The overall aims of this Project are to increase the proportion of patients with non-Hodgkin's and Hodgkin's lymphoma who are event- free and alive following hematopoietic cell transplantation through a series of clinical studies that feature a unique integration of immunotherapy, a novel cytotoxic preparatory regimen and new diagnostic studies. The ability of peri-transplant rituximab to improve survival to improve survival in recurrent B-cell diffuse large cell lymphoma will be determined in a large Phase III study in follow-up to our Phase II study. Radioimmunotherapy (RIT) with ibritumomab tiuxetan will be paired in a unique tandem in Phase I/II studies designed to test the ability of RIT to achieve sufficient cytoreduction prior to autologous hematopoietic cell transplantation (AHCT) with our standard preparatory regimen. In both of these studies RIT will be dose-escalated beyond marrow tolerance facilitated by AHCT. The study design of giving RIT with AHCT prior to either a non- myeloablative allogeneic or standard autologous transplant affords the ability to determine the independent efficacy of RIT, has the potential for excellent cytoreduction with modest toxicity, may extend the option for transplantation to a larger population and is additive to either transplant in that the preparatory regimens will not be modified. In Hodgkin's lymphoma, two new, active drugs, gemcitabine and vinorelbine, will be combined with a reduced dose of BCNU, etoposide and cyclophosphamide in Phase I study. We hypothesize that this preparatory regimen will be less toxic with equal or greater efficacy and we plan to extend the Phase II study to 3 other centers. Building upon an immunotherapy developed in the Program Project and successfully tested in a Phase I trial, we plan to administer cytokine-induced killer cells after high dose therapy and AHCT in Hodgkin's lymphoma patients with equal to or >1 adverse risk factor defined in our patient population.
Aim 3 is based upon the emerging molecular classification of diffuse large cell lymphoma and our preliminary studies that indicate that BCL-6 expression, a characteristic of germinal center B-cells, confers a favorable prognosis in patients with diffuse large cell lymphoma treated with high dose therapy and AHCT. We plan to construct tissue arrays of our transplanted patients to extend our observations and study new antibodies of interest as they are defined.
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