key: cord-0864149-fayba5k2 authors: Zhu, Xiaoyu; Tang, Baolin; Sun, Zimin title: Umbilical cord blood transplantation: Still growing and improving date: 2021-11-01 journal: Stem Cells Transl Med DOI: 10.1002/sctm.20-0495 sha: f7814e023d5066bc8aa870f62f7c4933dfc41e42 doc_id: 864149 cord_uid: fayba5k2 Umbilical cord blood transplantation (UCBT) has been performed in the clinic for over 30 years. The biological and immunological characteristics of umbilical cord blood (UCB) have been re‐recognized in recent years. UCB, previously considered medical waste, is rich in hematopoietic stem cells (HSCs), which are naïve and more energetic and more easily expanded than other stem cells. UCB has been identified as a reliable source of HSCs for allogeneic hematopoietic stem cell transplantation (allo‐HSCT). UCBT has several advantages over other methods, including no harm to mothers and donors, an off‐the‐shelf product for urgent use, less stringent HLA match, lower incidence and severity of chronic graft‐vs‐host disease (GVHD), and probably a stronger graft‐vs‐leukemia effect, especially for minimal residual disease‐positive patients before transplant. Recent studies have shown that the outcome of UCBT has been improved and is comparable to other types of allo‐HSCT. Currently, UCBT is widely used in malignant, nonmalignant, hematological, congenital and metabolic diseases. The number of UCB banks and transplantation procedures increased exponentially before 2013. However, the number of UCBTs increased steadily in Asia and China but decreased in the United States and Europe year‐on‐year from 2013 to 2019. In this review, we focus on the development of UCBT over the past 30 years, the challenges it faces and the strategies for future improvement, including increasing UCB numbers, cord blood unit selection, conditioning regimens and GVHD prophylaxis for UCBT, and management of complications of UCBT. survival than other allo-HSCT types. Future directions should focus on innovative research on the basic biology of UCB stem cells, novel randomized controlled clinical trials, and perfect quality control of UCB banking, making UCBT more popular for more patients. Allogeneic hematopoietic stem cell transplantation (allo-HSCT) remains an effective and curative therapy for malignant, nonmalignant, hematological, congenital, and metabolic diseases. 1, 2 Unfortunately, fully matched related donors, which is preferred, are not always available for the majority (approximately 70%) of patients 3 China because of the once one-child policy. Finding matched unrelated donors through the registry is also difficult and time consuming. Since the first successful umbilical cord blood transplantation (UCBT) was performed on a 5-year-old boy with Fanconi anemia in 1988 at Hospital Saint-Louis in Paris, France, 4 umbilical cord blood (UCB) has become an available graft source of allo-HSCT for over 30 years, with the advantages of rapid availability, no harm to mothers and donors, low immunogenicity, decreased chronic graft-vs-host disease (GVHD), and low relapse rate in minimal residual disease (MRD). 5, 6 Unrelated donor cord blood transplantation (CBT) is an effective and reliable alternative to peripheral blood (PB) or bone marrow (BM) transplant and has emerged as a widely accepted treatment for a wide variety of hematologic diseases such as: acute lymphoblastic leukemia (ALL), 7-9 acute myeloid leukemia (AML), [10] [11] [12] myelodysplastic syndrome (MDS), [13] [14] [15] and aplastic anemia (AA) [16] [17] [18] (Table 1) . UCB, previously considered medical waste, was suggested as a potential source of hematopoietic stem cells (HSCs) and hematopoietic progenitor cells (HPCs) by Hal Broxmeyer in a private meeting with the late Edward A. Boyse and Judith Bard in 1982. This conference led to the creation of a UCB company named Biocyte Corporation and a series of studies on the biology and cryopreservation of UCB cells. 19, 20 These studies identified the possibility of using UCB as an available source of HSCs and HPCs, leading to the first HLA-identical sibling UCBT 4 and subsequent UCBTs, including the first HLA-identical sibling UCBT in a patient with juvenile chronic myelogenous leukemia (JCML) at Johns Hopkins University in 1992, 21 the first unrelated UCBTs in children reported by Joanne Kurtzberg et al in 1996 22 and the initial unrelated UCBT experience with adults in 1996. 23 The first public UCB bank was established at the New York Blood Center in 1993, 24 and the Eurocord Netcord network was created by Gluckman et al in 1997, 25 and there are currently more than 100 UCB banks in Asia, Europe, Oceania, North America, and South America. 26 According to the World Marrow Donor Association (WMDA), over 778 000 cord blood units are available worldwide to be used for any patient in need, and approximately 35 have been attempted to address these issues to further improve UCBT as a feasible and more attractive option for allo-HSCT. Research on the biology and cryopreservation of UCB cells showed that UCB from a single donor could be used as a source of autologous or major histocompatibility complex-matched allogeneic transplantable hematopoietic repopulating cells. The process of cryopreservation of UCB cells should not require the need to discard any type of cells prior to freezing, and the cells should not be washed or otherwise handled after thawing, as all of these procedures would result in severe loss of HPCs. 19 The above-mentioned process allows UCB units to be rapidly available for patients in urgent need of transplantation. In addition, a UCB unit could be collected at birth without any harm to the newborn or mother. These scientific findings paved the way for UCB as a potential source of transplantable HSCs/HPCs. Since then, our understanding of the biological characteristics of UCB has increased, emphasizing the advantages of UCBT. UCB units usually contain one log less total nucleated cell (TNC) and CD34 + cells than a unit of bone marrow or peripheral blood, accompanied by delayed engraftment of neutrophils and platelets or higher incidence of graft failure. 27, 28 Many studies have revealed the proportions of hematopoietic progenitor cells such as primitive HPCs and multipotent colony-forming cells in UCB are significantly higher than those of BM CD34 + cells and peripheral blood stem cells. Moreover, UCB CD34 + progenitors have higher proliferation and multiple cell division potential. [29] [30] [31] Furthermore, the in vivo hematopoietic reconstitution capacity of UCB-derived HSCs in a nonobese diabetic/ severe combined immunodeficiency (NOD/SCID) repopulation assay is superior to that of BM CD34 + cells. 32, 33 Several unique characteristics of UCB HSCs may lead to the above observations, including longer telomeres, a higher self-renewal capacity due to overrepresentation of transcription factor such as NF-kB, and autocrine production of certain cytokines such as granulocyte-macrophage colony-stimulating factor and IL-3. 34, 35 T A B L E 1 Umbilical cord blood transplantation for acute lymphoblastic leukemia (ALL), acute myeloid leukemia (AML), myelodysplastic syndrome (MDS), and aplastic anemia (AA) 36 It should be noted that in addition to being a rich source of HSCs and HPCs, UCB contains an abundance of B cells with immunoregulatory functions. In patients who underwent UCBT, the recovery frequencies and absolute numbers of IL-10-producing Bregs were higher than those of Furthermore, the relapse rate was lower in the UCBT group than in the other groups. 5 In a multicenter retrospective study, 79 acute F I G U R E 1 Although UCBT is immediately available and associated with a lower Choosing the most suitable CB unit is the first step of successful to >3.5 Â 10 7 NC/kg and ≤1 HLA disparities in nonmalignant diseases. 97 The UK consensus guidelines state different requirements for HLA matching and cell dose. 98 CMV reactivation is a significant complication in UCBT patients, associated with increased transplant-related morbidity and mortality. 114, 115 Because of the difference in condition regimens and GVHD prophylactics, the infection rates of CMV post UCBT varies substantially in many studies. Recipient CMV serostatus was the most important risk factor that predicted the reactivation of CMV viremia or disease, while CMV serologies of cord blood donor infants and their mothers may not improve the risk of CMV reactivation. 116, 117 The association between CMV reactivation and the clinical outcome of cord blood transplantation is still controversial. In a recent largescale study, 3147 eligible UCBT patients older than 16 years showed a favorable effect of CMV reactivation on relapse and OS was observed in high-risk AML and MDS. 118 While a Korean study revealed that CMV reactivation did not impact leukemia relapse or survival, and CMV disease can resulted in higher TRM and lower survival. 119 The results were not consistent in different studies, this might be due to discrepancies in patient characteristics such as age and the use of antithymocyte globulin. 118 The authors declared no potential conflicts of interest. X.Z., B.T.: conception and design of the study as well as writing of the manuscript; Z.S.: conception and design of the study, final approval of the manuscript. Data sharing is not applicable to this article as no new data were created or analyzed in this study. 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