The goal of the proposed research is the development of novel and highly effective immunochemotherapy protocols for more successful treatment of poor prognosis B-lineage acute lymphoblastic leukemia (ALL) patients.
Under SPECIFIC AIM 1, we are proposing to examine the efficacy and toxicity of promising combinative immunochemotherapy regimens employing B43 (anti-CD19)-PAP immunotoxin in combination with topotecan, cytosine arabinoside, cyclophosphamide, etoposide, or cyclophosphamide in a preclinical SCID mouse model of human B-lineage ALL and subsequently implement regimens with the highest therapeutic index in phase I clinical trials. We will perform detailed comparative pharmacokinetic and pharmacodynamic studies in SCID mice and relapsed B-lineage All patients as part of LABORATORY PROGRAM II to confirm that the favorable therapeutic index of the best regimens is not due to interspecies differences in drug disposition. We will interface pharmacokinetic data from the SCID mouse model and from relapsed ALL patients to determine whether drug concentrations enhancing the anti-leukemic activity of B43- PAP immunotoxin without significant added toxicity can be achieved in ALL patients. Subsequently, the most promising drug pairs will be used under SPECIFIC AIM 2 in an """"""""upfront window approach"""""""" to examine their antileukemic activity in relapsed B-lineage ALL patients.
