To condition or not to condition—That is the question: The evolution of nonmyeloablative conditions for transplantation

In 1985, Eugene Cronkite and his colleagues published, in Experimental Hematology, data indicating that five consecutive “transfusions” of large numbers of marrow cells significantly increase the number of donor-derived cells detected by day 10 of a spleen colony-forming assay, the most primitive hematopoietic cells detectable at that time, present in the host for as long as 2 months posttransfusion (Cronkite EP, Bullis JE, Brecher G. Marrow transfusions increase pluripotent stem cells in normal hosts. Exp Hematol 1985;13:802–805). These data provided the first evidence that donor hematopoietic stem cells (HSCs) may persist in vivo for some time in recipients when transfused and not transplanted, that is, not subjected to treatments that deplete their marrow niches of endogenous HSCs. The limited technology available at the time prevented Dr. Cronkite from pursuing this observation into the development of nonmyeloablated transplantation procedures, and his experiment, as well as the term bone marrow transfusion, has since been long forgotten. In recent years, the scientific need to clarify HSC functions in nonstressed hosts and the clinical need to develop transplantation procedures with levels of morbidity/mortality acceptable for curing inherited hematologic disorders have inspired the search for nonmyeloablative transplantation procedures, including methods that “outcompete” endogenous host HSCs such as those pioneered by Dr. Cronkite's experiments using high transfusion doses. This review describes the technical progress made since Dr. Cronkite's insightful work, which has finally found its path to the clinic.