Dose-reduced conditioning and allogeneic hematopoietic stem cell transplantation from unrelated donors in 42 patients

Purpose: A fludarabine-based "nonmyeloablative" preparative regimen was inv estigated in 42 patients with hematological malignancies receiving hematopo ietic stem cell grafts from unrelated volunteer donors. Experimental Design: Recipient conditioning consisted of fludarabine 30 mg/ m(2) on days -6 to -2 and i.v. busulfan 3.3 mg/kg on days -6 to -5. Antithy mocyte globuline was added at 2.5 mg/kg i.v. on days -5 to -2. The patients were grafted with bone marrow (n = 13) or peripheral blood stem cells eith er unmanipulated (n = 20) or CD34+ selected (n = 9). Graft-versus-host dise ase prophylaxis was performed with cyclosporine A (CsA. n = 12). CsA/methot rexate (n = 12), or CsA/mycophenolate mofetil (n = 18). Results: With a median follow-up or 13 months (range, 5-26 months), the act uarial disease-free survival is 64% and 38% for patients with lymphoid mali gnancies and standard-risk leukemia compared with only 14% for patients wit h high-risk disease. The main cause of treatment failure was relapse of dis ease in high-risk patients (n = 14). An increased incidence of primary (n = 1) or secondary graft-failure (n = 8) was observed (21%). Chimerism analys is of CD56+/CD3--sorted natural killer (NK) cells, available in 10 patients , showed an impaired increase of donor NK cell chimerism between day 10 and 30 after transplantation in three of four patients with graft failure, whe reas the percentage of donor NK cells surpassed 75% in all of the six patie nts with stable engraftment. Conclusions: Unrelated transplants after dose-reduced conditioning are asso ciated with a higher risk of graft-failure. Pretransplant host immunosuppre ssion has to be optimized to overcome resistance to grafts from unrelated d onors after nonmyeloablative conditioning therapy.