) Childhood acute lymphoblastic leukemia (ALL) is a model of a curable malignancy. The best therapies to date have resulted in cure for 75-80 percent of childhood ALL, although only 35 percent for adult ALL. Most survivors of childhood ALL have sequelae of treatment. The goal of Project 4 is to maximize the therapeutic index (the efficacy:toxicity balance) in the treatment of ALL. We seek to increase the proportion of patients cured, assess the long-term outcome of anti-leukemia therapy, and augment the usual event-free survival comparisons of treatment programs by use of methods to adjust survival for its quality. In a randomized clinical trial, we will determine the relative efficacy of an augmented intensification regimen and a conventional intensification regimen (Core 9001). We will also extend our program to adult patients (ages 18-40 years) and assess biological (Projects 4, 7, 8, 9) and outcome differences of adults compared to children with ALL.
Specific Aim 1 will determine the efficacy and toxicity of pharmacokinetically-based, individualized dosing of E.coli asparaginase - a pillar of our successful program.
Specific Aim 2 will test the hypothesis that L-carnitine can decrease late doxorubicin-induced cardiomyopathy. (We will continue our long-term assessment of the value of serial cardiac monitoring during doxorubicin therapy, as well as the long-term natural history of doxorubicin-induced cardiomyopathy, continuous infusions of doxorubicin, and cardioprotection with dexrazoxane).
Specific Aim 3 will define the efficacy and neuropsychologic morbidity of either intensive intrathecal therapy or radiation therapy.
In Specific Aim 4 quality-adjusted analyses using Q-TWiST and QALY methods will evaluate the trade-off between the benefit of improved cure rates and the cost in terms of treatment-related toxicity. We seek to determine the most effective, least toxic therapies for ALL, balancing health-related quality of life against the proportion of patients cured, thus maximizing the therapeutic index.
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