Despite pre-transplant total body irradiation (TBI) and high dose chemotherapy, leukemic relapse remains a major obstacle in bone marrow transplantation (BMT) in acute lymphoblastic leukemia (ALL). At present, the major challenge in BMT for ALL is the development of more effective pretransplant conditioning strategies. OUr studies to date strongly indicate that the disappointingly high postransplant relapse rate is due to radioresistance of leukemic progenitor cells (LPC) in ALL and emphasize the need for alternative treatment modalities. It will also be important to develop laboratory methods which predict the response of leukemia to TBI. Such methods could eventually be used to apply TBI selectively in those ALL patients whose leukemia is radiosensitive and seek alternative treatment strategies for those patients whose leukemia is radioresistant. A first major goal of this proposal is to continue to analyze the radiosensitivity and radiation damage repair capacity of LPC from ALL patients using LPC colony assays and to correlate the in vitro radiation responses of LPC with the in vivo response of leukemia to TBI. Our hypothesis is that the in vitro radiation survival data on ALL LPC obtained in colony assays have a predictive value for the success or failure of TBI to eradicate the leukemic burden in vivo. Our second major goal is to explore the therapeutic potential of two combined treatment modalities: (1) Combination of radiation and immunotoxins (IT), and (2) Combination of radiation and hyperthermia. We postulate that these combinations will prove more effective against ALL LPC than radiation alone. To test this hypothesis, we will study in LPC colony assays the in vitro anti-leukemic efficacy of combined radioimmunotherapy and radiothermotherapy regimens against LPC from ALL patients. Furthermore, we will study the in vivo anti-leukemic efficacy of combined TBI plus IT and TBI plus whole body hyperthermia (WBH) regimens in leukemic nude mice. Our in vitro and in vivo basic research studies may provide the foundation for novel and effective TBI regimens for BMT in ALL.
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