Outcomes of Hematopoietic Stem Cell Transplantation in Children with Sickle Cell Disease: Does Donor Sickle Cell Trait Status Matter?

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Mohamed Bayoumy, Enass Raffa, Amal Al-Seraihy, Ibraheem Abosoudah, and 6 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-5309765/v1 This work is licensed under a CC BY 4.0 License Status: Published Journal Publication published 18 Apr, 2025 Read the published version in Bone Marrow Transplantation → Version 1 posted 12 You are reading this latest preprint version Abstract Allogeneic hematopoietic stem cell transplantation (HSCT) remains the gold standard curative therapy for sickle cell disease (SCD). A matched related donor (MRD) with sickle cell trait (SCT) is a viable option, with no evidence of adversely affecting transplant outcomes. We conducted a retrospective chart review of children (≤ 14 years) who underwent myeloablative HSCT from MRDs for SCD between 2013 and 2023, comparing outcomes for MRD with SCT to those with normal hemoglobin (Hgb) electrophoresis. Overall, 73 children underwent HSCT at a median age of 11.3 years. The main indication for HSCT was central nervous system insult in 43 (60%) patients. Among the donors, 48 (66%) had SCT, whereas 25 (34%) had normal Hgb electrophoresis. The mean time to neutrophil and platelet engraftment was 21.3 (10–84) and 22.61 (14–78) days, respectively. None of the patients developed graft rejection. The incidence of both acute and chronic graft-versus-host disease (GVHD) was similar across the donor groups. With a remarkable 5-year overall survival and disease-free survival rate of 97.3%, our findings demonstrate that there is no significant difference between donor groups. Our results align with international HSCT outcomes for SCD, reinforcing the efficacy of allogeneic HSCT from MRDs, regardless of SCT status. Health sciences/Health care/Paediatrics Health sciences/Diseases/Haematological diseases Figures Figure 1 Figure 2 Figure 3 Figure 4 Introduction Sickle cell disease (SCD) is a well-known homozygous inherited hemoglobinopathy that causes vaso-occlusive phenomena and chronic hemolysis with more than 3 million individuals affected worldwide ( 1 – 3 ). Vaso-occlusion results in sickle cell crisis and can eventually lead to progressive irreversible complications involving multiple organ systems ( 4 – 7 ). Sickle cell trait (SCT) is the heterozygous form of SCD and thus should have no complications ascribed to it and is considered a benign state ( 4 , 7 – 9 ). In Saudi Arabia, the burden of SCD is high, which may be related to the high prevalence of consanguineous marriages. The carrier status ranges from 2–27%; in some areas, up to 1.4% of individuals have SCD ( 6 , 10 – 13 ). Despite advancements in medical therapies, SCD remains a debilitating condition, with allogeneic hematopoietic stem cell transplantation (HSCT) recognized as the only established curative option ( 14 ). Gene therapy is a promising treatment modality in these patients; however, the long-term protective effect on disease-related organ damage is unclear ( 5 , 6 , 15 ). Allogeneic HSCT is indicated primarily for individuals with severe SCD who experience complications such as central nervous system (CNS) insult, acute chest syndrome (ACS), and recurrent vaso-occlusive pain crisis (VOC) ( 5 , 14 , and 16 ). This curative option is not readily available to all patients with SCD primarily due to the lack of a suitable donor ( 3 , 5 , 17 ). Among patients transplanted with matched related donors (MRDs), excellent survival rates with lower incidence of transplant-related complications have been demonstrated ( 18 – 20 ); however, recent modifications in the haploidentical donor transplantation platforms, involving in vivo or ex vivo T cell depletion, has also resulted in promising outcomes potentially expanding the donor pool for patients with SCD ( 17 ). For decades, HLA-identical donors with SCT have been donating HSCs for allogeneic transplantation ( 6 , 16 ). However, there is a scarcity of data regarding the impact of using donors with SCT compared to those with normal hemoglobin (Hgb) electrophoresis pattern on transplantation outcomes. This study aimed to compare those two donor groups, providing data on stem cell dose, time to engraftment, chimerism, post-HSCT complications (infectious and noninfectious), and survival outcomes (overall and disease-free). Materials and Methods Study design This is a retrospective single-center chart review study of children aged ≤ 14 years who underwent first allogeneic HSCT for SCD from January 2013 to August 2023. In this study, only HSCT from MRDs with either SCT or normal Hgb electrophoresis pattern were included. This study was conducted at King Faisal Specialist Hospital & Research Center (KFSH&RC), Jeddah, Saudi Arabia following approval by the institutional review board (IRB number: 2020-65). Waiver for a written informed consent was approved, and the overall conduct of this study complied with the Declaration of Helsinki and Good Clinical Practice guidelines. The following three components of the IRB-approved case report form were used to collect study data from the institutional electronic and paper medical records: ( 1 ) pretransplant essential data, including demographic data (gender, date of birth, and date of diagnosis), indication for transplant, source of stem cell, conditioning regimen, graft-versus-host disease (GVHD) prophylaxis, and stem cell dose (CD34 × 10 6 /kg and TNC × 10 8 ); ( 2 ) time to neutrophil and platelet engraftment and chimerism data; and ( 3 ) post-HSCT complication data, including GVHD, veno-occlusive disease (VOD), posterior reversible encephalopathy syndrome (PRES), and infectious toxicity. Study endpoints and definitions The primary endpoint of this study was 5-year overall survival (OS), defined by the probability of a recipient being alive measured from the date of stem cell product infusion and censored at the last contact, whereas death due to any cause was considered an event. Events for disease-free survival (DFS) were defined as graft failure, disease recurrence, and death. The following were the secondary endpoints: ( 1 ) stem cell dose; ( 2 ) neutrophil engraftment, which was defined as the first of three consecutive days of ≥ 500/սL; ( 3 ) platelet engraftment, which was defined as the first of three consecutive days of ≥ 20 × 10 9 /L, sustained without transfusion for a minimum of 7 days; ( 4 ) chimerism data (full donor chimerism was defined as ≥ 95% donor cells and mixed donor chimerism was defined as ≥ 20–94% donor cells); ( 5 ) Hgb electrophoresis data pre- and post-transplant; and ( 6 ) post-transplant complications, including infectious and noninfectious complications. Conditioning regimen The myeloablative conditioning regimen consisted of the following: intravenous (IV) busulfan, 0.8–1.2 mg/kg/dose, every 6 h on days − 10 to − 6 for a total of 16 doses; IV cyclophosphamide, 50 mg/kg, every 24 h on days − 5 to − 2 for a total of 4 doses; and rabbit-ATG (thymoglobulin), 2.5 mg/kg/dose every 24 h, on days − 5 to − 3 for a total of 3 doses. All patients received GVHD prophylaxis, which included IV cyclosporin (3mg/kg/dose every 12 h on day − 3) and four doses of IV methotrexate (15 mg/m 2 /dose on day + 1 and 10 mg/m 2 /dose on days + 3, +6, and + 11). Figure 1 depicts the conditioning regimen's roadmap schematically. Statistical analysis All statistical analyses were performed using IBM SPSS Statistics for Windows, version 20.0 (IBM Corp., Armonk, NY, USA). Data quality assurance measures were applied for data completeness and accuracy. Baseline clinical characteristics and demographic data were described using frequencies and percentages for categorical values, whereas continuous data were described using nonparametric median test. To report the incidence of infectious and noninfectious toxicities, descriptive statistics was used, and chi-square and independent t-tests were applied whenever applicable. To estimate the 5-year OS and DFS, the Kaplan–Meier survival analysis was used. To test the significance of differences between the survival times between groups, the Breslow (generalized Wilcoxon) test was employed, and a p-value of < 0.05 was considered statistically significant. Linear regression (analysis of variance model) was performed for variables with a value of significance (p-value ≤ 0.05). Results Demographic and transplant characteristics From January 2013 to August 2023, 73 patients with SCD underwent allogeneic HSCT at the Pediatric Stem Cell Transplantation Unit of KFSH&RC, Jeddah, Saudi Arabia. The median age at HSCT was 11.3 years. There were 39 (53%) males and 34 (47%) females in total, with the majority (62% [45]) referred from the Kingdom’s Western region. The most frequent indications for HSCT were CNS insult, recurrent VOC pain crisis with ACS, and recurrent VOC pain crisis in 44 (60%), 17 (23%), and 12 (17%) patients, respectively. All patients had a history of packed red blood cell transfusions before HSCT; however, none of them developed alloimmunization. The bone marrow (BM) was the main source of stem cell in 72 (99%) patients, and one patient (1%) received mobilized peripheral blood stem cell (PBSC). All donors were HLA-matched related, 48 (66%) had SCT, and 25 (34%) demonstrated normal Hgb electrophoresis pattern. The mean TNC and CD34 dose were 3.8× 10 8 /kg (1.4–8.2) and 6.3 × 10 6 /kg (2.3–17.3), respectively. The characteristics of the patients, donors, and transplant are presented in Table 1 . Table 1 Patient and transplant characteristics Patients by Donor groups Total Patients (n = 73) p-value Normal Hgb electrophoresis (n = 25) Sickle cell trait (n = 48) Gender - Male 15 24 39 (53%) Female 10 24 34 (67%) Age at HSCT Median (in yrs.) 10.5 11.3 11.3 - Indication for HSCT - CNS insult 14 30 44 (60%) Recurrent VOC pain crisis + ACS 6 11 17 (23%) Recurrent VOC pain crisis 5 7 12 (17%) Transplant essential data - Myeloablative conditioning 25 48 73 (100%) Stem cell source BM 25 47 72(99%) PBSC - 1 1 (1%) Cell count, mean (range) CD34 (x 10^6/Kg) 5.8 (2.5–12.1) 7.0 (2.3–17.3) 6.3 (2.3–17.3) 0.483 TNC (x 10^8/Kg) 3.3 (1.4–4.9) 4.0 (1.9–8.2) 3.8 (1.2– 8.2) 0.476 Engraftment data, mean (range) ANC recovery (in days) 23.6 (14–84) 20.1 (10–38) 21.3 (10–84) 0.627 Platelet recovery (in days) 25.4 (12–43) 21.1 (14–43) 22.6 (14–78) 0.114 Chimerism at last follow-up* Full 13 26 39 (53%) 0.598 Mixed 11 22 33 (47%) *Chimerism could not be performed in one-patient due to early death Hematopoietic recovery The mean time to neutrophil and platelet engraftment was 21.3 (10–84) and 22.61 (14–78) days, respectively. None of the patients developed graft rejection. Data on donor cell engraftment showed full chimerism in 39 (53%) and mixed chimerism in 33 (47%) recipients at last follow-up (p = 0.598). A comparison of the two donor groups regarding time to ANC, platelet recovery, and chimerism at the last follow up revealed no statistically significant differences, with p-values of 0.627, 0.114, and 0.598, respectively (Table 1 ). The chimerism (%) kinetics overtime is shown in Fig. 2 . Post-HSCT complications Acute GVHD (aGVHD) had a cumulative incidence of 30% ( 22 ), with grades I–II and III–IV being present in 14 and 8 patients, respectively. The skin was the major site of involvement in 10 (46%) patients, followed by the gut, skin + gut, and liver, in 6 (27%), 4 (18%) and 2 (9%), respectively. Fourteen patients (19%) developed chronic GVHD (cGVHD); of which 12 patients (86%) had mild disease, and 2 patients (14%) had extensive disease. The median time to the onset of cGVHD was 191 (ranging from 109 to 530) days. Notably, all patients were undergoing a tapering of immunosuppressive medication at the time of cGVHD development. Univariate analysis of the two donor groups demonstrated no statistically significant difference in the incidence of aGVHD and cGVHD, with p-values of 0.802 and 0.261, respectively (Table 2 ). Additionally, linear regression analysis revealed no associations between ABO incompatibility, donor cell count, age, and gender and the incidence of cGVHD (p = 0.791, 0.781, 0.123 and 0.517, respectively). Similarly, an analysis of recipient factors including age, gender, and indication for HSCT showed no statistically significant correlation with cGVHD (p = 0.562, 0.972, and 0.416, respectively). Table 2 Post-HSCT complications Transplant-related complications Patients by Donor groups Total Patients (n = 73) p-value Normal Hgb electrophoresis (n = 25) Sickle cell trait (n = 48) aGVHD 8 14 22 (30%) 0.802 cGVHD 3 11 14 (19%) 0.261 Hemorrhagic cystitis 4 6 10 (14%) 0.680 PRES 4 4 8 (11%) 0.320 VOD 2 3 5 (7%) 0.358 CMV re-activation 11 27 38 (52%) 0.423 The incidence rates of PRES, hemorrhagic cystitis, VOD, and CMV reactivation were 11% ( 8 ), 14% ( 10 ), 7% ( 5 ), and 52% (38) of the patients, respectively. When comparing these rates between the two groups, no statistically significant differences were observed, with p-values of 0.320 for PRES, 0.358 for VOD, 0.680 for hemorrhagic cystitis and 0.423 for CMV reactivation (Table 2 ). Survival analysis The median follow-up duration for the cohort was 4.4 years. The 5-year probability of OS was 97.3%, with two (3%) patients succumbing to transplant-related complications within the first 100 days, one from each group. There was no statistically significant difference in OS between the two groups, as reflected by the p-value of 0.628 (Fig. 3 ). As of the latest follow-up, none of the surviving patients exhibited any signs or symptoms of SCD. Furthermore, hemoglobin electrophoresis results strongly indicated that erythropoiesis was entirely donor-derived in both groups (Fig. 4 ). Discussion Excellent results have been reported in the literature using allogeneic MRD HSCT in pediatric patients with SCD ( 18 – 20 ). Bernaudin et al. evaluated 87 children with severe SCD aged 2–22 years who had undergone myeloablative conditioning before receiving grafts from a sibling donor. They reported that among these patients, the OS and event-free survival (EFS) were 93.1% and 86.1%, respectively. The incidence of aGVHD and cGVHD was 20% and 12.6% of the patients, respectively; with notable reduction in rejection rate from 22.6–2.9% after the addition of ATG ( 21 ). Another study conducted in Saudi Arabia reported a 2-year EFS of 90% in adults and 97% in children, with a corresponding OS of 100% in both cohorts ( 22 ). An international survey included 1,000 recipients of HLA-identical sibling transplants performed between 1986 and 2013. Myeloablative and reduced intensity conditioning regimens were administered to 87% and 13% of the recipients, respectively. The 5-year EFS and OS were 91.4% and 92.9%, respectively. Twenty-three (2.3%) patients developed graft failure, 7% ( 2 ) of whom died; infection was the most common cause of transplantation-related mortality ( 5 ). Our cohort included 73 pediatric patients with a median age of 11.3 years at transplant, and all of whom received myeloablative conditioning regimen. In the present study, the 5-year OS and DFS were 97.3%. In Saudi Arabia, due to the high prevalence of consanguineous marriages, there is a high likelihood that many of these family donors will have SCT ( 6 ). In our study, the ratio of donors with SCT to donors with a normal Hgb electrophoresis pattern was 2:1. Several studies have investigated the effects of HSCT donation on donors with SCT, particularly regarding the mobilization of stem cells using growth factors ( 23 ). However, the outcomes of HSCT in SCD involving donors with SCT have not been systematically examined. Additionally, research has shown that, even when a donor carries SCT, a minimum level of donor chimerism, approximately 20–25%, is necessary to prevent SCD-related complications and maintain HbS levels below 50% ( 24 ). This study focuses on outcomes from myeloablative MRD HSCT in patients with SCD, specifically comparing donor status (SCT versus normal Hgb electrophoresis pattern). Notably, none of the patients in either group experienced primary or secondary graft failure. At one-year follow-up, the median donor chimerism was 94.5% (ranging, 57.50–100%) in the SCT group and 94% (ranging, 66–100%) in the normal Hgb electrophoresis pattern donor group, with a p-value of 0.964. Throughout the follow-up period, donor chimerism remained > 20% for all patients, regardless of the donor group. Additionally, all patients achieved Hb A and S levels that closely aligned with the donor baseline levels (Fig. 4 ). The 5-year probability of OS and DFS was 97.9% in the SCT donor group (median follow-up, 4.51 [0.2–11.1] years) and 96% in the normal Hgb electrophoresis pattern donor group (median follow-up, 3.25 [0.1–10.1] years). In total, two patients from each group died within the first 100 days due to transplant-related complications. The incidence of aGVHD was 29% ( 14 ) in the SCT donor group and 32% ( 8 ) in the normal Hgb electrophoresis pattern donor group (p = 0.802). For cGVHD, the incidence was 23% ( 11 ) in the SCT group compared with 12% ( 3 ) in the normal HgB electrophoresis pattern donor group (p = 0.261), also suggesting no significant difference. Risk factors typically associated with the development of cGVHD- such as donor age, gender, stem cell source and dose, conditioning regimen and GVHD prophylaxis were comparable between both cohorts. Linear regression analysis did not identify any predictive factors for cGVHD in either group. No discernible difference was noted between the two groups in terms of transplant-related infectious and non-infectious complications (Table 2 ). Compared to the SCT group, the normal Hgb electrophoresis pattern group’s average length of hospital stay was marginally longer (52.8 [33–151] vs. 48.3 [21–116] days, respectively (p = 0.40). A significant strength of this study is the homogeneity of the patient population, as well as the consistent use of the same transplant protocol and follow up period across the study cohort. This uniformity reduces variability and allows for a more precise comparison of outcomes between the donor groups. However, the relatively small sample size may limit the statistical power to detect differences between the two groups. Despite its limitations, this study provides valuable insights on the use of HLA identical MRD irrespective of their SCT status. Our results are comparable to internationally reported post-transplant outcomes in patients with SCD. In this first-ever attempt, we have compared the outcomes of HSCT using HLA-identical donors with SCT with those who have normal Hgb electrophoresis pattern. Our findings showed there was no significant difference between the two donor groups' product cell dose (CD34 and TNC), post-HSCT cell recovery, chimerism, incidence of acute or chronic GVHD, and transplant-related complications. Additionally, our study did not find any differences in the OS or DFS linked with donor status. In conclusion, our findings indicate that in MRD HSCT for SCD, donors with SCT and those with normal hemoglobin provide comparable long-term outcomes, supporting the viability of both donor types in clinical practice. Future research should focus on long-term post-HSCT follow-up with emphasis on SCT-related complications such as papillary necrosis, bacteriuria, splenic infarction, and exercise-induced death. Declarations Declaration of interests The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper. Author contributions All authors contributed to the study conception, design, data collection, and analysis. Manuscript preparation were performed by Dr.Mohamed Bayoumy, Dr.Enass Raffa and Dr.Wasil Jastaniah. All authors reviewed and approved the final version. Acknowledgements We would like to express our appreciation for the help and support of the stem cell processing laboratory, and nursing staff. Additionally, we would to express our gratitude to the HSCT coordinators, Ms. Bayanah Alenezi and Ms. Ghada ElKhateeb from King Faisal Specialist Hospital & Research Centre, Jeddah, Saudi Arabia. Data availability statement The data that support the findings of this study are available on request from the corresponding author. The data are not publicly available due to privacy or ethical restrictions. References Brandow AM, Liem RI. Advances in the diagnosis and treatment of sickle cell disease. J Hematol Oncol. 2022; 15:20. Cappelli B, Volt F, Tozatto-Maio K, Scigliuolo GM, Ferster A, Dupont S, et al. Risk factors and outcomes according to age at transplantation with an HLA-identical sibling for sickle cell disease. Haematologica. 2019; 104:e543–e546. Kogel F, Hakimeh D, Sodani P, Lang P, Kühl JS, Hundsdoerfer P, et al. Allogeneic hematopoietic stem cell transplantation from sibling and unrelated donors in pediatric patients with sickle cell disease-A single center experience. 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Cite Share Download PDF Status: Published Journal Publication published 18 Apr, 2025 Read the published version in Bone Marrow Transplantation → Version 1 posted Editorial decision: revise 09 Dec, 2024 Review # 1 received at journal 19 Nov, 2024 Review # 3 received at journal 18 Nov, 2024 Review # 2 received at journal 17 Nov, 2024 Reviewer # 3 agreed at journal 04 Nov, 2024 Reviewer # 2 agreed at journal 04 Nov, 2024 Reviewer # 1 agreed at journal 02 Nov, 2024 Reviewers invited by journal 02 Nov, 2024 Submission checks completed at journal 23 Oct, 2024 First submitted to journal 22 Oct, 2024 Unknown event 22 Oct, 2024 Editor assigned by journal 22 Oct, 2024 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. 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Elhadidy","email":"","orcid":"","institution":"King Faisal Specialist Hospital \u0026 Research Center","correspondingAuthor":false,"prefix":"","firstName":"Marwa","middleName":"","lastName":"Elhadidy","suffix":""},{"id":373299198,"identity":"ce07b50b-06bc-4af4-ad71-37671699b35f","order_by":8,"name":"Lamis AlKhateeb","email":"","orcid":"","institution":"AlSalama Hospital","correspondingAuthor":false,"prefix":"","firstName":"Lamis","middleName":"","lastName":"AlKhateeb","suffix":""},{"id":373299199,"identity":"77b9d035-5fa6-4b77-966b-71e8b3e18e7e","order_by":9,"name":"Wasil Jastaniah","email":"","orcid":"https://orcid.org/0000-0002-2495-8796","institution":"King Faisal Specialist Hospital \u0026 Research Centre","correspondingAuthor":false,"prefix":"","firstName":"Wasil","middleName":"","lastName":"Jastaniah","suffix":""}],"badges":[],"createdAt":"2024-10-22 08:20:06","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-5309765/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-5309765/v1","draftVersion":[],"editorialEvents":[{"content":"https://doi.org/10.1038/s41409-025-02572-8","type":"published","date":"2025-04-18T04:00:00+00:00"}],"editorialNote":"","failedWorkflow":false,"files":[{"id":70287037,"identity":"5203919e-ac45-493e-a599-6140139840f2","added_by":"auto","created_at":"2024-12-01 16:48:25","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":242296,"visible":true,"origin":"","legend":"\u003cp\u003eRoadmap of the conditioning regimen\u003c/p\u003e","description":"","filename":"1.png","url":"https://assets-eu.researchsquare.com/files/rs-5309765/v1/d5ed186f05e52a25a8888326.png"},{"id":70286862,"identity":"05c87a4b-d860-4f35-ad68-d8e32fdcb478","added_by":"auto","created_at":"2024-12-01 16:40:25","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":70451,"visible":true,"origin":"","legend":"\u003cp\u003eThe chimerism kinetics overtime:\u003c/p\u003e","description":"","filename":"2.png","url":"https://assets-eu.researchsquare.com/files/rs-5309765/v1/3ac6182009d78e37709dead9.png"},{"id":70286859,"identity":"bee17b8a-82ea-4243-9dc4-d45bc9a69ae9","added_by":"auto","created_at":"2024-12-01 16:40:25","extension":"png","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":104627,"visible":true,"origin":"","legend":"\u003cp\u003eOverall survival (OS) by Donor group\u003c/p\u003e","description":"","filename":"3.png","url":"https://assets-eu.researchsquare.com/files/rs-5309765/v1/f8c3b3de9d6cd42bcb2c0f47.png"},{"id":70287036,"identity":"c373d58f-bd14-4601-b7cc-03fcbc1837fc","added_by":"auto","created_at":"2024-12-01 16:48:25","extension":"png","order_by":4,"title":"Figure 4","display":"","copyAsset":false,"role":"figure","size":38525,"visible":true,"origin":"","legend":"\u003cp\u003eHemoglobin electrophoresis for donor at HSCT and Recipient at latest follow-up\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFigure 4:\u003c/strong\u003e Hemoglobin (Hbg) level (%) by donor at HSCT and Recipient at latest follow-up: \u003cstrong\u003eA)\u003c/strong\u003e HbS level (%): Donor at HSCT, median, 33 (range: 0 – 43), mean: 23.1; Recipient at latest follow-up: median, 33 (range: 0 – 43), mean: 23.3 ; \u003cstrong\u003eB) \u003c/strong\u003eHbA level (%): Donor at HSCT, median, 63.0 (range: 53.1 – 98.2), mean: 73.4; Recipient at HSCT, median, 62.6 (range: 54.1 – 98.1), mean: 72.3\u003c/p\u003e","description":"","filename":"4.png","url":"https://assets-eu.researchsquare.com/files/rs-5309765/v1/b2de53212dcaeb02ba54f05f.png"},{"id":80934545,"identity":"56962999-56fa-4b38-b98f-46a5369e521e","added_by":"auto","created_at":"2025-04-19 07:08:37","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":1206966,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-5309765/v1/23cf4bb1-fdef-4ccd-9b85-e8807e7c9b0d.pdf"}],"financialInterests":"The authors have declared there is \u003cb\u003eNO\u003c/b\u003e conflict of interest to disclose.","formattedTitle":"Outcomes of Hematopoietic Stem Cell Transplantation in Children with Sickle Cell Disease: Does Donor Sickle Cell Trait Status Matter?","fulltext":[{"header":"Introduction","content":"\u003cp\u003eSickle cell disease (SCD) is a well-known homozygous inherited hemoglobinopathy that causes vaso-occlusive phenomena and chronic hemolysis with more than 3\u0026nbsp;million individuals affected worldwide (\u003cspan additionalcitationids=\"CR2\" citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e). Vaso-occlusion results in sickle cell crisis and can eventually lead to progressive irreversible complications involving multiple organ systems (\u003cspan additionalcitationids=\"CR5 CR6\" citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e). Sickle cell trait (SCT) is the heterozygous form of SCD and thus should have no complications ascribed to it and is considered a benign state (\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e, \u003cspan additionalcitationids=\"CR8\" citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e). In Saudi Arabia, the burden of SCD is high, which may be related to the high prevalence of consanguineous marriages. The carrier status ranges from 2\u0026ndash;27%; in some areas, up to 1.4% of individuals have SCD (\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e, \u003cspan additionalcitationids=\"CR11 CR12\" citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eDespite advancements in medical therapies, SCD remains a debilitating condition, with allogeneic hematopoietic stem cell transplantation (HSCT) recognized as the only established curative option (\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e). Gene therapy is a promising treatment modality in these patients; however, the long-term protective effect on disease-related organ damage is unclear (\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e, \u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e, \u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e). Allogeneic HSCT is indicated primarily for individuals with severe SCD who experience complications such as central nervous system (CNS) insult, acute chest syndrome (ACS), and recurrent vaso-occlusive pain crisis (VOC) (\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e, \u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e, and \u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eThis curative option is not readily available to all patients with SCD primarily due to the lack of a suitable donor (\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e, \u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e, \u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e). Among patients transplanted with matched related donors (MRDs), excellent survival rates with lower incidence of transplant-related complications have been demonstrated (\u003cspan additionalcitationids=\"CR19\" citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e); however, recent modifications in the haploidentical donor transplantation platforms, involving \u003cem\u003ein vivo\u003c/em\u003e or \u003cem\u003eex vivo\u003c/em\u003e T cell depletion, has also resulted in promising outcomes potentially expanding the donor pool for patients with SCD (\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eFor decades, HLA-identical donors with SCT have been donating HSCs for allogeneic transplantation (\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e, \u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e). However, there is a scarcity of data regarding the impact of using donors with SCT compared to those with normal hemoglobin (Hgb) electrophoresis pattern on transplantation outcomes. This study aimed to compare those two donor groups, providing data on stem cell dose, time to engraftment, chimerism, post-HSCT complications (infectious and noninfectious), and survival outcomes (overall and disease-free).\u003c/p\u003e"},{"header":"Materials and Methods","content":"\u003cdiv id=\"Sec3\" class=\"Section2\"\u003e \u003ch2\u003eStudy design\u003c/h2\u003e \u003cp\u003eThis is a retrospective single-center chart review study of children aged\u0026thinsp;\u0026le;\u0026thinsp;14 years who underwent first allogeneic HSCT for SCD from January 2013 to August 2023. In this study, only HSCT from MRDs with either SCT or normal Hgb electrophoresis pattern were included.\u003c/p\u003e \u003cp\u003eThis study was conducted at King Faisal Specialist Hospital \u0026amp; Research Center (KFSH\u0026amp;RC), Jeddah, Saudi Arabia following approval by the institutional review board (IRB number: 2020-65). Waiver for a written informed consent was approved, and the overall conduct of this study complied with the Declaration of Helsinki and Good Clinical Practice guidelines.\u003c/p\u003e \u003cp\u003eThe following three components of the IRB-approved case report form were used to collect study data from the institutional electronic and paper medical records: (\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e) pretransplant essential data, including demographic data (gender, date of birth, and date of diagnosis), indication for transplant, source of stem cell, conditioning regimen, graft-versus-host disease (GVHD) prophylaxis, and stem cell dose (CD34 \u0026times; 10\u003csup\u003e6\u003c/sup\u003e/kg and TNC \u0026times; 10\u003csup\u003e8\u003c/sup\u003e); (\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e) time to neutrophil and platelet engraftment and chimerism data; and (\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e) post-HSCT complication data, including GVHD, veno-occlusive disease (VOD), posterior reversible encephalopathy syndrome (PRES), and infectious toxicity.\u003c/p\u003e \u003c/div\u003e\n\u003ch3\u003eStudy endpoints and definitions\u003c/h3\u003e\n\u003cp\u003eThe primary endpoint of this study was 5-year overall survival (OS), defined by the probability of a recipient being alive measured from the date of stem cell product infusion and censored at the last contact, whereas death due to any cause was considered an event. Events for disease-free survival (DFS) were defined as graft failure, disease recurrence, and death. The following were the secondary endpoints: (\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e) stem cell dose; (\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e) neutrophil engraftment, which was defined as the first of three consecutive days of \u0026ge;\u0026thinsp;500/սL; (\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e) platelet engraftment, which was defined as the first of three consecutive days of \u0026ge;\u0026thinsp;20 \u0026times; 10\u003csup\u003e9\u003c/sup\u003e/L, sustained without transfusion for a minimum of 7 days; (\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e) chimerism data (full donor chimerism was defined as \u0026ge;\u0026thinsp;95% donor cells and mixed donor chimerism was defined as \u0026ge;\u0026thinsp;20\u0026ndash;94% donor cells); (\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e) Hgb electrophoresis data pre- and post-transplant; and (\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e) post-transplant complications, including infectious and noninfectious complications.\u003c/p\u003e\n\u003ch3\u003eConditioning regimen\u003c/h3\u003e\n\u003cp\u003eThe myeloablative conditioning regimen consisted of the following: intravenous (IV) busulfan, 0.8\u0026ndash;1.2 mg/kg/dose, every 6 h on days \u0026minus;\u0026thinsp;10 to \u0026minus;\u0026thinsp;6 for a total of 16 doses; IV cyclophosphamide, 50 mg/kg, every 24 h on days \u0026minus;\u0026thinsp;5 to \u0026minus;\u0026thinsp;2 for a total of 4 doses; and rabbit-ATG (thymoglobulin), 2.5 mg/kg/dose every 24 h, on days \u0026minus;\u0026thinsp;5 to \u0026minus;\u0026thinsp;3 for a total of 3 doses. All patients received GVHD prophylaxis, which included IV cyclosporin (3mg/kg/dose every 12 h on day \u0026minus;\u0026thinsp;3) and four doses of IV methotrexate (15 mg/m\u003csup\u003e2\u003c/sup\u003e/dose on day\u0026thinsp;+\u0026thinsp;1 and 10 mg/m\u003csup\u003e2\u003c/sup\u003e/dose on days\u0026thinsp;+\u0026thinsp;3, +6, and +\u0026thinsp;11). Figure\u0026nbsp;\u003cspan refid=\"Fig4\" class=\"InternalRef\"\u003e1\u003c/span\u003e depicts the conditioning regimen's roadmap schematically.\u003c/p\u003e \u003cdiv id=\"Sec6\" class=\"Section2\"\u003e \u003ch2\u003eStatistical analysis\u003c/h2\u003e \u003cp\u003eAll statistical analyses were performed using IBM SPSS Statistics for Windows, version 20.0 (IBM Corp., Armonk, NY, USA). Data quality assurance measures were applied for data completeness and accuracy. Baseline clinical characteristics and demographic data were described using frequencies and percentages for categorical values, whereas continuous data were described using nonparametric median test. To report the incidence of infectious and noninfectious toxicities, descriptive statistics was used, and chi-square and independent t-tests were applied whenever applicable. To estimate the 5-year OS and DFS, the Kaplan\u0026ndash;Meier survival analysis was used. To test the significance of differences between the survival times between groups, the Breslow (generalized Wilcoxon) test was employed, and a p-value of \u0026lt;\u0026thinsp;0.05 was considered statistically significant. Linear regression (analysis of variance model) was performed for variables with a value of significance (p-value\u0026thinsp;\u0026le;\u0026thinsp;0.05).\u003c/p\u003e \u003c/div\u003e"},{"header":"Results","content":"\u003cdiv id=\"Sec8\" class=\"Section2\"\u003e \u003ch2\u003eDemographic and transplant characteristics\u003c/h2\u003e \u003cp\u003eFrom January 2013 to August 2023, 73 patients with SCD underwent allogeneic HSCT at the Pediatric Stem Cell Transplantation Unit of KFSH\u0026amp;RC, Jeddah, Saudi Arabia. The median age at HSCT was 11.3 years. There were 39 (53%) males and 34 (47%) females in total, with the majority (62% [45]) referred from the Kingdom\u0026rsquo;s Western region. The most frequent indications for HSCT were CNS insult, recurrent VOC pain crisis with ACS, and recurrent VOC pain crisis in 44 (60%), 17 (23%), and 12 (17%) patients, respectively. All patients had a history of packed red blood cell transfusions before HSCT; however, none of them developed alloimmunization. The bone marrow (BM) was the main source of stem cell in 72 (99%) patients, and one patient (1%) received mobilized peripheral blood stem cell (PBSC). All donors were HLA-matched related, 48 (66%) had SCT, and 25 (34%) demonstrated normal Hgb electrophoresis pattern. The mean TNC and CD34 dose were 3.8\u0026times; 10\u003csup\u003e8\u003c/sup\u003e/kg (1.4\u0026ndash;8.2) and 6.3 \u0026times; 10\u003csup\u003e6\u003c/sup\u003e/kg (2.3\u0026ndash;17.3), respectively. The characteristics of the patients, donors, and transplant are presented in Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e.\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 and transplant characteristics\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"5\"\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=\"left\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\" morerows=\"1\" rowspan=\"2\"\u003e\u0026nbsp;\u003c/th\u003e \u003cth align=\"left\" colspan=\"2\" nameend=\"c3\" namest=\"c2\"\u003e \u003cp\u003ePatients by Donor groups\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003eTotal Patients\u003c/p\u003e \u003cp\u003e(n\u0026thinsp;=\u0026thinsp;73)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c5\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003ep-value\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eNormal Hgb electrophoresis\u003c/p\u003e \u003cp\u003e(n\u0026thinsp;=\u0026thinsp;25)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eSickle cell trait\u003c/p\u003e \u003cp\u003e(n\u0026thinsp;=\u0026thinsp;48)\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eGender\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=\"left\" colname=\"c5\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMale\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e15\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e24\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e39 (53%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eFemale\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e10\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e24\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e34 (67%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAge at HSCT\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=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMedian (in yrs.)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e10.5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e11.3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e11.3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eIndication for HSCT\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=\"left\" colname=\"c5\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCNS insult\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e14\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e30\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e44 (60%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eRecurrent VOC pain crisis\u0026thinsp;+\u0026thinsp;ACS\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e6\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e11\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e17 (23%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eRecurrent VOC pain crisis\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e7\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e12 (17%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eTransplant essential data\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=\"left\" colname=\"c5\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMyeloablative conditioning\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e25\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e48\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e73 (100%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eStem cell source\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=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eBM\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e25\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e47\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e72(99%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePBSC\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e1 (1%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCell count, mean (range)\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=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCD34 (x 10^6/Kg)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e5.8 (2.5\u0026ndash;12.1)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e7.0 (2.3\u0026ndash;17.3)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e6.3 (2.3\u0026ndash;17.3)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.483\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eTNC (x 10^8/Kg)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e3.3 (1.4\u0026ndash;4.9)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e4.0 (1.9\u0026ndash;8.2)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e3.8 (1.2\u0026ndash; 8.2)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.476\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eEngraftment data, mean (range)\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=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eANC recovery (in days)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e23.6 (14\u0026ndash;84)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e20.1 (10\u0026ndash;38)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e21.3 (10\u0026ndash;84)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.627\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePlatelet recovery (in days)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e25.4 (12\u0026ndash;43)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e21.1 (14\u0026ndash;43)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e22.6 (14\u0026ndash;78)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.114\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eChimerism at last follow-up*\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=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eFull\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e13\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e26\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e39 (53%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.598\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMixed\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e11\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e22\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e33 (47%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003ctfoot\u003e \u003ctr\u003e\u003ctd colspan=\"5\"\u003e*Chimerism could not be performed in one-patient due to early death\u003c/td\u003e\u003c/tr\u003e \u003c/tfoot\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003c/div\u003e\n\u003ch3\u003eHematopoietic recovery\u003c/h3\u003e\n\u003cp\u003eThe mean time to neutrophil and platelet engraftment was 21.3 (10\u0026ndash;84) and 22.61 (14\u0026ndash;78) days, respectively. None of the patients developed graft rejection. Data on donor cell engraftment showed full chimerism in 39 (53%) and mixed chimerism in 33 (47%) recipients at last follow-up (p\u0026thinsp;=\u0026thinsp;0.598). A comparison of the two donor groups regarding time to ANC, platelet recovery, and chimerism at the last follow up revealed no statistically significant differences, with p-values of 0.627, 0.114, and 0.598, respectively (Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e). The chimerism (%) kinetics overtime is shown in Fig.\u0026nbsp;\u003cspan refid=\"Fig5\" class=\"InternalRef\"\u003e2\u003c/span\u003e.\u003c/p\u003e\n\u003ch3\u003ePost-HSCT complications\u003c/h3\u003e\n\u003cp\u003eAcute GVHD (aGVHD) had a cumulative incidence of 30% (\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e), with grades I\u0026ndash;II and III\u0026ndash;IV being present in 14 and 8 patients, respectively. The skin was the major site of involvement in 10 (46%) patients, followed by the gut, skin\u0026thinsp;+\u0026thinsp;gut, and liver, in 6 (27%), 4 (18%) and 2 (9%), respectively. Fourteen patients (19%) developed chronic GVHD (cGVHD); of which 12 patients (86%) had mild disease, and 2 patients (14%) had extensive disease. The median time to the onset of cGVHD was 191 (ranging from 109 to 530) days. Notably, all patients were undergoing a tapering of immunosuppressive medication at the time of cGVHD development. Univariate analysis of the two donor groups demonstrated no statistically significant difference in the incidence of aGVHD and cGVHD, with p-values of 0.802 and 0.261, respectively (Table\u0026nbsp;\u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\u003e). Additionally, linear regression analysis revealed no associations between ABO incompatibility, donor cell count, age, and gender and the incidence of cGVHD (p\u0026thinsp;=\u0026thinsp;0.791, 0.781, 0.123 and 0.517, respectively). Similarly, an analysis of recipient factors including age, gender, and indication for HSCT showed no statistically significant correlation with cGVHD (p\u0026thinsp;=\u0026thinsp;0.562, 0.972, and 0.416, respectively).\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab2\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 2\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003ePost-HSCT complications\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"5\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" 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 \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003eTransplant-related complications\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colspan=\"2\" nameend=\"c3\" namest=\"c2\"\u003e \u003cp\u003ePatients by Donor groups\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003eTotal Patients\u003c/p\u003e \u003cp\u003e(n\u0026thinsp;=\u0026thinsp;73)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c5\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003ep-value\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eNormal Hgb electrophoresis\u003c/p\u003e \u003cp\u003e(n\u0026thinsp;=\u0026thinsp;25)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eSickle cell trait\u003c/p\u003e \u003cp\u003e(n\u0026thinsp;=\u0026thinsp;48)\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eaGVHD\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e8\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e14\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e22 (30%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.802\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ecGVHD\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e11\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e14 (19%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.261\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eHemorrhagic cystitis\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e4\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e6\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e10 (14%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.680\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePRES\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e4\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e4\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e8 (11%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.320\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eVOD\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e5 (7%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.358\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCMV re-activation\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e11\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e27\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e38 (52%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.423\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003eThe incidence rates of PRES, hemorrhagic cystitis, VOD, and CMV reactivation were 11% (\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e), 14% (\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e), 7% (\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e), and 52% (38) of the patients, respectively. When comparing these rates between the two groups, no statistically significant differences were observed, with p-values of 0.320 for PRES, 0.358 for VOD, 0.680 for hemorrhagic cystitis and 0.423 for CMV reactivation (Table\u0026nbsp;\u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\u003e).\u003c/p\u003e \u003cdiv id=\"Sec11\" class=\"Section2\"\u003e \u003ch2\u003eSurvival analysis\u003c/h2\u003e \u003cp\u003eThe median follow-up duration for the cohort was 4.4 years. The 5-year probability of OS was 97.3%, with two (3%) patients succumbing to transplant-related complications within the first 100 days, one from each group. There was no statistically significant difference in OS between the two groups, as reflected by the p-value of 0.628 (Fig.\u0026nbsp;\u003cspan refid=\"Fig6\" class=\"InternalRef\"\u003e3\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eAs of the latest follow-up, none of the surviving patients exhibited any signs or symptoms of SCD. Furthermore, hemoglobin electrophoresis results strongly indicated that erythropoiesis was entirely donor-derived in both groups (Fig.\u0026nbsp;\u003cspan refid=\"Fig8\" class=\"InternalRef\"\u003e4\u003c/span\u003e).\u003c/p\u003e \u003c/div\u003e"},{"header":"Discussion","content":"\u003cp\u003eExcellent results have been reported in the literature using allogeneic MRD HSCT in pediatric patients with SCD (\u003cspan additionalcitationids=\"CR19\" citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e). Bernaudin et al. evaluated 87 children with severe SCD aged 2\u0026ndash;22 years who had undergone myeloablative conditioning before receiving grafts from a sibling donor. They reported that among these patients, the OS and event-free survival (EFS) were 93.1% and 86.1%, respectively. The incidence of aGVHD and cGVHD was 20% and 12.6% of the patients, respectively; with notable reduction in rejection rate from 22.6\u0026ndash;2.9% after the addition of ATG (\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e). Another study conducted in Saudi Arabia reported a 2-year EFS of 90% in adults and 97% in children, with a corresponding OS of 100% in both cohorts (\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eAn international survey included 1,000 recipients of HLA-identical sibling transplants performed between 1986 and 2013. Myeloablative and reduced intensity conditioning regimens were administered to 87% and 13% of the recipients, respectively. The 5-year EFS and OS were 91.4% and 92.9%, respectively. Twenty-three (2.3%) patients developed graft failure, 7% (\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e) of whom died; infection was the most common cause of transplantation-related mortality (\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e). Our cohort included 73 pediatric patients with a median age of 11.3 years at transplant, and all of whom received myeloablative conditioning regimen. In the present study, the 5-year OS and DFS were 97.3%.\u003c/p\u003e \u003cp\u003eIn Saudi Arabia, due to the high prevalence of consanguineous marriages, there is a high likelihood that many of these family donors will have SCT (\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e). In our study, the ratio of donors with SCT to donors with a normal Hgb electrophoresis pattern was 2:1. Several studies have investigated the effects of HSCT donation on donors with SCT, particularly regarding the mobilization of stem cells using growth factors (\u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e). However, the outcomes of HSCT in SCD involving donors with SCT have not been systematically examined. Additionally, research has shown that, even when a donor carries SCT, a minimum level of donor chimerism, approximately 20\u0026ndash;25%, is necessary to prevent SCD-related complications and maintain HbS levels below 50% (\u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eThis study focuses on outcomes from myeloablative MRD HSCT in patients with SCD, specifically comparing donor status (SCT versus normal Hgb electrophoresis pattern). Notably, none of the patients in either group experienced primary or secondary graft failure. At one-year follow-up, the median donor chimerism was 94.5% (ranging, 57.50\u0026ndash;100%) in the SCT group and 94% (ranging, 66\u0026ndash;100%) in the normal Hgb electrophoresis pattern donor group, with a p-value of 0.964. Throughout the follow-up period, donor chimerism remained\u0026thinsp;\u0026gt;\u0026thinsp;20% for all patients, regardless of the donor group. Additionally, all patients achieved Hb A and S levels that closely aligned with the donor baseline levels (Fig.\u0026nbsp;\u003cspan refid=\"Fig8\" class=\"InternalRef\"\u003e4\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eThe 5-year probability of OS and DFS was 97.9% in the SCT donor group (median follow-up, 4.51 [0.2\u0026ndash;11.1] years) and 96% in the normal Hgb electrophoresis pattern donor group (median follow-up, 3.25 [0.1\u0026ndash;10.1] years). In total, two patients from each group died within the first 100 days due to transplant-related complications.\u003c/p\u003e \u003cp\u003eThe incidence of aGVHD was 29% (\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e) in the SCT donor group and 32% (\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e) in the normal Hgb electrophoresis pattern donor group (p\u0026thinsp;=\u0026thinsp;0.802). For cGVHD, the incidence was 23% (\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e) in the SCT group compared with 12% (\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e) in the normal HgB electrophoresis pattern donor group (p\u0026thinsp;=\u0026thinsp;0.261), also suggesting no significant difference. Risk factors typically associated with the development of cGVHD- such as donor age, gender, stem cell source and dose, conditioning regimen and GVHD prophylaxis were comparable between both cohorts. Linear regression analysis did not identify any predictive factors for cGVHD in either group.\u003c/p\u003e \u003cp\u003eNo discernible difference was noted between the two groups in terms of transplant-related infectious and non-infectious complications (Table\u0026nbsp;\u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\u003e). Compared to the SCT group, the normal Hgb electrophoresis pattern group\u0026rsquo;s average length of hospital stay was marginally longer (52.8 [33\u0026ndash;151] vs. 48.3 [21\u0026ndash;116] days, respectively (p\u0026thinsp;=\u0026thinsp;0.40).\u003c/p\u003e \u003cp\u003eA significant strength of this study is the homogeneity of the patient population, as well as the consistent use of the same transplant protocol and follow up period across the study cohort. This uniformity reduces variability and allows for a more precise comparison of outcomes between the donor groups. However, the relatively small sample size may limit the statistical power to detect differences between the two groups. Despite its limitations, this study provides valuable insights on the use of HLA identical MRD irrespective of their SCT status.\u003c/p\u003e \u003cp\u003eOur results are comparable to internationally reported post-transplant outcomes in patients with SCD. In this first-ever attempt, we have compared the outcomes of HSCT using HLA-identical donors with SCT with those who have normal Hgb electrophoresis pattern. Our findings showed there was no significant difference between the two donor groups' product cell dose (CD34 and TNC), post-HSCT cell recovery, chimerism, incidence of acute or chronic GVHD, and transplant-related complications. Additionally, our study did not find any differences in the OS or DFS linked with donor status. In conclusion, our findings indicate that in MRD HSCT for SCD, donors with SCT and those with normal hemoglobin provide comparable long-term outcomes, supporting the viability of both donor types in clinical practice. Future research should focus on long-term post-HSCT follow-up with emphasis on SCT-related complications such as papillary necrosis, bacteriuria, splenic infarction, and exercise-induced death.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eDeclaration of interests\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper\u003c/p\u003e\n\u003cp\u003e \u003ch2\u003eCompeting Interests:\u003c/h2\u003e \u003cp\u003eThe authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.\u003c/p\u003e \u003c/p\u003e\u003ch2\u003eAuthor contributions\u003c/h2\u003e \u003cp\u003eAll authors contributed to the study conception, design, data collection, and analysis. Manuscript preparation were performed by Dr.Mohamed Bayoumy, Dr.Enass Raffa and Dr.Wasil Jastaniah. All authors reviewed and approved the final version.\u003c/p\u003e\u003ch2\u003eAcknowledgements\u003c/h2\u003e \u003cp\u003eWe would like to express our appreciation for the help and support of the stem cell processing laboratory, and nursing staff. Additionally, we would to express our gratitude to the HSCT coordinators, Ms. Bayanah Alenezi and Ms. Ghada ElKhateeb from King Faisal Specialist Hospital \u0026amp; Research Centre, Jeddah, Saudi Arabia.\u003c/p\u003e\u003ch2\u003eData availability statement\u003c/h2\u003e \u003cp\u003eThe data that support the findings of this study are available on request from the corresponding author. The data are not publicly available due to privacy or ethical restrictions.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eBrandow AM, Liem RI. Advances in the diagnosis and treatment of sickle cell disease. 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Blood. 2000; 95:1918\u0026ndash;1924.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eWalters MC, Patience M, Leisenring W, Eckman JR, Buchanan GR, Rogers ZR, et al. Barriers to bone marrow transplantation for sickle cell anemia. Biol Blood Marrow Transplant. 1996; 2:100\u0026ndash;104.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eBernaudin F, Socie G, Kuentz M, Chevret S, Duval M, Bertrand Y, et al. Long-term results of related myeloablative stem-cell transplantation to cure sickle cell disease. Blood. 2007; 110:2749\u0026ndash;2756.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eAlzahrani M, Damlaj M, Essa M, Alahmari B, Alaskar A, Hejazi A, et al. Outcome of age-adapted approach to HLA-identical related hematopoietic stem cell transplantation in severe sickle cell disease: Saudi experience. Blood. 2018; 132:3468.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eDe Santis GC, Prado BP, Dotoli GM, Sim\u0026otilde;es BP, Covas DT. Mobilizing hematopoietic progenitor cells in donors with sickle cell trait is safe. Hematol Transfus Cell Ther. 2019; 41:101\u0026ndash;102.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eShah NC, Rangarajan HG, Ngwube A, Shenoy S. Mixed donor chimerism following stem cell transplantation for sickle cell disease. Curr Opin Hematol. 2023; 30:187\u0026ndash;193.\u003c/span\u003e\u003c/li\u003e\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":true,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"bone-marrow-transplantation","isNatureJournal":false,"hasQc":false,"allowDirectSubmit":false,"externalIdentity":"bmt","sideBox":"Learn more about [Bone Marrow Transplantation](http://www.nature.com/bmt/)","snPcode":"41409","submissionUrl":"https://mts-bmt.nature.com/cgi-bin/main.plex","title":"Bone Marrow Transplantation","twitterHandle":"@bmtjournal","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"ejp","reportingPortfolio":"Nature AJ","inReviewEnabled":true,"inReviewRevisionsEnabled":false},"keywords":"","lastPublishedDoi":"10.21203/rs.3.rs-5309765/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-5309765/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003eAllogeneic hematopoietic stem cell transplantation (HSCT) remains the gold standard curative therapy for sickle cell disease (SCD). A matched related donor (MRD) with sickle cell trait (SCT) is a viable option, with no evidence of adversely affecting transplant outcomes. We conducted a retrospective chart review of children (\u0026le;\u0026thinsp;14 years) who underwent myeloablative HSCT from MRDs for SCD between 2013 and 2023, comparing outcomes for MRD with SCT to those with normal hemoglobin (Hgb) electrophoresis. Overall, 73 children underwent HSCT at a median age of 11.3 years. The main indication for HSCT was central nervous system insult in 43 (60%) patients. Among the donors, 48 (66%) had SCT, whereas 25 (34%) had normal Hgb electrophoresis. The mean time to neutrophil and platelet engraftment was 21.3 (10\u0026ndash;84) and 22.61 (14\u0026ndash;78) days, respectively. None of the patients developed graft rejection. The incidence of both acute and chronic graft-versus-host disease (GVHD) was similar across the donor groups. With a remarkable 5-year overall survival and disease-free survival rate of 97.3%, our findings demonstrate that there is no significant difference between donor groups. Our results align with international HSCT outcomes for SCD, reinforcing the efficacy of allogeneic HSCT from MRDs, regardless of SCT status.\u003c/p\u003e","manuscriptTitle":"Outcomes of Hematopoietic Stem Cell Transplantation in Children with Sickle Cell Disease: Does Donor Sickle Cell Trait Status Matter?","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2024-12-01 16:40:19","doi":"10.21203/rs.3.rs-5309765/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"decision","content":"revise","date":"2024-12-09T14:09:06+00:00","index":"","fulltext":""},{"type":"editorInvitedReview","content":"This content is not available.","date":"2024-11-19T10:27:12+00:00","index":1,"fulltext":"This content is not available."},{"type":"editorInvitedReview","content":"This content is not available.","date":"2024-11-18T10:57:12+00:00","index":3,"fulltext":"This content is not available."},{"type":"editorInvitedReview","content":"This content is not available.","date":"2024-11-17T14:51:20+00:00","index":2,"fulltext":"This content is not available."},{"type":"reviewerAgreed","content":"This content is not available.","date":"2024-11-04T15:28:20+00:00","index":3,"fulltext":"This content is not available."},{"type":"reviewerAgreed","content":"This content is not available.","date":"2024-11-04T12:42:46+00:00","index":2,"fulltext":"This content is not available."},{"type":"reviewerAgreed","content":"This content is not available.","date":"2024-11-02T17:45:05+00:00","index":1,"fulltext":"This content is not available."},{"type":"reviewersInvited","content":"","date":"2024-11-02T15:25:24+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2024-10-23T09:26:50+00:00","index":"","fulltext":""},{"type":"submitted","content":"Bone Marrow Transplantation","date":"2024-10-22T13:11:07+00:00","index":"","fulltext":""},{"type":"checksFailed","content":"","date":"2024-10-22T10:32:51+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2024-10-22T08:15:07+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"bone-marrow-transplantation","isNatureJournal":false,"hasQc":false,"allowDirectSubmit":false,"externalIdentity":"bmt","sideBox":"Learn more about [Bone Marrow Transplantation](http://www.nature.com/bmt/)","snPcode":"41409","submissionUrl":"https://mts-bmt.nature.com/cgi-bin/main.plex","title":"Bone Marrow Transplantation","twitterHandle":"@bmtjournal","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"ejp","reportingPortfolio":"Nature AJ","inReviewEnabled":true,"inReviewRevisionsEnabled":false}}],"origin":"","ownerIdentity":"8eb8ab68-e816-4307-88c8-6020ac8f60a7","owner":[],"postedDate":"December 1st, 2024","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"published-in-journal","subjectAreas":[{"id":39735518,"name":"Health sciences/Health care/Paediatrics"},{"id":39735519,"name":"Health sciences/Diseases/Haematological diseases"}],"tags":[],"updatedAt":"2025-04-19T07:08:26+00:00","versionOfRecord":{"articleIdentity":"rs-5309765","link":"https://doi.org/10.1038/s41409-025-02572-8","journal":{"identity":"bone-marrow-transplantation","isVorOnly":false,"title":"Bone Marrow Transplantation"},"publishedOn":"2025-04-18 04:00:00","publishedOnDateReadable":"April 18th, 2025"},"versionCreatedAt":"2024-12-01 16:40:19","video":"","vorDoi":"10.1038/s41409-025-02572-8","vorDoiUrl":"https://doi.org/10.1038/s41409-025-02572-8","workflowStages":[]},"version":"v1","identity":"rs-5309765","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-5309765","identity":"rs-5309765","version":["v1"]},"buildId":"qtupq5eGEP_6zYnWcrvyt","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}