Childhood acute lymphoblastic leukemia (ALL) is a heterogeneous group of diseases. The major challenge in the treatment of childhood ALL is to save patients who have relapsed despite intensive multiagent chemotherapy. Among all age groups, CD19 antigen positive G-lineage ALL is the most prevalent ALL. Our proposal is designed to generate valuable information regarding (a) the biologic heterogeneity of newly diagnosed B-lineage ALL, and (b) the ability of novel combinative therapy regimens to reduce or eradicate the leukemia burden of relapsed B-lineage patients. A first major goal of this proposal is to determine the prognostic value of ALL blast clonogenicity in SCID mice for children with newly diagnosed ALL (SPECIFIC AIM 1). It is our central working hypothesis that blast clonogenicity in SCID mice is a powerful and independent predictor of relapse after chemotherapy. A second major goal is to measure the quality of second remission in relapsed B-lineage ALL patients after reinduction and intensification regimens using quantitative minimal residual leukemia detection assay system developed in our laboratory (SPECIFIC AIM 2). The major hypotheses to be tested under SPECIFIC AIM 2 are 1. In patients who do not undergo BMT, the quality of remission after reinduction, i.e., the residual LPC burden of Pre-BMT bone marrow will be a strong predictor of outcome.
Under SPECIFIC AIM 3, we will examine the impact of B43-PAP anti-CD19 immunotoxin therapy on the quality of second remission in relapsed B- lineage ALL patients. Our hypothesis is that the combination of chemotherapy with B43-PAP will prove more effective than chemotherapy alone in reducing or eradicating the residual LPC burden of relapsed ALL patients and will improve the event-free survival rate. We anticipate that the studies proposed under SPECIFIC AIMS 1-3 will allow us to accurately segregate B-lineage ALL patients into distinct prognostic groups both at the time of diagnosis as well as after induction of remission. The knowledge gained from our research may lead to the design of more successful treatment strategies for relapsed B-lineage ALL.
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