Project 2: Nonmyeloablative Hematopoietic Cell Allotransplants This project investigates allogeneic hematopoietic cell transplantation (HCT) after nonmyeloablative conditioning to treat patients with advanced hematological malignancies who are elderly and/or have cormobidities precluding high-dose HCT. Conditioning involves fludarabine (FLU) and 2 Gy total body irradiation (TBI), which lack serious toxicities. Post-grafting immunosuppresssion with mycophenolate motetil and a calcineurin inhibitor both aids engraftment and controls graft-vs.-host disease (GVHD). Graft-vs-tumor (GVT) effects are used to eradicate cancer. Avoiding toxicities has enabled us to surmount age and comorbidity limitations associated with myeloablative regimens. For these reasons and given that median ages of patients at diagnoses of most candidate diseases range from 65-70 years, the number of patients treatable by allogeneic HCT has greatly increased. To date, >1,600 patients have been enrolled on our nonmyeloablative protocols. This project will focus on relapse and acute GVHD. Specific Aim 1 consists of phase l/ll disease-specific protocols aimed at reducing relapse for patients with chronic lymphocytic lymphoma, acute myelocytic leukemia, and Hodgkin lymphoma. Seventy percent of patients who relapse do so Within the first year. We hypothesize that early relapse is due to blunting of GVT effects by early posttransplant immune compromise. Later, the immune system recovers as immunosuppressive drugs are being tapered or discontinued, thereby allowing powerful GVT effects to develop. The protocols intend to control tumor burden with specific drugs or an antibody-drug conjugate given after HCT, thereby bridging the early, immunocompromised post-transplant period without relapse until immune function recovers and GVT effects occur. Specific Aim 2 focuses on reducing acute GVHD. Aim 2a will use donor statin treatment to prevent acute GVHD among HLA-matched related recipients. Aim 2b is based on a just concluded, 3-arm, randomized, phase 11 study involving 208 HLA-matched unrelated recipients, which showed a significant reduction in acute GVHD with added sirolimus; Protocol 2448 is a phase 111 study comparing MMF/CSP/sirolimus to MMF/CSP. Aim 2c, HLA-mismatched grafts, will investigate the addition of sirolimus to MMF/CSP. Project 2 is a close collaboration with Project 1 to explore to what extent HLA typing can be refined, thereby extending donor options. A unique aspect of this project is that most of the proposed trials are conducted within a consortium that includes 23 academic centers outside of Seattle.