After completion ofinduction and restoration ofnormal hematopoiesis, patients begin consolidation. The goal of consolidation is to administer dose-intensive chemotherapy

in an effort to further reduce the burden of residual leukemic cells. It is in this and subsequent treatment phases that the presence of MRD is reduced by increasing the aggressiveness of the drug regimen. Several regimens use agents and schedules designed to minimize the development of drug cross-resistance. Studies have demonstrated that this phase of treatment has proven to be an effective strategy in the prevention of relapse in children with ALL, but its benefits in adults are less clear.

In children, the intensity of the consolidation treatment is now determined not only by the child's risk classification but also by the rate of cytoreduction during induction.5 Patients who respond slowly to induction therapy (as determined by bone marrow examination early in induction) are at higher risk of relapse and are treated on more aggressive regimens.

Delayed Intensification

The Berlin-Frankfurt-Munster (BFM) Study Group introduced a treatment element called delayed intensification (or reinduction) therapy. This therapy consisted of repetition of the initial remission induction therapy administered approximately 3 months after remission. This, like consolidation, has been adopted as a component of treatment by virtually all institutions.13

Intensification regimens may vary in their aggressiveness and the drugs they use depending on the patient's risk group and immunophenotype. For example, the use of very-high-dose methotrexate (5 g/m ) appears to improve outcome in patients with

T-cell ALL. The use of intensive asparaginase treatment in T-cell ALL patients also

has improved outcomes significantly. Maintenance

The purpose of maintenance therapy is to further eliminate leukemic cells and produce an enduring CCR. The two most important agents in maintenance chemotherapy are a combination of oral methotrexate and 6-mercaptopurine. Improved outcome has been associated with increasing 6-mercaptopurine dosages to the limits of individual tolerance based on absolute neutrophil count (ANC). The goal is to induce a moderate immunosuppression and leukemic cell kill. 6-Mercaptopurine at usual doses causes significant neutropenia and its use has been associated with increased rates of infection. At lower doses, it is associated with poor leukemic activity and a higher rate of relapse. In both instances, 6-mercaptopurine is associated with the inability to deliver planned appropriate therapy. 6-Mercaptopurine is metabolized by thiopurine methyl-transferase (TPMT). TPMT deficiency is inherited as an autosomal recessive trait, with 89% to 94% of whites having high activity, 6% to 11% having intermediate activ ity, and 0.3% having very low or no activity. This deficiency is explained largely by three polymorphisms in the TPMT gene (*2, *3A, and *3C) that also have a profound influence on 6-mercaptopurine tolerance and dose-intensity in children with ALL. While these polymorphisms are rare, they are certainly important, with case reports of toxic deaths attributed to 6-mercaptopurine dating back several decades.

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