Conditioning for allogeneic marrow transplantation in patients with lymphohematopoietic malignancies without the use of total body irradiation

Abstract

VIDENCE THAT INFUSION of syngeneic spleen or E marrow cells could protect mice and guinea pigs from lethal doses of irradiation' led Thomas et a1 to perform studies on total body irradiation (TBI) and marrow transplantation in dogs and eventually in human^.^-^ TBI was chosen because irradiation could be delivered expeditiously, did not generate metabolites that might interfere with the function of transplanted cells, had a powerful antileukemic effect, and reached privileged sites, such as the central nervous system, where drugs might not penetrate. Furthermore, irradiation was profoundly immunosuppressive as shown in murine and canine models. The latter effect was of particular importance because in the clinical situation identical (syngeneic) twin donors were only infrequently available and, therefore, for the vast majority of patients allogeneic tissue barriers would have to be overcome. In the early 1970s, following the observation that two patients prepared with TBI alone developed a recurrence of leukemia posttransplant in donor-derived cells, cyclophosphamide (Cy) was added to TBI in an attempt to increase leukemic cell kill. Early studies showed that allogeneic marrow transplantation, generally from a genotypically HLA-identical sibling, after TBI and Cy conditioning cured 10% to 15% of patients with endstage acute leukemia.6 Since then further improvement in the outcome of such patients has largely resulted from the performance of transplantation earlier in the disease c o u r ~ e ~ ~ and the application of more sophisticated supportive care measures, including prevention and treatment of graft-versus-host disease (GVHD).'-12