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Severe combined immunodeficiency (SCID) results from defects in the differentiation of hematopoietic stem cells into mature T lymphocytes, with additional lymphoid lineages affected in particular genotypes. In 2014, the Primary Immune Deficiency Treatment Consortium published criteria for diagnosing SCID, which are now revised to incorporate contemporary approaches. Patients with typical SCID must have less than 0.05 × 10

Overall survival following reduced intensity conditioning (RIC) allogeneic hematopoietic cell transplantation (HCT) using alemtuzumab, fludarabine, and melphalan is favorable in patients transplanted for inborn errors of immunity (IEI), but RIC is associated with high rates of mixed chimerism (MC) and secondary graft failure (GF). We hypothesized that peri-transplant alemtuzumab levels or specific patterns of inflammation would predict these risks. We assessed samples from BMT CTN 1204 (NCT01998633) to study the impact of alemtuzumab levels and cytokine patterns on MC and impending or established secondary GF (defined as donor chimerism 0.32μg/mL (p=0.008). Impending or established secondary GF was only observed in patients with day 0 alemtuzumab levels >0.32µg/mL (p=0.08). Unexpectedly, patients with impending or established secondary GF had lower CXCL9 levels. The cumulative incidence of impending or established secondary GF in patients with a day +14 CXCL9 level ≤2394pg/mL (day +14 median) was 73.6% versus 0% in patients >2394pg/mL (p=0.002). CXCL9 levels inversely correlated with alemtuzumab levels. These findings support a relationship between alemtuzumab levels, CXCL9 levels, and sustained engraftment. These data suggest a model in which higher levels of alemtuzumab at day 0 deplete donor T-cells, inhibit the graft-versus-marrow reaction (thereby suppressing CXCL9 levels), and adversely impact sustained engraftment in the non-myeloablative HCT setting. Clinical Trial # NCT01998633.

Immunodeficiency, whether acquired in the case of human immunodeficiency virus (HIV) infection or congenital due to inborn errors of immunity (IEIs), presents clinically with not only infection and immune dysregulation but also increased risk of malignancy. The range of malignancies seen is relatively limited and attributable to the particular cellular and molecular defects in each disease. CD4+ T-cell lymphopenia in people living with HIV infection (PLWH) and certain IEIs drive the predisposition to aggressive B-cell non-Hodgkin lymphomas, including certain rare subtypes rarely seen in immunocompetent individuals. PLWH and IEI that lead to profound T-cell lymphopenia or dysfunction also are at risk of cancers related to oncogenic viruses such as Kaposi sarcoma herpesvirus, Epstein-Barr virus, human papillomavirus (HPV), and Merkel cell polyomavirus. IEIs that affect natural killer cell development and/or function heavily predispose to HPV-associated epithelial cancers. Defects in DNA repair pathways compromise T- and B-lymphocyte development during immune receptor rearrangement in addition to affecting hematopoietic and epithelial DNA damage responses, resulting in both hematologic and nonhematologic cancers. Treatment of cancers in immunodeficient individuals should be curative in intent and pursued in close consultation with disease experts in immunology and infectious disease.

Shearer et al in 2014 articulated well-defined criteria for the diagnosis and classification of severe combined immunodeficiency (SCID) as part of the Primary Immune Deficiency Treatment Consortium's (PIDTC's) prospective and retrospective studies of SCID.Because of the advent of newborn screening for SCID and expanded availability of genetic sequencing, revision of the PIDTC 2014 Criteria was needed.We developed and tested updated PIDTC 2022 SCID Definitions by analyzing 379 patients proposed for prospective enrollment into Protocol 6901, focusing on the ability to distinguish patients with various SCID subtypes.According to PIDTC 2022 Definitions, 18 of 353 patients eligible per 2014 Criteria were considered not to have SCID, whereas 11 of 26 patients ineligible per 2014 Criteria were determined to have SCID. Of note, very low numbers of autologous T cells (0.05 × 10The PIDTC 2022 Definitions describe SCID and its subtypes more precisely than before, facilitating analyses of SCID characteristics and outcomes.

Innovations in programmable nucleases have expanded genetic engineering capabilities, raising the possibility of a new approach to curing monogenic hematological diseases. Feasibility studies using ex vivo targeted genome-editing, and nonintegrating viral vectors show outstanding potential for correcting genetic conditions at their root cause. This article reviews the latest technological advances in the CRISPR/Cas9 system alone and combined with engineered viruses as editing tools for human hematopoietic stem and progenitor cells (HSPCs). We discuss the early phase in human trials of genome editing-based therapies for hemoglobinopathies.

Key Points 3D organoid T-cell differentiation from a few hundred peripheral blood CD34+ cells was successfully achieved. 3D organoid T-cell differentiation could help physicians distinguish intrinsic from extrinsic defects underlying a clinical SCID phenotype.

Severe combined immunodeficiency (SCID) comprises rare inherited disorders of immunity that require definitive treatment through hematopoietic cell transplantation (HCT) or gene therapy for survival. Despite successes of allogeneic HCT, many SCID patients experience incomplete immune reconstitution, persistent T-cell lymphopenia, and poor long-term outcomes.We hypothesized that CD4We analyzed markers of exhaustion in blood samples from 61 SCID patients at a median of 10.4 years after HCT.Compared to post-HCT SCID patients with normal CD4Recipients of unconditioned HCT for SCID may develop late post-HCT T-cell exhaustion as a result of diminished production of T-lineage cells. Elevated expression of inhibitory receptors on their T cells may be a biomarker of poor long-term T-cell reconstitution.

Adenosine deaminase (ADA) deficiency causes ∼13% of cases of severe combined immune deficiency (SCID). Treatments include enzyme replacement therapy (ERT), hematopoietic cell transplant (HCT), and gene therapy (GT). We evaluated 131 patients with ADA-SCID diagnosed between 1982 and 2017 who were enrolled in the Primary Immune Deficiency Treatment Consortium SCID studies. Baseline clinical, immunologic, genetic characteristics, and treatment outcomes were analyzed. First definitive cellular therapy (FDCT) included 56 receiving HCT without preceding ERT (HCT); 31 HCT preceded by ERT (ERT-HCT); and 33 GT preceded by ERT (ERT-GT). Five-year event-free survival (EFS, alive, no need for further ERT or cellular therapy) was 49.5% (HCT), 73% (ERT-HCT), and 75.3% (ERT-GT; P < .01). Overall survival (OS) at 5 years after FDCT was 72.5% (HCT), 79.6% (ERT-HCT), and 100% (ERT-GT; P = .01). Five-year OS was superior for patients undergoing HCT at

BACKGROUND: Autoimmune hemolytic anemia (AIHA) after allogeneic hematopoietic stem cell transplant (HSCT) is a rare but complex and serious complication. Detailed descriptions of cases and management strategies are needed due to lack of prospective trials. OBJECTIVES: Describe the incidence, clinical characteristics, and management of AIHA after HSCT in a pediatric cohort. METHODS: This is a retrospective cohort study of 33 pediatric patients with AIHA after HSCT at an academic tertiary care center from 2003 to 2019. RESULTS: The overall incidence of AIHA after allogeneic HSCT was 3.8% (33/868). AIHA was significantly more common after transplant for nonmalignant versus malignant diagnoses (7.0% [26/370] vs. 1.4% [7/498], p < .0001). AIHA developed at a median of 4.7 months (range 1.0–29.7) after transplant. Sixteen of 33 patients (48.5%) required new AIHA-directed pharmacologic therapy; 17 (51.5%) were managed on their current immunosuppression and supportive care. Patients managed without additional therapy were significantly older, more likely to have a malignant diagnosis, and tended to develop AIHA at an earlier time point after transplant. Patients received a median of two red blood cell transfusions within the first 2 weeks of diagnosis and a median of one AIHA-directed medication (range one to four), most commonly corticosteroids and rituximab. CONCLUSIONS: AIHA after HSCT is rare but occurs more commonly in patients transplanted for nonmalignant diagnoses. While some pediatric patients who develop AIHA after transplant can be managed on current immunosuppression and supportive care, many require AIHA-directed therapy including second-line medications.

Granulocyte transfusions are sometimes used as adjunctive therapy for the treatment of infection in patients with chronic granulomatous disease (CGD). However, granulocyte transfusions can be associated with a high rate of alloimmunization, and their role in CGD patients undergoing hematopoietic cell transplantation (HCT) or gene therapy (GT) is unknown. We identified 27 patients with CGD who received granulocyte transfusions pre- (within 6months) and/or post-HCT or GT in a retrospective survey. Twelve patients received granulocyte transfusions as a bridge to cellular therapy. Six (50%) of these patients had a complete or partial response. However, six of 10 (60%) patients for whom testing was performed developed anti-HLA antibodies, and three of the patients also had severe immune-mediated cytopenia within the first 100days post-HCT or GT. Fifteen patients received granulocyte transfusions post-HCT only. HLA antibodies were not checked for any of these 15 patients, but there were no cases of early immune-mediated cytopenia. Out of 25 patients who underwent HCT, there were 5 (20%) cases of primary graft failure. Three of the patients with primary graft failure had received granulocyte transfusions pre-HCT and were subsequently found to have anti-HLA antibodies. In this small cohort of patients with CGD, granulocyte transfusions pre-HCT or GT were associated with high rates of alloimmunization, primary graft failure, and early severe immune-mediated cytopenia post-HCT or GT. Granulocyte transfusions post-HCT do not appear to confer an increased risk of graft failure.

Very early onset inflammatory bowel disease (VEO-IBD) is defined as IBD presenting before 6 years of age. When compared with IBD diagnosed in older children, VEO-IBD has some distinct characteristics such as a higher likelihood of an underlying monogenic etiology or primary immune deficiency. In addition, patients with VEO-IBD have a higher incidence of inflammatory bowel disease unclassified (IBD-U) as compared with older-onset IBD. In some populations, VEO-IBD represents the age group with the fastest growing incidence of IBD. There are contradicting reports on whether VEO-IBD is more resistant to conventional medical interventions. There is a strong need for ongoing research in the field of VEO-IBD to provide optimized management of these complex patients. Here, we provide an approach to diagnosis and management of patients with VEO-IBD. These recommendations are based on expert opinion from members of the VEO-IBD Consortium (www.VEOIBD.org). We highlight the importance of monogenic etiologies, underlying immune deficiencies, and provide a comprehensive description of monogenic etiologies identified to date that are responsible for VEO-IBD.

Background: Autoimmune hemolytic anemia (AIHA) after allogeneic hematopoietic stem cell transplant (HSCT) is a rare but complex and serious complication. Detailed descriptions of cases and management strategies are needed due to lack of prospective trials. Objectives: Describe the incidence, clinical characteristics, and management of AIHA after HSCT in a pediatric cohort. Methods: This is a retrospective cohort study of 33 pediatric patients with AIHA after HSCT at an academic tertiary care center from 2003 to 2019. A case-control analysis was performed to compare outcomes. Results: The overall incidence of AIHA after allogeneic HSCT was 3.8% (33/868). AIHA was significantly more common after transplant for non-malignant versus malignant diagnoses (7.0% (26/370) vs. 1.4% (7/498), p

Background Massachusetts began newborn screening (NBS) for severe combined immunodeficiency (SCID) using measurement of T-cell receptor excision circles (TRECs) from dried blood spots. Objective We describe developments and outcomes from the first 10 years of this program (February 1, 2009, to January 31, 2019). Methods TREC values, diagnostic, and outcome data from all patients screened for SCID were evaluated. Results NBS of 720,038 infants prompted immunologic evaluation of 237 (0.03%). Of 237, 9 were diagnosed with SCID/leaky SCID (4% of referrals vs 0.001% general population). Another 7 were diagnosed with other combined immunodeficiencies, and 3 with athymia. SCID/leaky SCID incidence was approximately 1 in 80,000, whereas approximately 1 in 51,000 had severe T-cell lymphopenia for which definitive treatment was indicated. All patients with SCID/leaky SCID underwent hematopoietic cell transplant or gene therapy with 100% survival. One patient with athymia underwent successful thymus transplant. No known cases of SCID were missed. Compared with outcomes from the 10 years before SCID NBS, survival trended higher (9 of 9 vs 4 of 7), likely due to a lower rate of infection before treatment. Conclusions Our data support a single NBS testing-and-referral algorithm for all gestational ages. Despite lower median TREC values in premature infants, the majority for all ages are well above the TREC cutoff and the algorithm, which selects urgent (undetectable TREC) and repeatedly abnormal TREC values, minimizes referral. We also found that low naive T-cell percentage is associated with a higher risk of SCID/CID, demonstrating the utility of memory/naive T-cell phenotyping as part of follow-up flow cytometry.

Patients lacking functional adenosine deaminase activity have severe combined immunodeficiency (ADA SCID), which can be treated with ADA enzyme replacement therapy (ERT), allogeneic hematopoietic stem cell transplantation (HSCT), or autologous HSCT with gene-corrected cells (gene therapy [GT]). A cohort of 10 ADA SCID patients, aged 3 months to 15 years, underwent GT in a phase 2 clinical trial between 2009 and 2012. Autologous bone marrow CD34(+) cells were transduced ex vivo with the MND (myeloproliferative sarcoma virus, negative control region deleted, dl587rev primer binding site)–ADA gammaretroviral vector (gRV) and infused following busulfan reduced-intensity conditioning. These patients were monitored in a long-term follow-up protocol over 8 to 11 years. Nine of 10 patients have sufficient immune reconstitution to protect against serious infections and have not needed to resume ERT or proceed to secondary allogeneic HSCT. ERT was restarted 6 months after GT in the oldest patient who had no evidence of benefit from GT. Four of 9 evaluable patients with the highest gene marking and B-cell numbers remain off immunoglobulin replacement therapy and responded to vaccines. There were broad ranges of responses in normalization of ADA enzyme activity and adenine metabolites in blood cells and levels of cellular and humoral immune reconstitution. Outcomes were generally better in younger patients and those receiving higher doses of gene-marked CD34(+) cells. No patient experienced a leukoproliferative event after GT, despite persisting prominent clones with vector integrations adjacent to proto-oncogenes. These long-term findings demonstrate enduring efficacy of GT for ADA SCID but also highlight risks of genotoxicity with gRVs. This trial was registered at www.clinicaltrials.gov as #NCT00794508.

Sickle cell disease is characterized by hemolytic anemia, pain, and progressive organ damage. A high level of erythrocyte fetal hemoglobin (HbF) comprising α- and γ-globins may ameliorate these manifestations by mitigating sickle hemoglobin polymerization and erythrocyte sickling.We enrolled patients with sickle cell disease in a single-center, open-label pilot study. The investigational therapy involved infusion of autologous CD34+ cells transduced with the BCH-BB694 lentiviral vector, which encodes a short hairpin RNA (shRNA) targetingAs of October 2020, six patients had been followed for at least 6 months after receiving BCH-BB694 gene therapy; median follow-up was 18 months (range, 7 to 29). All patients had engraftment, and adverse events were consistent with effects of the preparative chemotherapy. All the patients who could be fully evaluated achieved robust and stable HbF induction (percentage HbF/(F+S) at most recent follow-up, 20.4 to 41.3%), with HbF broadly distributed in red cells (F-cells 58.9 to 93.6% of untransfused red cells) and HbF per F-cell of 9.0 to 18.6 pg per cell. Clinical manifestations of sickle cell disease were reduced or absent during the follow-up period.This study validates BCL11A inhibition as an effective target for HbF induction and provides preliminary evidence that shmiR-based gene knockdown offers a favorable risk-benefit profile in sickle cell disease. (Funded by the National Institutes of Health; ClinicalTrials.gov number, NCT03282656).

Background Iron uptake mediated by transferrin receptor 1 (TfR1), encoded by the TFRC gene, is essential for lymphocyte development and proliferation. Autosomal-recessive mutations in the human TFRC gene cause a combined immunodeficiency characterized by defective T- and B-cell proliferation as well as impaired class-switching. Clinical presentations have been severe in all reported cases, with symptoms including recurrent sinopulmonary infections, hypogammaglobulinemia, chronic diarrhea, and intermittent cytopenias. Objective To describe outcomes of allogeneic hematopoietic stem cell transplantation (HSCT) in patients with TFRC deficiency. Methods Retrospective chart review study of 5 patients with TFRC deficiency who underwent allogeneic HSCT between July 2011 and May 2018 at Boston Children's Hospital. Results Intermittent thrombocytopenia and neutropenia were a predominant feature of the clinical presentation in our cohort, and 3 patients who underwent bone marrow evaluation before HSCT were found to have signs of dysmyelopoiesis and dysplasia. One patient, who had a transplant at age 11 years, developed a clonal cytogenetic abnormality concerning for myelodysplastic syndrome. All 5 patients tolerated myeloablative conditioning regimens and had robust donor cell engraftment with resolution of cytopenias and independence from intravenous immunoglobulin substitution. All 5 patients were alive at a median follow-up of 47.1 months posttransplant (range, 15.7-85.4) and none had developed acute or chronic graft-versus-host disease. Conclusions Allogeneic HSCT is curative for TFRC deficiency and rescues all known disease manifestations. Patients with TFRC deficiency may have a predisposition to malignant transformation of hematopoietic cells and may benefit from HSCT earlier in their disease course.

PURPOSE: The Primary Immune Deficiency Treatment Consortium (PIDTC) enrolled children with severe combined immunodeficiency (SCID) in a prospective natural history study of hematopoietic stem cell transplant (HSCT) outcomes over the last decade. Despite newborn screening (NBS) for SCID, infections occurred prior to HSCT. This study’s objectives were to define the types and timing of infection prior to HSCT in patients diagnosed via NBS or by family history (FH) and to understand the breadth of strategies employed at PIDTC centers for infection prevention. METHODS: We analyzed retrospective data on infections and pre-transplant management in patients with SCID diagnosed by NBS and/or FH and treated with HSCT between 2010 and 2014. PIDTC centers were surveyed in 2018 to understand their practices and protocols for pre-HSCT management. RESULTS: Infections were more common in patients diagnosed via NBS (55%) versus those diagnosed via FH (19%) (p = 0.012). Outpatient versus inpatient management did not impact infections (47% vs 35%, respectively; p = 0.423). There was no consensus among PIDTC survey respondents as to the best setting (inpatient vs outpatient) for pre-HSCT management. While isolation practices varied, immunoglobulin replacement and antimicrobial prophylaxis were more uniformly implemented. CONCLUSION: Infants with SCID diagnosed due to FH had lower rates of infection and proceeded to HSCT more quickly than did those diagnosed via NBS. Pre-HSCT management practices were highly variable between centers, although uses of prophylaxis and immunoglobulin support were more consistent. This study demonstrates a critical need for development of evidence-based guidelines for the pre-HSCT management of infants with SCID following an abnormal NBS. TRIAL REGISTRATION: NCT01186913