Project 1: Nonmyeloablative Hematopoietic Cell Allotransplants We propose to continue exploring nonmyeloablative conditioning regimens for allogeneic hematopoietic cell transplantation (HCT) in the treatment of patients with malignant blood disorders and those infected with human immunodeficiency virus 1 (HIV1). The principal regimens proposed have been translated from a preclinical canine model, use postgrafting immunosuppression to both enhance engraftment and control graft-vs-host disease (GVHD), rely on graft-vs-tumor effects for eradicating cancer, and can largely be administered in the ambulatory care setting owing to lack of serious regimen-related toxicities. The latter characteristic has enabled us to ignore the age and comorbidity limitations currently existing for myelo- ablative regimens. Given that and the fact that median ages at diagnoses for patients with most candidate diseases range from 65-70 years, the number of patients treatable and potentially curable by allogeneic HCT has been greatly increased. The first two Specific Aims will investigate HCT from HLA-matched and mismatched donors. While the focus is on unrelated HCT,several protocols will also include related donors. Two protocols are prospective randomized trials, one on prevention of acute GVHD, and one on outcomes for patients with myeldid malignancies given either myeloablative or nonmyeloablative conditioning. Several disease-specific protocols will assess the value of the nonmyeloablative HCT approach for patients with chronic myelocytic leukemia, Ph1+ acute lymphocytic leukemia, chronic lymphocytic leukemia, multiple myeloma, and patients with HIV1/AIDS.
The third Aim will validate the prognostic value of a newly developed HCT-specific comorbidity index in a multi-center study. Almost all studies are being conducted under the auspices of a multi-institutional consortium which includes 17 academic centers outside of Seattle, and in which the Fred Hutchinson Cancer Research Center serves as the coordinating center. Relevance to Public Health: These proposed studies are aimed at increasing the safety of allogeneic HCT, a therapy already used to treat thousands of patients each year. Success in this project will broaden considerably the application of allogeneic HCT by allowing its use in elderly patients and others with additional medical problems. Further, the proposed regimen allows for'the purest determination of graft-vs- tumor effects, apart from intensive conditioning, and provides an excellent foundation on which to add disease-specific modalities. Finally, comorbidity data will likely become as important as defining cancer diagnosis, stage, remission status, and other more familiar variables in predicting patient response and outcome.
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