This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Primary objectives 1.1 In conjunction with POG 9905, to compare short MTX infusion (2g/m2 over 4 hours) with a longer infusion (1g/m2 over 24 hours), primarily with respect to efficacy and secondarily with respect to toxicity. 1.2 In conjunction with POG 9905, to determine in a randomized trial, if a delayed multi-drug intensification, administered in the context of intensive anti-metabolite therapy, will improve outcome for children with ALL. Modern chemotherapy provides cure for 60-65% of children with newly diagnosed acute lymphoblastic leukemia (1,2). Favorable subgroups have much superior cure rates approaching 85% (3,4,5). In addition to age and white count risk groups, many studies have indicated a prognostic role for cytogenetic analysis of lymphoblasts (6). Analysis of data from ALinC 14 (POG 8602) indicates that favorable outcome may be best predicted by recognition of patients whose blasts contain simultaneous trisomies of chromosomes 4 and 10 (7). An interim analysis of ALinC 16 (POG 9201) continues to support this finding (POG Agenda Spring 1999). These patients continue to have an excellent prognosis when treated on an antimetabolite-based regimen that includes six courses of a 24-hour infusion of methotrexate. Given ever increasing economic pressures to limit hospitalizations, the recently completed ALinC 17 pilot protocol, (9705 and the amended 9201 protocol) explored the administration of IV MTX as a shorter, potentially out-patient, infusion of 2 gm/m2 over four hours. This pattern of MTX administration has been used at St Jude Children's Research Hospital for several years (8). Based on published data, this two gram infusion will maintain a plasma MTX concentration of > 0.2 micromolar for approximately 40 hours, as will a 200 mg/m2 dose infused over 20 minutes, followed by an 800 mg/m2 infusion over 23.6 hours. Note, though, that regardless of the similarities in the time above 0.2 micromolar, the pharmacokinetic differences between the two infusions are significant. The short infusion produces a much higher peak concentration, an area under the curve (AUC) of different shape, and never achieves a steady state concentration. Given that the schedule of MTX administration may be as, if not more important than the dose (9), these pharmacokinetic differences may be important to both the efficacy and toxicity of parenteral MTX therapy (10-12). Standardized suggestions for hydration, MTX and leucovorin administration are included in the protocol as hydration may also have a dramatic affect on MTX plasma concentrations and drug clearance (13). POG 9904 will compare these two methods of administration of the MTX infusions for the subgroup of patients who are classified as standard risk patients by the NCI Risk Group classification and in addition, have either: 1) trisomies of chromosomes 4 and 10 or 2) have the TEL/AML1 translocation (see below for rationale). Patients will be randomized to either a short intravenous infusion of MTX (2 gm/m2 over 4 hrs) versus standard MTX (1 gm/m2 over 24 hrs) to determine whether an outpatient based regimen can be given without a decrease in efficacy or increase in toxicity. Data from POG 9904 and 9905 will be pooled for statistical analysis of efficacy and toxicity.
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