Intentional induction of mixed chimerism and achievement of antitumor responses after nonmyeloablative conditioning therapy and HLA-matched donor bone marrow transplantation for refractory hematologic malignancies

Mixed lymphohematopoietic chimerism can be induced in mice with bone marrow transplantation (BMT) after a nonmyeloablative preparative regimen that in cludes cyclophosphamide, anti-T-cell antibody therapy, and thymic irradiati on. These mixed chimeras are resistant to the induction of graft-versus-hos t disease (GVHD) after delayed donor leukocyte infusions (DLIs), despite a potent lymphohematopoietic graft-versus-host reaction that converts the mix ed chimeric state to a full donor one. Based on this animal model, we initi ated a trial of nonmyeloablative therapy with HLA-matched or -mismatched do nor BMT and DLI for refractory hematologic malignancies. Twenty-one of 36 p atients enrolled in this trial received a genotypically (n = 20) or phenoty pically (n = 1) HLA-matched donor transplant; results reported here are for those patients only. Preparative therapy consisted of cyclophosphamide in doses of 150 to 200 mg/kg; peritransplant antithymocyte globulin; thymic ir radiation (in patients who had not received previous mediastinal radiation therapy); and cyclosporine. Eighteen of 20 evaluable patients developed per sistent mixed lymphohematopoietic chimerism as defined by >1% donor periphe ral white blood cells until at least day 35 posttransplantation. Ten patien ts received prophylactic DLI beginning 5 to 6 weeks after BMT for conversio n of mixed chimerism to full donor hematopoiesis and to optimize a graft-ve rsus-leukemia effect. Fourteen of 20 evaluable patients (70%) achieved an a ntitumor response; 8 of these responses were complete, and 6 were partial. Of the 8 evaluable patients who received prophylactic DLI, 6 showed convers ion to full donor chimerism. Five of the 9 evaluable patients (56%) who rec eived prophylactic DLI achieved a complete response, compared with 3 of 11 patients (27%) who did not receive prophylactic DLI. Currently 11 patients are alive, and 7 of these are free of disease progression at a median follo w-up time of 445 days (range, 105-548 days) posttransplantation. Transplant ation-related complications included cyclophosphamide-induced cardiac toxic ity in 3 of 21 patients (14%) and grade II or greater GVHD in 6 patients (2 9%). One patient (5%) died from a complication of BMT, and 1 patient (5%) d ied from GVHD after 2 prophylactic DLIs were given for conversion of chimer ism. In summary, mixed lymphohematopoietic chimerism was reproducibly induc ed after a novel nonmyeloablative preparative regimen incorporating chemoth erapy, peritransplant antithymocyte globulin, and thymic irradiation, allow ing for early administration of DLI in 10 of 21 patients. After treatment, striking antitumor responses were observed in the majority of patients with chemotherapy-refractory hematologic malignancies.