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Childhood Acute Lymphoblastic Leukemia Treatment (Professional) (cont.)

Treatment Option Overview

Treatment of childhood acute lymphoblastic leukemia (ALL) typically involves chemotherapy given for 2 to 3 years. Since myelosuppression and generalized immunosuppression are anticipated consequences of both leukemia and chemotherapy treatment, patients must be closely monitored at diagnosis and during treatment. Adequate facilities must be immediately available both for hematologic support and for the treatment of infections and other complications throughout all phases of therapy. Approximately 1% to 3% of patients die during induction therapy and another 1% to 3% die during the initial remission from treatment-related complications.[1,2] Children with ALL should be cared for at a center with specialized expertise in pediatric cancer.[3]

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 therapeutic innovations that produced increased survival rates in children with ALL have been established through nationwide clinical trials, and it is appropriate for children and adolescents with ALL to be offered participation in a clinical trial. 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.

Treatment for children with ALL is typically divided as follows:

  • Remission induction (at the time of diagnosis).
  • Postinduction therapy (after achieving complete remission).
    • Consolidation/intensification therapy.
    • Maintenance or continuation therapy.

Risk-Based Treatment Assignment

Risk-based treatment assignment is an important therapeutic strategy utilized for children with 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. The intensity of induction (some, but not all groups) is determined by National Cancer Institute (NCI) risk group and immunophenotype and postinduction therapy (all groups) is determined by prognostic factors such as early response determinations and cytogenetics.[4] With this treatment approach, 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.[5,6,7,8,9,10]

In COG protocols, a subset of the known prognostic factors (e.g., age, white blood cell [WBC] count at diagnosis, immunophenotype, and presence of extramedullary disease) 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 85% in children meeting good-risk criteria (aged 1–9 years, WBC count <50,000/ÁL, and precursor B-cell immunophenotype); in children meeting high-risk criteria, EFS rates are approximately 70%.[5,6,7,8,11] Additional factors, including cytogenetic abnormalities and measures of early response to therapy (e.g., day 7 and/or day 14 marrow blast percentage and minimal residual disease [MRD] levels at the end of induction), considered in conjunction with presenting age, WBC count, and immunophenotype, can identify patient groups with expected EFS rates ranging from less than 40% to greater than 95%.[11,12]

Subgroups of patients who have a poor prognosis with current risk-adapted, multiagent chemotherapy regimens may require different therapeutic approaches. For example, infants with ALL are at much higher risk for treatment failure than older children.[13,14] Infants with ALL are generally treated on separate protocols using more intensified regimens, although the likelihood of long-term EFS appears to be no better than 50% for infants with MLL translocations even with a more intensive therapeutic approach.[13,14,15,16] Infants with MLL translocations and other subsets of patients who have a less than 50% chance of long-term remission with current therapies (such as patients with hypodiploidy or with initial induction failure) are sometimes considered candidates for allogeneic stem cell transplantation in first remission.[15,17,18,19] However, because of small numbers, possible patient selection bias, and center preference, studies to definitively show whether CR1 transplantation is superior to intensive chemotherapy for these very high-risk patients have not been feasible.

Allogeneic bone marrow transplantation was once considered to be the treatment of choice for children with t(9;22) Philadelphia chromosome–positive (Ph+) ALL, especially those with high-risk clinical features (age >10 years or high initial leukocyte count) or poor early treatment response.[20,21] However, a COG study demonstrated a 3-year EFS rate of 80.5% in Ph+ patients treated with concurrent intensive chemotherapy and a tyrosine kinase inhibitor (imatinib) given daily during premaintenance therapy.[22] While longer follow-up is necessary to determine if this treatment regimen indeed improves cure rates or merely prolongs the duration of disease-free survival, these results suggest that the presence of the Philadelphia chromosome should no longer be considered an absolute indication for transplantation in first remission.

Treatment of Sanctuary Sites (Central Nervous System, Testes)

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). Approximately 3% of patients have detectable CNS involvement by conventional criteria at diagnosis (cerebrospinal fluid specimen with =5 WBC/ÁL with lymphoblasts and/or the presence of cranial nerve palsies). However, unless specific therapy is directed toward the CNS, the majority 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. Therapies that may be used for CNS prophylaxis include intrathecal chemotherapy and cranial radiation. CNS-penetrant systemic chemotherapy (such as intravenous methotrexate and high-dose cytarabine) and other drugs, including dexamethasone and asparaginase, may contribute to CNS prophylaxis as well. At present, most newly diagnosed children with ALL are treated without cranial radiation; many groups administer cranial radiation only to those patients considered to be at highest risk for subsequent CNS relapse, such as those with documented CNS leukemia at diagnosis (as defined above) (>5 WBC/ÁL with blasts; CNS3) and/or T-cell phenotype with high presenting WBC count.[23] Ongoing trials seek to determine if radiation can be eliminated from the treatment of all children with ALL without compromising survival or leading to increased rate of toxicities from upfront and salvage therapies.[7,8]

CNS-directed therapy is provided during premaintenance chemotherapy by all groups. Some protocols provide ongoing intrathecal chemotherapy during maintenance (COG, St. Jude Children's Research Hospital [SJCRH], and Dana-Farber Cancer Institute), while others do not (Berlin-Frankfurt-Muenster).

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.[24,25] The role of radiation therapy for testicular involvement is also unclear. A study from SJCRH suggests that a good outcome can be achieved with aggressive conventional chemotherapy without radiation.[24] The COG has also adopted this strategy for boys with testicular leukemia that resolves completely during induction chemotherapy.


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