of radiation therapy for testicular involvement is also unclear. A study from St. Jude Children's Research Hospital suggests that a good outcome can be achieved with aggressive conventional chemotherapy without radiation.[16] The Children's Oncology Group has also adopted this strategy.

Subgroups of patients who have a poor prognosis with current standard therapy may require different treatment. For example, infants with ALL are at higher risk for treatment failure, with the poorest prognosis for those with MLL gene rearrangements.[18-21] These children are generally treated with regimens designed specifically for infants.[21-24] Current regimens for infants employ intensified treatment approaches and may offer improved disease control compared with previous less intensive approaches, but long-term outcome and toxicity are unknown.[23-26] Certain children (older than 1 year) with ALL may have a less than 50% likelihood of long-term remission with current therapy (e.g., t[9;22] Philadelphia chromosome-positive ALL, hypodiploid patients, and those with initial induction failure). For these patients, allogeneic bone marrow transplantation from ahuman leukocyte antigen ( HLA)-matched sibling should be considered during first remission.[27-32] HLA-matched sibling donor transplant, however, has not been proven to be of benefit in patients defined as high-risk solely by WBC count, gender, and age.[33,34]

Since myelosuppression and generalized immunosuppression are an anticipated consequence of both leukemia and its treatment with chemotherapy, patients must be closely monitored during treatment. Adequate facilities must be immediately available both for hematologic support and for the treatment of infectious and other complications throughout all phases of leukemia treatment. Approximately 1% of patients die during induction therapy and another 1% to 3% die during first remission from treatment-related complications.[35]

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