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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., Competing Interests: Declaration of interests MST is a member of the Scientific Advisory Board for Proteios Technology. JMP has received royalties from Up-To-Date, and her spouse is employed by and owns stock in Invitae (a DNA sequencing company). MJC has received royalties from Up-to-Date and is on the scientific board of Homology Medicines, a gene therapy company, and is a data and safety monitoring board (DSMB) member for Bluebird Bio, Chiesi USA, and Rocket Pharmaceuticals. LFS is a member of the adjudication committee for Orchard Therapeutics and has received consulting fees from Takeda, CSL Behring, ADMA Biologics, Grifols, and Horizon. JH is on an Investigator-initiated grant at CSL Behring; is a consultant for ADMA, Horizon, and CIRM; and a clinical trial primary investigator (industry sponsored research) for Regeneron. LMB has received clinical trial support through the Fred Hutchinson Cancer Research Center by Medac including supply of treosulfan), is a member of the DSMB for clinical trials with Rocket Pharmaceuticals and Jasper Therapeutics, and has served on an advisory board for Horizon Therapeutics USA. BDS has undertaken ad-hoc consultancies for Sobi and Orchard Therapeutics. ShC is a member on the advisory board for SOBI. JJB is a member of an advisory board for Sobi and Horizon Therapeutics. GDEC has received consultancy fees from Miltenyi Biotech. FDG has received consultancy fees from GLG and Guidepoint Global, and is on the advisory board for Omerus. EBS is on the speaker's bureau for Sobi. EHC is an advisory board member for Pfizer. SP has received funding for the conduct of sponsored trials Atara Biotherapeutics, AlloVir, and Jasper Therapeutics and is on the advisory board for ADMA and Neovii; and is the inventor of IP Licensed to Atara with all rights assigned to Memorial Sloan Kettering Cancer Center. KES has served as a consultant for Enzyvant and the Immune Deficiency Foundation. AP is on the advisory boards for Orchard (MLD GT), Horizon, and Enzyvant, serves on the DSMB for ExCellTheraMK, and is a consultant for Enzyvant (2020). TCQ has been on the speaker's bureau and advisory board for Alexion Pharmaceuticals. SS is on the advisory board and provides consultancy for Graphite, Takeda, Janssen, Bristol Myers Squibb, data and safety monitoring committee for the National Heart, Lung, and Blood Institute (NHLBI), and Aruvant Sciences. HD was an advisor on an Eli Lilly Canada Scientific Advisory Board in April 2020. JWL in the past 12 months has been a speaker and consultant for Sobi; has been a speaker and consultant, and has received research funding from Horizon Therapeutics; has been a speaker, consultant, and on an advisory board for Pharming; has been a speaker and consultant for CSL Behring; is on the advisory board for ADMA Biologics; and is the site primary investigator for Therapure and a GreenCross employee and shareholder at Bluebird Bio. MAP has served on the advisory boards of Novartis, Medexus, Equillium, and Mesoblast; has received clinical study support from Adaptive and Miltenyi Biotech; and has received financial support for educational lectures for Miltenyi Biotech and Novartis. DBK is an inventor for the UC Regents on a lentiviral vector for gene therapy of ADA-SCID and is a member of the DSMB for Revcovi PEG-ADA (Chiesi USA). EH has received consultancy fees from JASPERS, Takeda, CSL-Behring, Octapharma, and Leadiant Biosciences. CCD is a member of the DSMB for Revcovi PEG-ADA and is a consultant for Orchard Therapeutics. All other authors declare no competing interests., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Despite improvements, mortality after allogeneic hematopoietic cell transplantation (HCT) for nonmalignant diseases remains a significant problem. We evaluated whether pre-HCT conditions defined by the HCT Comorbidity Index (HCT-CI) predict probability of posttransplant survival. Using the Center for International Blood and Marrow Transplant Research database, we identified 4083 patients with nonmalignant diseases transplanted between 2007 and 2014. Primary outcome was overall survival (OS) using the Kaplan-Meier method. Hazard ratios (HRs) were estimated by multivariable Cox regression models. Increasing HCT-CI scores translated to decreased 2-year OS of 82.7%, 80.3%, 74%, and 55.8% for patients with HCT-CI scores of 0, 1 to 2, 3 to 4, and ≥5, respectively, regardless of conditioning intensity. HCT-CI scores of 1 to 2 did not differ relative to scores of 0 (HR, 1.12 [95% CI, 0.93-1.34]), but HCT-CI of 3 to 4 and ≥5 posed significantly greater risks of mortality (HR, 1.33 [95% CI, 1.09-1.63]; and HR, 2.31 [95% CI, 1.79-2.96], respectively). The effect of HCT-CI differed by disease indication. Patients with acquired aplastic anemia, primary immune deficiencies, and congenital bone marrow failure syndromes with scores ≥3 had increased risk of death after HCT. However, higher HCT-CI scores among hemoglobinopathy patients did not increase mortality risk. In conclusion, this is the largest study to date reporting on patients with nonmalignant diseases demonstrating HCT-CI scores ≥3 that had inferior survival after HCT, except for patients with hemoglobinopathies. Our findings suggest that using the HCT-CI score, in addition to disease-specific factors, could be useful when developing treatment plans for nonmalignant diseases., (© 2019 by The American Society of Hematology.)

Competing Interests: Conflict-of interest disclosure: The authors declare no competing financial interests.

The HLH-2004 criteria are used to diagnose hemophagocytic lymphohistiocytosis (HLH), yet concern exists for their misapplication, resulting in suboptimal treatment of some patients. We sought to define the genomic spectrum and associated outcomes of a diverse cohort of children who met the HLH-2004 criteria. Genetic testing was performed clinically or through research-based whole-exome sequencing. Clinical metrics were analyzed with respect to genomic results. Of 122 subjects enrolled over the course of 17 years, 101 subjects received genetic testing. Biallelic familial HLH (fHLH) gene defects were identified in only 19 (19%) and correlated with presentation at younger than 1 year of age ( P < .0001). Digenic fHLH variants were observed but lacked statistical support for disease association. In 28 (58%) of 48 subjects, research whole-exome sequencing analyses successfully identified likely molecular explanations, including underlying primary immunodeficiency diseases, dysregulated immune activation and proliferation disorders, and potentially novel genetic conditions. Two-thirds of patients identified by the HLH-2004 criteria had underlying etiologies for HLH, including genetic defects, autoimmunity, and malignancy. Overall survival was 45%, and increased mortality correlated with HLH triggered by infection or malignancy ( P < .05). Differences in survival did not correlate with genetic profile or extent of therapy. HLH should be conceptualized as a phenotype of critical illness characterized by toxic activation of immune cells from different underlying mechanisms. In most patients with HLH, targeted sequencing of fHLH genes remains insufficient for identifying pathogenic mechanisms. Whole-exome sequencing, however, may identify specific therapeutic opportunities and affect hematopoietic stem cell transplantation options for these patients.

To test the feasibility of a single T-cell manipulation to eliminate alloreactivity while sparing antiviral and antitumor T cells, we infused 12 haploidentical hematopoietic stem cell transplant patients with increasing numbers of alloreplete haploidentical T cells expressing the inducible caspase 9 suicide gene (iC9-T cells). We determined whether the iC9-T cells produced immune reconstitution and if any resultant graft-versus-host disease (GVHD) could be controlled by administration of a chemical inducer of dimerization (CID; AP1903/Rimiducid). All patients receiving >10(4) alloreplete iC9-T lymphocytes per kilogram achieved rapid reconstitution of immune responses toward 5 major pathogenic viruses and concomitant control of active infections. Four patients received a single AP1903 dose. CID infusion eliminated 85% to 95% of circulating CD3(+)CD19(+) T cells within 30 minutes, with no recurrence of GVHD within 90 days. In one patient, symptoms and signs of GVHD-associated cytokine release syndrome (CRS-hyperpyrexia, high levels of proinflammatory cytokines, and rash) resolved within 2 hours of AP1903 infusion. One patient with varicella zoster virus meningitis and acute GVHD had iC9-T cells present in the cerebrospinal fluid, which were reduced by >90% after CID. Notably, virus-specific T cells recovered even after AP1903 administration and continued to protect against infection. Hence, alloreplete iC9-T cells can reconstitute immunity posttransplant and administration of CID can eliminate them from both peripheral blood and the central nervous system (CNS), leading to rapid resolution of GVHD and CRS. The approach may therefore be useful for the rapid and effective treatment of toxicities associated with infusion of engineered T lymphocytes. This trial was registered at www.clinicaltrials.gov as #NCT01494103., (© 2015 by The American Society of Hematology.)