Introduction Chronic granulomatous disease (CGD) is an inborn error of immunity characterized by life-threatening infections and inflammatory complications. Allogeneic hematopoietic cell transplantation (HCT) is a curative therapy with event-free survival approaching 80% with human leukocyte antigen (HLA)-matched donors. Objectives In patients without HLA-matched donors, mismatched related or unrelated donors (MMRD or MMUD) have been used, but detailed comparisons of HCT outcomes for these two options are limited. Methods This study investigated 46 patients with CGD who underwent MMRD (n=24) or MMUD (n=22) HCT at 21 Primary Immunodeficiency Treatment Consortium (PIDTC) centers between 1996 and 2023. HLA match was classified based on typing for 8 alleles. Results Most (n=42, 91%) were male, most (n=38, 83%) had X-linked CGD. Patients with MMRD were significantly older at HCT [median 5.6 (range 0.5-23.6) vs. median 2.2 (range 0.7-19) years, p=0.010] and had a higher incidence of pre-HCT inflammatory disease (63% vs. 19%, p=0.009) than patients with MMUD. Because of this, a significantly higher percentage of MMRD patients received systemic corticosteroids in the year prior to HCT (46% vs. 14%, p=0.018). Severe inflammation was the primary indication for MMRD HCT (42%); in contrast, severe infection (45%) or a diagnosis of CGD (45%) were the primary indications for MMUD HCT. MMRD HCTs were more likely to be T cell depleted, 7 (29%) with TCRαβ/CD19+ depletion and 11 (46%) with post-HCT cyclophosphamide (PTCy). Conversely, 11 (50%) MMUD grafts underwent ex vivo T cell depletion, and no patients received PTCy. Most (n=34, 74%) patients received busulfan-based conditioning and most (n=38, 83%) received serotherapy. Graft-versus-host disease (GVHD) prophylaxis regimens were different between the two groups. MMRD patients received primarily PTCy-based regimens (46%) or no prophylaxis with TCRαβ/CD19+ depletion (29%) whereas patients with MMUD received primarily calcineurin inhibitor-based (73%) regimens. Estimated 5-year overall (MMRD 70%, MMUD 77%, p=0.645) and event-free survival (MMRD 58%, MMUD 58%, p=0.88) (Figure 1), cumulative incidence of graft failure (MMRD 21%, MMUD 11%, p=0.242), and rates of Grade II-IV acute (MMRD 31%, MMUD 21%, p=0.314), Grade III-IV acute (MMRD15%, MMUD 11%, p=0.XXX) and chronic (MMRD 29%, MMUD 12%, p=0.576) GVHD (Figure 2) were similar between the two groups. Pre-existing infections and inflammatory disease resolved post-HCT in both groups with no new CGD-related infections or inflammatory disease for up to 10 years of follow up. Conclusion MMRD and MMUD HCT are associated with higher rates of GVHD and lower event-free survival than HLA-matched HCT but are feasible options for CGD patients without an HLA-matched donor, offering long-term survival and resolution of disease. Future efforts should be focused on the reduction of graft failure and GVHD.

Non-Helicobacter pylori Helicobacter (NHPH) species are recognized as a cause of chronic systemic infection, cellulitis, and osteomyelitis in patients with X-linked agammaglobulinemia (XLA). Diagnosis and treatment are challenging due to fastidious growth, lack of standardized therapies, and frequent recurrence. We describe two cases of disseminated NHPH infection in XLA, including a patient where allogeneic hematopoietic cell transplant (HCT) was incorporated into management to achieve durable immune reconstitution and cure infection. One patient with disseminated Helicobacter bilis osteomyelitis discontinued antibacterials 14 months post-HCT following immune reconstitution. Another patient with disseminated Helicobacter cinaedi remains on antibacterials and is being evaluated for HCT. In select cases, HCT may represent a potential option to correct the immunodeficiency and enable infection clearance, with antibacterial therapy continued through HCT until systemic immunosuppression is withdrawn, immune reconstitution is documented, and infection resolves.

BACKGROUND:Severe intestinal or hepatobiliary cryptosporidiosis affects patients with inborn errors of immunity (IEI), particularly those with CD40 ligand or CD40 deficiency, major histocompatibility complex class II deficiency, interleukin-21 receptor deficiency, and DOCK8 deficiency. Susceptibility to Cryptosporidium reflects defects in lymphocyte development, activation, and effector function. METHODS:We conducted a retrospective chart review of IEI patients with cryptosporidiosis, focusing on 17 individuals with chronic infection who underwent hematopoietic cell transplant (HCT), to characterize their clinical course, diagnostic evaluation, management, and outcomes. A literature review was also performed to summarize current knowledge of cryptosporidiosis in IEI patients. RESULTS:Patients frequently presented with secondary sclerosing cholangitis, posing significant diagnostic and therapeutic challenges. Molecular diagnostic assays offered higher sensitivity than conventional microscopy. Antiparasitic agents had limited efficacy against hepatobiliary disease. Durable immune reconstitution through HCT remained the mainstay of management, though it carries risk, especially in patients with established liver disease. Prophylactic strategies for at-risk individuals remain underexplored but should include exposure avoidance and consideration of antiparasitic prophylaxis. CONCLUSIONS:Cryptosporidium-related sclerosing cholangitis imposes a substantial disease burden in susceptible IEI patients, underscoring the importance of early recognition and proactive management, particularly timely immune reconstitution in this population.

TLR8 gain-of-function (GOF) somatic variants were recently identified as causing severe neutropenia, lymphoproliferation, and immune dysregulation. We report the expanded clinical and laboratory phenotype and management of 10 patients, including the original cohort of 6 male patients. We identify the first female patient with TLR8 GOF who presented during infancy with pure red cell aplasia due to a germline TLR8 variant, and two new disease-causing somatic variants in male patients. Eight patients had somatic mosaicism with peripheral blood variant allele fractions of 7-26% and age of disease onset of 9 months to 28 years. All patients had neutropenia, most with severe neutropenia refractory to medical therapy. Anemia and thrombocytopenia were common. Bone marrow characteristically demonstrated severe myeloid hypoplasia and activated T-cell infiltrates and/or aggregates. An increased number of large granular lymphocytes (LGLs) were identified in five patients. Seven patients underwent allogeneic hematopoietic cell transplantation (HCT). High rates of post-HCT cytopenia of unclear etiology and graft-versus-host disease were observed. Five are surviving at 1 to 3 years post-HCT with full donor myeloid and T-cell chimerism and resolution of disease phenotype. The two patients who presented during childhood and did not undergo HCT ultimately died from disease. In conclusion, TLR8 GOF is an X-linked dominant disorder that should be considered in male and female patients with cytopenia, particularly severe neutropenia, lymphoproliferation with immune dysregulation, increased LGLs, and new to this cohort, red cell aplasia. Disease is refractory to medical management, and curative, allogeneic HCT should be considered early after diagnosis. (NCT04339777)

BACKGROUND:Signal transducer and activator of transcription 3 hyper-IgE syndrome (STAT3-HIES) is a multisystem disorder with both immunologic and nonimmunologic manifestations. OBJECTIVE:We sought to characterize the spectrum of clinical manifestations, genetics, treatment approaches, and long-term outcomes of patients with STAT3-HIES. METHODS:Clinical features, laboratory findings, treatment, and survival were reviewed in the largest single-center STAT3-HIES cohort (n = 164) prospectively followed under a natural history protocol (NCT00006150). RESULTS:In addition to the classic skin, lung, dental, and musculoskeletal manifestations captured in the 1999 scoring system, we comprehensively characterized disease phenotypes across multiple organ systems, including previously underrecognized features. Lung disease remained the major morbidity with both infectious and parenchymal complications. During longitudinal follow-up, age-related vascular and skeletal degeneration emerged and significantly affected quality of life in patients 45 years and older. No genotype-phenotype correlations were identified. In terms of management, optimal supportive measures, including antimicrobials and immunoglobulin replacement therapy, tailored to disease features and individual risk factors, remained the primary approach. Dupilumab was used primarily for the eczematous dermatitis and demonstrated significant clinical benefit. In highly selected cases (n = 6), allogeneic hematopoietic stem cell transplantation was performed and showed reduction in infection burden. The median overall survival was 55 years-significantly shorter than that of the general United States population-and was not affected by sex, variant location, or proband status. CONCLUSIONS:STAT3-HIES is a multisystem disorder that requires multidisciplinary care. Early diagnosis and supportive measures have altered its natural history. Recognition and improved understanding of the nonimmunologic manifestations of this disorder will further improve patient outcomes.

BACKGROUND:Evaluating natural history and outcomes of rare inborn errors of immunity (IEIs) has been challenging due to the diverse disease manifestations and lack of standardized data. OBJECTIVE:To develop a set of standardized, quantitative, generalizable data collection modules to measure organ dysfunction in IEIs, modeled on the previously validated Common Terminology Criteria for Adverse Event system for grading treatment toxicity. METHODS:Disease conditions were organized by organ system. Experts from the Primary Immune Deficiency Treatment Consortium identified essential features of severe combined immunodeficiency, chronic granulomatous disease, Wiskott-Aldrich syndrome, and primary immune regulatory disorders and compared these to Common Terminology Criteria for Adverse Event conditions, adding and refining features as needed. Dates of onset and resolution, disease-specific laboratory values, and therapeutic interventions were also incorporated. Modules were reviewed by protocol teams, key stakeholders, clinical coordinators, and statisticians to improve feasibility and completeness. RESULTS:We developed a tool called IMPACT (Immune Monitoring and Phenotype Assessment of Clinical Trajectory) containing 15 modules assessing 196 disease conditions. A grading system from 1 to 5 (mild, moderate, severe, life-threatening, fatal) permits longitudinal tracking of disease condition severity. Outcomes of interventions can be measured quantitatively by comparing scores before and after treatment. CONCLUSIONS:Standardized, quantitative assessment tools for IEIs can yield uniform data sets to illuminate their natural history and evaluate outcomes of interventions, not only to understand specific diseases but also to compare effects between disease entities. Tools, such as IMPACT, are essential for therapeutic trials for rare, complex multisystem diseases such as IEIs and other disorders with protean manifestations.

Chronic granulomatous disease (CGD) is an inborn error of immunity caused by defects in NADPH oxidase, which causes phagocyte dysfunction. CGD is characterized by recurrent infections and autoimmunity. Allogeneic hematopoietic stem cell transplantation (HSCT) is a curative therapy. However, data regarding patient satisfaction with post-HSCT state of health and quality of life are lacking. A Primary Immune Deficiency Treatment Consortium (PIDTC) working group designed online surveys to assess post-HSCT quality of life and satisfaction with transplantation. Surveys were distributed from November 2023 to March 2024 to all members of the CGD Association of America (CGDAA). Adults who personally underwent or parents of children who underwent HSCT for CGD were asked to participate. Two surveys were offered: one for participants who were 18 years or older and one for parents of patients. Complete surveys representing 54 unique patients were included for analysis. Forty-four were from parents whose children were a median of 12 years old and a median of 6 years post-transplant. Nine were returned from patients who were a median of 30 years old and a median of 4 years post-transplant (Table 1). Table 1. Seventy-eight percent of patient and parent respondents reported that quality of life was better after transplant and 89% felt that the transplant improved their physical health (Figure 1). Figure 1. (A) Do you feel quality of life is better now post-transplant than it was pre-transplant? (B) Do you feel that the transplant has been beneficial from a medical perspective? PROMIS Global Health scoring tool revealed 84% of patients had mental health scores within 1 SE of the mean. Only a few mental health diagnoses were self-reported (Figure 2). Figure 2. (A) PROMIS Mental Health Report Scores. (B) Mental health condition diagnosed by a physician. After transplant, there were no self-reported cases of autoimmune disease or malignancy. Three participants were able to conceive children. One respondent used sperm banking; two did not use fertility preservation or treatments. Our data demonstrate that the majority of patients who undergo allogeneic HSCT for definitive treatment of CGD experience improvements in physical and/or mental health and enjoy an improved quality of life after transplant. Overall, this study supports positive outcomes for patients treated with allogeneic HSCT.

This abstract has been removed: please see Elsevier policy on article withdrawal (https://www.elsevier.com/about/policies-and-standards/article-withdrawal). This article has been removed at the request of the author. This abstract has been removed because it was not presented at the 2025 BMT Tandem Meeting.

BACKGROUND:Allogeneic hematopoietic cell transplantation corrects the phagocytic defect in patients with chronic granulomatous disease (CGD) and resolves infection risk and immune dysregulation. Umbilical cord blood transplantation (UCBT) is an option for patients lacking suitable HLA-matched bone marrow or peripheral blood stem cell donors. However, information related to UCBT for CGD is limited to a few small case series and limited subsets of larger cohorts where detailed information is lacking. OBJECTIVES:To describe UCBT procedures and outcomes in patients with CGD. STUDY DESIGN:Thirty-nine patients with CGD who underwent UCBT at Primary Immune Deficiency Treatment Consortium (PIDTC) centers between 2001 and 2019 were included. RESULTS:All patients were male, and most (97%) had X-linked CGD due to pathogenic variants in CYBB. High infection burden (1.72/person years) and inflammatory disease (38%) were common in the year pre-UCBT. Median age at receipt of UCBT was 2.1 (range 0.3-14.0) years. Most (87%) patients received UCB from unrelated donors, and most (72%) patients received busulfan and cyclophosphamide-based conditioning. All but two (95%) patients received serotherapy with anti-thymocyte globulin or alemtuzumab. Neutrophil and platelet recovery occurred at a median of 18 (range 12-46) and 38 (range 21-186) days, respectively. Nine patients experienced early graft failure [donor myeloid chimerism <10% or receipt of second hematopoietic cell transplantation (HCT) within 100 days] for a cumulative incidence of 23.1% (95% CI 11.3-37.3). There were no cases of late graft failure (after 100 days), and median whole blood and myeloid donor chimerism of engrafted patients were >95% at all time points. One of the nine patients with early graft failure had autologous reconstitution. The remaining 8 patients underwent repeat HCT; six of the patients survived and achieved durable myeloid engraftment on long-term follow-up. Twenty-eight patients were alive at a median follow-up of 4.28 (IQR 2.66-6.08) years. Estimated 3-year overall and event-free survival were 73.7% (95% CI 56.5-84.9) and 56.2% (95% CI 39.3-70.1), respectively. No identifiable factors, including history of infection or inflammatory disease in the year prior to UCBT, year of UCBT, age at UCBT, conditioning regimen, cell dose, and recipient and donor HLA match, were associated with graft failure or survival. Infections decreased with time post-UCBT and pre-existing inflammatory disease resolved in all surviving patients CONCLUSIONS: UCBT for CGD is associated with high rates of early graft failure. Nevertheless, UCBT can provide an effective alternative for CGD patients when HLA-matched donors are not available with resolution of disease. Strategies to overcome high rates of early graft failure while optimizing conditioning regimens to minimize toxicity are needed.

Cutaneous squamous-cell carcinoma (SCC) is primarily caused by oncogenesis mediated by ultraviolet radiation, and β-human papillomavirus (β-HPV) is believed to be a mere facilitator that is dispensable for the maintenance of cutaneous SCC. Here, we describe a woman with benign and malignant HPV-related diseases that include a recurrent, unresectable, invasive cutaneous SCC with β-HPV19 genomic integration in the context of germline pathogenic mutations in ZAP70, an adapter required for T-cell receptor (TCR) signal transduction. Restoration of the integrity of TCR signaling by allogeneic hematopoietic-cell transplantation led to the resolution of all HPV-related diseases, thereby revealing a direct role of β-HPV in skin carcinogenesis in hosts with defective adaptive T-cell responses. (Funded by the National Institutes of Health.).

Background:Toxoplasmosis is an early post-transplant complication in recipients of allogeneic hematopoietic cell transplant (HCT), typically arising from reactivation of latent infection. Toxoplasma gondii polymerase chain reaction (PCR) has improved detection. Methods:Single-center, retrospective review of allogeneic HCT recipients who developed toxoplasmosis from August 2008 to November 2024. Results:We identified 31 cases of toxoplasmosis among 1235 HCT recipients. Ten had infection and 21 had end-organ disease. Fever was the most common clinical manifestation (74.2%). Patients with pulmonary or central nervous system disease often lacked organ-specific symptoms. Toxoplasmosis primarily occurred in patients not on prophylaxis (90.3%), at a median of 28 days post-HCT (interquartile range 20-69 days). Whole blood Toxoplasma PCR diagnosed 80.6% cases and showed a cumulative sensitivity of 93.3%. However, PCR was not always positive at symptom onset, and some asymptomatic patients already had end-organ disease at the time of first PCR positivity. Trimethoprim-sulfamethoxazole (TMP-SMX) was the most used treatment (48.4%). Mortality directly attributable to toxoplasmosis was 12.9%, but all-cause mortality was 61.3%. Conclusions:Toxoplasmosis is an early post-HCT complication with high morbidity and mortality. Prophylaxis is essential. TMP-SMX is effective, but sometimes it is withheld early post-HCT due to potential myelotoxicity. Given the short window between infection and progression to disease, we recommend twice-weekly monitoring with whole blood PCR while off TMP-SMX and early initiation of TMP-SMX post-HCT for Toxoplasma seropositive patients. Atovaquone may be considered as a bridging prophylaxis until TMP-SMX is started, but its absorption may be compromised early post-HCT and breakthrough cases have been reported.

NADPH oxidase (NOX) family members are major resources of intracellular reactive oxygen species (ROS). In the immune system, ROS derived from phagocytic NOX (NOX2) participate in both pathogen clearance and signaling transduction. The role of NOX2 in neutrophils and macrophages has been well studied as mutations in NOX2 subunits cause chronic granulomas disease (CGD). NOX2 is expressed across a wide range of immune cells and recent reports have demonstrated that NOX2-derived ROS play important roles in other immune cells during an immune response. In this review, we summarize current knowledge of functions of NADPH oxidase 2 in each subset of leukocytes, as well as associations of NOX2 deficiency with diseases associated specifically with autoimmunity and immune deficiency. We also discuss important knowledge gaps as well as potential future directions for NOX2 research.

Background The CDC and ACIP recommend COVID-19 vaccination for patients with inborn errors of immunity (IEI). Not much is known about vaccine safety in IEI, and whether vaccination attenuates infection severity in IEI. Objective To estimate COVID-19 vaccination safety and examine effect on outcomes in patients with IEI. Methods We built a secure registry database in conjunction with the US Immunodeficiency Network to examine vaccination frequency and indicators of safety and effectiveness in IEI patients. The registry opened on January 1, 2022, and closed on August 19, 2022. Results Physicians entered data on 1245 patients from 24 countries. The most common diagnoses were antibody deficiencies (63.7%). At least one COVID-19 vaccine was administered to 806 patients (64.7%), and 216 patients received vaccination prior to the development of COVID-19. The most common vaccines administered were mRNA-based (84.0%). Seventeen patients were reported to seek outpatient clinic or emergency room care for a vaccine-related complication, and one patient was hospitalized for symptomatic anemia. Eight hundred twenty-three patients (66.1%) experienced COVID-19 infection. Of these, 156 patients required hospitalization (19.0%), 47 required ICU care (5.7%), and 28 died (3.4%). Rates of hospitalization (9.3% versus 24.4%, p < 0.001), ICU admission (2.8% versus 7.6%, p = 0.013), and death (2.3% versus 4.3%, p = 0.202) in patients who had COVID-19 were lower in patients who received vaccination prior to infection. In adjusted logistic regression analysis, not having at least one COVID-19 vaccine significantly increased the odds of hospitalization and ICU admission. Conclusion Vaccination for COVID-19 in the IEI population appears safe and attenuates COVID-19 severity.

Background: P47phox (neutrophil cytosolic factor -1) deficiency is the most common cause of autosomal recessive chronic granulomatous disease (CGD) and is considered to be associated with a milder clinical phenotype. Allogeneic hematopoietic cell transplantation (HCT) for p47phox CGD is not well described. Objectives: We sought to study HCT for p47phox CGD in North America. Methods: Thirty patients with p47phox CGD who received allogeneic HCT at Primary Immune Deficiency Treatment Consortium centers since 1995 were included. Results: Residual oxidative activity was present in 66.7% of patients. In the year before HCT, there were 0.38 CGD-related infections per person -years. Inflammatory diseases, predominantly of the lungs and bowel, occurred in 36.7% of the patients. The median age at HCT was 9.1 years (range 1.5-23.6 years). Most HCTs (90%) were performed after using reduced intensity/toxicity conditioning. HCT sources were HLAmatched (40%) and -mismatched (10%) related donors or HLA-matched (36.7%) and -mismatched (13.3%) unrelated donors. CGD-related infections after HCT decreased significantly to 0.06 per person -years ( P 5 .038). The frequency of inflammatory bowel disease and the use of steroids also decreased. The cumulative incidence of graft failure and second HCT was 17.9%. The 2 -year overall and event -free survival were 92.3% and 82.1%, respectively, while at 5 years they were 85.7% and 77.0%, respectively. In the surviving patients evaluated, >= 95% donor myeloid chimerism at 1 and 2 years after HCT was 93.8% and 87.5%, respectively. Conclusions: Patients with p47phox CGD suffer from a significant disease burden that can be effectively alleviated by HCT. Similar to other forms of CGD, HCT should be considered for patients with p47phox CGD.

Abstract Background Immune reconstitution inflammatory syndrome (IRIS) was first described in patients with HIV and opportunistic infections starting antiretroviral therapy, but may be seen following hematopoietic cell transplantation (HCT) in patients with pre-existing infections. GATA2 deficiency is a genetic disorder with a marked susceptibility to mycobacterial infections, and is treated definitively with HCT. The clinical factors and pathogenesis of IRIS in HCT require further investigation. Methods We conducted a retrospective review of 32 patients with GATA2 deficiency and mycobacterial infections who completed > 6 months of follow-up after HCT. Uniform criteria were used to define cases of IRIS (Image 1). IRIS cases were classified as either early (post-HCT day < 60), intermediate (days 61-120), or late (day > 120). Image 1. Post-Hematopoietic Cell Transplant IRIS Criteria Criteria were adapted to hematopoietic cell transplantation from the AIDS Clinical Trial Group IRIS criteria. Results Clinical characteristics are shown in Image 2. IRIS was identified in 12 (35%) patients (Images 2-3). These patients were more likely to have disseminated infection (P=0.03), an elevated pre-HCT ferritin (P=0.03), and a lower day 30 post-HCT CD4 count (P=0.04). Median time to IRIS was 100 days (Image 4). Pre-transplant duration of mycobacterial therapy correlated with time to IRIS (Pearson’s r=0.58, P=0.05). Conditioning regimens using total body irradiation with or without cyclophosphamide were associated with longer time to IRIS (hazard ratio=0.04, P=0.02). A rise in CD3 chimerism was seen during early cases of IRIS, but not intermediate to late (P=0.002). IRIS emerged during tapering of systemic immunosuppressive therapy in 33% of cases. IRIS was managed conservatively (50%), by intensification of anti-mycobacterial treatment (8%) or by intensification of immunosuppression (42%). Conclusion Development of mycobacterial IRIS after HCT for GATA2 deficiency was associated with disseminated infection, a high pre-transplant ferritin, and low day 30 CD4 count. These findings suggest that antigen burden, a hyperinflammatory state leading into transplantation, and CD4 nadir after HCT have a role in its pathogenesis. Early cases of IRIS may emerge during lymphoid engraftment and CD4 recovery, whereas late cases may emerge with decreases in immunosuppressive therapy and more intensive conditioning regimens. Clinical outcomes were similar to non-IRIS patients. Disclosures All Authors: No reported disclosures

Toll-like receptor 8 gain-of-function (TLR8 GOF) is a recently described inborn error of immunity due to germline or somatic mutations in the TLR8 gene and characterized by severe neutropenia, infections, lymphoproliferation, humoral immune defects, and in some cases, bone marrow failure. Treatment of TLR8 GOF has been challenging to date, and guidance for optimal therapy is lacking. We describe the clinical characteristics and management of 10 patients with TLR8 GOF variants, including the first female patient and further clinical outcome on the 6 patients initially reported with this disease with a focus on the role of allogeneic hematopoietic cell transplantation (HCT). All but one patient were male ranging from 0.5 months to 28 years at age of symptom onset. Eight patients had somatic mutations with variant allele frequencies of 7-26%; two patients had germline mutations. The 9 male patients all had severe neutropenia and varying degrees of anemia and/or thrombocytopenia. Oral ulcers, recurrent infections, hepatosplenomegaly, and hypogammaglobulinemia were common. Immune phenotype was variable, ranging from severe lymphopenia to marked T cell lymphoproliferation. Several patients had an inverted CD4:CD8 T cell ratio and skewing of T cell subsets to the terminal effector memory phenotype. Increased double-negative T cells were also observed. All patients had low class switched memory B cells. Bone marrows were hypo- to hypercellular with marked myeloid hypoplasia, and in most cases, with increased T cells, large granular lymphocytes, and/or lymphoid aggregates. Neutropenia was initially responsive to granulocyte colony stimulating factor (GCSF) +/- steroids in several patients but ultimately become refractory to therapy. Immunomodulatory agents and chemotherapy were unsuccessful. Six patients underwent allogeneic HCT; two patients died at 8 and 18 years without definitive therapy; and one patient was lost to follow-up. The female patient had germline disease and presented with pure red blood cell aplasia at 2 weeks of life and is scheduled to undergo HCT. Transplant data were available for 5 of 6 patients who underwent HCT. Age at transplant was 3 to 21 years. One patient who received a graft from a 7/8 HLA-matched unrelated donor developed severe veno-occlusive disease and secondary graft failure. The patient underwent a second transplant and ultimately died. Another patient received a matched sibling donor HCT while critically ill from Candida lusitaniae and mucormycosis infection with associated multisystem organ failure. The patient engrafted with 100% donor chimerism but died on day +15 post-HCT. The remaining 3 patients are alive and well 8 months to 2 years post-HCT. Two patients received grafts from HLA-matched donors (1 sibling and 1 unrelated) with reduced intensity conditioning and cyclophosphamide, mycophenolate mofetil and vorinostat for graft-versus-host disease (GVHD) prophylaxis. The third patient underwent a haploidentical HCT with myeloablative conditioning and post-transplant cyclophosphamide. Post-HCT complications included acute skin and/or gastrointestinal GVHD that was responsive to therapy in all patients, and severe lung GVHD in one patient. There were no major infectious complications. All three patients had full donor chimerism in myeloid and T cells with complete resolution of disease phenotype at last follow-up. The patient for whom detailed transplant data is not available received a haploidentical HCT. He developed mixed myeloid chimerism for which he received multiple donor lymphocyte infusions and was alive at last contact >3 years post-HCT. TLR8 GOF should be considered in male and female patients with severe, unexplained neutropenia refractory to GCSF, and particular care should be taken when investigating for mutations given the disease-causing variant allele frequencies as low as 7%. Neutropenia and immune dysregulation were refractory to all therapies in our cohort, and TLR8 GOF was fatal in two patients who did not receive definitive therapy. Allogeneic HCT is curative and should be considered without delay for medically suitable patients.

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) enrolled from 2004 to 2018 or with HCT from 1996 to 2018. Median follow-up after HCT was 3.7 years with a 3-year overall survival of 82% and event-free survival of 69%. In a multivariate analysis, a Lansky/Karnofsky score <90 and use of HLA-mismatched donors negatively affected survival. Age, genotype, and oxidase status did not affect outcomes. Before HCT, patients had higher infection density, higher frequency of noninfectious lung and liver diseases, and more steroid use than conventionally treated patients; however, 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 a second HCT occurred in 17.6% of the patients and was associated with melphalan-based conditioning and/or early mixed chimerism. At 3 to 5 years after HCT, patients had improved growth and nutrition, resolved infections and inflammatory disease, and lower rates of antimicrobial prophylaxis or corticosteroid use compared with both their baseline and those of conventionally treated patients. HCT leads to durable resolution of CGD symptoms and lowers the burden of the disease. Patients with active infection or inflammation are candidates for transplants; HCT should be considered before the development of comorbidities that could affect performance status. This trial was registered at www.clinicaltrials.gov as #NCT02082353.

Purpose of review Hematopoietic stem cell-based therapies, including allogeneic hematopoietic cell transplantation (HCT) and autologous gene therapy (GT), have been used as curative therapy for many inborn errors of immunity (IEI). As the number of genetically defined IEI and the use of HCT and GT increase, valuable data on outcomes and approaches for specific disorders are available. We review recent progress in HCT and GT for IEI in this article. Recent findings Novel approaches to prevention of allogeneic complications and experience in adolescents and young adults have expanded the use of HCT. Universal newborn screening for severe combined immunodeficiency (SCID) has led to improved outcome after HCT. Analysis of outcomes of HCT and GT for SCID, Wiskott-Aldrich syndrome (WAS) and chronic granulomatous disease (CGD) reveal risk factors for survival, the impact of specific conditioning regimens, and vector- or disease-specific impacts on efficacy and safety. Preclinical studies of GT and gene editing show potential for translation to the clinic. Summary Emerging data on outcome after HCT for specific IEI support early evaluation and treatment, before development of co-morbidities. Data in large cooperative retrospective databases continues to yield valuable insights clinicians can use in patient selection and choice of therapy.

PURPOSE OF REVIEW:GATA2 deficiency is a haploinsufficiency syndrome associated with a wide spectrum of disease, including severe monocytopenia and B and NK lymphopenia, predisposition to myeloid malignancies, human papillomavirus infections, and infections with opportunistic organisms, particularly nontuberculous mycobacteria, herpes virus, and certain fungi. GATA2 mutations have variable penetrance and expressivity with imperfect genotype-phenotype correlations. However, approximately 75% of patients will develop a myeloid neoplasm at some point. Allogeneic hematopoietic cell transplantation (HCT) is the only currently available curative therapy. Here, we review the clinical manifestations of GATA2 deficiency, characterization of the hematologic abnormalities and progression to myeloid malignancy, and current HCT practices and outcomes.RECENT FINDINGS:Cytogenetic abnormalities are common with high rates of trisomy 8, monosomy 7, and unbalanced translocation der(1;7) and may suggest an underlying GATA2 deficiency in patients presenting with myelodysplastic syndrome (MDS). Mutations in ASXL1 and STAG2 are the most frequently encountered somatic mutations and are associated with lower survival probability. A recent report of 59 patients with GATA2 deficiency who underwent allogenic HCT with myeloablative, busulfan-based conditioning and post-transplant cyclophosphamide reported excellent overall and event-free survival of 85% and 82% with reversal of disease phenotype and low rates of graft versus host disease. Allogeneic HCT with myeloablative conditioning results in disease correction and should be considered for patients with a history of recurrent, disfiguring and/or severe infections, organ dysfunction, MDS with cytogenetic abnormalities, high-risk somatic mutations or transfusion dependence, or myeloid progression. Improved genotype/phenotype correlations are needed to allow for greater predictive capabilities.