Autologous bone marrow transplants to hematopoietic stem cell support with peripheral blood stem cells: a historical perspective.

Abstract

233 TH E FIELD O F A U TOLO GO U S H EM ATO PO IETIC cell support began in 1949, when Jacobson et al. discovered that shielding of the spleen effectively protected mice from BM damage caused by otherwise lethal total body irradiation (1,2). Subsequent studies by Lorenz et al. in 1951 demonstrated radiation protection by infusion of syngeneic, allogeneic, and xenogeneic bone marrow in guinea pigs (3). Although it was first thought that a humoral factor from bone marrow or spleen stimulated hematopoietic recovery after lethal doses of TBI, in 1954, Barnes and Loutit suggested that protection more likely resulted from a cellular than a humoral factor (4). Early investigators understood the profound clinical implications of syngeneic BM transplantation and applied this technique to experimental malignancies to determine its therapeutic potential in a preclinical setting. Barnes et al., in 1956, showed that the majority of mice with an induced lymphoid leukemia could be cured by 15 Gy of TBI plus normal syngeneic BM but not by 9.5 Gy of TBI and syngeneic BM (5). Early clinical trials of syngeneic transplants for malignant disease in humans were disappointing because of the advanced stage at which patients were treated, the unavailability of platelet transfusions, the lack of effective antibiotics for neutropenic patients, and the paucity of effective agents other than TBI to treat malignancies (6,7). However, these studies, led by transplant pioneer E. Donall Thomas, clearly established the feasibility of administering supralethal doses of TBI with rescue by syngeneic BM infusion in humans (6,7). Because of the rarity of syngeneic donors, it was logical for early investigators to ask if autologous BM could be substituted for allogeneic or syngeneic marrow for transplant purposes. Studies with dogs established that BM could be aspirated, set aside and infused after a supralethal dose of TBI, with rapid marrow repopulation (8,9). However, as BM does not survive long at ambient temperature, techniques for effective cryopreservation and storage of BM destined for autologous transplantation were developed. In 1949, Polge et al. developed a method for freezing bull sperm with glycerol as a cryoprotectant (10). This technique was found in 1957 to successfully cryopreserve BM (11,12). In 1959, Lovelock and Bishop introduce dimethylsulfoxide as a cryoprotectant for BM (13), and this is the current cryoprotectant of choice (14). The first human trials with cryopreserved autologous BM were performed in the late 1950s and early 1960s (15–18). By this time, techniques for performing autologous BMT had been well refined, but clinical application of these techniques developed slowly because of limitations of supportive care, lack of knowledge about effective high-dose regimens and concern that BM containing malignant cells would lead inevitably to relapse. Also, there was the prevalent concept that only allogeneic BMT with the potential for a GvL effect would be curative. At the time, most investigators simply did not believe that any high-dose treatment regimen would eradicate malignancy in the absence of an immunologic booster effect from the graft. However, continued investigation of syngeneic BMT demonstrated that a small fraction of patients with advanced hematologic malignancies could be cured without an apparent immunologic GvL effect (19). In the 1970s and 1980s, there were major efforts to determine the effectiveness of autologous BMT for a variety of malignant diseases. Fortunately, by this time, ma-