Nonmyeloablative stem cell transplantation for congenital immunodeficiencies

The optimal approach for stem cell transplantation in children with immunod eficiency has yet to be determined. Conditioning therapy is necessary for r eliable engraftment and full immune reconstitution; however, the beneficial effect of cytoreductive conditioning is counterbalanced by increased short - and long-term treatment-related toxicity, Whether bone marrow transplanta tion with a nonmyeloablative preparative regimen was sufficient for the est ablishment of donor immune reconstitution, with the resultant correction of disease phenotype, was investigated, Eight patients with severe immunodefi ciency states underwent T-cell replete bone marrow transplantation from a h uman leukocyte antigen-matched unrelated (n = 6) or sibling (n = 2) donor w ith nonmyeloablative conditioning using a fludarabine-melphalan-anti-lympho cyte globulin-based regimen. All patients had severe organ dysfunction that precluded transplantation with conventional conditioning, All patients wer e engrafted with predominantly donor hematopoiesis, and the duration of neu tropenia was brief, Significant acute graft-versus-host disease (GVHD) did not develop, but one patient had limited chronic GVHD, One patient died of disease recurrence, and 3 have stable, mixed chimerism, At a median follow- up of 1 year, all patients have had good recovery of CD3(+) T-cell numbers, and 6 of 7 evaluable patients have normal phytohemagglutinin stimulation i ndices. The rate of immune reconstitution is comparable with that of histor ical controls undergoing standard myeloablative protocols, Two patients wit h CD40 ligand deficiency now show significant expression, and a patient wit h adenosine deaminase deficiency has improved deoxy adenosine triphosphate metabolites. In summary, it has been demonstrated that nonmyeloablative ste m cell transplantation permits rapid engraftment from both sibling and unre lated donors with minimal toxicity even in the presence of severe organ dys function. If long-term immune reconstitution of patients treated with this protocol is demonstrated, it is believed this approach might offer signific ant advantages compared with standard protocols by combining adequate immun e reconstitution with reduced short- and long-term toxicity. (Blood, 2000;9 6: 1239-1246) (C) 2000 by The American Society of Hematology.