BACKGROUND The majority of patients in need of a hematopoietic-cell transplant do not have a matched related donor. Data are needed to inform the choice among various alternative donor-cell sources. METHODS In this retrospective analysis, we compared outcomes in 582 consecutive patients with acute leukemia or the myelodysplastic syndrome who received a first myeloablative hematopoietic-cell transplant from an unrelated cord-blood donor (140 patients), an HLA-matched unrelated donor (344), or an HLA-mismatched unrelated donor (98). RESULTS The relative risks of death and relapse between the cord-blood group and the two other unrelated-donor groups appeared to vary according to the presence of minimal residual disease status before transplantation. Among patients with minimal residual disease, the risk of death was higher in the HLA-mismatched group than in the cord-blood group (hazard ratio, 2.92; 95% confidence interval [CI], 1.52 to 5.63; P = 0.001); the risk was also higher in the HLA-matched group than in the cord-blood group but not significantly so (hazard ratio, 1.69; 95% CI, 0.94 to 3.02; P = 0.08). Among patients without minimal residual disease, the hazard ratios were lower (hazard ratio in the HLA-mismatched group, 1.36; 95% CI, 0.76 to 2.46; P = 0.30; hazard ratio in the HLA-matched group, 0.78; 95% CI, 0.48 to 1.28; P = 0.33). The risk of relapse among patients with minimal residual disease was significantly higher in the two unrelated-donor groups than in the cord-blood group (hazard ratio in the HLA-mismatched group, 3.01; 95% CI, 1.22 to 7.38; P = 0.02; hazard ratio in the HLA-matched group, 2.92; 95% CI, 1.34 to 6.35; P = 0.007). Among patients without minimal residual disease, the magnitude of these associations was lower (hazard ratio in the HLA-mismatched group, 1.28; 95% CI, 0.51 to 3.25; P = 0.60; hazard ratio in the HLA-matched group, 1.30; 95% CI, 0.65 to 2.58; P = 0.46). CONCLUSIONS Our data suggest that among patients with pretransplantation minimal residual disease, the probability of overall survival after receipt of a transplant from a cord-blood donor was at least as favorable as that after receipt of a transplant from an HLA-matched unrelated donor and was significantly higher than the probability after receipt of a transplant from an HLA-mismatched unrelated donor. Furthermore, the probability of relapse was lower in the cord-blood group than in either of the other groups.

Despite progress in our understanding of the growth factors that support the progressive maturation of the various cell lineages of the hematopoietic system, less is known about factors that govern the self-renewal of hematopoietic stem and progenitor cells (HSPCs), and our ability to expand human HSPC numbers ex vivo remains limited. Interest in stem cell expansion has been heightened by the increasing importance of HSCs in the treatment of both malignant and nonmalignant diseases, as well as their use in gene therapy. To date, most attempts to ex vivo expand HSPCs have used hematopoietic growth factors but have not achieved clinically relevant effects. More recent approaches, including our studies in which activation of the Notch signaling pathway has enabled a clinically relevant ex vivo expansion of HSPCs, have led to renewed interest in this arena. Here we briefly review early attempts at ex vivo expansion by cytokine stimulation followed by an examination of our studies investigating the role of Notch signaling in HSPC self-renewal. We will also review other recently developed approaches for ex vivo expansion, primarily focused on the more extensively studied cord bloodderived stem cell. Finally, we discuss some of the challenges still facing this field. (Blood. 2011;117(23):6083-6090) IntroductionThe hierarchical development of the hematopoietic system has become progressively better understood over the past few decades, aided in part by significant advances in identifying and isolating hematopoietic stem cells (HSCs) and their progeny. 1 Although advances have been made in understanding the hematopoietic growth factors that support the progressive maturation of the various cell lineages, less is known about factors that govern the self-renewal of hematopoietic stem cells and multipotent progenitor cells (MPPs) that consist of short-term repopulating stem cells and give rise to the different cell lineages, thereby impacting the ability to expand HSC and MPP (hematopoietic stem and progenitor cell [HSPC]) numbers ex vivo. Initial attempts at ex vivo expansion of HSCs focused on the use of soluble cytokines known to support lineage committed cells with the expectation that some of these factors also supported HSC proliferation. 2 These studies were based on the belief that cell lineage determination was a stochastic process combined with positive and negative cytokinemediated regulatory responses controlling survival and expansion of the stem cell population. 3 More recently, recognition of factors critical for embryologic development as well as discovery of other novel pathways that may influence HSC self-renewal have led to renewed interest in ex vivo expansion, which has been heightened by the increasing importance of HSPCs in the treatment of both malignant and nonmalignant diseases as well as their use in gene therapy.To date, most attempts to expand HSPC ex vivo for enhanced in vivo engraftment in patients have been clinically unsuccessful because of generation of insufficient cell numbers or improper...