Haploidentical hematopoietic stem cell transplantation as first-line therapy for aplastic anemia in children: A single-center experience

Haploidentical hematopoietic stem cell transplantation as first-line therapy for aplastic anemia in children: A single-center experience | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Article Haploidentical hematopoietic stem cell transplantation as first-line therapy for aplastic anemia in children: A single-center experience Hao Xiong, Zuofeng Li, Zhi Chen, Li Yang, Ming Sun, Wenjie Lu, and 3 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-3821593/v1 This work is licensed under a CC BY 4.0 License Status: Posted Version 1 posted You are reading this latest preprint version Abstract HID-HSCT is considered a viable treatment option for children with AA who do not have a suitable identical donor or an unrelated donor, but there are not enough studies on how it fares in comparison to with stem cells from MSD-HSCT and UD-HSCT. Therefore, this study compared the outcomes of three ways as the first-line treatment for children with AA. We retrospectively compared the outcomes of 85 pediatric patients who underwent HID-HSCT (n = 41), MSD-HSCT (n = 10), and UD-HSCT (n = 34)from August 2016 toJune 2023. Cumulative rates of neutrophil and platelet implantation, incidence of aGVHD, cGVHD, and 6-year OS were not statistically significant in the three groups. In the univariate and multivariate analyses, the survival outcome for the entire population was adversely associated with TMA (P = 0.040), but was not related to other factors. In summary, there were no statistically significant differences in terms of hematopoietic reconstruction and prognosis between the three transplantation methodologies. Thus, for individuals without HLA-matched siblings or unrelated donors, HID-HSCT might be a practical and promising primary treatment option. Biological sciences/Stem cells/Haematopoietic stem cells Health sciences/Medical research/Stem-cell research Biological sciences/Stem cells/Cancer stem cells Severe aplastic anemia Haploidentical hematopoietic stem cell transplantation Unrelated donor Sibling matched donor Pediatric aplastic anemia Figures Figure 1 Figure 2 Figure 3 1 Introduction Aplastic anemia (AA) is a common and potentially life-threatening condition that causes bone marrow failure in children. It is characterized by a decrease in peripheral blood and bone marrow cells [1–2] . Children with severe aplastic anemia (SAA) and very severe aplastic anemia (VSAA) experience fast progression of the disease, which greatly affects their long-term well-being, and also have a high risk of fatality. Currently, the two main treatment options are hematopoietic stem cell transplantation (HSCT) and immunosuppressive treatment. Allogeneic hematopoietic stem cell transplantation (HSCT) is recommended as first-line treatment for patients ≤ 40 years of age with an available matched sibling donor (MSD), as the effectiveness of immunosuppressive treatment is limited by non-responsiveness to treatment, relapse, and clonal evolution [3] . Matching sibling donor HSCT (MSD-HSCT) is the preferred initial treatment for children with SAA and SVAA, but less than 30% of children have HLA-matched siblings and actually undergo this procedure. Unrelated matched donor HSCT (UD-HSCT) is another option, but finding a suitable unrelated donor for HSCT can take several months due to the challenges related to screening unrelated donors, extracting bone marrow hematopoietic stem cells, and the limited supply of hematopoietic stem cells. This waiting period is too long for children with severe disease or co-existing infections. A third option is haploidentical donor HSCT (HID-HSCT), which is suitable to and beneficial for nearly all patients when an HLA genotypically matched sibling is not available [4] .In comparison with MSD-HSCT and UD-HSCT, the preparation for this procedure is relatively straightforward and can be achieved within a concise timeframe. It offers the advantages of speed, accessibility, and long-term sustainability [5] . Further, with advancements in pretreatment protocols, such as in vivo depleted T-cell counts and combinations with bone marrow mesenchymal stem cells, as well as improvements in supportive therapies and donor screening methods, the effectiveness of HID-HSCT has been increasing. Consequently, HID-HSCT has been widely used in many treatment centers worldwide in recent years [6–8] . There is a scarcity of studies that directly compare the outcomes of HID-HSCT recipients with those of MSD-HSCT and UD-HSCT recipients. According to Xu et al.’s study on data from the Chinese Bone Marrow Transplantation Registry, which is currently the largest Chinese registry for bone marrow transplantation [9] , among 157 patients with SAA from 11 transplant centers in China who underwent HID-HSCT between June 2012 and September 2015, the 3-year overall survival (OS) rates for HID-HSCT and MSD-HSCT were comparable, as were the 3-year failure-free survival (FFS) rates and the 1-year graft-versus-host disease failure survival (GFFS) rates. However, the report did not analyze and compare the efficacy of UD-HSCT or focus on the pediatric population, and there is also a high risk of bias due to the significant age difference between the HID-HSCT and MSD-HSCT cohorts. Given these limitations of previous studies, it is necessary to obtain and analyze the current data on the outcomes of the three HSCT strategies, as it could assist in treatment decision-making for children with AA undergoing this procedure. Therefore, in order to fill in this knowledge gap, in the present study, we will compare the outcomes of MSD-HSCT, HID-HSCT, and UMD-HSCT as first-line treatments for children with SAA. 2 Methods 2.1 Patients A comprehensive retrospective analysis was conducted on a total of 85 children diagnosed with AA who underwent HSCT at our institution between August 2016 and December 2022. According to the enrollment criteria, children with SAA and VSAA, as defined by clinical guidelines [10] , who opted to undergo HSCT and did not have severe organ dysfunction were included. All the children underwent myelocyte assessments, and patients with underlying inherited marrow failure disorders, such as Fanconi anemia, myelodysplastic syndrome, and paroxysmal nocturnal hemoglobinuria, were excluded. The protocol of this clinical observation study adhered to the tenets of the Declaration of Helsinki and was approved by the Ethics Committee of Wuhan Children's Hospital (approval no. 2022R071-E01). Due to complications, such as severe infection and long-term transfusion dependency, in cases where it was not possible to wait for the MSD or suitable UD for transplantation, at the insistence of the parents and in accordance with the Declaration of Helsinki, HID-HSCT was selected as the treatment of choice. Written informed consent was obtained from the patients or their relatives before the procedures were conducted. 2.2 Donor mobilization, and stem cell harvesting Eligibility criteria for donors included full HLA match or semi-compatibility, and the donors included relatives (such as parents, siblings, and cousin) and unrelated donors who were available to the patient. Donors with donor-specific antibodies (based on a mean fluorescence intensity level > 1000 according to solid phase immunoassay) were excluded. The donors received an infusion of granulocyte colony-stimulating factor (G-CSF) at a dose of 5–10 µg/kg for 5 days prior to transplantation. Peripheral blood stem cells (PBSCs) were collected on the 4th and 5th day. Mobilization was considered successful when the CD34 cell count was 4–6 × 10 6 /kg and the MNC count was 6–8 × 10 8 /kg. 2.3 Pretreatment protocol Patients with an MSD and UD were treated according to the FLU/CY-based regimen: fludarabine (FLU), 50 mg/m 2 /day, intravenously (i.v.) on day − 7 to − 4; cyclophosphoramide (CY), 50 mg/kg/day (i.v.) on day − 5 to − 3; and antithymocyte immunoglobulin (ATG, rabbit), 10 mg/kg/day (i.v.) on day − 4 to − 2. Patients with haploidentical donors were treated according to the BU/FLU/CY-based regimen, which consisted of busulfan (Bu), 3.2 mg/kg/day (i.v.) on day − 7 and − 6; CY, 120 mg/kg/day (i.v.) on day − 5 to − 2; and ATG, 10 mg/kg/day (i.v.) on day − 4 to − 2. 2.4 Prophylactic treatment for graft-versus-host disease The current standard of care for MSD-HSCT involves a combination of Cy and ATG, and in the UD-HSCT group, anti-CD25 monoclonal antibodies were also added. In the HID-HSCT group, MTX, MMF, and an anti-CD25 monoclonal antibody were used, based on previous recommendations [16] . 2.5 Definitions The prognosis was assessed using several key indicators, including OS, FFS, and GFFS. OS was measured from the first day of therapy until death or the last follow-up. FFS was defined as survival without treatment failure, including death, graft failure, and relapse. GFFS was defined as survival without grade III–IV acute GVHD (aGVHD), moderate-to-severe chronic GVHD (cGVHD), or treatment failure, including death, primary or secondary graft failure, and relapse [11] . Neutrophil engraftment was defined as an absolute neutrophil count > 0.5 × 10 9 /L for three consecutive days. Platelet engraftment was defined as an absolute platelet count > 20 × 10 9 /L for three consecutive days without transfusion. Failure to achieve engraftment by day + 28 was considered to be indicative of low donor chimerism, and it was assumed that primary graft failure had occurred in such cases. The diagnostic and classification criteria for aGVHD and cGVHD were based on the Glucksberg-Seattle criteria [12–13] , and hemorrhagic cystitis was defined based on the criteria established by Vela-Ojeda et al. [14] 2.6 Statistical analysis Statistical analyses were performed using SPSS version 22.0 (SPSS Inc., Chicago, IL). Graphs were generated using Prism 8.0 (GraphPad software). For quantitative variables, mean ± SD values and ANOVA were used for analyzing normally distributed data, while the median (P25, P75) values and the Kruskal-Wallis H-test were used for analyzing non-normally distributed data. To compare qualitative variables presented as rates or percentages, the chi-square test, Fisher’s exact test, and the rank-sum test were utilized. Survival estimation was performed using the Kaplan-Meier method, and differences between the three groups were assessed using either the Kruskal-Wallis test or one-way ANOVA (for normally distributed variables). Variables with a P value of < 0.05 in the one-way analysis were further analyzed through multifactorial analysis, and the HR (95% CI) values of the influencing factors were calculated. Statistical significance was set at P < 0.05. 3 Results 3.1 Patient characteristics The pediatric patients were categorized into three distinct groups based on the different transplantation methods: 41 children underwent HID-HSCT; 10 children, MSD-HSCT; and 34 children, UD-HSCT. The cohort included 43 males and 42 females, and the median age was 6.1 years (age range, 1–16.9 years). The median ages of patients in the HID-HSCT, MSD-HSCT, and UD-HSCT groups were 24 months (range, 1–62 months), 30 months (range, 0–76 months), and 28.5 months (range, 2–57 months) (P = 0.121), respectively. The variations in age distribution and the degree of donor-recipient blood group compatibility were not significantly different between the three groups (P > 0.05). However, the distribution of gender among the three groups varied significantly (P = 0.023). There was no discernible variation in gender distribution between the other two groups, with the exception of the MSD group, which had a male-to-female ratio of 8:10. 3.2 Hematopoietic reconstitution As shown in Table 1 , the neutrophil and platelet implantation times were not significantly different between the three groups (P > 0.05). However, platelet engraftment occurred first in the UD-HSCT group, which was followed by the MSD-HSCT group and then the HID-HSCT group. Table 1 Patient characteristics Variable HID-HSCT MSD-HSCT UD-HSCT X 2 P No. of patients (n) 41 10 34 Age, years (median ± SD) 6.72 ± 3.86 8.70 ± 3.24 6.02 ± 3.32 0.121 Age group 4.672 0.097 ≤ 6 years 21 (51.2%) 2 (20%) 20 (58.8%) > 6 years 20 (39.2%) 8 (80%) 14 (41.2%) Sex 7.584 0.023 Boy 17 (41.5%) 9 (90%) 17 (50%) Girl 24 (58.5%) 1 (10%) 17 (50%) Classification of diseases 1.011 0.603 SAA 27 (66%) 7 (70%) 26 (76%) VSAA 14 (34%) 3 (30%) 8 (24%) ABO match 12.394 0.37* Matched 15 (36.6%) 9 (90%) 13 (38.2%) Minor mismatched 10 (24.4%) 1 (10%) 7 (20.6%) Major mismatched 14 (34.1%) 0 8 (23.5%) Different 2 (4.9%) 0 6 (17.6%) Neutrophil engraftment 13 (12–15) 14.5 (11–16.5) 12 (12–15) 0.572 Platelet engraftment 16.5 (12.3–19) 16 (11.7–21) 13 (12–17.5) 0.228 aGVHD classification 1.338 0.512 Grade I and II aGVHD 9 (22.0%) 1 (10.0%) 7 (20.6%) Grade III and IV aGVHD 2 (4.9%) 1 (10.0%) 4 (11.8%) Follow-up period, months 25 ± 18.1 33.2 ± 32.1 26.5 ± 18.4 0.911 Abbreviations: SAA, severe aplastic anemia; VSAA, very severe aplastic anemia Values are presented as n (%), mean ± SD, or median (range). Significant P values are indicated in bold. *P value determined with the Fischer exact test. 3.3 Graft-versus-host disease Out of the 85 patients in the cohort, 24 (28.2%) experienced grade I–IV aGVHD. The 100-day cumulative incidence of aGVHD was similar among the three groups: 33.4% (95% CI = 19.1–49.2%) in the UD-HSCT group, 20.0% (95% CI = 5.7–51.0%) in the MSD-HSCT group, and 26.8% (95% CI = 16.7–41.9%) in the HID-HSCT group (P = 0.3987) (Fig. 1 A). Over the course of six years, the cumulative incidence of cGVHD was 17.03% in the HID-HSCT group, 20.0% in the MSD-HSCT group, and 11.77% in the UD-HSCT group (Fig. 1 B). There were no statistically significant differences between the three groups in terms of aGVHD and cGVHD (Fig. 1 B). Additionally, the incidence of grade I and II aGVHD was significantly higher than that of grade III and IV aGVHD within the three groups, but there was no statistically significant difference between the three groups (Table 1 ). Furthermore, we reviewed the data and discovered that gastrointestinal and cutaneous graft-versus-host responses were common, often occurring within a month of transplantation. 3.4 Post-transplantation infection The most common infection observed after HSCT in this cohort was reactivation of Epstein-Barr virus (EBV) and cytomegalovirus (CMV). A total of 50 patients had post-transplantation EBV infection. The incidence of EBV infection was 73.2% for patients in the HID group, 40.0% in the MSD group, and 53.3% for patients in the UD group, and was not significantly different (P = .076). Among the 50 patients with post-transplantation CMV infection, 1 progressed to CMV encephalitis and 2 progressed to CMV retinitis. Additionally, 26 (63.4%) HID-HSCT patients, 5 (50.0%) MSD-HSCT patients, and 15 (45.5%) UD-HSCT patients developed Epstein-Barr virus infection, but the difference was not significant (P = 0.289). Further, 3 subsequently developed lymphoid tissue proliferative disease. All the patients received prophylactic treatment with acyclovir and ganciclovir and were regularly monitored for EBV-DNA and CMV-DNA copy number. If viral replication occurred, antiviral therapy with appropriate medications was administered promptly and therapy was adjusted to creatine phosphate and melphalan if necessary. 3.5 Other complications Transplant-associated thrombotic microangiopathy (TMA) was present in 7 and hypertension was present in 7, 2, and 3 cases in the HID, MSD, and UD groups, respectively. Additionally, hemorrhagic cystitis was found in 4 cases in the HID group and in 3 cases in the UD group. 3.6 Survival The median follow-up for the children who participated and survived was 23 months (range, 0–76 months). The OS rate was 89.6%, and the GFFS rate was 84.7% (Fig. 2 A and B ). The median follow-up period was 29 months (range, 6–82) for all patients, and the primary causes of death were chronic GVHD in 2 cases, severe infection in 1 case, TMA in 3 cases, and chronic GVHD and CMV infection in 2 cases each. There was no significant difference in the 6-year OS rates between the HID-HSCT, MSD-HSCT, and UD-HSCT groups (85.7%, 80.0%, and 97.1%, respectively; P = 0.1922) (Fig. 3 ). 3.7 Univariate and multivariate analysis According to the univariate and multivariate analyses, the survival outcomes for the entire population were significantly associated with the occurrence of TMA (P = 0.0040), but donor type and other factors did not have a significant influence on survival ( Supplementary Table 1 ). 4 Discussion The present study compares the therapeutic efficacy of HID-HSCT, MSD-HSCT, and UD-HSCT in the treatment of AA in children. The objective was to examine how HID-HSCT compares to MSD-HSCT and UD-HSCT, as HID-HSCT has recently gained popularity as a potentially advantageous alternative to MSD-HSCT and UD-HSCT and there are not enough comparative studies on this method in the pediatric population. This study confirmed excellent outcomes in cases of AA treated with HID-HSCT. One of the most important metrics for evaluating the efficacy of treatment is survival. The findings of a trial on first-line therapy with HID-HSCT in pediatric patients with SAA by Xiaojun Huang’s team anticipated a 10-year OS of 89.3%, which is close to our team's expected 6-year OS of 85.7% [15] . Furthermore, our findings indicate that there was no significant difference between the three transplantation modalities—HID-HSCT, MSD-HSCT, and UD-HSCT. This is consistent with the conclusion made by Xu et al. [2] regarding the differences in survival rates between patients who underwent MSD-HSCT and HID-HSCT. Thus, HID-HSCT results in similar survival outcomes to the other two HSCT methods. In our study, the implantation failure rate in the 85 patients was less than 4.70%, and the HID-HSCT group had comparable implantation rates and time to the other two groups, and little difference was observed in hematopoietic function between the three groups, as reported in several previous reports [16] . This could be attributed to our thorough pretreatment with CY and ATG. Additionally, we used G-CSF-mobilized peripheral blood stem cells as grafts [17] , which contain more T cells, NK cells, and CD34 + cells than bone marrow cells and may have contributed to implantation success, to some extent. The HID-HSCT group experienced a slight delay in platelet implantation compared to the other two groups, but the difference was not significant. Since aplastic anemia is generally considered to be a benign condition, we ought to try to prevent deaths from severe GVHD [18] . The cumulative incidence of aGVHD and cGVHD in HID-HSCT group was 26.8% and 17.03%, respectively, which is similar with recent results that have reported an aGVHD incidence of 21.89–60.0% and a cGVHD incidence of 15–26.47% in transplantation [19–23] . Furthermore, our analysis showed that there were no significant differences in the rates of aGVHD and cGVHD among the three groups over six years of follow-up; this is consistent with the results of previous studies [24] . Our study revealed a low incidence of severe aGVHD (III–IV) in the HID-HSCT group, with the incidence being only 4.9%. This is lower than the prevalence of 7.1% reported in a previous study on patients with SAA who underwent HID-HSCT and implies that severe GVHD was effectively controlled in our study. However, given the significance and complexity of GVHD, its early diagnosis is crucial [25] . Therefore, it is necessary to identify one or more biomarkers associated with its occurrence for both its preventive management and assessment of severity and prognosis. Additionally, there is currently no standardized protocol for monitoring children with drug-resistant GVHD, highlighting the need for further research in this direction. Patients undergoing HID-HSCT often receive stronger doses of immunosuppressants to ensure successful implantation and to prevent GVHD. However, this approach also increases the risk of infection throughout the transplantation process and in the later stages. One of the major challenges is the prevalence of CMV and EBV infections among children undergoing remyelination [26] . In our cohort, the incidence of CMV and EBV infection was not significantly different between the three groups. The relatively low infection rate could be improved by administering antiviral drugs as a preventative measure after transplantation. In addition to standard antiviral therapy (ganciclovir, phosphonoformate, CD20 antibody, and gammaglobulin), CTL treatment can be used in the HID-HSCT group [27] . This study has several limitations. Firstly, the retrospective approach used in the study restricted its scope. Additionally, there was a notable disparity in the clinical characteristics of the three groups in terms of gender distribution (9 out of 10 patients in the MSD-HSCT group were male). Nevertheless, our study provides valuable insights into the clinical features of China’s three main transplantation techniques. In order to validate our findings, future research should focus on well-designed prospective studies with larger sample sizes that take into account these limitations. Nonetheless, based on this retrospective review, it can be concluded that HID-HSCT is a safe and effective treatment option that yields outcomes which are comparable to those of MSD-HSCT and UD-HSCT in children with AA. Declarations Acknowledgments Data availability statement: The data generated and analyzed in the present study can be made available by the corresponding author upon reasonable request. Financial disclosure: This study did not receive any funding. Conflict of interest disclosure: There are no conflicts of interest to report. Ethics approval statement: Written informed consent from the participants’ legal guardian/next of kin was obtained for participation in this study, in accordance with the national legislation and the institutional requirements. The protocol of this clinical observation study was approved by the Ethics Committee of Wuhan Children's Hospital (approval no. 2022R071-E01). Patient consent statement: Written informed consent was obtained from the patients or their relatives before the procedures were conducted. References Killick SB, Bown N, Cavenagh J, et al. Guidelines for the diagnosis and management of adult aplastic anaemia. Br J Haematol. 2016;172(2):187–207. 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Supplementary Files SupplementaryTable.doc Supplementary Table 1. Univariate and multivariate analysis Cite Share Download PDF Status: Posted Version 1 posted You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. Our growing team is made up of researchers and industry professionals working together to solve the most critical problems facing scientific publishing. Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-3821593","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Article","associatedPublications":[],"authors":[{"id":268237245,"identity":"578cdd8a-1e98-4910-8405-ae727a5e3477","order_by":0,"name":"Hao Xiong","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAAwklEQVRIiWNgGAWjYBACfvb+h4//8Njw8BOtRbLnDLMBj0yajGQDsVoMbuSwSfDYHLYxOEC0NQdyDxtI5KTxGB9P3sDwo2IbYR2MDecSHxicseExO/OsgLHnzG3CWpgZG4wNEnvSeMxu5BgwM7YRoYWNmcFM4uC/wzzGM4jVwsPGYybZwHOYB+ghIrVI8LAlGzPwpPFIAP1ykCi/2N9/fPAxA4+NPX978sYHPyqI0IIEEkiIGrgWUnWMglEwCkbBCAEA77c6ht6l5LMAAAAASUVORK5CYII=","orcid":"","institution":"Wuhan Children's Hospital","correspondingAuthor":true,"prefix":"","firstName":"Hao","middleName":"","lastName":"Xiong","suffix":""},{"id":268237246,"identity":"e96a3090-0e8c-40b4-80fb-010378d4dc2a","order_by":1,"name":"Zuofeng Li","email":"","orcid":"","institution":"Wuhan Children's Hospital","correspondingAuthor":false,"prefix":"","firstName":"Zuofeng","middleName":"","lastName":"Li","suffix":""},{"id":268237247,"identity":"2eb71e31-ca34-437b-b996-475b7cd2a9c6","order_by":2,"name":"Zhi Chen","email":"","orcid":"","institution":"Wuhan Children’s Hospital (Wuhan Maternal and Child Healthcare Hospital), Tongji Medical College, Huazhong University of Science \u0026 Technology","correspondingAuthor":false,"prefix":"","firstName":"Zhi","middleName":"","lastName":"Chen","suffix":""},{"id":268237248,"identity":"2d6a0164-29c5-444d-8ecd-90971d8d3eb7","order_by":3,"name":"Li Yang","email":"","orcid":"","institution":"Wuhan Children’s Hospital (Wuhan Maternal and Child Healthcare Hospital), Tongji Medical College, Huazhong University of Science \u0026 Technology","correspondingAuthor":false,"prefix":"","firstName":"Li","middleName":"","lastName":"Yang","suffix":""},{"id":268237249,"identity":"4d46d836-148b-43a9-9f26-09a1889c4550","order_by":4,"name":"Ming Sun","email":"","orcid":"https://orcid.org/0000-0002-6416-312X","institution":"Wuhan Children’s Hospital (Wuhan Maternal and Child Healthcare Hospital), Tongji Medical College, Huazhong University of Science \u0026 Technology","correspondingAuthor":false,"prefix":"","firstName":"Ming","middleName":"","lastName":"Sun","suffix":""},{"id":268237250,"identity":"8092a97e-7ba9-4613-987c-5602dc67c6ec","order_by":5,"name":"Wenjie Lu","email":"","orcid":"","institution":"Wuhan Children’s Hospital (Wuhan Maternal and Child Healthcare Hospital), Tongji Medical College, Huazhong University of Science \u0026 Technology","correspondingAuthor":false,"prefix":"","firstName":"Wenjie","middleName":"","lastName":"Lu","suffix":""},{"id":268237251,"identity":"f7a2f374-b5a3-413b-b493-76f3eb66e565","order_by":6,"name":"Shanshan Qi","email":"","orcid":"","institution":"Wuhan Children's Hospital","correspondingAuthor":false,"prefix":"","firstName":"Shanshan","middleName":"","lastName":"Qi","suffix":""},{"id":268237252,"identity":"04112ead-c73f-4440-8c6e-c1d9ed4959f6","order_by":7,"name":"Fang Tao","email":"","orcid":"","institution":"Wuhan Children’s Hospital (Wuhan Maternal and Child Healthcare Hospital), Tongji Medical College, Huazhong University of Science \u0026 Technology","correspondingAuthor":false,"prefix":"","firstName":"Fang","middleName":"","lastName":"Tao","suffix":""},{"id":268237253,"identity":"66e1ad68-35ba-4363-b4a3-ea62d5508dc4","order_by":8,"name":"Linlin Luo","email":"","orcid":"","institution":"Wuhan Children's Hospital","correspondingAuthor":false,"prefix":"","firstName":"Linlin","middleName":"","lastName":"Luo","suffix":""}],"badges":[],"createdAt":"2023-12-29 14:35:33","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-3821593/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-3821593/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":50054729,"identity":"ec51ae60-320f-42eb-aeb2-6513317e8c0a","added_by":"auto","created_at":"2024-01-23 17:26:03","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":83322,"visible":true,"origin":"","legend":"\u003cp\u003eCumulative incidence plots for (A) acute GVHD and (B) chronic GVHD\u003c/p\u003e","description":"","filename":"floatimage1.png","url":"https://assets-eu.researchsquare.com/files/rs-3821593/v1/4cdbae7df28a777fd916159d.png"},{"id":50054727,"identity":"58430160-7e08-458d-9b24-684ed1f436f6","added_by":"auto","created_at":"2024-01-23 17:26:03","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":55344,"visible":true,"origin":"","legend":"\u003cp\u003eKaplan–Meier estimates of (A) overall survival (OS) and (B) graft-versus-host disease failure-free survival (GFFS)\u003c/p\u003e","description":"","filename":"floatimage2.png","url":"https://assets-eu.researchsquare.com/files/rs-3821593/v1/6916deda95dc05924f03e92b.png"},{"id":50054730,"identity":"7cff5051-b14b-4259-bfea-63c36b6adac5","added_by":"auto","created_at":"2024-01-23 17:26:03","extension":"jpeg","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":160144,"visible":true,"origin":"","legend":"\u003cp\u003eKaplan–Meier plot of overall survival by treatment group\u003c/p\u003e","description":"","filename":"floatimage3.jpeg","url":"https://assets-eu.researchsquare.com/files/rs-3821593/v1/19af555af6c79ecc6725fcb2.jpeg"},{"id":77820001,"identity":"753651e3-24fa-485c-b7b5-09304b961559","added_by":"auto","created_at":"2025-03-05 19:58:18","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":993640,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-3821593/v1/1b5854e9-c435-4b2e-a3b8-d93e69b824cd.pdf"},{"id":50054728,"identity":"3203f2a0-24b5-43ee-ae40-ae308d2a1b0f","added_by":"auto","created_at":"2024-01-23 17:26:03","extension":"doc","order_by":1,"title":"","display":"","copyAsset":false,"role":"supplement","size":25600,"visible":true,"origin":"","legend":"\u003cp\u003eSupplementary Table 1. Univariate and multivariate analysis\u003c/p\u003e","description":"","filename":"SupplementaryTable.doc","url":"https://assets-eu.researchsquare.com/files/rs-3821593/v1/9d06e308026fda8eefa04077.doc"}],"financialInterests":"The authors have declared there is \u003cb\u003eNO\u003c/b\u003e conflict of interest to disclose.","formattedTitle":"Haploidentical hematopoietic stem cell transplantation as first-line therapy for aplastic anemia in children:\r\n A single-center experience","fulltext":[{"header":"1 Introduction","content":"\u003cp\u003eAplastic anemia (AA) is a common and potentially life-threatening condition that causes bone marrow failure in children. It is characterized by a decrease in peripheral blood and bone marrow cells\u003csup\u003e[1\u0026ndash;2]\u003c/sup\u003e. Children with severe aplastic anemia (SAA) and very severe aplastic anemia (VSAA) experience fast progression of the disease, which greatly affects their long-term well-being, and also have a high risk of fatality. Currently, the two main treatment options are hematopoietic stem cell transplantation (HSCT) and immunosuppressive treatment. Allogeneic hematopoietic stem cell transplantation (HSCT) is recommended as first-line treatment for patients\u0026thinsp;\u0026le;\u0026thinsp;40 years of age with an available matched sibling donor (MSD), as the effectiveness of immunosuppressive treatment is limited by non-responsiveness to treatment, relapse, and clonal evolution \u003csup\u003e[3]\u003c/sup\u003e. Matching sibling donor HSCT (MSD-HSCT) is the preferred initial treatment for children with SAA and SVAA, but less than 30% of children have HLA-matched siblings and actually undergo this procedure. Unrelated matched donor HSCT (UD-HSCT) is another option, but finding a suitable unrelated donor for HSCT can take several months due to the challenges related to screening unrelated donors, extracting bone marrow hematopoietic stem cells, and the limited supply of hematopoietic stem cells. This waiting period is too long for children with severe disease or co-existing infections. A third option is haploidentical donor HSCT (HID-HSCT), which is suitable to and beneficial for nearly all patients when an HLA genotypically matched sibling is not available \u003csup\u003e[4]\u003c/sup\u003e.In comparison with MSD-HSCT and UD-HSCT, the preparation for this procedure is relatively straightforward and can be achieved within a concise timeframe. It offers the advantages of speed, accessibility, and long-term sustainability\u003csup\u003e[5]\u003c/sup\u003e. Further, with advancements in pretreatment protocols, such as in vivo depleted T-cell counts and combinations with bone marrow mesenchymal stem cells, as well as improvements in supportive therapies and donor screening methods, the effectiveness of HID-HSCT has been increasing. Consequently, HID-HSCT has been widely used in many treatment centers worldwide in recent years\u003csup\u003e[6\u0026ndash;8]\u003c/sup\u003e.\u003c/p\u003e \u003cp\u003eThere is a scarcity of studies that directly compare the outcomes of HID-HSCT recipients with those of MSD-HSCT and UD-HSCT recipients. According to Xu et al.\u0026rsquo;s study on data from the Chinese Bone Marrow Transplantation Registry, which is currently the largest Chinese registry for bone marrow transplantation\u003csup\u003e[9]\u003c/sup\u003e, among 157 patients with SAA from 11 transplant centers in China who underwent HID-HSCT between June 2012 and September 2015, the 3-year overall survival (OS) rates for HID-HSCT and MSD-HSCT were comparable, as were the 3-year failure-free survival (FFS) rates and the 1-year graft-versus-host disease failure survival (GFFS) rates. However, the report did not analyze and compare the efficacy of UD-HSCT or focus on the pediatric population, and there is also a high risk of bias due to the significant age difference between the HID-HSCT and MSD-HSCT cohorts. Given these limitations of previous studies, it is necessary to obtain and analyze the current data on the outcomes of the three HSCT strategies, as it could assist in treatment decision-making for children with AA undergoing this procedure. Therefore, in order to fill in this knowledge gap, in the present study, we will compare the outcomes of MSD-HSCT, HID-HSCT, and UMD-HSCT as first-line treatments for children with SAA.\u003c/p\u003e"},{"header":"2 Methods","content":"\u003cdiv id=\"Sec3\" class=\"Section2\"\u003e \u003ch2\u003e2.1 Patients\u003c/h2\u003e \u003cp\u003eA comprehensive retrospective analysis was conducted on a total of 85 children diagnosed with AA who underwent HSCT at our institution between August 2016 and December 2022. According to the enrollment criteria, children with SAA and VSAA, as defined by clinical guidelines\u003csup\u003e[10]\u003c/sup\u003e, who opted to undergo HSCT and did not have severe organ dysfunction were included. All the children underwent myelocyte assessments, and patients with underlying inherited marrow failure disorders, such as Fanconi anemia, myelodysplastic syndrome, and paroxysmal nocturnal hemoglobinuria, were excluded.\u003c/p\u003e \u003cp\u003e The protocol of this clinical observation study adhered to the tenets of the Declaration of Helsinki and was approved by the Ethics Committee of Wuhan Children's Hospital (approval no. 2022R071-E01). Due to complications, such as severe infection and long-term transfusion dependency, in cases where it was not possible to wait for the MSD or suitable UD for transplantation, at the insistence of the parents and in accordance with the Declaration of Helsinki, HID-HSCT was selected as the treatment of choice. Written informed consent was obtained from the patients or their relatives before the procedures were conducted.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec4\" class=\"Section2\"\u003e \u003ch2\u003e2.2 Donor mobilization, and stem cell harvesting\u003c/h2\u003e \u003cp\u003eEligibility criteria for donors included full HLA match or semi-compatibility, and the donors included relatives (such as parents, siblings, and cousin) and unrelated donors who were available to the patient. Donors with donor-specific antibodies (based on a mean fluorescence intensity level\u0026thinsp;\u0026gt;\u0026thinsp;1000 according to solid phase immunoassay) were excluded. The donors received an infusion of granulocyte colony-stimulating factor (G-CSF) at a dose of 5\u0026ndash;10 \u0026micro;g/kg for 5 days prior to transplantation. Peripheral blood stem cells (PBSCs) were collected on the 4th and 5th day. Mobilization was considered successful when the CD34 cell count was 4\u0026ndash;6 \u0026times; 10\u003csup\u003e6\u003c/sup\u003e/kg and the MNC count was 6\u0026ndash;8 \u0026times; 10\u003csup\u003e8\u003c/sup\u003e/kg.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec5\" class=\"Section2\"\u003e \u003ch2\u003e2.3 Pretreatment protocol\u003c/b\u003e\u003c/h2\u003e \u003cp\u003ePatients with an MSD and UD were treated according to the FLU/CY-based regimen: fludarabine (FLU), 50 mg/m\u003csup\u003e2\u003c/sup\u003e/day, intravenously (i.v.) on day \u0026minus;\u0026thinsp;7 to \u0026minus;\u0026thinsp;4; cyclophosphoramide (CY), 50 mg/kg/day (i.v.) on day \u0026minus;\u0026thinsp;5 to \u0026minus;\u0026thinsp;3; and antithymocyte immunoglobulin (ATG, rabbit), 10 mg/kg/day (i.v.) on day \u0026minus;\u0026thinsp;4 to \u0026minus;\u0026thinsp;2. Patients with haploidentical donors were treated according to the BU/FLU/CY-based regimen, which consisted of busulfan (Bu), 3.2 mg/kg/day (i.v.) on day \u0026minus;\u0026thinsp;7 and \u0026minus;\u0026thinsp;6; CY, 120 mg/kg/day (i.v.) on day \u0026minus;\u0026thinsp;5 to \u0026minus;\u0026thinsp;2; and ATG, 10 mg/kg/day (i.v.) on day \u0026minus;\u0026thinsp;4 to \u0026minus;\u0026thinsp;2.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec6\" class=\"Section2\"\u003e \u003ch2\u003e2.4 Prophylactic treatment for graft-versus-host disease\u003c/h2\u003e \u003cp\u003eThe current standard of care for MSD-HSCT involves a combination of Cy and ATG, and in the UD-HSCT group, anti-CD25 monoclonal antibodies were also added. In the HID-HSCT group, MTX, MMF, and an anti-CD25 monoclonal antibody were used, based on previous recommendations\u003csup\u003e[16]\u003c/sup\u003e.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec7\" class=\"Section2\"\u003e \u003ch2\u003e2.5 Definitions\u003c/h2\u003e \u003cp\u003eThe prognosis was assessed using several key indicators, including OS, FFS, and GFFS. OS was measured from the first day of therapy until death or the last follow-up. FFS was defined as survival without treatment failure, including death, graft failure, and relapse. GFFS was defined as survival without grade III\u0026ndash;IV acute GVHD (aGVHD), moderate-to-severe chronic GVHD (cGVHD), or treatment failure, including death, primary or secondary graft failure, and relapse \u003csup\u003e[11]\u003c/sup\u003e. Neutrophil engraftment was defined as an absolute neutrophil count\u0026thinsp;\u0026gt;\u0026thinsp;0.5 \u0026times; 10\u003csup\u003e9\u003c/sup\u003e/L for three consecutive days. Platelet engraftment was defined as an absolute platelet count\u0026thinsp;\u0026gt;\u0026thinsp;20 \u0026times; 10\u003csup\u003e9\u003c/sup\u003e/L for three consecutive days without transfusion. Failure to achieve engraftment by day\u0026thinsp;+\u0026thinsp;28 was considered to be indicative of low donor chimerism, and it was assumed that primary graft failure had occurred in such cases. The diagnostic and classification criteria for aGVHD and cGVHD were based on the Glucksberg-Seattle criteria\u003csup\u003e[12\u0026ndash;13]\u003c/sup\u003e, and hemorrhagic cystitis was defined based on the criteria established by Vela-Ojeda et al.\u003csup\u003e[14]\u003c/sup\u003e\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec8\" class=\"Section2\"\u003e \u003ch2\u003e2.6 Statistical analysis\u003c/h2\u003e \u003cp\u003eStatistical analyses were performed using SPSS version 22.0 (SPSS Inc., Chicago, IL). Graphs were generated using Prism 8.0 (GraphPad software). For quantitative variables, mean\u0026thinsp;\u0026plusmn;\u0026thinsp;SD values and ANOVA were used for analyzing normally distributed data, while the median (P25, P75) values and the Kruskal-Wallis H-test were used for analyzing non-normally distributed data. To compare qualitative variables presented as rates or percentages, the chi-square test, Fisher\u0026rsquo;s exact test, and the rank-sum test were utilized. Survival estimation was performed using the Kaplan-Meier method, and differences between the three groups were assessed using either the Kruskal-Wallis test or one-way ANOVA (for normally distributed variables). Variables with a P value of \u0026lt;\u0026thinsp;0.05 in the one-way analysis were further analyzed through multifactorial analysis, and the HR (95% CI) values of the influencing factors were calculated. Statistical significance was set at P\u0026thinsp;\u0026lt;\u0026thinsp;0.05.\u003c/p\u003e \u003c/div\u003e"},{"header":"3 Results","content":"\u003cdiv id=\"Sec10\" class=\"Section2\"\u003e \u003ch2\u003e3.1 Patient characteristics\u003c/h2\u003e \u003cp\u003eThe pediatric patients were categorized into three distinct groups based on the different transplantation methods: 41 children underwent HID-HSCT; 10 children, MSD-HSCT; and 34 children, UD-HSCT. The cohort included 43 males and 42 females, and the median age was 6.1 years (age range, 1\u0026ndash;16.9 years). The median ages of patients in the HID-HSCT, MSD-HSCT, and UD-HSCT groups were 24 months (range, 1\u0026ndash;62 months), 30 months (range, 0\u0026ndash;76 months), and 28.5 months (range, 2\u0026ndash;57 months) (P\u0026thinsp;=\u0026thinsp;0.121), respectively. The variations in age distribution and the degree of donor-recipient blood group compatibility were not significantly different between the three groups (P\u0026thinsp;\u0026gt;\u0026thinsp;0.05). However, the distribution of gender among the three groups varied significantly (P\u0026thinsp;=\u0026thinsp;0.023). There was no discernible variation in gender distribution between the other two groups, with the exception of the MSD group, which had a male-to-female ratio of 8:10.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec11\" class=\"Section2\"\u003e \u003ch2\u003e3.2 Hematopoietic reconstitution\u003c/h2\u003e \u003cp\u003eAs shown in Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e, the neutrophil and platelet implantation times were not significantly different between the three groups (P\u0026thinsp;\u0026gt;\u0026thinsp;0.05). However, platelet engraftment occurred first in the UD-HSCT group, which was followed by the MSD-HSCT group and then the HID-HSCT group.\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab1\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 1\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003ePatient characteristics\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"6\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c6\" colnum=\"6\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003eVariable\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eHID-HSCT\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eMSD-HSCT\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003eUD-HSCT\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c5\"\u003e \u003cp\u003eX\u003csup\u003e2\u003c/sup\u003e\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c6\"\u003e \u003cp\u003eP\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eNo. of patients (n)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e41\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e10\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e34\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eAge, years (median\u0026thinsp;\u0026plusmn;\u0026thinsp;SD)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e6.72\u0026thinsp;\u0026plusmn;\u0026thinsp;3.86\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e8.70\u0026thinsp;\u0026plusmn;\u0026thinsp;3.24\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e6.02\u0026thinsp;\u0026plusmn;\u0026thinsp;3.32\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e0.121\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eAge group\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e4.672\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e0.097\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u0026le;\u0026thinsp;6 years\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e21 (51.2%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e2 (20%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e20 (58.8%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u0026gt;\u0026thinsp;6 years\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e20 (39.2%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e8 (80%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e14 (41.2%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eSex\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e7.584\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e\u003cb\u003e0.023\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eBoy\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e17 (41.5%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e9 (90%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e17 (50%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eGirl\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e24 (58.5%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1 (10%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e17 (50%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eClassification of diseases\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e1.011\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e0.603\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSAA\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e27 (66%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e7 (70%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e26 (76%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eVSAA\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e14 (34%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e3 (30%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e8 (24%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eABO match\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e12.394\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e0.37*\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMatched\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e15 (36.6%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e9 (90%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e13 (38.2%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMinor mismatched\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e10 (24.4%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1 (10%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e7 (20.6%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMajor mismatched\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e14 (34.1%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e8 (23.5%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eDifferent\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e2 (4.9%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e6 (17.6%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eNeutrophil engraftment\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e13 (12\u0026ndash;15)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e14.5 (11\u0026ndash;16.5)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e12 (12\u0026ndash;15)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e0.572\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003ePlatelet engraftment\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e16.5 (12.3\u0026ndash;19)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e16 (11.7\u0026ndash;21)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e13 (12\u0026ndash;17.5)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e0.228\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eaGVHD classification\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e1.338\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e0.512\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eGrade I and II aGVHD\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e9 (22.0%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1 (10.0%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e7 (20.6%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eGrade III and IV aGVHD\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e2 (4.9%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1 (10.0%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e4 (11.8%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eFollow-up period, months\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e25\u0026thinsp;\u0026plusmn;\u0026thinsp;18.1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e33.2\u0026thinsp;\u0026plusmn;\u0026thinsp;32.1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e26.5\u0026thinsp;\u0026plusmn;\u0026thinsp;18.4\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e0.911\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003ctfoot\u003e \u003ctr\u003e\u003ctd colspan=\"6\"\u003eAbbreviations: SAA, severe aplastic anemia; VSAA, very severe aplastic anemia\u003c/td\u003e\u003c/tr\u003e \u003ctr\u003e\u003ctd colspan=\"6\"\u003eValues are presented as n (%), mean\u0026thinsp;\u0026plusmn;\u0026thinsp;SD, or median (range).\u003c/td\u003e\u003c/tr\u003e \u003ctr\u003e\u003ctd colspan=\"6\"\u003eSignificant P values are indicated in bold.\u003c/td\u003e\u003c/tr\u003e \u003ctr\u003e\u003ctd colspan=\"6\"\u003e*P value determined with the Fischer exact test.\u003c/td\u003e\u003c/tr\u003e \u003c/tfoot\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec12\" class=\"Section2\"\u003e \u003ch2\u003e3.3 Graft-versus-host disease\u003c/h2\u003e \u003cp\u003eOut of the 85 patients in the cohort, 24 (28.2%) experienced grade I\u0026ndash;IV aGVHD. The 100-day cumulative incidence of aGVHD was similar among the three groups: 33.4% (95% CI\u0026thinsp;=\u0026thinsp;19.1\u0026ndash;49.2%) in the UD-HSCT group, 20.0% (95% CI\u0026thinsp;=\u0026thinsp;5.7\u0026ndash;51.0%) in the MSD-HSCT group, and 26.8% (95% CI\u0026thinsp;=\u0026thinsp;16.7\u0026ndash;41.9%) in the HID-HSCT group (P\u0026thinsp;=\u0026thinsp;0.3987) (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003eA). Over the course of six years, the cumulative incidence of cGVHD was 17.03% in the HID-HSCT group, 20.0% in the MSD-HSCT group, and 11.77% in the UD-HSCT group (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003eB). There were no statistically significant differences between the three groups in terms of aGVHD and cGVHD (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003eB). Additionally, the incidence of grade I and II aGVHD was significantly higher than that of grade III and IV aGVHD within the three groups, but there was no statistically significant difference between the three groups (Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e). Furthermore, we reviewed the data and discovered that gastrointestinal and cutaneous graft-versus-host responses were common, often occurring within a month of transplantation.\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec13\" class=\"Section2\"\u003e \u003ch2\u003e3.4 Post-transplantation infection\u003c/h2\u003e \u003cp\u003eThe most common infection observed after HSCT in this cohort was reactivation of Epstein-Barr virus (EBV) and cytomegalovirus (CMV). A total of 50 patients had post-transplantation EBV infection. The incidence of EBV infection was 73.2% for patients in the HID group, 40.0% in the MSD group, and 53.3% for patients in the UD group, and was not significantly different (P\u0026thinsp;=\u0026thinsp;.076).\u003c/p\u003e \u003cp\u003eAmong the 50 patients with post-transplantation CMV infection, 1 progressed to CMV encephalitis and 2 progressed to CMV retinitis. Additionally, 26 (63.4%) HID-HSCT patients, 5 (50.0%) MSD-HSCT patients, and 15 (45.5%) UD-HSCT patients developed Epstein-Barr virus infection, but the difference was not significant (P\u0026thinsp;=\u0026thinsp;0.289). Further, 3 subsequently developed lymphoid tissue proliferative disease. All the patients received prophylactic treatment with acyclovir and ganciclovir and were regularly monitored for EBV-DNA and CMV-DNA copy number. If viral replication occurred, antiviral therapy with appropriate medications was administered promptly and therapy was adjusted to creatine phosphate and melphalan if necessary.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec14\" class=\"Section2\"\u003e \u003ch2\u003e3.5 Other complications\u003c/h2\u003e \u003cp\u003eTransplant-associated thrombotic microangiopathy (TMA) was present in 7 and hypertension was present in 7, 2, and 3 cases in the HID, MSD, and UD groups, respectively. Additionally, hemorrhagic cystitis was found in 4 cases in the HID group and in 3 cases in the UD group.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec15\" class=\"Section2\"\u003e \u003ch2\u003e3.6 Survival\u003c/h2\u003e \u003cp\u003eThe median follow-up for the children who participated and survived was 23 months (range, 0\u0026ndash;76 months). The OS rate was 89.6%, and the GFFS rate was 84.7% (Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003eA \u003cb\u003eand B\u003c/b\u003e). The median follow-up period was 29 months (range, 6\u0026ndash;82) for all patients, and the primary causes of death were chronic GVHD in 2 cases, severe infection in 1 case, TMA in 3 cases, and chronic GVHD and CMV infection in 2 cases each. There was no significant difference in the 6-year OS rates between the HID-HSCT, MSD-HSCT, and UD-HSCT groups (85.7%, 80.0%, and 97.1%, respectively; P\u0026thinsp;=\u0026thinsp;0.1922) (Fig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003e).\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec16\" class=\"Section2\"\u003e \u003ch2\u003e3.7 Univariate and multivariate analysis\u003c/h2\u003e \u003cp\u003eAccording to the univariate and multivariate analyses, the survival outcomes for the entire population were significantly associated with the occurrence of TMA (P\u0026thinsp;=\u0026thinsp;0.0040), but donor type and other factors did not have a significant influence on survival (\u003cb\u003eSupplementary Table\u0026nbsp;1\u003c/b\u003e).\u003c/p\u003e \u003c/div\u003e"},{"header":"4 Discussion","content":"\u003cp\u003eThe present study compares the therapeutic efficacy of HID-HSCT, MSD-HSCT, and UD-HSCT in the treatment of AA in children. The objective was to examine how HID-HSCT compares to MSD-HSCT and UD-HSCT, as HID-HSCT has recently gained popularity as a potentially advantageous alternative to MSD-HSCT and UD-HSCT and there are not enough comparative studies on this method in the pediatric population.\u003c/p\u003e \u003cp\u003eThis study confirmed excellent outcomes in cases of AA treated with HID-HSCT. One of the most important metrics for evaluating the efficacy of treatment is survival. The findings of a trial on first-line therapy with HID-HSCT in pediatric patients with SAA by Xiaojun Huang\u0026rsquo;s team anticipated a 10-year OS of 89.3%, which is close to our team's expected 6-year OS of 85.7%\u003csup\u003e[15]\u003c/sup\u003e. Furthermore, our findings indicate that there was no significant difference between the three transplantation modalities\u0026mdash;HID-HSCT, MSD-HSCT, and UD-HSCT. This is consistent with the conclusion made by Xu et al.\u003csup\u003e[2]\u003c/sup\u003e regarding the differences in survival rates between patients who underwent MSD-HSCT and HID-HSCT. Thus, HID-HSCT results in similar survival outcomes to the other two HSCT methods.\u003c/p\u003e \u003cp\u003eIn our study, the implantation failure rate in the 85 patients was less than 4.70%, and the HID-HSCT group had comparable implantation rates and time to the other two groups, and little difference was observed in hematopoietic function between the three groups, as reported in several previous reports\u003csup\u003e[16]\u003c/sup\u003e. This could be attributed to our thorough pretreatment with CY and ATG. Additionally, we used G-CSF-mobilized peripheral blood stem cells as grafts\u003csup\u003e[17]\u003c/sup\u003e, which contain more T cells, NK cells, and CD34\u0026thinsp;+\u0026thinsp;cells than bone marrow cells and may have contributed to implantation success, to some extent. The HID-HSCT group experienced a slight delay in platelet implantation compared to the other two groups, but the difference was not significant.\u003c/p\u003e \u003cp\u003eSince aplastic anemia is generally considered to be a benign condition, we ought to try to prevent deaths from severe GVHD\u003csup\u003e[18]\u003c/sup\u003e. The cumulative incidence of aGVHD and cGVHD in HID-HSCT group was 26.8% and 17.03%, respectively, which is similar with recent results that have reported an aGVHD incidence of 21.89\u0026ndash;60.0% and a cGVHD incidence of 15\u0026ndash;26.47% in transplantation\u003csup\u003e[19\u0026ndash;23]\u003c/sup\u003e. Furthermore, our analysis showed that there were no significant differences in the rates of aGVHD and cGVHD among the three groups over six years of follow-up; this is consistent with the results of previous studies\u003csup\u003e[24]\u003c/sup\u003e. Our study revealed a low incidence of severe aGVHD (III\u0026ndash;IV) in the HID-HSCT group, with the incidence being only 4.9%. This is lower than the prevalence of 7.1% reported in a previous study on patients with SAA who underwent HID-HSCT and implies that severe GVHD was effectively controlled in our study. However, given the significance and complexity of GVHD, its early diagnosis is crucial \u003csup\u003e[25]\u003c/sup\u003e. Therefore, it is necessary to identify one or more biomarkers associated with its occurrence for both its preventive management and assessment of severity and prognosis. Additionally, there is currently no standardized protocol for monitoring children with drug-resistant GVHD, highlighting the need for further research in this direction.\u003c/p\u003e \u003cp\u003ePatients undergoing HID-HSCT often receive stronger doses of immunosuppressants to ensure successful implantation and to prevent GVHD. However, this approach also increases the risk of infection throughout the transplantation process and in the later stages. One of the major challenges is the prevalence of CMV and EBV infections among children undergoing remyelination\u003csup\u003e[26]\u003c/sup\u003e. In our cohort, the incidence of CMV and EBV infection was not significantly different between the three groups. The relatively low infection rate could be improved by administering antiviral drugs as a preventative measure after transplantation. In addition to standard antiviral therapy (ganciclovir, phosphonoformate, CD20 antibody, and gammaglobulin), CTL treatment can be used in the HID-HSCT group\u003csup\u003e[27]\u003c/sup\u003e.\u003c/p\u003e \u003cp\u003eThis study has several limitations. Firstly, the retrospective approach used in the study restricted its scope. Additionally, there was a notable disparity in the clinical characteristics of the three groups in terms of gender distribution (9 out of 10 patients in the MSD-HSCT group were male). Nevertheless, our study provides valuable insights into the clinical features of China\u0026rsquo;s three main transplantation techniques. In order to validate our findings, future research should focus on well-designed prospective studies with larger sample sizes that take into account these limitations. Nonetheless, based on this retrospective review, it can be concluded that HID-HSCT is a safe and effective treatment option that yields outcomes which are comparable to those of MSD-HSCT and UD-HSCT in children with AA.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eAcknowledgments\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eData availability statement: The data generated and analyzed in the present study can be made available by the corresponding author upon reasonable request.\u003c/p\u003e\n\u003cp\u003eFinancial disclosure: This study did not receive any funding.\u003c/p\u003e\n\u003cp\u003eConflict of interest disclosure: There are no conflicts of interest to report.\u003c/p\u003e\n\u003cp\u003eEthics approval statement: Written informed consent from the participants\u0026rsquo; legal guardian/next of kin was obtained for participation in this study, in accordance with the national legislation and the institutional requirements. The protocol of this clinical observation study was approved by the Ethics Committee of Wuhan Children\u0026apos;s Hospital (approval no. 2022R071-E01).\u003c/p\u003e\n\u003cp\u003ePatient consent statement: Written informed consent was obtained from the patients or their relatives before the procedures were conducted.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n \u003cli\u003e\u003cspan\u003eKillick SB, Bown N, Cavenagh J, et al. Guidelines for the diagnosis and management of adult aplastic anaemia. Br J Haematol. 2016;172(2):187\u0026ndash;207.\u003c/span\u003e\u003c/li\u003e\n \u003cli\u003e\u003cspan\u003eXu L, Chen H, Chen J, et al. The consensus on indications, conditioning regimen, and donor selection of allogeneic hematopoietic cell transplantation for hematological diseases in China-recommendations from the Chinese Society of Hematology. J Hematol Oncol. 2018;11(1):33.\u003c/span\u003e\u003c/li\u003e\n \u003cli\u003e\u003cspan\u003eXu L P, Wang S Q, Ma Y R, et al. Who is the best haploidentical donor for acquired severe aplastic anemia? Experience from a multicenter study. J Hematol Oncol, 2019; 12(1): 87.\u003c/span\u003e\u003c/li\u003e\n \u003cli\u003e\u003cspan\u003eD\u0026apos;souza A, Fretham C, Lee S J, et al. Current Use of and Trends in Hematopoietic Cell Transplantation in the United States. Biol Blood Marrow Transplant, 2020; 26(8): 177\u0026ndash;182.\u003c/span\u003e\u003c/li\u003e\n \u003cli\u003e\u003cspan\u003eGao L, Liu J, Zhang Y, et al. Low incidence of acute graft-versus-host disease with short-term tacrolimus in haploidentical hematopoietic stem cell transplantation. Leuk Res. 2017;57:27\u0026ndash;36.\u003c/span\u003e\u003c/li\u003e\n \u003cli\u003e\u003cspan\u003eStocker N, Dul\u0026eacute;ry R, Battipaglia G, et al. Impact of cyclosporine A concentration on acute graft-vs-host disease incidence after haploidentical hematopoietic cell transplantation. Eur J Haematol. 2019;103(1):10\u0026ndash;17.\u003c/span\u003e\u003c/li\u003e\n \u003cli\u003e\u003cspan\u003eKharfan-Dabaja M, Mhaskar R, Reljic T, et al. Mycophenolate mofetil versus methotrexate for prevention of graft-versus-host disease in people receiving allogeneic hematopoietic stem cell transplantation. Cochrane Database Syst Rev. 2014;(7):CD010280.\u003c/span\u003e\u003c/li\u003e\n \u003cli\u003e\u003cspan\u003eXu L P, Jin S, Wang S Q, et al. Upfront haploidentical transplant for acquired severe aplastic anemia: registry-based comparison with matched related transplant. J Hematol Oncol, 2017; 10(1): 25.\u003c/span\u003e\u003c/li\u003e\n \u003cli\u003e\u003cspan\u003eFu R, Wang T. Interpretiation of guidelines for the diagnosis and management of aplastic anemia in China (2022). Zhonghua Xue Ye Xue Za Zhi. 2023;44(3):188\u0026ndash;192.\u003c/span\u003e\u003c/li\u003e\n \u003cli\u003e\u003cspan\u003eChoi YB, Yi ES, Lee JW, et al. Immunosuppressive therapy versus alternative donor hematopoietic stem cell transplantation for children with severe aplastic anemia who lack an HLA-matched familial donor. Bone Marrow Transplant. 2017;52(1):47\u0026ndash;52.\u003c/span\u003e\u003c/li\u003e\n \u003cli\u003e\u003cspan\u003ePrzepiorka D, Weisdorf D, Martin P, et al. 1994 Consensus Conference on Acute GVHD Grading. Bone Marrow Transpl.1995;15(6):825\u0026ndash;828.\u003c/span\u003e\u003c/li\u003e\n \u003cli\u003e\u003cspan\u003eSullivan KM, Shulman HM, Storb R, et al. Chronic graft-versus-host disease in 52 patients: adverse natural course and successful treatment with combination immunosuppression. Blood. 1981;57(2):267\u0026ndash;276.\u003c/span\u003e\u003c/li\u003e\n \u003cli\u003e\u003cspan\u003eVela-Ojeda J, Tripp-Villanueva F, Sanchez-Cort\u0026eacute;s E, et al. Intravesical rhGM-CSF for the treatment of late onset hemorrhagic cystitis after bone marrow transplant. Bone Marrow Transplant. 1999;24(12):1307\u0026ndash;1310.\u003c/span\u003e\u003c/li\u003e\n \u003cli\u003e\u003cspan\u003eCheng Y, Xu Z, Zhang Y, et al. First-line choice for severe aplastic anemia in children: Transplantation from a haploidentical donor vs immunosuppressive therapy. Clin Transplant. 2018;32(2):10.\u003c/span\u003e\u003c/li\u003e\n \u003cli\u003e\u003cspan\u003eLu J, Wu D, Hu S, et al. Hematopoietic reconstitution and prognosis of different types of hematopoietic stem cell transplantation for severe aplastic anemia. Zhonghua Xue Ye Xue Za Zhi. 2015;36(8):633\u0026ndash;636.\u003c/span\u003e\u003c/li\u003e\n \u003cli\u003e\u003cspan\u003eBodine DM, Seidel NE, Orlic D. Bone marrow collected 14 days after in vivo administration of granulocyte colony-stimulating factor and stem cell factor to mice has 10-fold more repopulating ability than untreated bone marrow. 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Pediatr Transplant. 2018;22(5):13204.\u003c/span\u003e\u003c/li\u003e\n \u003cli\u003e\u003cspan\u003eXu ZL, Huang XJ. Optimizing outcomes for haploidentical hematopoietic stem cell transplantation in severe aplastic anemia with intensive GVHD prophylaxis: a review of current findings. Expert Rev Hematol. 2021;14(5):449\u0026ndash;455.\u003c/span\u003e\u003c/li\u003e\n \u003cli\u003e\u003cspan\u003eYang S, Yuan X, Ma R, et al. Comparison of Outcomes of Frontline Immunosuppressive Therapy and Frontline Haploidentical Hematopoietic Stem Cell Transplantation for Children with Severe Aplastic Anemia Who Lack an HLA-Matched Sibling Donor. Biol Blood Marrow Transplant. 2019;25(5):975\u0026ndash;980.\u003c/span\u003e\u003c/li\u003e\n \u003cli\u003e\u003cspan\u003eXu LP, Jin S, Wang SQ, et al. Upfront haploidentical transplant for acquired severe aplastic anemia: registry-based comparison with matched related transplant. 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Steroid-resistant intestinal aGVHD and refractory CMV and EBV infections complicated by haplo-HSCT were successfully rescued by FMT and CTL infusion. J Int Med Res. 2021;49(12):1473\u0026ndash;2300.\u003c/span\u003e\u003c/li\u003e\n \u003cli\u003e\u003cspan\u003eGrimaldi F, Potter V, Perez-Abellan P, et al. Mixed T Cell Chimerism After Allogeneic Hematopoietic Stem Cell Transplantation for Severe Aplastic Anemia Using an Alemtuzumab-Containing Regimen Is Shaped by Persistence of Recipient CD8 T Cells. Biol Blood Marrow Transplant. 2017;23(2):293\u0026ndash;299.\u003c/span\u003e\u003c/li\u003e\n\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":true,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true},"keywords":"Severe aplastic anemia, Haploidentical hematopoietic stem cell transplantation, Unrelated donor, Sibling matched donor, Pediatric aplastic anemia","lastPublishedDoi":"10.21203/rs.3.rs-3821593/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-3821593/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003eHID-HSCT is considered a viable treatment option for children with AA who do not have a suitable identical donor or an unrelated donor, but there are not enough studies on how it fares in comparison to with stem cells from MSD-HSCT and UD-HSCT. Therefore, this study compared the outcomes of three ways as the first-line treatment for children with AA. We retrospectively compared the outcomes of 85 pediatric patients who underwent HID-HSCT (n = 41), MSD-HSCT (n = 10), and UD-HSCT (n = 34)from August 2016 toJune 2023. Cumulative rates of neutrophil and platelet implantation, incidence of aGVHD, cGVHD, and 6-year OS were not statistically significant in the three groups. In the univariate and multivariate analyses, the survival outcome for the entire population was adversely associated with TMA (P = 0.040), but was not related to other factors. In summary, there were no statistically significant differences in terms of hematopoietic reconstruction and prognosis between the three transplantation methodologies. Thus, for individuals without HLA-matched siblings or unrelated donors, HID-HSCT might be a practical and promising primary treatment option.\u003c/p\u003e","manuscriptTitle":"Haploidentical hematopoietic stem cell transplantation as first-line therapy for aplastic anemia in children:\n A single-center experience","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2024-01-23 17:25:58","doi":"10.21203/rs.3.rs-3821593/v1","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"4801dc91-68ca-4d70-b5a9-782d05121c56","owner":[],"postedDate":"January 23rd, 2024","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[{"id":28263003,"name":"Biological sciences/Stem cells/Haematopoietic stem cells"},{"id":28263004,"name":"Health sciences/Medical research/Stem-cell research"},{"id":28263005,"name":"Biological sciences/Stem cells/Cancer stem cells"}],"tags":[],"updatedAt":"2025-03-05T19:50:11+00:00","versionOfRecord":[],"versionCreatedAt":"2024-01-23 17:25:58","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-3821593","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-3821593","identity":"rs-3821593","version":["v1"]},"buildId":"qtupq5eGEP_6zYnWcrvyt","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}