Treatment Option Overview
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 a human 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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