Translational and clinical immunology Hematopoietic cell transplantation in severe combined immunodeficiency: The SCETIDE 2006-2014 European cohort Arjan C. Lankester, MD, PhD,a Benedicte Neven, MD, PhD,b,c,d Nizar Mahlaoui, MD, PhD,e Erik G. J. von Asmuth, MD,a Virginie Courteille,e Mikael Alligon,e Michael H. Albert, MD, PhD,f Isabelle Badell Serra, MD,g Peter Bader, MD, PhD,h Dmitry Balashov, MD,i Rita Beier, MD,j Yves Bertrand, MD, PhD,k Stephane Blanche, MD, PhD,b Victoria Bordon, MD, PhD,l Robbert G. Bredius, MD, PhD,a Andrew Cant, MD,m Marina Cavazzana, MD, PhD,c,n,o,p Cristina Diaz-de-Heredia, MD,q Figen Dogu, MD,r Karoline Ehlert, MD,s,t Natacha Entz-Werle, MD, PhD,u Anders Fasth, MD, PhD,v Francesca Ferrua, MD, PhD,w Alina Ferster, MD,x Renata Formankova, MD, PhD,y Wilhelm Friedrich, MD, PhD,z Marta Gonzalez-Vicent, MD, PhD,aa Jolanta Gozdzik, MD, PhD,bb Tayfun Gu € ngo€ r, MD, PhD,cc Manfred Hoenig, MD, PhD,z Aydan Ikinciogullari, MD,r Krzysztof Kalwak, MD, PhD,dd Savas Kansoy, MD, PhD,ee Alphan Kupesiz, MD, PhD,ff Arnalda Lanfranchi, MD,gg Caroline A. Lindemans, MD, PhD,hh,ii Roland Meisel, MD, PhD,jj Gerard Michel, MD, PhD,kk Nuno A. A. Miranda, MD,ll Jose Moraleda, MD, PhD,mm Despina Moshous, MD, PhD,b,c,p Herbert Pichler, MD,nn Kanchan Rao, MD,oo Petr Sedlacek, MD, PhD,y Mary Slatter, MD, PhD,m Elena Soncini, MD,pp Carsten Speckmann, MD,qq Mikael Sundin, MD, PhD,rr Amos Toren, MD, PhD,ss Kim Vettenranta, MD, PhD,tt Austen Worth, MD, PhD,oo Mehmet A. Yes‚ilipek, MD, PhD,uu Marco Zecca, MD,vv Fulvio Porta, MD,pp Ansgar Schulz, MD, PhD,z Paul Veys, MD,oo Alain Fischer, MD, PhD,b,c and Andrew R. Gennery, MD, PhDm Leiden and Utrecht, The Netherlands; Paris, Lyon, Strasbourg, and Marseille, France; Munich, Frankfurt, Hannover, M€ unster, Greifswald, Ulm, D€usseldorf, and Freiburg, Germany; Barcelona, Madrid, and Murcia, Spain; Moscow, Russia; Ghent, Belgium; Newcastle upon Tyne and London, United Kingdom; Ankara, Izmir, and Antalya, Turkey; Gothenburg, Sweden; Milan, Brescia, and Pavia, Italy; Brussels, Belgium; Prague, Czech Republic; Krakow and Wroclaw, Poland; Zurich, Switzerland; Lisbon, Portugal; Vienna, Austria; Stockholm, Sweden; Tel-Hashomer, Israel; and Helsinki, Finland Background: Hematopoietic stem cell transplantation (HSCT) Objective: We performed a comprehensive multicenter analysis represents a curative treatment for patients with severe of genotype-specific HSCT outcome, including detailed analysis combined immunodeficiency (SCID), a group of monogenic of immune reconstitution (IR) and the predictive value for immune disorders with an otherwise fatal outcome. clinical outcome. From athe Pediatric Stem Cell Transplantation Program and Laboratory for Pediatric Transplantation, Hospital Universitario Vall d’Hebron, Barcelona; rthe Department Immunology, Willem-Alexander Children’s Hospital, Leiden University Medical of PIA and the BMT Unit, Ankara University, Ankara; sthe Department of Pediatric Center, Leiden; bthe Unite d’Immuno-hematologie et Rhumatologie Pediatrique, Hematology and Oncology, Universit€atsklinikum M€unster, M€unster; tthe Department H^opital Universitaire Necker-Enfants Malades, Assistance Publique-H^opitaux de of Pediatric Hematology and Oncology, University of Greifswald, Greifswald; uthe Pe- Paris (AP-HP), Paris, France; cthe Universite de Paris, Paris; dthe Institut Imagine, IN- diatric Onco-hematology Department–Pediatrics III, University Hospital of Stras- SERM UMR1163, Laboratory of Immunogenetics of Pediatric Autoimmune Diseases, bourg, Strasbourg; vthe Department of Pediatrics, Institute of Clinical Sciences, Paris; ethe French National Reference Center for Primary Immunodeficiencies (CER- University of Gothenburg, Gothenburg; wthe Pediatric Immunohematology and EDIH) and European Registry for Stem Cell Transplantation for Primary Immunode- Bone Marrow Transplantation Unit and the San Raffaele Telethon Institute for Gene ficiencies (SCETIDE), H^ opital Universitaire Necker-Enfants malades, Assistance Therapy (SR-Tiget), IRCCS San Raffaele Scientific Institute, Milan; xthe Department Publique-H^ opitaux de Paris (AP-HP), Paris; fDr von Haunersches University Chil- of Hemato-oncology, H^opital Universitaire des Enfants Reine Fabiola, Brussels; ythe g dren’s Hospital, Munich; the Hospital Clınic, Sant Creu i Sant Pau Hospital, Bone Department of Pediatric Hematology and Oncology, Teaching Hospital Motol, 2nd Marrow Transplantation Unit, Barcelona; hthe Department for Children and Adoles- Medical School, Charles University Motol, Prague; zthe Department of Pediatrics, cents Medicine, Division for Stem Cell Transplantation and Immunology, University University Medical Center Ulm, Ulm; aathe Hematopoietic Stem Cell Transplantation Hospital Frankfurt, Frankfurt; ithe Department for Hematopoietic Stem Cell Trans- and Cellular Therapy Unit, Hospital Infantil Universitario ‘‘Ni~no Jesus,’’ Madrid; bbthe plantation, Dmitriy Rogachev National Center for Pediatric Hematology, Oncology Department of Clinical Immunology and Transplantation, Jagiellonian University and Immunology, Moscow; jthe Klinik f€ur P€adiatrische H€amatologie und Onkologie, Medical College, Krakow; ccthe Department of Hematology, Oncology, Immunology, Hannover Medical School, Hannover; kthe Institut d’Hematologie et d’Oncologie Gene Therapy and Stem Cell Transplantation, and Children’s Research Center (CRC), Pediatrique, Hospices Civils de Lyon and Universite Claude Bernard Lyon 1, Lyon; University Children’s Hospital, Zurich; ddthe Department of Pediatric Hematology, l the Department of Pediatric Hemato-oncology and Stem Cell Transplant, Ghent Uni- Oncology, and BMT, Wroclaw Medical University, Wroclaw; eethe Department of Pe- versity Hospital, Ghent; mthe Translational and Clinical Research Institute, Newcastle diatric Hematology and Oncology, Ege University Hospital, Izmir; ffthe Department of University, and the Paediatric Haematopoietic Stem Cell Transplant Unit, Great North Pediatrics, Hematology, and Oncology, Akdeniz University School of Medicine, Ant- Children’s Hospital, Newcastle upon Tyne; nthe Paris Biotherapy Department, Necker alya; ggthe Diagnostic Department, Stem Cell Laboratory, Section of Hematology and Children’s Hospital Assistance, and othe Biotherapy Clinical Investigation Center, Blood Coagulation, Clinical Chemistry Laboratory, ASST Spedali Civili, Brescia; Assistance Publique Hopitaux de Paris, INSERM, Paris; pthe Laboratory of Genomic hh the Department of Stem Cell Transplantation, Princess Maxima Center for Pediatric Dynamics in the Immune System, Institut Imagine, INSERM UMR1163, Paris; qthe Oncology, Utrecht; iithe Department of Pediatrics, University Medical Center Utrecht, Department of Pediatric Oncology and Hematology, and Hematopoietic Stem Cell University of Utrecht, Utrecht; jjthe Department of Pediatric Oncology, Hematology, 1744 J ALLERGY CLIN IMMUNOL LANKESTER ET AL 1745 VOLUME 149, NUMBER 5 Methods: HSCT outcome was studied in 338 patients with genetically confirmed SCID who underwent transplantation in Abbreviations used 2006-2014 and who were registered in the SCETIDE registry. In ADA: Adenosine deaminase a representative subgroup of 152 patients, data on IR and long- BM: Bone marrow term clinical outcome were analyzed. CI: Confidence interval EFS: Event-free survival Results: Two-year OS was similar with matched family and GvHD: Graft-versus-host disease unrelated donors and better than mismatched donor HSCT HSCT: Hematopoietic stem cell transplantation (P < .001). The 2-year event-free survival (EFS) was similar in IL2Rg: IL-2 receptor gamma chain matched and mismatched unrelated donor and less favorable in IL7R: IL-7 receptor mismatched related donor (MMRD) HSCT (P < .001). Genetic IR: Immune reconstitution subgroups did not differ in 2-year OS (P 5 .1) and EFS JAK3: Janus kinase 3 (P 5 .073). In multivariate analysis, pretransplantation infections MAC: Myeloablative conditioning and use of MMRDs were associated with less favorable OS and (M)MD: (Mis)matched donor EFS. With a median follow-up of 6.2 years (range, 2.0-11.8 years), (M)MRD: (Mis)matched related donor 73 of 152 patients in the IR cohort were alive and well without Ig (M)MUD: (Mis)matched unrelated donor MSD: Matched sibling donor dependency. IL-2 receptor gamma chain/Janus kinase 3/IL-7 OS: Overall survival receptor–deficient SCID, myeloablative conditioning, matched RAG: Recombinase activating gene donor HSCT, and naive CD4 T lymphocytes >0.5 3 10e3/mL SCETIDE: Stem Cell Transplant in Primary Immune Deficiency in at 11 year were identified as independent predictors of favorable Europe clinical and immunologic outcome. SCID: Severe combined immunodeficiency Conclusion: Recent advances in HSCT in SCID patients have resulted in improved OS and EFS in all genotypes and donor types. To achieve a favorable long-term outcome, treatment strategies should aim for optimal naive CD4 T lymphocyte regeneration. (J Allergy Clin Immunol 2022;149:1744-54.) improved over time, mostly as a result of our better understanding of the biology of SCID, improvements in supportive care, advances Key words: SCID, genetic subgroups, conditioning, pretransplanta- in HLA typing technology, expanded donor sources, optimization of tion infections, immune reconstitution conditioning regimens, and graft manipulation to limit transplant- related toxicity and prevent graft-versus-host disease (GvHD).4-8 In that context, the quality of survival from a clinical and immuno- Severe combined immunodeficiency (SCID) is a group of logic perspective has become increasingly important. Previous inherited conditions typically defined by lack of T lymphocytes single-center and multicenter reports have pointed to the effect of resulting from an intrinsic T lymphocyte differentiation defect SCID type, donor type, and conditioning on overall survival (OS), associated or not with lack of B lymphocyte and/or natural killer cell immune reconstitution (IR), and clinical outcome.7,9-11 differentiation, depending on the underlying monogenic defect.1 We here report the transplant outcome in a cohort of 338 Untreated, SCID is usually fatal in the first year of life as a result genetically defined SCID patients transplanted in European of life-threatening infections. Five decades ago, the curative poten- centers between 2006 and 2014 as registered in the SCETIDE tial of allogeneic hematopoietic stem cell transplantation (HSCT) database. The availability of HLA high-resolution DNA typing was first demonstrated in SCID patients,2,3 and since then, the data plus a genetic diagnosis in all patients for the first time Stem Cell Transplant in Primary Immune Deficiency in Europe permitted comprehensive subgroup analysis. In addition, detailed (SCETIDE) registry has collected data on more than 1500 trans- longitudinal IR and clinical outcome data were studied in a planted SCID patients. Survival of transplanted SCID patients has representative subgroup of 152 SCID patients. and Clinical Immunology, Medical Faculty, Division of Pediatric Stem Cell Therapy, considered senior author. Heinrich-Heine-University, D€usseldorf; kkthe Service d’Hematologie Immunologie E. G. J. von Asmuth received support from the Dutch Rare Disease Foundation/Stichting Oncologie Pediatrique, CHU La Timone, Marseille; llthe BMT Unit, Instituto Zeldzame Ziekten Fonds. Portugu^es de Oncologia de Lisboa, Lisbon; mmthe Department of Hematology and He- Disclosure of potential conflict of interest: The authors declare that they have no relevant motherapy, Hospital Virgen de la Arrixaca-IMIB, Murcia; nnthe Department of Stem conflicts of interest. Cell Transplantation, Children’s Cancer Institute, St Anna Hospital, Vienna; oothe Received for publication June 23, 2021; revised October 14, 2021; accepted for publica- Great Ormond Street (GOS) Hospital for Children NHS Foundation Trust and Univer- tion October 20, 2021. sity College London GOS Institute of Child Health, London; ppthe Pediatric Oncohae- Available online October 27, 2021. matology and BMT Unit, Children’s Hospital Brescia, Brescia; qqthe Department of Corresponding author: Arjan C. Lankester, MD, PhD, Willem-Alexander Children’s Pediatric Hematology and Oncology, Center for Pediatrics and Adolescent Medicine, Hospital, Pediatric Stem Cell Transplantation Program and Laboratory for Pediatric and Institute for Immunodeficiency, Center for Chronic Immunodeficiency (CCI), Fac- Immunology, Leiden University Medical Center, Albinusdreef 2, 2300RC, Leiden, ulty of Medicine, Medical Center, University of Freiburg, Freiburg; rrthe Section of Pe- The Netherlands. E-mail: a.lankester@lumc.nl. diatric Hematology, Immunology, and HCT, Astrid Lindgren Children’s Hospital, The CrossMark symbol notifies online readers when updates have been made to the Karolinska University Hospital, and Division of Pediatrics, CLINTEC, Karolinska In- article such as errata or minor corrections stitutet, Stockholm; ssPaediatric Hemato-oncology and BMT, Sheba Medical Center, 0091-6749 Tel-Hashomer; ttthe University of Helsinki and Children’s Hospital, University of Hel- Ó 2021 The Authors. Published by Elsevier Inc. on behalf of the American Academy of sinki, Helsinki; uuthe Pediatric Hematology, Oncology, and Pediatric Stem Cell Trans- Allergy, Asthma & Immunology. This is an open access article under the CC BY li- plantation Unit, Medicalpark Antalya & G€oztepe Hospitals, Antalya; and vvPediatric cense (http://creativecommons.org/licenses/by/4.0/). Hematology/Oncology, Fondazione IRCCS Policlinico San Matteo, Pavia. https://doi.org/10.1016/j.jaci.2021.10.017 The first 2 authors contributed equally to this article, and both should be considered first author. The last 2 authors contributed equally to this article, and both should be 1746 LANKESTER ET AL J ALLERGY CLIN IMMUNOL MAY 2022 METHODS we used the Kaplan-Meier estimator to determine event-free survival (EFS), with an event defined as either a second HSCT, boost, or death. Overall Study population survival (OS) and EFS were determined at 1, 2, and 8 years after HSCT. All P The study population consisted of 338 genetically defined SCID patients values were considered statistically significant when below .05. We used R who received transplants between 2006 and 2014, and whose cases were 4.0.2 statistical software (https://www.r-project.org/). IR was investigated reported to the SCETIDE registry. This cohort of 338 patients represented by visualizing cell counts split by diagnosis, conditioning, donor relation, 79% of the overall group of 429 transplanted patients registered as SCID in the and outcome; relevant categories were compared by chi-square test for cate- 2006-2014 period transplanted in 43 centers. This well-characterized and gorical effects, Fisher exact test if a cell count was less than 5, and well-documented cohort was used to avoid bias by patients with atypical SCID Wilcoxon-Mann-Whitney test for continuous effects. To investigate the ef- and uncertain diagnoses. Clinical and laboratory data were collected after fects of outcome on the basis of total and naive CD4 counts in a multivariate receipt of informed consent of the parents/caregivers. SCID patients were context, we used logistic regression. defined as follows: typical SCID: genetically confirmed IL-2 receptor gamma chain (IL2Rg), Janus kinase 3 (JAK3), or IL-7 receptor deficiency, recombi- nase activating gene (RAG) 1, RAG2, or DCLRE1C deficiency, or adenosine deaminase (ADA) deficiency; all patients were diagnosed before the age of 1 RESULTS year and received a transplant before the age of 15 months; and other SCID: Similar OS and EFS in different SCID genotypes patients with PNP, RMRP, ZAP70, LIG1, LIG4, XLF, AK2, and CD3 defi- In this cohort of 338 genetically defined SCID patients (Table I), ciency diagnosed before the age of 1 year with CD31 T lymphocytes of OS was 83.6% and 81.1% at 1 and 2 years, respectively, and 75.8% <300 cells/mL and received a transplant before the age of 15 months. None of the SCID patients was diagnosed by newborn screening programs. at LFU (median, 4.5 years; range, 0.16-11.8 years). In the major ge- Patients with Omenn syndrome (70 in this study period) were excluded from notype specific groups, 2-year OS was 85.7% in ADA (n 5 32), this study because it is a distinct entity with respect to clinical manifestations 87.1% in IL2Rg (n 5 87), 84.0% in JAK3 (n 5 19), and 64.6% and treatment requirements. in IL-7 receptor (IL7R)-deficient SCID (n 5 12), while 2-year OS in RAG1/2 (n 5 53) and DCLRE1C-deficient SCID (n 5 26) Data and definitions was 79.7% and 79.4%, respectively (not significant). The 2-year Pretransplantation active infections were defined as mycobacterial infec- OS of the pooled IL2Rg-JAK3-IL7R–deficient (previously known tion, symptomatic bacillus Calmette-Guerin–itis, and respiratory viral as T2/B1) SCID patients (83.6%; 95% confidence interval [CI], (excluding rhinovirus) and systemic viral infections. Conditioning regimens 78.0-89.7), RAG1/2- and DCLRE1C-deficient (T2/B2) SCID pa- were classified as none/serotherapy only, myeloablative conditioning tients (79.8%; 95% CI, 72.5-87.7), ADA-deficient patients (MAC) with busulfan > _8 mg/kg and treosulfan > _30 g/m2 total dose, mostly (85.7%; 95% CI, 75.8-97.0), and the minor ‘‘other’’ subgroup combined with either cyclophosphamide (200 mg/kg) or fludarabine (150 (64.3%; 95% CI, 48.7-84.7) showed no significant differences mg/m2), and reduced-intensity conditioning using lower doses of the afore- (Fig 1, A; P 5 .1). EFS in the overall cohort at 1 and 2 years and mentioned chemotherapy combinations or fludarabine/melphalan. Serother- LFU was 77.6%, 74.0%, and 67.9%, respectively. In this cohort, apy included anti-thymocyte globulin or alemtuzumab. Donor type and 37 patients received a second transplant, and 14 patients received HLA matching were categorized as matched sibling donor (MSD), matched related donor (MRD), matched unrelated donor (MUD; 10/10 or 8/8 in case a stem cell boost. The 2-year EFS was similar in ADA-deficient of unrelated donor, and 6/6 in case of cord blood), mismatched unrelated donor (78.4%; 95% CI, 66.8-91.9), IL2Rg-JAK3-IL7R–deficient (MMUD), and mismatched related donor (MMRD). Stem cell sources (77.7%; 95% CI, 71.3-84.6), RAG1/2-DCLRE1C–deficient included bone marrow (BM), mobilized peripheral blood, and umbilical (71.4%; 95% CI, 63.4-80.5), and the group of ‘‘other’’ SCID cord blood. Detailed information on clinical problems and sequelae was (57.1%; 95% CI, 41.4-78.7) patients (Fig 1, B; P 5 .073). collected with a specific questionnaire via the SCETIDE office in a represen- tative subgroup of patients from centers with more than 10 patients trans- planted over the study period with at least 2 years’ follow-up (Table I). The Impact of donor type on overall and EFS posttransplantation events and complications used for the assessment of ‘‘alive Two-year OS was similar with MSD (n 5 64; 91.9%), MRD and well’’ included the following: invasive/chronic infections, chronic GvHD, (n 5 36; 91.7%), and MUD (n 5 66; 87.9%, Fig E1, A, in this ar- pulmonary disease, liver disease, renal disease, endocrine dysfunction, nutri- ticle’s Online Repository available at www.jacionline.org). OS tional deficiency with support, and autoimmunity. Sequelae were defined as with these matched donors (MD) was superior to MMUD (n 5 neurocognitive and motor impairment, growth retardation, orthopedic prob- 56) and MMRD (n 5 116) with 2-year OS of 90.2%, 76.7%, lems, hearing loss, and sequelae from infections that occurred before HSCT. and 70.3%, respectively; Fig 1, C; P < .001). However, 2-year EFS was similar with MD (2-year EFS 82.6%; 95% CI, 77.0- Immune reconstitution 88.7) and MMUD (2-year EFS 75.0%; 95% CI, 64.5-87.2), while Data on absolute numbers of CD31/CD41, CD31/CD81 T lymphocytes, it was less favorable with MMRD (2-year EFS 61.6%; 95% CI, NK cells (CD32/CD161 and/or CD561), naive CD4 T lymphocytes, and Ig 53.3-71.2; Fig 1, D; P < .001). replacement therapy were collected at 11 year, 12 years, and last follow- Donor-related OS and EFS were analyzed in the 3 genetic _3 years after stem cell transplantation). Naive CD4 T lymphocytes up (LFU) (> subgroups. In the MD group, 2-year OS in ADA-deficient (n 5 were defined as CD41/CD45RA1/CCR71, CD41/CD45RA1/CD271, or 33), IL2Rg-JAK3-IL7R–deficient (n 5 70), and RAG- CD41/CD45RA1/CD311. DCLRE1C–deficient (n 5 53) SCID patients was 90.7%, 89.9%, and 92.4%, respectively (not significant). In mismatched Statistical analyses donor (MMD) transplants in IL2Rg-JAK3-IL7R–deficient SCID We used median (minimum, maximum) to display descriptive variables for patients, a similar 2-year OS was reported for MMUD (n 5 25) continuous quantitative variables. Survival probabilities were estimated by the and MMRD (n 5 60), with 80% and 78.2%, respectively (not sta- Kaplan-Meier method. The log-rank test was applied to compare survival tistically significant). In contrast, in the group of RAG- probabilities between groups. A semiparametric Cox regression model DCLRE1C–deficient patients, 2-year OS was significantly better approach was used to identify independent risk factors associated with when using MMUD (n 5 17) compared to MMRD (n 5 42), with outcome after the first HSCT using stepwise backward selection. In particular, 81.9% and 63.3%, respectively (P 5 .02). The number of ADA J ALLERGY CLIN IMMUNOL LANKESTER ET AL 1747 VOLUME 149, NUMBER 5 TABLE I. Overview of 338 subjects comprising the SCID cohort TABLE I. (Continued) SCID cohort IR subcohort SCID cohort IR subcohort Total (n 5 338) (n 5 152) Total (n 5 338) (n 5 152) Demographics Busulfan–cyclophosphamide 30 (18) 13 (17) Sex Busulfan–fludarabine 40 (25) 21 (28) Female 113 (33) 45 (30) Treosulfan–cyclophosphamide 16 (10) 8 (11) Male 225 (67) 107 (70) Treosulfan–fludarabine 59 (36) 31 (41) Age at diagnosis (years), 0.33 (0-1) 0.29 (0-0.75) Other 18 (11) 3 (4) median (min-max) Reduced-intensity conditioning 32 (10) 8 (5) Age at transplantation 0.52 (0.04-1.22) 0.48 (0.04-1.2) No CR/serotherapy only 137 (41) 68 (45) (years), median Acute GvHD (min-max) 0 191 (60) 85 (59) Length of follow-up (years), 4.0 (0-11.8) 6.3 (2.0-11.8) Grade I 39 (12) 24 (17) median (min-max), Grade II 51 (16) 20 (14) excluding deaths Grade III 29 (9) 11 (8) Pretransplantation infections Grade IV 7 (2) 2 (1) Yes 138 (41) 88 (58) Grade unknown 4 (1) 2 (1) No 200 (59) 64 (42) Data are presented as no. (%) unless otherwise indicated. PBSC, Peripheral blood stem Genetic diagnosis cell. ADA 43 (13) 19 (12) DCLRE1C 34 (10) 19 (13) patients transplanted with a MMD was too small for subgroup RAG1 46 (13.9) 23 (15) analysis. RAG2 30 (9) 11 (7) In the MD group, 2-year EFS was 81.0% in ADA-deficient RAG (unknown) 2 (0.1) patients, 85.4% in IL2Rg-JAK3-IL7R–deficient patients, and RAG1DCLRE1C 112 (33) 53 (35) 84.4 % in RAG-DCLRE1C–deficient patients (P 5 .88). In the IL2Rg 109 (32) 61 (40) JAK3 26 (8) 13 (9) MMD cohort, 2-year EFS in the IL2Rg-JAK3-IL7R–deficient IL7R 20 (6) 6 (4) group was 80.0% and 68.1% in MMUD and MMRD, respectively IL2Rg1JAK31IL7R 155 (46) 80 (53) (P 5 .29), and in the RAG-DCLRE1C–deficient patients 76.5% AK2 9 (2.7) and 53.6%, respectively (P 5 .11). In the overall cohort, OS LAT 2 (0.6) and EFS were not significantly different in the 2006-2010 and CD3D 2 (0.6) 2011-2014 time periods (data not shown). CD3E 5 (1.5) PNP 3 (0.9) LIG1 1 (0.3) Impact of pretransplantation infections and age at LIG4 2 (0.6) XLF 1 (0.3) transplantation on OS ZAP70 1 (0.3) Pretransplantation infections were reported in 138 patients and CHH 2 (0.6) absent in the remaining 200 patients. They had a strong negative Transplantation impact, leading to a 2-year OS of 73% (95% CI, 65.9-80.8) in Other SCID 28 (8) infected patients compared to 86.6% (95% CI, 82.0-91.5) in Year of transplantation noninfected patients, respectively (Fig 2, A; P < .001) and 2-year 2006 38 (11) 14 (9) EFS of 65.5% (95% CI, 58.0-74.0) and 79.9% (95% CI, 74.5- 2007 41 (12) 26 (17) 85.7), respectively (Fig 2, B; P 5 .002). In contrast, age at trans- 2008 28 (8) 13 (9) 2009 50 (15) 21 (14) plantation, set at below or above 3.5 months as in previous 2010 37 (11) 17 (11) studies,6 was not correlated with either 2-year OS (87.8% vs 2011 35 (10) 14 (9) 82.0%) or 2-year EFS (78.8 vs 72.2%, Fig 2, C and D; P 5 .15). 2012 44 (13) 19 (13) 2013 35 (10) 12 (8) 2014 30 (9) 16 (11) Impact of conditioning on OS Source of hematopoietic In the IL2Rg-JAK3-IL7R–deficient SCID group, MAC or stem cells reduced-intensity conditioning was applied in half of the patients BM 181 (54) 97 (64) (73/155, 47%) whereas the majority of RAG-DCLRE1C–defi- PBSC 89 (26) 27 (18) cient SCID patients (85/112, 76%) received such preparative BM 1 PBSC 2 (0.6) 2 (1) Cord blood 66 (20) 26 (17) treatment. In both SCID genotype groups, patients transplanted Type of donor with and without conditioning had similar survival. In the MSD 64 (19) 26 (17) IL2Rg-JAK3-IL7R group, 2-year OS was 84.8% versus 82.7%, Matched related 36 (11) 22 (14) and 2-year EFS 80.4% versus 75.1% (Fig 3, A and B; P 5 .8 Mismatched related 116 (34) 52 (34) and P 5 .28, respectively); in the RAG-DCLRE1C group, 2- MUD 66 (20) 32 (21) year OS was 77.2% versus 88.0%, and 2-year EFS was 73.5% MMUD 56 (17) 20 (13) versus 65.0% (Fig 3, C and D, P 5 .35 and P 5 .85, respectively). Type of conditioning Within the MAC group, the 2-year OS with fludarabine- and MAC 163 (49) 76 (50) cyclophosphamide-containing conditioning was 89.6% and (Continued) 73.8%, respectively (P 5 .064). 1748 LANKESTER ET AL J ALLERGY CLIN IMMUNOL MAY 2022 FIG 1. OS and EFS in genetic subgroups and donor types. OS (A) and EFS (B) for ADA-, IL2Rg-JAK3-IL7R–, RAG-DCLRE1C–deficient, and ‘‘other’’ SCID group (P 5 .1 and P 5 .073, respectively). OS (C) and EFS (D) are shown for matched, MMUD, and MMRD groups (P < .001 and P < .001, respectively). Impact of acute GvHD disease on OS Multivariate analysis on OS and EFS Data on acute GvHD were reported in 318 patients, as follows: In multivariate survival analysis, 2 independent factors were grade 0-I, 72.6%; grade II, 16%; and grade III-IV, 11.3%. Using strongly associated with unfavorable OS and EFS: the presence of landmark analysis (3 months), the occurrence of severe acute pretransplantation infections (P < .001 and P < .001, respectively) GvHD (grade III-IV) was negatively correlated with survival and a MMRD (P 5 .006 and P 5 .003, respectively; Table II). (P 5 .0031, Fig E1, B); 2-year OS was 93.4% in grade 0-I, 89.5% in grade II, and 75.5% in grade III-IV patients (P 5 .0052). Acute grade II or higher GvHD occurred at the same frequency in MD Clinical outcome (27.4%) and MMD (27.3%) transplants (not significant [P 5 Comprehensive data on long-term clinical outcome (median, 1]). Conditioning did not affect the occurrence of acute GvHD 6.2 years; range, 2.0-11.8 years), and IR at 1 year and beyond of any grade (data not shown). were analyzed in a representative cohort of 152 SCID patients J ALLERGY CLIN IMMUNOL LANKESTER ET AL 1749 VOLUME 149, NUMBER 5 FIG 2. Impact of pretransplantation infections and age at HSCT on OS and EFS. Impact of pretransplantation infections (negative vs positive) on OS (A) and EFS (B) (P < .001 and P 5 .002). Impact of age at transplan- tation on OS (C) and EFS (D) (P 5 .15 and P 5 .45, respectively). (Table I). Within this cohort, 93 (61.2%) of 152 patients were re- 23 (15.1%) of 152 patients, with significant differences between ported to be alive and well, of whom 73 (48%) of 152 were alive the genetic subgroups: 57.9% of ADA-, 15.8% of DCLRE1C-, and well without Ig therapy dependency (Table E1 in the Online 10.0% of IL2Rg-JAK3–, and 2.9% of RAG-deficient patients Repository available at www.jacionline.org). Eight patients died (P < .001; Table E1). A detailed description of reported clinical after 24 months at year 2-3 (n 5 4), year 4 (n 5 2), or later problems and sequelae is provided in Table E3 in the Online (n 5 2). Causes of death were infections (n 5 5), secondary ma- Repository. lignancy (n 5 2), and other cause (n 5 1; see Table E2 in the On- line Repository). Patients were scored as alive and well without Ig supplementation in 15.8% of ADA-, 42.1% of DCLRE1C-, Long-term IR and correlation with clinical outcome 47.1% of RAG-, and 57.5% of IL2Rg-JAK3-IL7R–deficient pa- IR data were collected at 11 year, 12 years, and LFU (median, tients (P 5 .011). Posttransplantation clinical problems were re- 6.4 years; range, 2.8-10.8 years) in the same 152 patients. The ported in 28 (18.4%) of 152 patients, with the lowest frequency analysis focused on total CD4 and naive CD4 T lymphocyte in the IL2Rg-JAK3-IL7R group (12.5%) and the highest in the numbers as a surrogate marker for the quality of immune function. DCLRE1C group (36.8%, P 5 .096). Sequelae were reported in Naive CD4 T lymphocyte counts at 1 and 2 years after 1750 LANKESTER ET AL J ALLERGY CLIN IMMUNOL MAY 2022 FIG 3. Impact of conditioning on OS and EFS in the IL2Rg-JAK3-IL7R and RAG-DCLRE1C SCID subgroups. OS and EFS in patients with or without chemotherapy conditioning in IL2Rg-JAK3-IL7R– (A, B; P 5 .8 and P 5 .28, respectively) and RAG-DCLRE1C–deficient (C, D; P 5 .35 and P 5 .085, respectively) SCID groups. TABLE II. Multivariate adjusted survival analysis on OS and EFS OS EFS Characteristic Variable HR 95% CI P value HR 95% CI P value SCID Group ADA 1 — — 1 — — IL2Rg-JAK3-IL7R 0.97 0.39-2.38 .94 0.88 0.42-1.84 .73 RAG-DCLRE1C 1.36 0.56-3.35 .5 1.33 0.64-2.8 .45 Other 2.18 0.77-6.15 .14 1.83 0.75-4.44 .18 Pre-HSCT relevant infections Absent 1 — — 1 — — Present 2.32 1.44-3.72 <.001 1.99 1.33-2.98 <.001 Donor Matched 1 — — 1 — —- MMRD 2.46 1.3-4.67 .006 2.23 1.31-3.81 .003 MMUD 1.96 0.8-4.8 .14 1.26 0.57-2.77 .57 Source of hematopoietic stem cells BM 1 — — 1 — — Cord blood 1.08 0.44-2.64 .87 1.12 0.52-2.41 .78 PBSC 1.28 0.7-2.34 .42 1.15 0.68-1.94 .59 Transplantation period 2006-2010 1 — — 1 — — 2011-2014 0.74 0.44-1.23 .24 0.74 0.48-1.14 .17 PBSC, Peripheral blood stem cell. transplantation showed a good correlation (adjusted R2 0.53; see follow-up period (Fig E2, B). This pattern was observed in all ge- Fig E2, A, in this article’s Online Repository at www.jacionline. netic subgroups in the nonconditioned and MAC cohorts (Fig E2, org), whereas this correlation was less clear for total CD4 T C). The median naive CD4 T lymphocyte value was highest in the lymphocyte numbers (data not shown). Naive CD4 T lymphocyte IL2Rg-JAK3-IL7R subgroup at all evaluable time points, at numbers showed the largest dispersion at the 1-year time point 0.81 3 10e3/mL; ADA was 0.22 3 10e3/mL, and RAG- and gradually narrowed thereafter. Naive CD4 T lymphocyte pro- DCLRE1C was 0.47 3 10e3/mL (year 1; P 5 .006). In IL2Rg- files revealed that patients in the lower 2 quartiles at 1 year JAK3-IL7R patients, median naive CD4 T lymphocyte values (<0.5 3 10e3/mL) remained in this lower range during the entire were similar in the MAC and nonconditioned group during J ALLERGY CLIN IMMUNOL LANKESTER ET AL 1751 VOLUME 149, NUMBER 5 TABLE III. Correlation between conditioning and Ig dependency at LFU Characteristic MAC (n 5 71) Reduced-intensity conditioning (n 5 8) None/serotherapy only (n 5 65) Total (N 5 144) P value Ig independent at LFU <.001 Yes 62 (87%) 6 (75%) 38 (59%) 106 (74%) No 9 (13%) 2 (25%) 27 (42%) 38 (26%) P values calculated by chi-square test, with continuity correction applied for 2 3 2 tables. follow-up (P 5 .93) in the MD and MMD groups. In contrast, NK of naive CD4 T lymphocyte reconstitution at 1 year after HSCT cell reconstitution in IL2Rg-JAK3-IL7R patients was signifi- strongly predicts long-term clinical and immunologic outcome. cantly better when treated with MAC compared to no condition- Whereas previous studies consistently reported superior OS in ing (Fig E2, D; P 5 .04) compatible with engraftment of the the T2/B1 compared to T2/B2 subgroup of SCID patients,4,5 our respective progenitors and hematopoietic stem cells. In the study is the first to show similar OS and EFS can be achieved in RAG-DCLRE1C and ADA patients, naive CD4 T lymphocyte these subgroups of SCID patients, specifically in IL2Rg-JAK3- numbers were significantly lower in the nonconditioned IL7R and RAG-DCLRE1C SCID subgroups. In contrast to a compared to MAC patients (Fig E2, C; P 5 .009). In patients recent North American study,7 but concordant with earlier obser- who had received MAC, median naive CD4 T lymphocyte recov- vations by Schuetz et al,12 we observed similar survival in the ery at 1 year was similar in the IL2Rg-JAK3-IL7R (n 5 24) and RAG- and DCLRE1C-deficient patients. This may be related to the RAG-DCLRE1C (n 5 37) subgroups (P 5 .106). Umbilical the fact that the patients in our study were transplanted in a cord blood graft recipients had significantly higher median naive more recent time period, and mainly with tailored conditioned CD4 T lymphocyte numbers compared to those grafted with BM transplants, which results in superior graft function. The favorable after MAC at all evaluable time points (Fig E2, E; year 1, P < OS in ADA-SCID patients compared to other reports7 may well .001). be explained by the high proportion of patients transplanted using Ig replacement therapy dependence at LFU was reported in a MD—a bias likely related to inclusion of patients lacking a MD 26.4% of patients and was significantly lower in conditioned (11/ in gene therapy trials during the last decade and the use of enzyme 79, 13.9%) compared to nonconditioned/serotherapy-only pa- replacement therapy. tients (27/68, 39.7%) (Table III, P <.001). Within the MAC group, Multivariate analysis identified relevant pretransplantation Ig dependence was observed in 1 of 29 of IL2Rg-JAK3-IL7R– infections use of MMRDs as major independent risk factors deficient and 8 of 40 of RAG-DCLRE1C–deficient patients associated with inferior OS and EFS. Our study confirms previous (P 5 .10) (Fig E2, F). Notably, Ig dependence strongly correlated observations that pretransplantation infections are a strong with the number of naive CD4 T lymphocytes. At 11 year and 12 independent predictor for unfavorable outcome after years, and particularly at LFU, a minor and decreasing fraction of HSCT.5,6,13 This emphasizes the crucial importance of early patients with more than 0.5 3 10e3/mL naive CD4 T lymphocytes recognition of SCID patients to allow for timely initiation of was dependent on Ig supplementation (Fig 4). To study the predic- protective measurements to bridge patients toward curative tive level of naive CD4 T lymphocyte reconstitution on clinical stem cell therapy treatment without infectious burden. Newborn outcome, logistic regression was applied (Fig E2, G). screening programs have been established in many countries to A threshold of 0.5 3 10e3 naive CD4 T lymphocytes/mL at 1 achieve this goal, but no patients in this cohort were identified year after transplantation was identified to strongly correlate via newborn screening.14 with favorable clinical outcome, defined as alive and well plus In previous SCID studies, OS was consistently inferior in Ig independence as well as with alive with sequelae only (Table patients transplanted with unrelated donor compared to MSD.5-7 IV, P 5 .017 and P < .001, respectively). A weaker correlation Our study is the first to demonstrate similar OS in SCID patients was observed for CD4 T lymphocytes at 1 year after transplanta- transplanted with MSD and MUD, most likely reflecting the tion (cutoff level 0.75 3 10e3/mL, P 5 .019 and P 5 .003, respec- impact of high-resolution HLA typing on unrelated donor selec- tively). The low number of late deaths (>2 years after tion, and thereby a more precise manner to analyze the impact transplantation) did not allow for a correlative analysis with naive of matching grade on transplantation outcome. Our finding is in CD4 T lymphocytes at 1 year. Acute GvHD did not negatively line with recent pediatric HSCT studies in non-SCID inborn er- affect naive CD4 T lymphocyte numbers at 1 year or Ig depen- rors of immunity.15-17 Whereas our current and previous studies dence (data not shown). In multivariate analysis, naive CD4 reported slightly less favorable outcome with MM(R)D, several T lymphocyte counts, IL2Rg-JAK3-IL7R–deficient SCID, and recent studies in patients with inborn errors of immunity have re- MAC were each positively correlated with a favorable outcome ported encouraging results with MMUD and MMRD (haploident- (ie, alive and well plus Ig independent), whereas a MMRD ical) donors using either TCR ab/CD19 depletion or showed a negative correlation (Table V). posttransplantation cyclophosphamide approaches.18-22 Future studies will reveal whether these novel approaches may contribute to reduce the current gap in outcome between MD DISCUSSION and MMD transplants and whether this will be the same for the We report here what is to our knowledge the largest cohort of different SCID genotypes. Eventually, the steadily improving transplanted, genetically defined SCID patients as registered in transplantation results with alternative donors may have an impli- SCETIDE, with a similar favorable outcome observed for all cation for future donor hierarchy, and for the positioning of gene genotypes. Pretransplantation infections and MMRDs were therapy, which is currently mainly reserved for patients lacking a identified as the main independent risk factors at transplantation MD and for which excellent results have recently been reported in for inferior OS and EFS. Moreover, we demonstrate that the level ADA-SCID.23 1752 LANKESTER ET AL J ALLERGY CLIN IMMUNOL MAY 2022 FIG 4. Ig dependence is correlated with naive CD4 T lymphocyte numbers. Dependency on Ig supplemen- tation at LFU in relation to the numbers of naive CD4 T lymphocytes at different time points (11 year, 12 years, LFU) after HSCT. TABLE IV. Correlation between numbers of naive and total CD4 T lymphocytes at 11 year and clinical outcome Naive CD4 count at 1 year CD4 count at 1 year Characteristic _500 (n 5 63) < >500 (n 5 68) P value _750 (n 5 58) < >750 (n 5 88) P value Alive and well and Ig independent .017 .019 Yes 22(35%) 39 (57%) 20(34%) 49 (56%) No 41(65%) 29 (3%) 38(66%) 39 (44%) Alive and well or only sequelae, Ig independent <.001 .003 Yes 26 (41%) 49 (72%) 25 (43%) 61 (69%) No 37 (59%) 19 (28%) 33 (57%) 27 (31%) P values calculated by chi-square test, with continuity correction applied for 2 3 2 tables. TABLE V. Multivariate analysis of being alive and well and Ig independent at LFU 95% confidence interval Characteristic Variable Odds ratio Lower Upper P value Naive CD4 T lymphocytes at 1 year (per 500 cells/mL) 1.62 1.18 2.30 .004 Diagnosis IL2Rg-JAK3-IL7R 1.00 RAG-DCLRE1C 0.28 0.09 .78 .019 ADA 0.09 0.02 .38 .002 Conditioning MAC 1.00 None/serotherapy only 0.19 0.06 .57 .004 Reduced-intensity conditioning 0.23 0.03 1.47 .12 Donor type MSD 1.00 MRD 0.42 0.08 2.04 .3 MUD 0.99 0.21 4.66 >.9 MMUD 0.22 0.03 1.24 .092 MMRD 0.21 0.05 .78 .023 In the last decades, there has been ongoing debate on the risk/ mediated by protective donor T lymphocyte engraftment—with benefit ratio of conditioning in SCID. Unconditioned infusions, the caveat that GvHD remains a point of attention and IR predominantly used in T2/B1 SCID and in patients with severe, longevity is not ensured.24-26 Moreover, omitting intensive mostly infection-driven comorbidity, have often been lifesaving, chemotherapy-based conditioning may reduce the occurrence of J ALLERGY CLIN IMMUNOL LANKESTER ET AL 1753 VOLUME 149, NUMBER 5 general late effects like fertility, late cancers, or effects on neuro- with clinical outcome characteristics, as we did in our study.7 As cognitive development, as well as specific late effects in suscep- a result of the small number of late deaths in our cohort, we tible genetic subgroups like DCLRE1C SCID.12 Still, in the could not demonstrate a correlation between (naive) T lympho- absence of MAC, BM and thymic niches occupied by host pro- cyte reconstitution and survival. Our findings demonstrate that genitor cells will not be effectively depleted, thus preventing 0.5 3 10e3 naive CD4 T lymphocytes/mL at 1 year after optimal repopulation by donor equivalents.27 In those cases, transplantation strongly predicts a favorable clinical course thymic function and sustained output of naive donor–derived T and Ig dependency during further follow-up, and can therefore lymphocytes is often insufficiently corrected. In addition to con- be instrumental to guide clinical decision making. Delmonte ditioning, the stem cell source may also have an impact on recon- et al32 recently reported preliminary data that TCR b repertoire stitution because naive CD4 T lymphocyte reconstitution was early after HSCT represented a useful biomarker to predict T di- more favorable with umbilical cord blood compared to BM in versity of T lymphocyte reconstitution and also correlated with the setting of MAC. This has been reported previously and reflects absolute numbers of naive CD4 T lymphocytes at 6 months. the properties of fetal cord blood CD41 T lymphocytes.28 Our re- In summary, we demonstrate that transplantation outcome in sults also highlight clear genotype-dependent differences, with SCID patients has continued to improve in the recent time the most pronounced reconstitution of naive CD4 T lymphocytes period. Serious pretransplantation infections and use of MMRDs in IL2Rg-JAK3-IL7R patients, which seems similar with or remain associated with a less favorable outcome. Ongoing without conditioning at the time points analyzed in this study. implementation of newborn screening programs, recent ad- The favorable IR likely contributes to the favorable clinical and vances in MMD transplantation strategies, increasing availabil- immunologic outcome of this genetic subgroup, as observed in ity of gene therapy options, and optimization of conditioning the multivariate analysis. In contrast, naive CD4 T lymphocyte regimens will be the main tools to further improve survival, and numbers in RAG-DCLRE1C patients were significantly inferior particularly clinical and immunologic long-term outcome in in the absence of conditioning. Likewise, in the absence of SCID patients. MAC, B lymphocyte development will often not be successfully restored in B2 SCID variants or will remain of host origin in We would like to thank the medical and nursing staff and the data managers IL2Rg/JAK3-deficient SCID, thereby maintaining the status of of the participating centers for their valuable contributions. intrinsically impaired B lymphocyte function.29 We here show that contemporary MAC, in contrast to previous experience,7 is Key messages not associated with an inferior OS or increased occurrence of acute GvHD. This may reflect the recent use of less toxic regi- d In transplanted SCID patients, 2-year EFS is similar for mens, the use of treosulfan or targeted (reduced intensity) genetic subgroups, while pretransplantation infections busulfan plus fludarabine instead of 2 alkylating agents, as per and use of MMRDs are associated with an unfavorable the guidelines of the Inborn Errors Working Party.30 Develop- EFS. ments in antibody-based conditioning, targeting the stem cell d Naive CD4 T lymphocytes at the >0.5 3 10e3/mL level at 1 niche without collateral systemic acute and late toxicity, may year after transplantation strongly predict a favorable lead to future regimens with a more favorable profile.31 clinical course and lessened Ig dependency during further Detailed analysis of clinical and immunologic outcome in a follow-up. representative subgroup of 152 patients showed that almost two thirds of these patients are alive and well at 2 or more years after HSCT, whereas half of the patients are alive and well without the REFERENCES need for Ig support, with no significant difference among the 1. 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Biol hematopoietic stem cell ablation using CD117-antibody–drug-conjugates enables Blood Marrow Transplant 2020;26:1923-9. safe and effective transplantation with immunity preservation. Nat Commun 20. Laberko A, Sultanova E, Gutovskaya E, Shipitsina I, Shelikhova L, Kurnikova E, 2019;10:617. et al. Mismatched related vs matched unrelated donors in TCRalphabeta/CD19- 32. Delmonte OM, Castagnoli R, Yu J, Dvorak CC, Cowan MJ, Davila Saldana BJ, depleted HSCT for primary immunodeficiencies. Blood 2019;134:1755-63. et al. Poor T-cell receptor beta repertoire diversity early posttransplant for severe 21. Neven B, Diana JS, Castelle M, Magnani A, Rosain J, Touzot F, et al. Haploident- combined immunodeficiency predicts failure of immune reconstitution. J Allergy ical hematopoietic stem cell transplantation with post-transplant cyclophosphamide Clin Immunol 2022;149:1113-9. J ALLERGY CLIN IMMUNOL LANKESTER ET AL 1754.e1 VOLUME 149, NUMBER 5 FIG E1. A, OS in MDs comparing MSDs, MRDs, and MUDs. OS is shown for SCID patients transplanted with 1 of the 3 MD types; MSDs, MRDs, and MUDs (P 5 .94). B, Impact of acute GvHD on OS. Impact of acute GvHD grade 0-1, grade 2, and grade 3-4 on OS using 3-month Landmark analysis (P 5 .003). 1754.e2 LANKESTER ET AL J ALLERGY CLIN IMMUNOL MAY 2022 FIG E2. A, Correlation naive CD4 T lymphocytes at 1 and 2 years after HSCT. Correlation between absolute numbers of naive CD4 T lymphocytes measured at 11 and 2 years after HSCT (adjusted R2, 0.526). B, Naive CD4 T lymphocyte levels at 1 and 2 years, and LF in per quantile (patient quantiles assigned by naive CD4 level in year 1). Absolute naive CD4 T lymphocyte levels at 1 and 2 years, and LF per quantile (patient quan- tiles assigned by naive CD4 level T lymphocyte numbers in year 1). C, Naive CD4 T lymphocyte numbers at 11 and 12 years and LFU (top to bottom) and matched versus mismatched transplantation (left to right) in the genetic subgroups in relation to type of conditioning. Naive CD4 T lymphocyte numbers at 11 and 12 years and LFU (top to bottom) in matched (left column) versus mismatched (right column) donor transplan- tation per genetic subgroup (ADA, IL2Rg-JAK3-IL7R, and RAG-DCLRE1C) and in relation to type of condition- ing: red indicates MAC; blue, reduced-intensity conditioning (RIC); green, no conditioning; and purple, serotherapy only. D, NK cell numbers at 11 and 12 years and LFU (top to bottom) and matched versus mis- matched transplantation (left to right) in the genetic subgroups in relation to type of conditioning. Absolute numbers of NK cells at 11 and 12 years and LFU (top to bottom), in matched (left column) versus mis- matched (right column) donor transplantation per genetic subgroup (ADA, IL2Rg-JAK3-IL7R, and RAG- DCLRE1C) and in relation to type of conditioning: red indicates MAC; blue, RIC; green, no conditioning; and purple, serotherapy only. E, Naive CD4 T lymphocyte numbers at 11 and 12 years and LFU (top to bot- tom) and matched versus mismatched transplantation (left to right) in the genetic subgroups in relation to type of graft source. Absolute numbers of naive CD4 T lymphocyte numbers at 11 and 12 years and LFU (top to bottom), in matched (left column) versus mismatched (right column) donor transplantation per ge- netic subgroup (ADA, IL2Rg-JAK3-IL7R, and RAG-DCLRE1C), and in relation to type of graft source: red in- dicates BM; green, cord blood; and blue, peripheral blood stem cells (PBSCs). F, Ig dependence at 1 and 2 year and LFU in relation to genetic subgroup and conditioning. Ig dependence (in percentage of patients, y- axis) at 1 and 2 years and LFU (top to bottom) in relation to genetic subgroup (ADA, IL2Rg-JAK3-IL7R, and RAG-DCLRE1C, left to right) and conditioning (no MAC vs MAC). (G) CD4 naive and total CD4 numbers in relation to outcome (A/W and Ig independent). Absolute naive CD4 (top) and total CD4 T lymphocyte numbers (bottom) in relation to outcome (A/W and Ig independent; P < .001 and P < .001, respectively) using logistic regression analysis. J ALLERGY CLIN IMMUNOL LANKESTER ET AL 1754.e3 VOLUME 149, NUMBER 5 FIG E2. (Continued). 1754.e4 LANKESTER ET AL J ALLERGY CLIN IMMUNOL MAY 2022 FIG E2. (Continued). J ALLERGY CLIN IMMUNOL LANKESTER ET AL 1754.e5 VOLUME 149, NUMBER 5 FIG E2. (Continued). 1754.e6 LANKESTER ET AL J ALLERGY CLIN IMMUNOL MAY 2022 TABLE E1. Clinical outcome in 152 genetically defined SCID patients Total ADA DCLRE1C RAG1/2 IL2Rg JAK3 IL7R Characteristic No. % No. % No. % No. % No. % No. % No. % Alive and well, without Ig therapy* 73 48 3 16 8 42 16 47 35 57 6 46 5 83 Alive and well, with Ig 20 13 1 5.5 1 5 6 17 9 15 3 23 Alive with clinical problems, without Ig 16 11 4 21 6 32 4 12 2 3 Alive with clinical problems, with Ig 12 8 1 5 3 9 6 10 2 15 Alive with sequelae, without Ig 17 11 8 42 2 11 1 3 5 8 1 8 Alive with sequelae, with Ig 6 4 3 15.5 1 5 2 3.5 Late death 8 5 4 12 2 3.5 1 8 1 17 Total 152 19 19 34 61 13 6 4 *Three IL2Rg and 1 JAK3 patients presenting warts. Including patients with sequelae. J ALLERGY CLIN IMMUNOL LANKESTER ET AL 1754.e7 VOLUME 149, NUMBER 5 TABLE E2. Causes of death Total <1 year after HSCT <1 and >2 years after HSCT >2 years after HSCT Main cause of death No. % No. % No. % No. % Infection 71 67 59 68 5 62.5 7* 63.5 Toxicity 15 14 15 17 GvHD 5 5 3 3.5 1 12.5 1 9 Nonengraftment 3 2.5 3 3.5 Neoplasia 2 2 2 18.5 Posttransplantation lymphoproliferative disease 1 1 1 12.5 Other 3 2.5 2 2 1à 9 Unknown 6 6 5 5 1 12.5 Total 106 87 82 8 8 11 10 *Five patients from IR cohort. Two patients from IR cohort. àOne patient from IR cohort. 1754.e8 LANKESTER ET AL J ALLERGY CLIN IMMUNOL MAY 2022 TABLE E3. Clinical problems and sequelae in 152 genetically defined SCID patients Characteristic Total ADA DCLRE1C RAG1/2 IL2Rg JAK3 IL7R Clinical problems 47 Endocrine dysfunction 7 2 3 1 1 Nutritional deficiency with support 10 1 3 1 3 1 1 Liver disease 1 1 Lung disease 7 1 2 3 1 Renal disease 1 1 Other autoimmunity* 14 2 1 4 6 1 Autoimmune cytopenia 3 3 Neoplasia 3 2 1à Other 1 1 Sequelae 40 Growth retardation 12 2 5 1 3 1 Hearing loss 12 10 2 Neurocognitive and motor impairment 9 4 1 1 2 1 Sequelae from infection 2 2 Orthopedic problems 3 1 1 1 Other 2 1 1 Serious infection 8 2 2 3 1 Persistent chronic GvHD 5 3 2 Second transplant (>2 years after first) 3 2 1 Late death 8 4 2 1 1 Patients could have more than 1 clinical problem. *Hepatitis (n 5 5), dysthyroidism (n 5 4), skin (n 5 3), myasthenia (n 5 1), oligoarticular juvenile idiopathic arthritis (n 5 1). Osteosarcoma (n 5 1), acute lymphoblastic leukemia (n 5 1). àOsteosarcoma (n 5 1).