Omenn Syndrome in Two Infants with Different Hypomorphic Variants in Janus Kinase 3.

Biallelic null or hypomorphic variants in JAK3 cause SCID and less frequently Omenn syndrome. We investigated homozygous hypomorphic JAK3 mutations in two patients, and expression and function of a novel JAK3R431P variant in Omenn syndrome. Immunophenotyping of PBMC from the patient with the novel JAK3R431P variant was undertaken, by flow cytometry and Phosflow after stimulation with IL-2, IL-7, and IL-15. JAK3 expression was investigated by Western blotting. We report two patients with homozygous hypomorphic JAK3 variants and clinical features of Omenn syndrome. One patient had a previously described JAK3R775H variant, and the second had a novel JAK3R431P variant. One patient with a novel JAK3R431P variant had normal expression of JAK3 in immortalised EBV-LCL cells but reduced phosphorylation of STAT5 after stimulation with IL-2, IL-7, and IL-15 consistent with impaired kinase activity. These results suggest the JAK3R431P variant to be hypomorphic. Both patients are alive and well after allogeneic haematopoietic stem cell transplantation. They have full donor chimerism, restitution of thymopoiesis and development of appropriate antibody responses following vaccination. We expand the phenotype of hypomorphic JAK3 deficiency and demonstrate the importance of functional testing of novel variants in disease-causing genes.

Outcomes of HLA-mismatched HSCT with TCRαß/CD19 depletion or post-HSCT cyclophosphamide for inborn errors of immunity.

HLA-mismatched transplants with either in vitro depletion of CD3+TCRαß/CD19 (TCRαß) cells or in vivo T-cell depletion using post-transplant cyclophosphamide (PTCY) have been increasingly used for patients with inborn errors of immunity (IEI). We performed a retrospective multicenter study via the EBMT registry on 306 children with IEI undergoing first transplant between 2010-2019 from an HLA-mismatched donor using TCRαß (n=167) or PTCY (n=139). Median age at HSCT was 1.2 years (range, 0.03-19.6 years). The 3-year overall survival (OS) was 78% (95% confidence interval (CI), 71-84%) after TCRαß and 66% (57-74%) after PTCY (p=0.013). Pre-HSCT morbidity score (hazard ratio (HR) 2.27, 1.07-4.80, p=0.032) and non-Busulfan/Treosulfan conditioning (HR 3.12, 1.98-4.92, p<0.001) were the only independent predictors of unfavorable OS. The 3-year event-free survival (EFS) was 58% (50-66%) after TCRαß and 57% (48-66%) after PTCY (p=0.804). Cumulative incidence of severe acute GvHD was higher after PTCY (15%, 9-21%) than TCRαß (6%, 2-9%, p=0.007), with no difference in chronic GvHD (PTCY, 11%, 6-17%; TCRαß, 7%, 3-11%, p=0.173). The 3-year GvHD-free EFS was 53% (44-61%) after TCRαß and 41% (32-50%) after PTCY (p=0.080). PTCY had significantly higher rates of veno-occlusive disease (14.4% versus TCRαß 4.9%, p=0.009), acute kidney injury (12.7% versus 4.6%, p=0.032) and pulmonary complications (38.2% versus 24.1%, p=0.017). Adenoviraemia (18.3% versus PTCY 8.0%, p=0.015), primary graft failure (10%, versus 5%, p=0.048), and second HSCT (17.4% versus 7.9%, p=0.023) were significantly higher in TCRαß. In conclusion, this study demonstrates that both approaches are suitable options in IEI patients, although characterized by different advantages and outcomes.

Wiskott-Aldrich Syndrome: A study on 577 patients defining the genotype as a predictive biomarker for disease severity.

WAS is a multifaceted monogenic disorder with a broad disease spectrum and variable disease severity and a variety of treatment options including allogeneic hematopoietic stem cell transplantation (HSCT) and gene therapy (GT). No reliable biomarker exists to predict disease course and outcome for individual patients. A total of 577 patients with a WAS variant from 26 countries and a median follow-up of 8.9 years (0.3-71.1), totaling 6118 patient-years, were included in this international retrospective study. Overall survival (OS) of the cohort (censored at HSCT or GT) was 82% (95% CI 78-87) at 15 years and 70% (61-80) at 30 years of age. The type of variant was predictive of outcome: patients with a missense variant in exons 1 or 2 or with the intronic hotspot variant c.559+5G>A (class I variants) had a 15-year OS of 93% (89-98) and a 30-year OS of 91% (86-97), compared to 71% (62-81) and 48% (34-68) in patients with any other variant (class II; p<0.0001). The cumulative incidence rates of disease-related complications such as severe bleeding (p=0.007), life-threatening infection (p<0.0001), and autoimmunity (p=0.004) occurred significantly later in patients with a class I variant. The cumulative incidence of malignancy (p=0.6) was not different between classes I and II. This study represents the largest cohort of WAS patients studied so far. It confirms the spectrum of disease severity and quantifies the risk for specific disease-related complications. The class of variant is a biomarker to predict the outcome for WAS patients.

Inflammatory Complications in Chronic Granulomatous Disease.

Chronic granulomatous disease (CGD) is a rare inborn error of immunity that typically manifests with infectious complications. As the name suggest though, inflammatory complications are also common, often affecting the gastrointestinal, respiratory, urinary tracts and other tissues. These can be seen in all various types of CGD, from X-linked and autosomal recessive to X-linked carriers. The pathogenetic mechanisms underlying these complications are not well understood, but are likely multi-factorial and reflect the body's attempt to control infections. The different levels of neutrophil residual oxidase activity are thought to contribute to the large phenotypic variations. Immunosuppressive agents have traditionally been used to treat these complications, but their use is hindered by the fact that CGD patients are predisposed to infection. Novel therapeutic agents, like anti-TNFa monoclonal antibodies, anakinra, ustekinumab, and vedolizumab offer promise for the future, while hematopoietic stem cell transplantation should also be considered in these patients.

JAK inhibitor treatment for inborn errors of JAK/STAT signaling: An ESID/EBMT-IEWP retrospective study.

BACKGROUND: Inborn errors of immunity (IEI) with dysregulated JAK/STAT signaling present with variable manifestations of immune dysregulation and infections. Hematopoietic stem cell transplantation (HSCT) is potentially curative, but initially reported outcomes were poor. JAK inhibitors (JAKi) offer a targeted treatment option that may be an alternative or bridge to HSCT. However, data on their current use, treatment efficacy and adverse events are limited. OBJECTIVE: We evaluated the current off-label JAKi treatment experience for JAK/STAT inborn errors of immunity (IEI) among European Society for Immunodeficiencies (ESID)/European Society for Blood and Marrow Transplantation (EBMT) Inborn Errors Working Party (IEWP) centers. METHODS: We conducted a multicenter retrospective study on patients with a genetic disorder of hyperactive JAK/STAT signaling who received JAKi treatment for at least 3 months. RESULTS: Sixty-nine patients (72% children) were evaluated (45 STAT1 gain of function [GOF], 21 STAT3-GOF, 1 STAT5B-GOF, 1 suppressor of cytokine signaling 1 [aka SOCS1] loss of function, 1 JAK1-GOF). Ruxolitinib was the predominantly prescribed JAKi (80%). Overall, treatment resulted in improvement (partial or complete remission) of clinical symptoms in 87% of STAT1-GOF and in 90% of STAT3-GOF patients. We documented highly heterogeneous dosing and monitoring regimens. The response rate and time to response varied across different diseases and manifestations. Adverse events including infection and weight gain were frequent (38% of patients) but were mild (grade I-II) and transient in most patients. At last follow-up, 52 (74%) of 69 patients were still receiving JAKi treatment, and 11 patients eventually underwent HSCT after receipt of previous JAKi bridging therapy, with 91% overall survival. CONCLUSIONS: Our study suggests that JAKi may be highly effective to treat symptomatic JAK/STAT IEI patients. Prospective studies to define optimal JAKi dosing for the variable clinical presentations and age ranges should be pursued.

Alemtuzumab, Dual Graft-versus-Host Disease Prophylaxis, and Lower CD3+ T Cell Doses Equalize Rates of Acute and Chronic Graft-versus-Host Disease in Pediatric Patients Receiving Allogeneic Hematopoietic Stem Cell Transplantation with Matched Unrelated Donor Peripheral Blood Stem Cells or Bone Marrow Grafts.

Data comparing hematopoietic stem cell transplantation (HSCT) using bone marrow (BM) or peripheral blood stem cell (PBSC) grafts in children after alemtuzumab-based conditioning are lacking. We investigated whether in vivo T cell depletion using alemtuzumab could reduce the risk of severe acute graft-versus-host disease (aGVHD) and chronic GVHD (cGVHD) after HSCT with matched unrelated donor (MUD) BM or PBSCs. This retrospective multicenter study included 397 children (BM group, n = 202; PBSC group, n = 195) who underwent first MUD HSCT at 9 pediatric centers in the United Kingdom between 2015 and 2019. The median age at transplantation was 7.0 years (range, .1 to 19.3 years), and the median duration of follow-up was 3.1 years (range, .3 to 7.5 years). The 3-year overall survival was 81% for the entire cohort (BM group, 80%; PBSC group, 81%). The incidence of grade II-IV aGVHD was significantly higher in the PBSC group (31%) compared to the BM group (31% versus 19%; P = .003), with no difference in the incidence of grade III-IV aGVHD (BM, 7%; PBSC, 12%; P = .17). CD3+ T cell dose >5 × 108/kg and the use of PBSCs were independent predictors of grade II-IV aGVHD. When considering CD3+ T cell dose and GVHD prophylaxis, PBSC transplantation with a calcineurin inhibitor (CNI) and mycophenolate mofetil (MMF) and a CD3+ T cell dose ≤5 × 108/kg had a comparable grade II-IV aGVHD to BM transplantation plus a CNI (20% versus 18%; P = .52). PBSC transplantation was associated with a lower incidence of cGVHD compared to BM transplantation (6% versus 11%; P = .03). Within the limits of this study, we identified a potential strategy to reduce the risk of severe GVHD in pediatric PBSC recipients that includes a combination of in vivo T cell depletion using alemtuzumab and dual GVHD prophylaxis (with a CNI and MMF) and limiting the CD3+ T cell dose to ≤5 × 108/kg.

Too much of a good thing: a review of primary immune regulatory disorders.

Primary immune regulatory disorders (PIRDs) are inborn errors of immunity caused by a loss in the regulatory mechanism of the inflammatory or immune response, leading to impaired immunological tolerance or an exuberant inflammatory response to various stimuli due to loss or gain of function mutations. Whilst PIRDs may feature susceptibility to recurrent, severe, or opportunistic infection in their phenotype, this group of syndromes has broadened the spectrum of disease caused by defects in immunity-related genes to include autoimmunity, autoinflammation, lymphoproliferation, malignancy, and allergy; increasing focus on PIRDs has thus redefined the classical 'primary immunodeficiency' as one aspect of an overarching group of inborn errors of immunity. The growing number of genetic defects associated with PIRDs has expanded our understanding of immune tolerance mechanisms and prompted identification of molecular targets for therapy. However, PIRDs remain difficult to recognize due to incomplete penetrance of their diverse phenotype, which may cross organ systems and present to multiple clinical specialists prior to review by an immunologist. Control of immune dysregulation with immunosuppressive therapies must be balanced against the enhanced infective risk posed by the underlying defect and accumulated end-organ damage, posing a challenge to clinicians. Whilst allogeneic hematopoietic stem cell transplantation may correct the underlying immune defect, identification of appropriate patients and timing of transplant is difficult. The relatively recent description of many PIRDs and rarity of individual genetic entities that comprise this group means data on natural history, clinical progression, and treatment are limited, and so international collaboration will be needed to better delineate phenotypes and the impact of existing and potential therapies. This review explores pathophysiology, clinical features, current therapeutic strategies for PIRDs including cellular platforms, and future directions for research.

Immunology of THymectomy And childhood CArdiac transplant (ITHACA): protocol for a UK-wide prospective observational cohort study to identify immunological risk factors of post-transplant lymphoproliferative disease (PTLD) in thymectomised children.

INTRODUCTION: Paediatric heart transplant patients are disproportionately affected by Epstein-Barr virus (EBV)-related post-transplant lymphoproliferative disease (PTLD) compared with other childhood solid organ recipients. The drivers for this disparity remain poorly understood. A potential risk factor within this cohort is the routine surgical removal of the thymus-a gland critical for the normal development of T-lymphocyte-mediated antiviral immunity-in early life, which does not occur in other solid organ transplant recipients. Our study aims to describe the key immunological differences associated with early thymectomy, its impact on the temporal immune response to EBV infection and subsequent risk of PTLD. METHODS AND ANALYSIS: Prospective and sequential immune monitoring will be performed for 34 heart transplant recipients and 6 renal transplant patients (aged 0-18 years), stratified into early (<1 year), late (>1 year) and non-thymectomy groups. Peripheral blood samples and clinical data will be taken before transplant and at 3, 6, 12 and 24 months post-transplant. Single cell analysis of circulating immune cells and enumeration of EBV-specific T-lymphocytes will be performed using high-dimensional spectral flow cytometry with peptide-Major Histocompatibilty Complex (pMHC) I/II tetramer assay, respectively. The functional status of EBV-specific T-lymphocytes, along with EBV antibodies and viral load will be monitored at each of the predefined study time points. ETHICS AND DISSEMINATION: Ethical approval for this study has been obtained from the North of Scotland Research Ethics Committee. The results will be disseminated through publications in peer-reviewed journals, presentations at scientific conferences and patient-centred forums, including social media. TRIAL REGISTRATION NUMBER: ISRCTN10096625.

Allogeneic HSCT for Symptomatic Female X-linked Chronic Granulomatous Disease Carriers.

X-linked chronic granulomatous disease (XL-CGD) is an inherited disorder of superoxide production, causing failure to generate the oxidative burst in phagocytes. It is characterized by invasive bacterial and fungal infections, inflammation, and chronic autoimmune disease. While XL-CGD carriers were previously assumed to be healthy, a range of clinical manifestations with significant morbidity have recently been described in a subgroup of carriers with impaired neutrophil oxidative burst due to skewed lyonization. Allogeneic hematopoietic stem cell transplantation (HSCT) is the standard curative treatment for CGD but has rarely been reported in individual symptomatic carriers to date. We undertook a retrospective international survey of outcome of HSCT for symptomatic XL-CGD carriers. Seven symptomatic female XL-CGD carriers aged 1-56 years underwent HSCT in four centers, indicated for severe and recurrent infection, colitis, and autoimmunity. Two patients died from transplant-related complications, following donor engraftment and restoration of oxidative burst. All surviving patients demonstrated resolution of their neutrophil oxidative burst defect with concordant reduction in infection and inflammatory symptoms and freedom from further immunosuppressive therapy. In conclusion, allogeneic HSCT may cure the phagocyte defect in symptomatic XL-CGD carriers and improve their recurrent and disabling infective and inflammatory symptoms but risks transplant-related complications.

Outcome of Second Allogeneic HSCT for Patients with Inborn Errors of Immunity: Retrospective Study of 20 Years' Experience.

A significant complication of HSCT is graft failure, although few studies focus on this problem in patients with inborn errors of immunity (IE). We explored outcome of second HSCT for IEI by a retrospective, single-centre study between 2002 and 2022. Four hundred ninety-three patients underwent allogeneic HSCT for severe combined immunodeficiency (SCID; n = 113, 22.9%) or non-SCID IEI (n = 380, 77.1%). Thirty patients (6.0%) required second HSCT. Unconditioned infusion or no serotherapy at first HSCT was more common in patients who required second transplant. Median interval between first and second HSCT was 0.97 years (range: 0.19-8.60 years); a different donor was selected for second HSCT in 24/30 (80.0%) patients. Conditioning regimens for second HSCT were predominately treosulfan-based (with thiotepa: n = 18, 60.0%; without, n = 6, 20.0%). Patients received grafts from peripheral blood stem cell (n = 25, 83.3%) or bone marrow (n = 5, 16.7%) with median stem cell dose 9.5 × 106 CD34 + cells/kilogram (range: 1.4-32.3). Median follow-up was 1.92 years (0.22-16.0). Overall survival was 80.8% and event-free survival was 64.7%. Four patients died, two of early-transplant related complications, and two of late sepsis post-second HSCT. Three patients required third HSCT; all are alive with 100% donor chimerism. Cumulative incidence of acute graft-versus-host disease was 28.4%, (all grade I-II). Viral reactivation was seen in 13/30 (43.3%) patients, including HHV6 (n = 6), CMV (n = 4), and adenovirus (n = 2). At latest follow-up, 25/26 surviving patients have donor chimerism ≥ 90% and 16/25 (64.0%) have discontinued immunoglobulin replacement. Second HSCT offers IEI patients with graft failure curative treatment with good overall survival and immunological recovery.

An International Survey of Allogeneic Hematopoietic Cell Transplantation for X-Linked Agammaglobulinemia.

PURPOSE: X-linked agammaglobulinemia (XLA) is an inborn error of immunity caused by variants in Bruton's tyrosine kinase (BTK). XLA patients require lifelong immunoglobulin replacement therapy (IgRT). Only few XLA patients are indicated for allogeneic hematopoietic cell transplantation (HCT) because of severe complications. Accordingly, the published transplantation experience in XLA is minimal. We aimed to collect clinical data of XLA patients who received HCT in an international framework and to establish appropriate transplantation criteria and methods for XLA patients. METHODS: XLA patients were recruited through a questionnaire and a literature review. The data are on patient characteristics and transplantation methods and outcomes. RESULTS: In this study, twenty-two XLA patients who underwent HCT were recruited. The indication for HCT was recurrent or life-threatening infection in sixteen patients, malignancy in three, and other factors in three. A myeloablative conditioning, reduced toxicity myeloablative conditioning (RT-MAC), and reduced intensity conditioning (RIC) were selected in four, ten, and eight patients, respectively. Engraftment was achieved in 21 patients (95%). In all patients, 2-year overall survival (OS) and event-free survival (EFS) were 86% and 77%, respectively. In patients who received RT-MAC or RIC using treosulfan, busulfan, or melphalan, 2-year OS and EFS were 82% and 71%, respectively. Finally, twenty-one patients (95%) obtained complete or stable high-level mixed chimerism (50-95%), and the 1-year discontinuation rate of IgRT was 89%. CONCLUSION: Based on the concept in which IgRT is the standard treatment for XLA, HCT may be an effective and safe alternative treatment option for XLA patients, and IgRT can be discontinued following transplantation. It is ideal to perform HCT in XLA patients for whom transplantation is indicated before they develop organ damage.

CD3+TCRαß/CD19+-Depleted Mismatched Family or Unrelated Donor Salvage Stem Cell Transplantation for Graft Dysfunction in Inborn Errors of Immunity.

A minority of children experience significant graft dysfunction after undergoing allogeneic hematopoietic stem cell transplantation (HSCT) for inborn errors of immunity (IEI). The optimal approach to salvage HSCT in this scenario is unclear with respect to conditioning regimen and stem cell source. This single-center retrospective case series reports the outcomes of salvage CD3+TCRαß/CD19-depleted mismatched family or unrelated donor stem cell transplantation (TCRαß-SCT) between 2013 and 2022 for graft dysfunction in 12 children with IEI. Outcomes of interest were overall survival (OS), event-free survival (EFS), graft-versus-host disease (GVHD)-free and event-free survival (GEFS), toxicities, GVHD, viremia and long-term graft function. In this retrospective audit of patients who underwent second CD3+TCRαß/CD19-depleted mismatched donor HSCT using treosulfan-based reduced-toxicity myeloablative conditioning, the median age at first HSCT was 8.76 months (range, 2.5 months to 6 years), and that at second TCRαß-SCT was 3.6 years (range, 1.2 to 11 years). The median interval between first and second HSCTs was 1.7 years (range, 3 months to 9 years). The primary diagnoses were severe combined immunodeficiency (SCID) (n = 5) and non-SCID IEI (n = 7). Indications for second HSCT were primary aplasia (n = 1), secondary autologous reconstitution (n = 6), refractory acute GVHD (aGVHD) (n = 3), and secondary leukemia (n = 1). Donors were either haploidentical parental donors (n = 10) or mismatched unrelated donors (n = 2). All patients received TCRαß/CD19-depleted peripheral blood stem cell (PBSC) grafts with a median CD34+ cell dose of 9.3 × 106/kg (range, 2.8 to 32.3 × 106/kg) and a median TCRαß+ cell dose of 4 × 104/kg (range, 1.3 to 19.2 × 104/kg). All patients engrafted, with a median time neutrophil and platelet recovery of 15 days (range, 12 to 24 days) and 12 days (range, 9 to 19 days). One patient developed secondary aplasia, and 1 had secondary autologous reconstitution; both underwent a successful third HSCT. Four (33%) had grade II aGVHD, and none had grade III-IV aGVHD. No patients had chronic GVHD (cGVHD), but 1 patient developed extensive cutaneous cGVHD after their third HSCT using PBSCs and antithymocyte globulin. Nine (75%) had at least 1episode of blood viremia with human herpesvirus 6 (n = 6; 50%), adenovirus (n = 6; 50%), Epstein-Barr virus (n = 3; 25%), or cytomegalovirus (n = 3; 25%). The median duration of follow-up was 2.3 years (range, .5 to 10 years), and the 2-year OS, EFS, and GEFS were 100% (95% confidence interval [CI], 0 to 100%), 73% (95% CI, 37% to 90%), and 73% (95% CI, 37% to 90%), respectively. TCRαß-SCT from mismatched family or unrelated donors, using a chemotherapy-only conditioning regimen, is a safe alternative donor salvage transplantation strategy for second HSCT in patients without a suitably matched donor.

Case report: Single-stage facial reanimation with bilateral lengthening temporalis myoplasties for immune dysregulation, polyendocrinopathy, enteropathy, X-linked (IPEX) syndrome related developmental facial palsy.

Immune dysregulation, polyendocrinopathy, enteropathy, X-linked (IPEX) syndrome is a rare primary immunodeficiency, typically associated with clinical features of intractable diarrhoea, type 1 diabetes mellitus and eczema. We present a case of IPEX syndrome referred to our regional facial palsy service for smile restoration surgery. The patient presented with dissatisfaction of facial appearance, including mask-like facies and no functional smile. Pre-operative electromyography confirmed normal temporalis muscle activation. Consequently, the patient was offered single-stage bilateral lengthening temporalis myoplasties. The patient reported improved satisfaction with facial appearance. Surgery resulted in good early resting and voluntary symmetry. Oral commissures were elevated at rest improving oral incompetence. This is the first description of facial animation surgery in the context of IPEX syndrome. With careful consideration and patient selection, successful surgical restoration of resting symmetry and dynamic commissural smile can be achieved in this complex cohort of patients.

Extracorporeal photopheresis as an immunomodulatory treatment modality for chronic GvHD and the importance of emerging biomarkers.

Haematopoietic stem cell transplantation (HSCT) is the treatment of choice for malignant haematological diseases. Despite continuous improvements in pre- and post-transplantation procedures, the applicability of allo-HSCT is limited by life-threatening complications such as graft-versus-host disease (GvHD), engraftment failure, and opportunistic infections. Extracorporeal photopheresis (ECP) is used to treat steroid resistant GvHD with significant success. However, the molecular mechanisms driving its immunomodulatory action, whilst preserving immune function, require further understanding. As ECP is safe to administer with few significant adverse effects, it has the potential for earlier use in the post-HSCT treatment of GvHD. Thus, further understanding the immunomodulatory mechanisms of ECP action may justify more timely use in clinical practice, as well as identify biomarkers for using ECP as first line or pre-emptive GvHD therapy. This review aims to discuss technical aspects and response to ECP, review ECP as an immunomodulatory treatment modality for chronic GvHD including the effect on regulatory T cells and circulating vs. tissue-resident immune cells and consider the importance of emerging biomarkers for ECP response.

Haploidentical CD3+ TCR αß/CD19+-depleted HSCT for MHC class II deficiency and persistent SARS-CoV-2 pneumonitis.

Background: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection leads to coronavirus disease 2019 (COVID-19), which can range from a mild illness to a severe phenotype characterized by acute respiratory distress needing mechanical ventilation. Children with combined immunodeficiencies might be unable to mount a sufficient cellular and humoral immune response against COVID-19 and have persistent disease. Objective: Our aim was to describe a child with combined immunodeficiency and a favorable post-hematopoietic stem cell transplant (HSCT) course following a haploidentical HSCT in the presence of persistent SARS-CoV-2 infection. Methods: A 13-month-old girl with MHC class II deficiency developed persistent pre-HSCT SARS-CoV-2 infection. Faced with a significant challenge of balancing the risk of progressive infection due to an incompetent immune system with the danger of inflammatory pneumonitis peri-immune reconstitution after HSCT, the patient's physicians performed a maternal (with a recent history of COVID-19 infection) haploidentical HSCT. The patient received regdanvimab (after stem cell infusion) and remdesivir (before and after stem cell infusion). Results: The patient exhibited a gradual increase in her cycle threshold values, implying a reduction in viral RNA with concomitant expansion in the CD3 lymphocyte subset and clinical and radiologic improvement. Conclusions: Combination of adoptive transfer of maternal CD45RO+ memory addback T lymphocytes after haploidentical HSCT and use of regdanvimab (a SARS-CoV-2-neutralizing mAb) and remdesivir may have led to the successful outcome in our patient with severe immunodeficiency after she had undergone HSCT. This case highlights the role of novel antiviral strategies (mAbs and CD45RO+ memory T lymphocytes) in contributing to viral clearance in a challenging clinical scenario.

Advances in the treatment of severe combined immunodeficiency.

Severe Combined Immunodeficiency (SCID) is the most profound inborn error of immunity affecting cellular and humoral immunity. Hematopoietic stem cell transplantation has been a curative treatment since 1968. Huge progress has been made since then in understanding the underlying genetics, improving outcomes from transplant, and introducing gene therapy in particular for adenosine deaminase deficient- and IL2 receptor gamma-deficient SCID. Newborn screening has been widely introduced across the world to enable definitive treatment before infection occurs. This article aims to review the latest evidence on how to achieve curative treatment with minimal short- and long-term toxicity, normal immune reconstitution and good quality of life.

The efficacy and safety of allogeneic stem cell transplantation in Mevalonate Kinase Deficiency.

OBJECTIVES: Mevalonate kinase deficiency (MKD) is a rare autoinflammatory syndrome. Several reports have described allogeneic hematopoietic stem cell transplantation in severely affected patients, sometimes with promising results. In view of the scarcity of data, this study aims to analyse the efficacy and safety of allogeneic hematopoietic stem cell transplantation (HSCT) to give a more complete overview of this treatment. METHODS: This multicentre retrospective study on behalf of the European Society for Blood and Marrow Transplantation aimed to include all MKD patients who had undergone allogeneic HSCT. All centres related to EMBT and centres that have reported cases of allogeneic HSCT in the literature were contacted via the EBMT data office. RESULTS: We analyzed 9 patients (5 male). Treosulfan based conditioning was the most frequently used conditioning regimen. Engraftment occurred in all but one patient. Source of stem cells was cord blood (n = 2), peripheral blood stem cells (n = 4) and bone marrow (n = 5). Two patients needed a second transplantation due to an incomplete response or primary graft failure. Seven patients went into complete remission after stem cell transplantation. At final follow-up these patients reported no symptoms of MKD. Four patients suffered from grade II-IV acute graft-versus-host disease (GvHD). During follow-up two patients died due to transplantation related complications. CONCLUSION: In conclusion, allogeneic stem cell transplantation represents an effective treatment for the most severely affected MKD patients. However, treatment-related morbidity and mortality are significant. Transplantation may be justified in patients with a severe disease course on conservative therapy.

Consensus Recommendations for the Clinical Management of Hematological Malignancies in Patients with DNA Double Stranded Break Disorders.

Patients with double stranded DNA repair disorders (DNARDs) (Ataxia Telangiectasia (AT) and Nijmegen Breakage syndrome (NBS)) are at a very high risk for developing hematological malignancies in the first two decades of life. The most common neoplasms are T-cell lymphoblastic malignancies (T-cell ALL and T-cell LBL) and diffuse large B cell lymphoma (DLBCL). Treatment of these patients is challenging due to severe complications of the repair disorder itself (e.g., congenital defects, progressive movement disorders, immunological disturbances and progressive lung disease) and excessive toxicity resulting from chemotherapeutic treatment. Frequent complications during treatment for malignancies are deterioration of pre-existing lung disease, neurological complications, severe mucositis, life threating infections and feeding difficulties leading to significant malnutrition. These complications make modifications to commonly used treatment protocols necessary in almost all patients. Considering the rarity of DNARDs it is difficult for individual physicians to obtain sufficient experience in treating these vulnerable patients. Therefore, a team of experts assembled all available knowledge and translated this information into best available evidence-based treatment recommendations.