By transplanting two cord blood units at the same time or a second transplant to increase the chance of success, positive results have also been achieved [19],[81].
1.2.3.2. Graft-versus-host disease complications
In contrast to the complication of delayed graft emergence, cases of transplantation using cord blood had significantly lower graft-versus-host disease complications than those using adult donor stem cell sources. In terms of manifestations, graft-versus-host disease in cases using cord blood was similar to other cell sources such as: skin rash/itching, digestive disorders, liver damage... however, the incidence and severity were lower. A study by Marks et al. (2014) on 802 cases of stem cell transplantation from cord blood and from adult donors to treat acute lymphoblastic leukemia showed that the incidence of acute graft-versus-host disease at mild to severe levels in the group using cord blood was 1.57 to 1.89 times lower than that of transplantation from adult stem cells (p<0.05), while the incidence of chronic graft-versus-host disease was not different [64]. Laughlin et al.'s study (2004) also had similar results when it found that the bone marrow transplant group had a graft-versus-host disease rate of up to 48%-52% while this rate in the cord blood transplant group was lower, at 40% [60]. Notably, in this study group, the mortality rate due to graft-versus-host disease in the cord blood transplant group was significantly lower (9.4% compared to 20.2%). Satoshi et al. (2004) also found that the severe graft-versus-host disease rate in the cord blood transplant group was 3 times lower than in the bone marrow transplant group and there were no cases of death due to graft-versus-host disease when using cord blood [59]. The reason for this difference is that cord blood cells originate from newborns, who have not been exposed to many external agents. Meanwhile, stem cell masses from adult donors contain many immune cells, especially T lymphocytes that have been exposed to many antigens during the donor's maturation, which are the main source leading to graft-versus-host disease [82].
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To prevent graft versus host disease, many regimens using immunosuppressive drugs are also applied depending on each facility. Although graft versus host disease is a complication of allogeneic hematopoietic stem cell transplantation, in the treatment of malignant diseases, maintaining it at a low level is beneficial because it helps increase the attack of the graft on cancer cells. The most commonly used regimen is the combination of cyclosporin A (CSA) + mycophenolate mofetil (MMF) + methotrexate (MTX) as reported by Satoshi (2004), Jaime (2010), Zheng (2013), José (2014) [59],[71],[65],[83]. Some other reports by Lee (2015) or Mark (2014) choose other groups of drugs such as tacrolimus combined with MMF [64],[84]. In general, all drug combinations are effective, but which regimen to use often depends on the availability and ability of the transplant facility to monitor drug concentrations to assess the appropriate dose for each individual patient.
1.2.3.3. Infectious complications
Cord blood stem cell transplantation often has a slow graft growth time, a prolonged post-conditioning bone marrow depression phase, and this is the cause of increased risk of infection for transplant patients. According to Burik (2007), infection is the cause of 30-40% of deaths after cord blood transplantation, including viral and bacterial infections [85]. According to Victor (2011), common infections in cord blood transplantation include bacterial, fungal and CMV infections, of which pneumonia is the leading cause of death [86]. CMV reactivation is one of the very common complications in allogeneic stem cell transplantation when the patient's immune system has not fully recovered. This is the cause of death for 11% of patients with CMV after transplantation [87]. According to Mikulska et al (2012), although cord blood transplantation has a longer engraftment time when compared with other stem cell sources, the incidence and mortality rate due to CMV in transplant patients are not different [88].
1.3. FACTORS AFFECTING THE RESULTS OF UNIVERSAL CORD BLOOD STEM CELL TRANSPLANTATION TO TREAT HEMATOLOGIC DISEASES
1.3.1. Level of leukocyte antigen compatibility
Human leukocyte antigen (HLA) is the primary criterion in selecting stem cell sources for transplantation in general and selecting suitable cord blood units in particular. According to the usual standard for stem cell sources from adult donors, the minimum HLA compatibility level required is 8/10 alleles of the HLA-A, -B, -C, -DR, -DQ loci at high resolution [35]. If the compatibility level is lower, the risk of graft failure as well as graft-versus-host disease increases many times. However, the standard for cord blood is quite different, requiring only a minimum compatibility of 4/6 loci of HLA-A, -B at low resolution and HLA-DR at high resolution [35],[89]. This is because stem cells in cord blood are quite young, so their immune tolerance to the recipient's body is better than stem cells from adult donors. In addition, the HLA-A and HLA-B loci usually belong to HLA class I, which is common in all types of nucleated cells, so only low-resolution matching is required, while HLA-DR belongs to HLA class II, which is present mainly on immune cells such as B lymphocytes and T lymphocytes, which are cells that are mainly involved in mechanisms of graft rejection and graft-versus-host disease, so high resolution is required. Kogler (2012) compared the role of HLA loci as well as the requirement for high or low resolution when selecting a suitable cord blood unit and found that the requirement for high or low resolution matching for HLA class I loci did not significantly affect the transplant efficiency [90]. The most important factor is the number of compatible HLA alleles. A study by Eapen et al (2014) on a group of malignant patients transplanted from umbilical cord blood showed that the 6/6 allele compatibility level gave the best transplant results with a 3-year overall survival rate of 52%, followed by 5/6 and 4/6 compatibility with overall survival rates of 47% and 42%, respectively [91].
1.3.2. Nucleated cell dose and CD34 cell dose
Similar to other cell sources, the stem cell dose is very important in determining the success of each cord blood transplant in addition to HLA compatibility. In peripheral blood stem cell transplantation, the CD34 cell dose plays a decisive role in the graft engraftment efficiency, while the bone marrow stem cell source uses the mononuclear cell (MNC) dose. However, in cord blood stem cell transplantation, the nucleated cell dose and the CD34 cell dose both play a very important role in the graft efficiency [35]. According to the common standard in the world, the minimum nucleated cell dose for cord blood transplantation is 2 x 10 7 cells/kg of patient weight, and the CD34 cell dose needs to reach a minimum of 0.8 x 10 5 /kg of body weight [37]. This dose is lower than the required dose of mobilized peripheral blood stem cells, which is 2 x 10 6 CD34 cells/kg of patient weight. The main reason is that cord blood contains many cellular components at a lower level of differentiation than hematopoietic stem cells such as mesenchymal stem cells, etc., so the potential of cord blood cannot be assessed solely based on the hematopoietic stem cell marker CD34. Therefore, although the dose of CD34 cells in cord blood used for transplantation may be lower than that of CD34 cells in peripheral blood, it is still sufficient to grow grafts in the recipient's body [92]. In addition, some studies in the world have also set higher standards to increase the ability to grow grafts in cases of cord blood transplantation, reducing the time of profound bone marrow failure and hospitalization for patients. In particular, some authors use the dose of nucleated cells and the dose of CD34 cells to compensate for the poor HLA compatibility between cord blood and the patient, with the minimum dose of nucleated cells and CD34 cells increasing gradually if the HLA compatibility level decreases [93]. Laughlin's study (2001) found that if the dose of nucleated cells was above 1.87 x 10 7 /kg body weight, the patient's ability to grow grafts as well as the probability of overall survival were statistically higher than in cases where the dose of nucleated cells was below 1.87 x 10 7 /kg body weight [94].
1.3.3. Conditioning protocol
In each transplant, before stem cell infusion, the patient must undergo a conditioning process according to a different chemotherapy regimen and may be combined with radiation therapy. This is a mandatory process to destroy as many abnormal cells and old normal cells remaining in the bone marrow as possible, eliminating immune cells to help the newly introduced cells grow a sustainable graft, avoiding recurrence and complications such as graft-versus-host disease and graft rejection. Umbilical cord blood has an obvious disadvantage that the number of cells in each stem cell unit is much lower than other stem cell sources such as mobilized peripheral blood or bone marrow fluid. Therefore, to ensure that umbilical cord blood cells can grow well in the patient's body, the conditioning regimen when transplanting with this type of stem cell is also different and tends to use a higher dose. In Japan, Satoshi Takahashi and colleagues (2004) performed cord blood stem cell transplantation for 68 cases of patients with malignant hematological diseases using a regimen using total body irradiation (TBI) combined with cyclophosphamide and possibly combined with cytarabine [59]. Mark and colleagues (2014) also summarized in a multicenter study in the US and UK that the conditioning regimen combining TBI with a number of other groups of drugs such as cyclophosphamide and/or fludarabine was the most widely used [64]. Thus, it can be said that total body irradiation is quite commonly used in conditioning regimens for this stem cell source. Total body irradiation is a highly effective conditioning method for both myeloablative and immunosuppressive purposes. This method does not cause cross-drug resistance and can reach places where chemotherapy cannot reach. In addition, the effectiveness of radiation does not depend on the blood supply to the cancerous tissue. With shielding techniques to protect important organs in
High-dose radiation therapy can be performed safely and effectively.
However, many places in the world do not have enough human resources and equipment for whole-body radiation equipment and are afraid of the high toxicity of this technique. Therefore, regimens based on chemotherapy alone have been applied very effectively and successfully in many facilities. Jaime (2010) used a combination regimen of thiotepa + busulfan + cyclophosphamide/fludarabine and ATG (anti-thymocyte, anti-thymocyte antibody) for a group of patients with chronic myeloid leukemia to receive cord blood transplantation [83]. The results showed that the overall survival rate after 12 years was 59%, the disease-free survival rate was 41% for cases still in the chronic phase. Jose Pinana reported a multicenter study in Spain (2014) using cord blood for patients with poor prognosis acute leukemia also showing very positive results with overall survival rates ranging from 46%-60% at 5 years [65]. The conditioning regimen used here was busulfan + thiotepa + cyclophosphamide / fludarabine with the addition of ATG.
Figure 1.7. Results of allogeneic stem cell transplantation for acute leukemia using conditioning regimen with busulfan+fludarabine+etoposide (Lee-2014)
In some facilities where thiotepa and TBI are not available, some regimens using busulfan+fludarabine+etoposide also have equivalent efficacy. Lee et al. (2014) applied this regimen in cord blood stem cell transplantation.
for patients with childhood acute leukemia with very high 5-year overall survival and disease-free survival (86.2% and 83.8%) [95].
Kato et al (2011) when transplanting for the pediatric acute lymphoblastic leukemia group selected a variety of regimens, including regimens with TBI such as TBI + cyclophosphamide + etoposide/or other agents, or regimens without TBI such as Busulfan + cyclophosphamide + other agents [67].
1.3.4. Blood group incompatibility
Although blood group incompatibility between the patient and the donor is not a contraindication when selecting stem cells, it is one of the factors that can significantly affect the effectiveness of the transplant process [5]. The most affected cell line is usually the red blood cell line. Many studies have found that when the patient and the stem cell donor have blood group incompatibility, especially major blood group incompatibility in which the patient's body has antibodies against the donor's red blood cells, the ability to grow grafts of the red blood cell line as well as the conversion of blood groups occurs significantly slower than in cases of secondary incompatibility or blood group similarity. The main reason here is that the conversion of the red blood cell line is often much slower than that of the white blood cell and platelet lines. In addition, the natural antibodies in the patient's body against the donor's red blood cells also exist for a long time, interacting with newly born red blood cells carrying the donor's new antigens [5]. Therefore, only when these antibodies are completely neutralized over time will the patient's blood group completely convert. This is also an important basis when choosing suitable cord blood units for patients in addition to HLA and cell dose standards. Evaluation of blood group conversion is also a form of evaluating the effectiveness of grafting through a number of techniques such as ABO blood group testing, subgroup blood grouping, and conversion of natural antibody titers [5].
1.3.5. Graft-versus-host disease
The role of graft versus host disease in preventing relapse has been studied by many authors around the world. Boyiadzis (2015) when studying the impact of chronic graft versus host disease (cGVHD) on the possibility of late relapse and overall survival of 7489 patients with leukemia groups found that the cGVHD effect helps reduce the risk of relapse for patients with chronic granulocytic leukemia after transplantation by nearly 2 times, but there was no statistically significant relationship with acute leukemia, myelodysplasia [96]. In addition, this study also found that graft versus host increased the mortality rate in all groups by 1.56 times. Kataoka's study (2004) found that cGVHD helped reduce relapse after transplantation in the group of chronic granulocytic leukemia and acute lymphoblastic leukemia but had no effect on acute myeloid leukemia [97]. However, the mortality and complication rates are significantly increased in patients with graft-versus-host disease [98]. The graft-versus-host effect helps the graft to increase conflict and elimination of residual malignant cells in the body, thereby reducing the risk of disease recurrence. However, this effect is only valuable in some disease groups such as chronic granulocytic leukemia and must be in the stable graft phase after 100 days. On the contrary, the risk of death due to acute graft-versus-host disease in the early stages of 100 days after transplantation is still a factor that significantly affects the desired results. Even according to Kanda's study (2004) on 2114 patients in Japan, having moderate and severe acute graft-versus-host disease also reduces the probability of disease-free survival in all groups of chronic granulocytic leukemia, acute leukemia, and myelodysplasia [82]. Compared with stem cells from adult donors, umbilical cord blood cells with a lower risk of graft versus host also bring certain advantages, helping to reduce the mortality rate due to graft versus host, limiting many side effects caused by graft versus host prophylaxis and treatment drugs, including liver and kidney dysfunction and most dangerously, immunosuppression, which makes infectious diseases at risk of outbreak. Reducing the risk of