Sources of Hematopoietic Stem Cells

Hematopoietic stem cells for transplantation can be obtained from bone marrow (BM) or peripheral blood (PB). Bone marrow was the traditional source for stem cells until the 1980s. At that time, antibodies were developed that could recognize CD34+ hematopoietic progenitors, and it was recognized that these CD34+ cells circulate in PB. Moreover, the number of these CD34+ cells in the periphery increased during recovery from myelosuppressive chemotherapy and after administration of growth factors, particularly granulo-cyte colony-stimulating growth factor (G-CSF).37-39 Strategies to mobilize stem cells from the marrow out into PB with chemotherapy, growth factors, or a combination of the two were developed. Full lymphohematopoietic reconstitution was observed after ablation and infusion of these mobilized PB stem cells in the autologous transplant setting. Using mobilized PB containing a minimum of 2.0 x 106 CD34+ cells/kg, engraftment of both neutrophils and platelets is considerably more rapid than when BM is used.40,41 For autolo-gous transplantation, mobilized PB has replaced BM as the stem cell source in most centers. It is notable, however, that the use of peripheral blood stem cells (PBSCs) has not led to improved survival after autologous transplantation but has been associated with decreased duration of hospitalization.

Physicians were initially reluctant to use PB for allogeneic transplantation as it was feared that the increased number of T lymphocytes infused with PB would increase the incidence and severity of graft-versus-host-disease (GHVD). The first trials published in the 1990s demonstrated rapid engraftment without apparent increases in GVHD.42,43 A number of randomized trials comparing allogeneic PBSC versus BM have been reported, as have a meta-analysis and registry data.44-49 As in the autologous setting, neutrophil and platelet engraft-ment were more rapid with PBSCs. There have been conflicting reports on the risk of acute GVHD posed by PBSCs. In a randomized trial involving 350 patients, both acute GVHD (grade II-IV) and severe acute GVHD (grade III-IV) were significantly increased in the PBSCT group (52% versus 39%, P = 0.014 and 28% versus 16%, P = 0.01, respectively).50 Other trials have found differences in acute GVHD that were not statistically significant. An IBMTR/EBMT retrospective review of 288 PBSC and 536 BM transplants revealed a borderline increase in grades II-IV acute GVHD [relative risk (RR), 1.19; 95% CI, 0.9-1.56].51 A meta-analysis of 15 studies (9 cohorts, 5 randomized trials, and 1 database review) suggested that use of PBSCs did increase risk of acute GVHD (RR, 1.16; 95% CI, 1.04-1.28).46

A number of studies have suggested a higher incidence of chronic GVHD with PB.44-46,51 An updated meta-analysis of the randomized trials demonstrated an overall relative risk of 1.57 (95% CI, 1.28-1.94) for chronic GVHD after PBSCT when compared with bone marrow transfer (BMT). The explanation for the increase in chronic GVHD may lie with the increase in the number of T cells infused, although there there may be an association between the development of chronic GVHD and the number of CD34 cells infused.52,53

It has been speculated that the larger number of T cells infused with mobilized peripheral blood might translate into improved immune reconstitution and a reduction in disease relapse posttransplant. In several studies, higher levels of B cells and T cells were noted after PBSCT compared to BMT,54

with the increase in T-cell number associated with a lower incidence of confirmed infections (RR, 0.59; P < 0.001).55 With regard to relapse, several randomized studies have demonstrated a decrease in the rate of relapse after PBSCT compared to BMT.48,49 In the largest U.S. randomized trial, the hazard ratio for relapse was 0.49 (95% CI, 0.38-1.28) among patients transplanted with PBSCs.44 Unfortunately, despite these effects on lymphoid recovery and disease relapse, most randomized studies have yet to demonstrate a convincing improvement in overall survival for PBSCs.

All the comparative studies of PBSCs and BM referenced previously have involved related donors. For unrelated donors, a single-arm cohort of PBSCT resulted in outcomes similar to that noted with BMT.56 Comparative rates of engraftment, acute and chronic GVHD, and survival in the unrelated setting await completion of large multiinstitutional randomized studies now under way.

If there turns out to be no survival advantage to PBSCT compared with BMT in the allogeneic setting, policies regarding donor source may be determined by quality of life or economic issues. Donor preference for either PBSC or BM donation has been evaluated in one series of allogeneic donors with no differences in self-reported quality of life measures; however, patients randomized to donate autologous PBSC or BM have preferred PBSC collection.57,58 Because of the reduction in hospital stay associated with PBSCT, costs have been lower in comparative analyses although these studies did not factor in the potentially added economic burden of a higher incidence of chronic GVHD.59

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