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[Therapeutic efficacy of hematopoietic stem cell transplantation for Wiskott-Aldrich syndrome in 60 children]
Zhou, C., Luo, C. Y., Wang, J. M., Luo, C. J., Qin, X., Huang, X. H., Chen, J.
Zhonghua er ke za zhi = Chinese journal of pediatrics. 2023;61(4):351-356
Abstract
Objective: To evaluate the therapeutic efficacy of hematopoietic stem cell transplantation (HSCT) for Wiskott-Aldrich syndrome (WAS), and to analyze the factors related to the outcomes. Methods: The clinical data of 60 children with WAS received HSCT in Shanghai Children's Medical Center from January 2006 to December 2020 were retrospectively analyzed. All cases were treated with a myeloablative conditioning regimen with busulfan and cyclophosphamide, and a graft-versus-host disease (GVHD) prevention regimen based on cyclosporine and methotrexate. Implantation, GVHD, transplant-related complications, immune reconstitution and survival rate were observed. Survival analysis was performed by Kaplan-Meier method, and Log-Rank method was used for univariate comparison. Results: The 60 male patients had main clinical features as infection and bleeding. The age at diagnosis was 0.4 (0.3, 0.8) years, and the age at transplantation was 1.1 (0.6, 2.1) years. There were 20 cases of human leukocyte antigen matched transplantation and 40 mismatched transplantation; 35 patients received peripheral blood HSCT, and 25 cord blood HSCT. All cases were fully implanted. The incidence of acute GVHD (aGVHD) was 48% (29/60) and only 2 (7%) developed aGVHD of grade Ⅲ; the incidence of chronic GVHD (cGVHD) was 23% (13/56), and all cases were limited. The incidence of CMV and EBV infection was 35% (21/60) and 33% (20/60) respectively; and 7 patients developed CMV retinitis. The incidence of sinus obstruction syndrome was 8% (5/60), of whom 2 patients died. There were 7 cases (12%) of autoimmune hemocytopenia after transplantation. Natural killer cells were the earliest to recover after transplantation, and B cells and CD4(+)T cells returned to normal at about 180 days post HSCT. The 5-year overall survival rate (OS) of this group was 93% (95%CI 86%-99%), and the event free survial rate (EFS) was 87% (95%CI 78%-95%). EFS of non-CMV reactivation group is higher than that of CMV reactivation group (95% (37/39) vs.71% (15/21), χ(2)=5.22, P=0.022). Conclusions: The therapeutic efficacy of HSCT for WAS is satisfying, and the early application of HSCT in typical cases can achieve better outcome. CMV infection is the main factor affecting disease-free survival rate, which can be improved by strengthening the management of complications.
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Heterogeneity in RAG 1/2 Deficiency: 35 Cases From A Single Center
Karaatmaca, B., Cagdas, D., Esenboga, S., Erman, B., Tan, C., Ozgur, T. T., Boztug, K., Van Der Burg, M., Sanal, O., Tezcan, I.
Clinical and experimental immunology. 2023
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Abstract
Recombination activating genes (RAG) 1/2 deficiency leads to combined T/B cell deficiency with varying clinical presentations. This study aimed to define the clinical/laboratory spectrum of RAG1/2 deficiency. We retrospectively reviewed the clinical/laboratory data of 35 patients, grouped them as severe combined immunodeficiency (SCID), Omenn Syndrome (OS), and delayed-onset combined immunodeficiency (CID) and reported nine novel mutations. Male/female ratio was 23/12. Median age of clinical manifestations was 1 months (mo) (0.5-2), 2 mo (1.25-5), and 14 mo (3.63-27), age at diagnosis was 4 mo (3-6), 4.5 mo (2.5-9.75), and 27 mo (14.5-70) in SCID (n=25;71.4%), OS (n=5;14.3%), and CID (n=5;14.3%) patients, respectively. Common clinical manifestations were recurrent sinopulmonary infections 82.9%, oral moniliasis 62.9%, diarrhea 51.4%, and eczema/dermatitis 42.9%. Autoimmune features were present in 31.4% of the patients; 80% was in CID patients. Lymphopenia was present in 92% of SCID, 80% of OS, and 80% of CID patients. All SCID and CID patients had low T (CD3, CD4, and CD8), low B, and increased NK cell numbers. Twenty-eight patients underwent hematopoietic stem cell transplantation (HSCT), whereas seven patients died before HSCT. Median age at HSCT was 7 months (4-13,5). Survival differed in groups; maximum in SCID patients who had an HLA-matched family donor, minimum in OS. Totally 19 (54.3%) patients survived. Early molecular genetic studies will give both individualized therapy options, and a survival advantage because of timely diagnosis and treatment. Further improvement in therapeutic outcomes will be possible if clinicians gain time for HSCT.
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Measuring the effect of newborn screening on survival after haematopoietic cell transplantation for severe combined immunodeficiency: a 36-year longitudinal study from the Primary Immune Deficiency Treatment Consortium
Thakar, M. S., Logan, B. R., Puck, J. M., Dunn, E. A., Buckley, R. H., Cowan, M. J., O'Reilly, R. J., Kapoor, N., Satter, L. F., Pai, S. Y., et al
Lancet (London, England). 2023
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Editor's Choice
Abstract
BACKGROUND Severe combined immunodeficiency (SCID) is fatal unless durable adaptive immunity is established, most commonly through allogeneic haematopoietic cell transplantation (HCT). The Primary Immune Deficiency Treatment Consortium (PIDTC) explored factors affecting the survival of individuals with SCID over almost four decades, focusing on the effects of population-based newborn screening for SCID that was initiated in 2008 and expanded during 2010-18. METHODS We analysed transplantation-related data from children with SCID treated at 34 PIDTC sites in the USA and Canada, using the calendar time intervals 1982-89, 1990-99, 2000-09, and 2010-18. Categorical variables were compared by χ(2) test and continuous outcomes by the Kruskal-Wallis test. Overall survival was estimated by the Kaplan-Meier method. A multivariable analysis using Cox proportional hazards regression models examined risk factors for HCT outcomes, including the variables of time interval of HCT, infection status and age at HCT, trigger for diagnosis, SCID type and genotype, race and ethnicity of the patient, non-HLA-matched sibling donor type, graft type, GVHD prophylaxis, and conditioning intensity. FINDINGS For 902 children with confirmed SCID, 5-year overall survival remained unchanged at 72%-73% for 28 years until 2010-18, when it increased to 87% (95% CI 82·1-90·6; n=268; p=0·0005). For children identified as having SCID by newborn screening since 2010, 5-year overall survival was 92·5% (95% CI 85·8-96·1), better than that of children identified by clinical illness or family history in the same interval (79·9% [69·5-87·0] and 85·4% [71·8-92·8], respectively [p=0·043]). Multivariable analysis demonstrated that the factors of active infection (hazard ratio [HR] 2·41, 95% CI 1·56-3·72; p<0·0001), age 3·5 months or older at HCT (2·12, 1·38-3·24; p=0·001), Black or African-American race (2·33, 1·56-3·46; p<0·0001), and certain SCID genotypes to be associated with lower overall survival during all time intervals. Moreover, after adjusting for several factors in this multivariable analysis, HCT after 2010 no longer conveyed a survival advantage over earlier time intervals studied (HR 0·73, 95% CI 0·43-1·26; p=0·097). This indicated that younger age and freedom from infections at HCT, both directly driven by newborn screening, were the main drivers for recent improvement in overall survival. INTERPRETATION Population-based newborn screening has facilitated the identification of infants with SCID early in life, in turn leading to prompt HCT while avoiding infections. Public health programmes worldwide can benefit from this definitive demonstration of the value of newborn screening for SCID. FUNDING National Institute of Allergy and Infectious Diseases, Office of Rare Diseases Research, and National Center for Advancing Translational Sciences.
PICO Summary
Population
Children with severe combined immunodeficiency (SCID) treated at 34 centres in The Primary Immune Deficiency Treatment Consortium (PIDTC) in the USA and Canada (n=902)
Intervention
Calendar time interval 2010-18 (n=268)
Comparison
Calendar time intervals 1982-89 (n=115), 1990-99 (n=224), 2000-09 (n=268)
Outcome
For 902 children with confirmed SCID, 5-year overall survival remained unchanged at 72%-73% for 28 years until 2010-18, when it increased to 87% (95% CI 82·1-90·6). For children identified as having SCID by newborn screening since 2010, 5-year overall survival was 92·5% (95% CI 85·8-96·1), better than that of children identified by clinical illness or family history in the same interval (79·9% [69·5-87·0] and 85·4% [71·8-92·8], respectively). Multivariable analysis demonstrated that the factors of active infection (hazard ratio [HR] 2·41, 95% CI 1·56-3·72;), age 3·5 months or older at HCT (2·12, 1·38-3·24), Black or African-American race (2·33, 1·56-3·46), and certain SCID genotypes to be associated with lower overall survival during all time intervals. Moreover, after adjusting for several factors in this multivariable analysis, HCT after 2010 no longer conveyed a survival advantage over earlier time intervals studied (HR 0·73, 95% CI 0·43-1·26). This indicated that younger age and freedom from infections at HCT, both directly driven by newborn screening, were the main drivers for recent improvement in overall survival.
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Genotype, Oxidase Status, and Preceding Infection or Autoinflammation Do Not Affect Allogeneic HCT Outcomes for CGD
Leiding, J. W., Arnold, D. E., Parikh, S. H., Logan, B. R., Marsh, R. A., Griffith, L. M., Wu, R., Kidd, S., Mallhi, K. K., Chellapandian, D., et al
Blood. 2023
Abstract
Chronic granulomatous disease (CGD) is a primary immunodeficiency characterized by life-threatening infections and inflammatory conditions. Hematopoietic cell transplantation (HCT) is the definitive treatment for CGD, but questions remain regarding patient selection and impact of active disease on transplant outcomes. We performed a multi-institutional retrospective and prospective study of 391 patients with CGD treated either conventionally (non-HCT;n=151) enrolled from 2004-2018 or who underwent HCT (n=240) from 1996-2018. Median follow-up post-HCT was 3.7 years with a 3-year overall survival of 82% and event-free survival of 69%. In multivariate analysis, Lansky/Karnofsky score <90 and use of HLA-mismatched donors negatively impacted survival. Age, genotype, and oxidase status did not impact outcomes. Pre-HCT, patients had higher infection density, higher frequency of non-infectious lung and liver disease, and more steroid use compared to conventionally-treated patients, yet these issues did not adversely affect HCT survival. Presence of pre-HCT inflammatory conditions was associated with chronic graft versus host disease. Graft failure or receipt of second HCT occurred in 17.6% and was associated with melphalan-based conditioning and/or early mixed chimerism. By 3-5 years post-HCT, patients had improved growth and nutrition, resolved infections and inflammatory disease, and lower rates of anti-microbial prophylaxis or corticosteroid use compared to both their baseline and to conventionally-treated patients. HCT leads to durable resolution of CGD symptoms and lowers burden of disease. Patients with active infection or inflammation are candidates for transplant; HCT should be considered prior to the development of co-morbidities that could impact performance status. Clinical trial # NCT02082353.
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Age Impacts Risk of Mixed Chimerism Following RIC HCT for Non-SCID Inborn Errors of Immunity
Fitch, T., Lane, A., McDonnell, J., Bleesing, J., Jordan, M., Kumar, A., Khandelwal, P., Khoury, R., Marsh, R., Chandra, S.
Transplantation and cellular therapy. 2023
Abstract
BACKGROUND Alemtuzumab, fludarabine and melphalan containing reduced intensity conditioning (RIC) is commonly used in patients undergoing allogeneic hematopoietic cell transplantation (HCT) for definitive treatment of high-risk inborn errors of immunity (IEI). Although survival is favorable, there is increased risk of mixed chimerism leading to secondary graft failure. OBJECTIVES Evaluate factors associated with risk of developing mixed chimerism, particularly the influence of age in patients undergoing allogeneic HCT for non-SCID IEI who received a uniform RIC regimen that included intermediate schedule alemtuzumab, fludarabine and melphalan. We hypothesized that age would impact incidence of mixed chimerism. STUDY DESIGN We retrospectively reviewed records of patients who underwent HCT for non-SCID IEIs with a uniform RIC regimen that included intermediate schedule alemtuzumab (1 mg/kg divided over days -14 to - 10), fludarabine (150 mg/m2 or 5 mg/kg if weight <10 kg divided over days -9 to -4), and melphalan (140 mg/m2 or 4.7 mg/kg if weight <10 kg on day-3) between 2010 and 2020 at our institution. Mixed chimerism was defined as <95% donor on 2 or more consecutive occasions on whole blood. RESULTS Ninety-three patients who underwent RIC-HCT for non-SCID IEI using intermediate schedule alemtuzumab, fludarabine, and melphalan were evaluated and categorized into 3 groups: <1, 1-5, and > 5 years of age. Forty-nine patients (52.7%) developed mixed chimerism at a median of 34 days post-HCT (range, 10-1396 days). Mixed chimerism developed in 88.9 % (n=16/18) for <1 year, 57.1% (n=20/35) for 1-5 years, and 35% (n=14/40) for those >5 years. Patients <5 years of age were significantly more likely to develop mixed chimerism (X(2) (3, N = 93) = 14.8, p =0.001). We observed a significantly increased cumulative incidence of developing mixed chimerism if < 1 year of age (p=0.0002). Competing risk regression analysis demonstrated an increase in odds of development of mixed chimerism for age <1 (OR 3.72, p = 0.006, 95% CI 1.46-19.46) compared to age >5 years and decrease in odds of mixed chimerism in patients who developed acute GVHD prior to any intervention (OR 0.24, p=0.005, 95% CI 0.09-0.65) There was no significant association between mixed chimerism and graft source, graft type, CD34+ or CD3+ cell dose, HLA match or underlying disease (HLH vs non-HLH). Additionally, the need for secondary intervention was evaluated; 27 patients (29.0%) required one or more secondary intervention(s) (DLI, CD34 Boost, or second HCT). Patients <1 year of age with mixed chimerism were significantly more likely to require secondary intervention for mixed chimerism than patients > 5 years (p =0.004). CONCLUSION Our study demonstrates that young age <5 years, especially age <1 year is associated with an increased risk of developing mixed chimerism in patients undergoing RIC-HCT for non-SCID IEI using intermediate schedule alemtuzumab, fludarabine, and melphalan. Our data suggest tailoring regimen intensity based on age to reduce the incidence of mixed chimerism. Children <5 years, particularly those <1 year of age, require a higher intensity regimen. Possible strategies include adding thiotepa or using a busulfan-based reduced toxicity regimen.
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Haematopoietic Stem Cell Transplantation (HSCT) for Primary Immune System Disorders in Children: A Single Centre Experience
Kerio, A. A., Khattak, T. A., Ghafoor, T., Yousaf, M., Shahbaz Br, N., Chaudary, Q. U. N.
Journal of the College of Physicians and Surgeons--Pakistan : JCPSP. 2023;33(3):341-345
Abstract
OBJECTIVE To determine the outcomes of allogeneic HSCT in children with primary immune system disorders (PID). STUDY DESIGN Descriptive Cross-sectional study. Place and Duration of the Study: Armed Forces bone marrow transplant centre / National Institute of Bone Marrow Transplant (AFBMTC / NIBMT), Rawalpindi, Pakistan, from October 2012 to December 2021. METHODOLOGY Data of all cases undergoing HSCT for immune system disorders were analysed for variables affecting outcome and overall survival in the first 180 days after allogeneic HSCT. All patients presenting to AFBMTC / NIBMT with PID, age <12 years. Patients with organ dysfunction secondary to repeated infections were excluded from the study. Data of all patients and their donors undergoing HSCT for immune system disorders were analysed for variables affecting outcome and overall survival in the first 180 days after allogeneic bone marrow transplant. Neutrophil engraftment was defined as absolute neutrophil count ≥0.5 × 109/L for 3 consecutive days, while platelet engraftment as platelet count ≥20 × 109/L without platelet transfusion for one week. Overall survival (OS) was taken as time from the date of HSCT till day + 180 post-transplant. RESULTS A total of 42children including 29 boys and 13 girls underwent HSCT for PID. The mean age was 2.1±2.8 years. Underlying diagnosis was haemophagocytic lymphohistiocytosis (HLH), severe immune deficiency (SCID), leukocyte adhesion defect (LAD), X-linked agammaglobulinemia, chronic granulomatous disease (CGD) and Job's syndrome in 18 (42.9%), 16 (38.1%), 3(7.1%), 2 (4.8%), 2 (4.8%) and 1 (2.4%) patients respectively. Thirty-one (73.8%) children had fully HLA-matched donors while 11 (26.2%) had haplo-matched donors. Major immediate post-transplant complications were febrile neutropenia, mucositis and SOS/VOD in 31 (73.8%), 9 (21.4%) and 4 (10.0%) cases, respectively. Eight (19.0%) had CMV reactivation, acute GVHD was seen in 17 (40.4%) cases, while 1 (2.3%) case had chronic GVHD. Twelve (28.6%) patients died, out of which 5 had graft failure, 3 had VOD, 2 had pneumonia, 1 had severe GVHD, and 1 died due to seizures. Overall survival (OS) in this study was 71.4% with survival reaching up to 80.6% in fully matched HSCT. CONCLUSION HLH and SCID were the commonest immune disorders requiring HSCT. Graft failure leading to neutropenic sepsis was the commonest cause of mortality. OS was better in fully matched HSCT as compared to haplo-identical HSCT. KEY WORDS Immune deficiency, Severe combined immunodeficiency, Haematopoietic stem cell transplantation.
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The research on the treatment of primary immunodeficiency diseases by hematopoietic stem cell transplantation: A bibliometric analysis from 2013 to 2022
Hu, S., Xu, S., Lu, W., Si, Y., Wang, Y., Du, Z., Wang, Y., Feng, Z., Tang, X.
Medicine. 2023;102(13):e33295
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Abstract
Hematopoietic stem cell transplantation (HSCT) is curative in patients with primary immunodeficiency syndrome. The safety and efficacy of HSCT as a therapeutic option for primary immunodeficiency diseases (PID) have been studied by many research groups. The purpose of our study was to perform a bibliometric analysis of research on HSCT for the treatment of PID, to assess research trends in this field, and note future research priorities. The Web of Science Core Collection (WOSCC) was used to identify relevant publications. VOSviewer and CiteSpace software were used to analyze bibliometric parameters, such as yearly records, authors, grouped authors, countries, institutions, categories and keywords. There are 602 relevant records for the last decade (2013-2022). The top 5 productive authors and high-quality paper journals are listed. Reference co-citations analysis demonstrated recent research trends were "inborn errors of immunity," "gene editing," and "enteropathy." Research on HSCT for the treatment of PID has increased rapidly in the last decade, and bibliometrics are valuable for researchers to obtain an overview of hot categories, academic collaborations and trends in this study field.
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Safety and Efficacy of Hizentra® Following Pediatric Hematopoietic Cell Transplant for Treatment of Primary Immunodeficiencies
Patel, N. C., Torgerson, T., Thakar, M. S., Younger, M. E. M., Sriaroon, P., Pozos, T. C., Buckley, R. H., Morris, D., Vilkama, D., Heimall, J.
Journal of clinical immunology. 2023
Abstract
Primary immunodeficiency disease (PIDD) comprises a group of disorders of immune function. Some of the most severe PIDD can be treated with hematopoietic cell transplant (HCT). Hizentra® is a 20% liquid IgG product approved for subcutaneous administration in adults and children greater than 2 years of age with PIDD-associated antibody deficiency. Limited information is available on the use of Hizentra® in children following HCT for PIDD. A multicenter retrospective chart review demonstrated 37 infants and children (median age 70.1 [range 12.0 to 176.4] months) with PIDD treated by HCT who received Hizentra® infusions over a median duration of 31 (range 4-96) months post-transplant. The most common indication for HCT was IL2RG SCID (n = 16). Thirty-two patients switched from IVIG to SCIG administration, due to one or more of the following reasons: patient/caregiver (n = 17) or physician (n = 12) preference, discontinuation of central venous catheter (n = 16), desire for home infusion (n = 12), improved IgG serum levels following lower levels on IVIG (n = 10), and loss of venous access (n = 8). Serious bacterial infections occurred at a rate of 0.041 per patient-year while on therapy. Weight percentile increased by a mean of 16% during the observation period, with females demonstrating the largest gains. Mild local reactions were observed in 24%; 76% had no local reactions. One serious adverse event (death from sepsis) was reported. Hizentra® was discontinued in 15 (41%) patients, most commonly due to recovery of B cell function (n = 11). These data demonstrate that Hizentra® is a safe and effective option in children who have received HCT for PIDD.
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The Effect of Early BCG-Vaccination of SCID Pediatric Patients on the Outcome of Hematopoietic Stem Cell Transplantation Using Reduced Conditioning Regimen
Hamidieh, A. A., Jafari, L., Behfar, M., Karamlou, Y., Shamsipour, M., Mohseni, R., Farajifard, H., Salajegheh, P.
Transplantation and cellular therapy. 2022
Abstract
BACKGROUND The eminence of Bacillus Calmette-Guerin (BCG) vaccine in the vaccination program of newborns, especially in low-income developing countries where tuberculosis is prevalent, has been conspicuous throughout the years; however, the application of the aforementioned vaccine is not without constraints, especially in patients afflicted with immunodeficiency diseases, such as Severe Combined Immunodeficiency (SCID). OBJECTIVE The desideratum of this study is to evaluate whether or not the administration of BCG vaccine upon birth could attenuate the success of hematopoietic stem cell transplantation (HSCT) in SCID pediatric patients STUDY DESIGN In the current study, 30 SCID patients who underwent HSCT using reduced intensity conditioning regimen (RIC) were followed-up for 2 years post-HSCT. The outcome of HSCT was evaluated in both non-BCG-vaccinated (12 patients) and BCG-vaccinated (18 patients) groups. RESULTS Our results demonstrated that patients who had been BCG vaccinated displayed higher incidences of acute GvHD (aGvHD); however, the incidence of chronic GvHD did not differ between the two groups. The overall survival (OS) rate in patients who received the BCG vaccine was similar than their non-vaccinated counterparts. We speculate that the reason that BCG-vaccinated individuals' survival rate, despite having the risk factor of being BGC-vaccinated, was similar to the non-BCG-vaccinated group was due to the fact that they received RIC as their conditioning regimen. CONCLUSION The result of our study indicated that early BCG vaccination was associated with a higher risk of aGVHD. Additionally, the OS of BCG-vaccinated patients was similar in comparison to their non-vaccinated counterparts; alluding to the possibility that the same RIC regimen might be the reason for such outcome, since no other variation between the two groups existed. Regarding to the BCG vaccine affect the outcome of HSCT, we suggest that the administration of BCG vaccine should be deferred until three months of age so that apt testing, without the interference of maternal antibodies, could be performed; however, it is noteworthy that this study could benefit from a bigger cohort in order to further validate the outcome, as the possible reason for some factors not becoming statistically significant was the small sample size of this study.
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Hematopoietic Cell Transplantation for Adenosine Deaminase Severe Combined Immunodeficiency-Improved Outcomes in the Modern Era
Ghimenton, E., Flinn, A., Lum, S. H., Leahy, T. R., Nademi, Z., Owens, S., Williams, E., Flood, T., Hambleton, S., Slatter, M., et al
Journal of clinical immunology. 2022;42(4):819-826
Abstract
Current treatment for adenosine deaminase (ADA)-deficient severe combined immunodeficiency (SCID) includes enzyme replacement therapy (ERT), allogeneic hematopoietic stem cell transplant (HSCT), or ex vivo corrected autologous hematopoietic stem cell gene therapy. Historic data show HSCT survival is superior using unconditioned matched sibling and family compared to matched unrelated and haploidentical donors. Recent improvement in HSCT outcomes prompted us to retrospectively examine HSCT survival and long-term graft function in ADA-SCID transplanted at our center. Thirty-three ADA-deficient patients received HSCT between 1989 and 2020, with follow-up data to January 2021. Chemotherapy conditioning regimens were defined as myeloablative (MAC-busulfan/cyclophosphamide), reduced-toxicity myeloablative (RT-MAC-treosulfan-based, since 2007), or no conditioning. Serotherapy used included alemtuzumab (with or without other conditioning agents) or antithymocyte globulin (ATG). ERT was introduced routinely in 2010 until commencement of conditioning. Median age at HSCT was 3.2 (0.8-99.8) months. Twenty-one (63.6%) received stem cells from unrelated or haploidentical donors. Seventeen (51.5%) received chemotherapy conditioning and 16 (48.5%) received alemtuzumab. Median follow-up was 7.5 (0.8-25.0) years. Overall survival (OS) and event-free survival (EFS) at 8 years were 90.9% (95% CI: 79.7-100.0%) and 79% (55-91%), respectively. OS after 2007 (n = 21) was 100% vs 75% before 2007 (n = 12) (p = 0.02). Three (9.1%) died after HSCT two from multiorgan failure and one from unexplained encephalopathy. There were no deaths after 2007, among those who received ERT and treosulfan-based conditioning pre-HSCT. Ten (30.3%) developed acute GvDH (3 grade II, 2 grade III); no chronic GvHD was observed. In the modern era, conditioned HSCT with MUD has a favorable outcome for ADA-deficient patients.