Using Allogeneic Graft Engineering to Improve Long-Term Survival
I. INTRODUCTION Over the last two decades, allogeneic bone marrow transplantation (BMT) has provided a means of delivering potentially curative therapy to patients with hematological malignancies (Santos 1990). Unfortunately, approximately 70% of allogeneic BMT patients receiving unmodified (marrow is immediately infused) grafts develop acute graft-versus-host disease (GVHD) with one third of these patients rapidly succumbing to this complication (Noga and Hess, 1993; Vogelsang, 1993). Of patients surviving more than 100 days, half will later develop chronic GVHD which has an attendant mortality of almost 50% (Vogelsang et al., 1988). These complications increase still further for those individuals who receive a histocompatibility antigen (HLA)-mismatched or unrelated donor graft. The lack of suitable donors and high morbidity has popularized other high-dose chemotherapy/stem cell rescue approaches such as autologous BMT and peripheral blood stem cell (PBSC) transplantation. To date, allogeneic BMT still generates the highest cure rates, largely owing to its inherent antitumor [or graft-vs-leukemia (GVL)] properties which results in low relapse rates (Ringden and Horowitz 1989; Horowitz et al., 1990). The dilemma often facing the transplant physician is whether to suggest that a patient undergo a less morbid transplant approach with a higher relapse risk or accept the greater mortality risk of allogeneic BMT in hopes of achieving a cure. In many cases, the patient’s age, performance status, and diagnosis (e.g., low-risk leukemia and lymphoma, breast and ovarian cancer) preclude the use of allogeneic BMT. In other cases, the choice is more difficult. As improvements in supportive care, antimicrobial and immunosuppressant therapy, growth factor utilization, and health care delivery are assimilated into transplantation regimens, there
has been increasing emphasis placed on an improved quality of life following transplantation. If the beneficial properties of allogeneic BMT are to be exploited in this new era, the 40-50% up-front mortality must be significantly reduced and the quality of life must be improved for the survivors.