Allogeneic hematopoietic stem cell transplantation is the only treatment that promises a cure for hematologic malignant diseases. However, the lack of suitable HLA-matched donors has severely limited the development of allogeneic HSCT. Although HLA-matched siblings are the preferred donor source, HLA-matched sibling donors are not available for approximately 70% of patients [1,2]. HLA-matched unrelated donors can be an alternative donor source that can provide HSCs for 30% of patients. To date, there are more than 10 million volunteers registered in bone marrow banks worldwide, and the chance of finding a suitable HLA-matched unrelated donor depends on ethnicity and racial background, and undoubtedly the probability of finding a suitable HLA-matched unrelated donor for those patients of rare ethnicity is extremely low [3]. In addition, considering the long duration of the mating procedure and donor medical examination, collection, and other uncontrollable factors such as donor remorse, a large proportion of patients die during the search for a suitable donor or their disease progresses to be unsuitable for transplantation. Therefore, it is especially important to find a new source of HSC donor. Unrelated umbilical cord blood (UCB) is a new source of HSC donor. In vitro and in vivo studies have shown that UCB contains a high percentage of HSC/progenitor cells with strong proliferative capacity. Compared with unrelated bone marrow donors or mobilized peripheral blood HSC donors, cord blood has the advantages of easy and rapid acquisition, no damage to donor health, low incidence of graft-versus-host disease, and relatively lenient HLA matching requirements [4]. In recent years, cord blood HSCT has played an increasingly important role in the treatment of malignant hematological diseases in children and adults, saving the lives of numerous patients. This article reviews the current status of cord blood HSCT for the treatment of hematologic malignant diseases. History of hematopoietic stem cell transplantation from umbilical cord blood * Corresponding author: Siguo Hao, MD, PhD, PhD, main research interests: immunotherapy of malignant tumors and hematopoietic stem cell transplantation The world’s first successful hematopoietic stem cell transplantation from umbilical cord blood was performed in close collaboration between French and American doctors. The patient was a 5-year-old male child with severe Fanconi anemia. The umbilical cord blood of the child’s sister was collected and frozen at Indiana University School of Medicine in the United States, where it was found to be a perfect HLA match for the child after prenatal testing and was not suffering from Fanconi anemia. Dr. Gluckman at St. Louis Hospital in Paris, France, has a long history of experience in bone marrow transplantation for the treatment of Faconi anemia. Ultimately, the child received a cord blood HSCT at the Saint Louis Hospital in France. The pretreatment regimen was low-dose cyclophosphamide 20mg/kg combined with 5Gy total body lymphoid tissue irradiation. Frozen cord blood was transported from Indiana, USA to Paris at -175°C, resuscitated and transfused directly to the child without additional treatment. The child showed signs of successful implantation at d22 post-transplantation and eventually achieved hematopoietic and immune reconstitution. The child did not develop graft-versus-host disease and has survived long-term for almost 26 years to date. Since then, along with the establishment of public cord blood banks in many countries, cord blood hematopoietic stem cell transplantation has sprung up. In China, cord blood banks have been established in Beijing, Shanghai, Guangzhou and other cities since 1990, and the scale of cord blood HSCT has been expanding. The status of cord blood HSCT is becoming more and more important in the field of clinical HSCT treatment. Childhood umbilical cord blood HSCT For many years, it was believed that the number of HSCs in umbilical cord blood was too small to meet the needs of adult hematopoietic reconstruction, and therefore the majority of cord blood HSCTs were mainly used to treat pediatric hematologic diseases. In view of the fact that most mothers of children do not become pregnant again and the lack of cord blood banks for specific families, cord blood stored in domestic and international cord blood banks is mainly unrelated cord blood, and only 8% of cord blood in European cord blood banks is related sibling cord blood [5]. The CIBMTR-European Umbilical Cord Blood Study Group compared the incidence of acute and chronic GVHD with delayed granulocyte and platelet implantation in umbilical cord blood transplants, but both had similar survival rates. This study was the first to clarify that cord blood transplantation has a lower incidence of GVHD than bone marrow transplantation [6]. It summarized the efficacy of kinship HLA-allogeneic cord blood transplantation for hematologic malignancies. 147 children with acute leukemia received kinship HLA-allogeneic cord blood transplantation with a cumulative neutrophil recovery rate of 90%; 2-year acute and chronic GVHD incidence rates of 12% and 10%, respectively; 5-year cumulative relapse-free mortality and relapse rates of 9% and 47%, respectively; disease-free survival DFS of Kurtzberg [7] first reported the outcome of 25 children treated with unrelated cord blood transplantation. The d100 overall survival rate after transplantation was 64%, which fully demonstrates the feasibility of unrelated cord blood transplantation. In addition, the results of a retrospective clinical study of unrelated HLA incompletely matched cord blood transplantation and unrelated HLA fully matched bone marrow or peripheral blood HSCT showed that delayed cord blood implantation was associated with a lower incidence of acute and chronic GVHD compared to bone marrow or peripheral blood, but the relapse rate, overall survival and leukemia-free survival (LFS) were similar to the former two [8]. A study from the CIBMTR found that HLA-all-compatible unrelated cord blood transplantation was more effective than HLA-all-compatible unrelated bone marrow transplantation for the treatment of acute leukemia in children. In contrast, HLA incompatible unrelated bone marrow transplantation was associated with a higher incidence of acute and chronic GVHD in bone marrow transplantation compared to cord blood transplantation [9]. There was also a study comparing the efficacy of unrelated HLA incompletely matched cord blood transplantation and hemi-compatible transplantation for children with combined immunodeficiency, with similar DFS but better cord blood immune reconstitution and chimerism [10]. Adult cord blood HSCT Single-copy cord blood HSCT Cord blood HSCT has been highly successful in the treatment of hematologic disorders in children; however, the initial phase of single-copy cord blood transplantation in adult patients has not been very promising, with approximately 40% of patients dying before d100 post-transplantation [11]. A multicenter clinical study of 514 adult single-copy cord blood transplant patients showed an overall 1-year survival rate of 37%, with age and disease status as risk factors associated with prognosis [12]. In addition, adult single-copy cord blood transplantation was found to be effective in patients with myelodysplastic syndromes, with a 2-year DFS of 30% [13]; furthermore, adult single-copy cord blood transplantation has achieved encouraging results in patients with early stages of hematologic malignancies, with a 5-year DFS of 46% [14]. Japanese researchers have even reported a 5-year EFS of 63% after adult single-copy cord blood transplantation, although this may be related to the Asian ethnicity, patient selection and small case size [15]. Bipartite cord blood HSCT During adult single-copy cord blood transplantation, many research centers have found that the number of cord blood cells transfused is closely related to the patient’s cord blood implantation and overall survival. In 2005, the University of Minnesota Transplant Center reported for the first time that after pretreatment with the RIC protocol (Flu+Cy+TBI), patients received a single cord blood transplant if the cord blood cell count was >3.5 × 107 NC/kg and a double cord blood transfusion if it was <3.5 × 107 NC/kg, resulting in The implantation rate was higher in patients who received double cord blood than single cord blood [16]. Since then, double cord blood transplantation in adults has been carried out in many centers with significant clinical outcomes, and the DFS of double cord blood transplantation after pretreatment with the RIC protocol ranged from 30% to 50% [17-19].Barker JN et al. found in a retrospective study that double cord blood significantly increased the implantation rate and reduced transplant-related mortality in adults and high weight children compared to single cord blood [ 20]. Only 1 dominant cord blood is eventually implanted after double cord blood transplantation, but it is difficult to predict which of the double cord blood will become the dominant cord blood and be successfully implanted. Only one study has suggested an association between CD3+ cell ratio (p=0.04) and post-resuscitation CD34 cell viability (p=0.008) and cord blood dominance [21]. Some authors have suggested that the high implantation rate of double cord blood is due to the fact that at least 1 of the double copies will implant and therefore the probability of successful implantation is increased, while other researchers have suggested that 1 of the double copies of cord blood provides the hematopoietic microenvironment for the other, but the underlying mechanism of double cord blood implantation is unclear so far. Therefore, single-copy cord blood may be most suitable for transplantation in pediatric patients, while the efficacy of single-copy and double-copy cord blood transplantation in adults needs further study to elucidate [22]. Selection of cord blood HSCT donors The selection of cord blood donors for a transplantation center, whether single or double cord blood transplantation, generally follows the following three principles: the recipient's kilogram weight cord blood single nuclei cell count (TNC/kg); the degree of HLA-A,-B low-resolution and DRB1 high-resolution compatibility (4-6/6); and the choice of cord blood bank. Cord blood cell count Since there is no ideal model to guide the number of cord blood single nucleated cells (TNC/kg) in kilograms of recipient body weight, most centers use the actual weight of the recipient for calculation. It is recommended to use the actual weight at the time of transplantation so as to exclude the effect of chemotherapy and hormonal agents on the recipient's weight. The number of cord blood cells required for a single cord blood and double cord blood transplant is different. The New York Blood Bank Center analyzed 1061 patients with hematologic malignancies who underwent single-copy cord blood marrow transplantation and used this as the basis for developing guidelines for the number of cord blood cells needed for transplantation using HLA incompatibility trade-offs [23]. This guideline states that 6/6-compatible transplantation is most effective regardless of the number of individual nucleated cells in cord blood (median 4.0 × 10 7/kg), suggesting that the degree of HLA-A, B, and DRB1 compatibility is a more important influencing factor for transplantation success. Even though the requirement of cord blood TNC/kg for 6/6 full compatibility is low, it is important to note that few transplant centers have TNC <1.5 × 10< span=""> 7/kg . HLA-matched 5/6 compatible recipients require cord blood TNC ≥2.5 × 10 7/kg, while HLA-matched 4/6 compatible patients require cord blood TNC ≥5.0 × 10 7/kg. based on the above studies, most centers reached the following The consensus is that the higher the degree of HLA incompatibility, the more cord blood TNC is required, and vice versa. Duplex cord blood transplantation improves implantation rates and reduces transplant-related mortality and recurrence rates. Given the potential for each of the two cord bloods to become the dominant cord blood for successful implantation, both cord bloods are equally important and the selection criteria for a single cord blood are equally applicable to the selection of the two cord bloods. It is unclear how HLA compatibility is used to weigh the TNC in the dual cord blood. One study showed a strong correlation between total TNC (p=0.0007) and the proportion of CD3+ cells (p=0.001) in duplex cord blood and implantation rate [21]. This center recommends a TNC of no less than 2.0×10 7/kg per cord blood in duplexes, and this criterion is expected to be further optimized in the future as the scale of duplex cord blood transplantation continues to expand. Matching Many clinical studies have found that HLA-A, B, and DRB1 loci do not match resulting in delayed implantation and increased incidence of GVHD. All large sample studies have shown that HLA incompatibility increases transplant-related mortality and decreases survival. Therefore, the standard process for cord blood transplantation matching is HLA-A and -B low-resolution and DRB1 high-resolution testing [24]. Although there is no clear evidence to support the importance of HLA-C loci, the results of a retrospective clinical study suggest that transplant-related mortality is higher in patients with HLA-C loci incompatible leukemia and MDS than in compatible patients [25]. Of course, some transplant centers suggest that if there are several HLA-A and -B low-resolution and DRB1 high-resolution matched cord blood, and one of them has a perfect match for HLA-A, B, C, and DRB1 high-resolution, then there is no doubt that this cord blood is preferred, but this is less likely because many cord blood banks do not perform high-resolution testing for all of the above loci before cord blood freezing, and it is clearly impractical to perform high-resolution testing after thawing. It is clearly impractical to perform high-resolution testing after thawing. In addition, some investigators have given preference to unidirectional incompatibility (GVHD direction) over bidirectional incompatibility or unidirectional incompatibility (rejection direction) when selecting HLA incompatible cord blood because the former has a clear survival advantage after transplantation [26]. Interestingly, two research centers reported a significant decrease in graft-related mortality and recurrence rates after transplantation when patients carried HLA loci similar to the non-inherited maternal HLA antigen of cord blood, probably because immune tolerance was induced early after contact between cord blood and the non-inherited maternal antigen, and the immune response was reduced when cord blood was transplanted with a patient carrying an antigen similar to the non-inherited maternal antigen of that cord blood. The immune response is relatively weakened after antigen contact [27,28]. HLA typing of bipartite cord blood is generally consistent with the criteria for single-copy cord blood. It has been shown that the degree of HLA compatibility between bipartite cord blood-cord blood does not affect implantation and patient survival. In addition, it was found that the degree of high-resolution compatibility at a total of 10 loci of HLA-A, B, C, DRB1, and DQB1 of double cord blood did not affect cord blood implantation (p=0.66) [21]. Cord blood banking It is self-evident that there are quality differences between cord blood and cord blood, and differences between cord blood banks and cord blood banks. McCullough et al [29] found that 56% of the 268 cord blood tested had quality problems, 10% of which were harmful to patients. One research center found that cord blood from different cord blood bank sources had different cell viability and CD34+ cell ratios after resuscitation, and that cord blood with low viability among them was difficult to implant successfully [30]. Therefore, this difference in cord blood quality between cord blood banks also reinforces the importance of double cord blood transplantation, as it ensures at least 1 high quality cord blood. In addition, some cord blood banks have poor quality cryopreservation bags, which sometimes result in accidents such as bag rupture during resuscitation. Finally, quality control and pathogen detection are difficult to standardize across cord blood banks, as there is no standardized process available in China, while the United States strictly follows the American Association of Blood Banks (AABB) standards. Cord blood HSCT pre-treatment protocols Cord blood transplantation pre-treatment protocols are critical to the success of transplantation. The type of disease, disease status, age and concomitant diseases of the patient need to be taken into account when developing a proper pretreatment protocol. Common pretreatment regimens for cord blood transplantation include high-dose TBI-based marrow clearance (MA) and non-high-dose TBI-based pretreatment regimens and reduced-dose pretreatment regimens (RIC). The former, for example, 13.2C13.75 Gy TBI + 120 mg/kg CY + 90 mg/kg equine ATG [31]; 13.2 Gy TBI + 75 mg/m2 FLU + 120 mg/kg CY [20]; the latter, for example, 100 mg/m2 MEL + 180 mg/m2 FLU + 6 mg/kg rabbit ATG [17]; 200 mg/m2 FLU + 50 mg/kg CY + 2 Gy TBI ± 90 mg/kg equine ATG [32]; 50 mg/kg CY + 150 mg/m2 FLU + 10 mg/kg thiotepa + 400 cGy TBI [33]. All of the above pretreatment regimens yielded ideal cord blood implantation rates and can be used as a reference for individual transplantation centers. Which is the choice between adult cord blood HSCT and unrelated donor transplantation? If a patient does not have a suitable related HLA-compatible donor, which is the most appropriate choice: cord blood HSCT or unrelated donor transplantation? Which is the most appropriate choice. There are no complete prospective clinical studies that provide definitive answers to this question [34]. Eapen et al [35] compared the outcomes of 165 adult single-copy cord blood transplants, 888 HLA-compatible unrelated peripheral blood HSCTs and 472 HLA-compatible unrelated bone marrow transplants. Cord blood transplantation had higher transplant-related mortality but lower incidence of acute and chronic GVHD. The DFS of cord blood transplantation, HLA-compatible unrelated transplantation and HLA-incompatible unrelated transplantation were comparable, and disease status at the time of transplantation was an important factor in prognosis.Brunstein et al [36] demonstrated comparable efficacy of double cord blood transplantation, HLA-compatible allogeneic related donor transplantation and HLA-compatible allogeneic, incompatible unrelated donor transplantation under a clear marrow pretreatment regimen. Two other retrospective clinical studies have shown similar efficacy of double cord blood transplantation and HLA-compatible unrelated donor transplantation under RIC pretreatment regimens. Therefore, if a suitable HLA-compatible allogeneic donor is not available, some centers prefer to look for a 10/10-compatible unrelated donor, and if one is not found, or in patients with an urgent need for transplantation, cord blood transplantation may be the best option. In summary: Over the past 20 years, cord blood HSCT has made rapid advances, and the outcomes of cord blood transplantation in children in particular have been very encouraging. Adult cord blood transplantation has also progressed from the single-copy to the double-copy stage, and many retrospective clinical studies have shown comparable efficacy between unrelated donor cord blood transplantation and unrelated donor bone marrow transplantation or peripheral blood stem cell transplantation. However, there are no multicenter prospective studies yet, so in-depth studies in this area are needed in the future. In addition, cord blood transplantation is associated with delayed implantation and slow rebuilding of the immune system, which increases late viral infections. To address these problems, strategies such as cord blood ex vivo expansion, cord blood intrathecal injection, promotion of stem cell homing and mesenchymal stem cell support are expected to finally solve these problems. It is believed that with the development and growth of cord blood banks, more optimal selection of cord blood donors, more reasonable pretreatment protocols, and more standardized and effective management of complications, cord blood transplantation will definitely shine in clinical practice.