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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.)

Allogeneic hematopoietic stem cell transplant (HSCT) for relapsed pediatric non-Hodgkin lymphoma (NHL) is often reserved for patients with certain NHL subtypes or high-risk disease whereas the remainder receive autologous HSCT. Given the aggressive nature of pediatric NHL, we performed allogeneic HSCTs for all patients regardless of disease risk. We report overall survival (OS) and prognostic variables in 36 pediatric patients who underwent allogeneic HSCT between 1998 and 2016. OS at 3 years was 67%. The 3-year OS varied based on NHL subtype: 100% for anaplastic large cell lymphoma (n = 14), 63% for diffuse large B-cell lymphoma (n = 8), 17% for lymphoblastic lymphoma (LL; n = 9) and 80% for other subtypes combined (n = 5). Disease status influenced outcome with 3-year OS of 100% for patients in complete remission (n = 15), 59% with partial remission (PR; n = 17), and 0% with progressive/stable disease (n = 3) ( P = .004). Of the 17 patients in PR, all 6 with LL died of relapsed disease, whereas the other 11 attained remission after HSCT and remained disease-free. The cumulative incidence of relapse after HSCT for LL was 78% compared with 15% for all other NHL subtypes combined ( P < .0001). Cumulative incidence of nonrelapse mortality (NRM) was low in our cohort at 6%. Hence, allogeneic HSCT is a well-tolerated and useful therapeutic option with low rates of NRM and relapse for all NHL subtypes except LL with active disease at HSCT., (© 2019 by The American Society of Hematology.)

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.)

There is a lack of consensus regarding the role and method of hematopoietic stem cell transplantation (HSCT) on patients with chronic granulomatous disease (CGD). Long-term follow-up after HSCT in these patient population is essential to know its potential complications and decide who will benefit the most from HSCT. We report the outcome of HSCT and long-term follow-up in 24 patients with CGD, transplanted in our center from either related (n = 6) or unrelated (n = 18) donors, over a 12-year period (2003 to 2015), using high-dose alemtuzumab in the preparative regimen. We evaluated the incidence and timing of adverse events and potential risk factors. We described in detailed the novel finding of increased autoimmunity after HSCT in patients with CGD. At a median follow-up of 1460 days, 22 patients were full donor chimeras, and 2 patients had stable mixed chimerism. All assessable patients showed normalization of their neutrophil oxidative burst test. None of the patients developed grades II to IV acute graft-versus-host disease, and no patient had chronic graft-versus-host disease. Twelve of 24 patients developed 17 autoimmune diseases (ADs). Severe ADs (cytopenia and neuropathy) occurred exclusively in the unrelated donor setting and mainly in the first year after HSCT, whereas thyroid AD occurred in the related donor setting as well and more than 3 years after HSCT. Two patients died due to infectious complications after developing autoimmune cytopenias. One additional patient suffered severe brain injury. The remaining 21 patients have long-term Lansky scores ≥ 80. The outcome of HSCT from unrelated donors is comparable with related donors but might carry an increased risk of developing severe AD. A lower dose of alemtuzumab may reduce this risk and should be tested in further studies., (Copyright © 2018. Published by Elsevier Inc.)

Hematopoietic stem cell transplantation (HSCT) is the only curative option for a subset of patients with high-risk or relapsed acute lymphoblastic leukemia (ALL). Given evolving practices, it is important to continually evaluate outcomes for pediatric ALL following HSCT. Outcomes after HSCT are influenced by the type of donor used as this determines the degree and method of T cell depletion used and, consequently, specific transplant-related morbidities. We retrospectively analyzed HSCT data from our center for transplants performed between January 2008 and May 2016, comparing outcomes among different donor types. One hundred and twenty-four pediatric patients underwent HSCT from a matched sibling donor (MSD; n = 48), an unrelated matched donor (UMD; n = 56), or a haploidentical donor (n = 20). We observed a similar 3-year event-free survival (EFS) for MSD recipients (of .64) and for UMD recipients (.62), but a significantly lower EFS for recipients of haploidentical transplants (.35; P = .01). Relapse was the main cause of HSCT failure and was significantly higher in the haploidentical donor group (.47 versus .19 for MSD and .24 for UMD; P = .02). Treatment-related mortality was evenly distributed among the donor groups (.17, .16, and .15 for the MSD, UMD, and haploidentical groups, respectively). Rates of infection-related mortality were lower than previously reported. Relapse is the main obstacle for successful HSCT in the contemporary era, and this effect is most evident in recipients of haploidentical donor grafts. Newer methods to improve graft-versus-leukemia effect are being evaluated and will need to be incorporated into the management of high-risk patients., (Copyright © 2018 The American Society for Blood and Marrow Transplantation. Published by Elsevier Inc. All rights reserved.)

Purpose Improvement of cure rates for patients treated with allogeneic hematopoietic stem-cell transplantation (HSCT) will require efforts to decrease treatment-related mortality from severe viral infections. Adoptively transferred virus-specific T cells (VSTs) generated from eligible, third-party donors could provide broad antiviral protection to recipients of HSCT as an immediately available off-the-shelf product. Patient and Methods We generated a bank of VSTs that recognized five common viral pathogens: Epstein-Barr virus (EBV), adenovirus (AdV), cytomegalovirus (CMV), BK virus (BKV), and human herpesvirus 6 (HHV-6). The VSTs were administered to 38 patients with 45 infections in a phase II clinical trial. Results A single infusion produced a cumulative complete or partial response rate of 92% (95% CI, 78.1% to 98.3%) overall and the following rates by virus: 100% for BKV (n = 16), 94% for CMV (n = 17), 71% for AdV (n = 7), 100% for EBV (n = 2), and 67% for HHV-6 (n = 3). Clinical benefit was achieved in 31 patients treated for one infection and in seven patients treated for multiple coincident infections. Thirteen of 14 patients treated for BKV-associated hemorrhagic cystitis experienced complete resolution of gross hematuria by week 6. Infusions were safe, and only two occurrences of de novo graft-versus host disease (grade 1) were observed. VST tracking by epitope profiling revealed persistence of functional VSTs of third-party origin for up to 12 weeks. Conclusion The use of banked VSTs is a feasible, safe, and effective approach to treat severe and drug-refractory infections after HSCT, including infections from two viruses (BKV and HHV-6) that had never been targeted previously with an off-the-shelf product. Furthermore, the multispecificity of the VSTs ensures extensive antiviral coverage, which facilitates the treatment of patients with multiple infections.

Background: Viral infections are a leading fatal complication for patients with primary immunodeficiencies (PIDs) who require hematopoietic stem cell transplantation (HSCT). Use of virus-specific T lymphocytes (VSTs) has been successful for the treatment and prevention of viral infections after HSCT for malignant and nonmalignant conditions. Here we describe the clinical use of VSTs in patients with PIDs at 4 centers., Objective: We sought to evaluate the safety and efficacy of VSTs for treatment of viral infections in patients with PIDs., Methods: Patients with PIDs who have received VST therapy on previous or current protocols were reviewed in aggregate. Clinical information, including transplantation details, viral infections, and use of antiviral and immunosuppressive pharmacotherapy, were evaluated. Data regarding VST production, infusions, and adverse reactions were compared., Results: Thirty-six patients with 12 classes of PID diagnoses received 37 VST products before or after HSCT. Twenty-six (72%) patients had received a diagnosis of infection with cytomegalovirus, EBV, adenovirus, BK virus, and/or human herpesvirus 6. Two patients were treated before HSCT because of EBV-associated lymphoproliferative disease. Partial or complete responses against targeted viruses occurred in 81% of patients overall. Time to response varied from 2 weeks to 3 months (median, 28 days). Overall survival at 6 months after therapy was 80%. Four patients had graft-versus-host disease in the 45 days after VST infusion, which in most cases was therapy responsive., Conclusion: VSTs derived from either stem cell donors or third-party donors are likely safe and effective for the treatment of viral infections in patients with PIDs., (Copyright © 2016 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.)

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.)

Adoptive transfer of virus-specific T cells can prevent and treat serious infections with Epstein-Barr virus (EBV), cytomegalovirus (CMV), and adenovirus (Adv) after allogeneic hematopoietic stem cell transplant. It has, however, proved difficult to make this approach widely available since infectious virus and viral vectors are required for T cell activation, followed by an intensive and prolonged culture period extending over several months. We now show that T cells targeting a range of viral antigens derived from EBV, CMV, and Adv can be reproducibly generated in a single culture over a 2-3-week period, using methods that exclude all viral components and employ a much-simplified culture technology. When administered to recipients of haploidentical (n = 5), matched unrelated (n = 3), mismatched unrelated (n = 1) or matched related (n = 1) transplants with active CMV (n = 3), Adv (n = 1), EBV (n = 2), EBV+Adv (n = 2) or CMV+Adv (n = 2) infections, the cells produced complete virological responses in 80%, including all patients with dual infections. In each case, a decrease in viral load correlated with an increase in the frequency of T cells directed against the infecting virus(es); both immediate and delayed toxicities were absent. This approach should increase both the feasibility and applicability of T cell therapy. The trial was registered at www.clinicaltrials.gov as NCT01070797.

Background: Matched related donor (MRD) hematopoietic stem cell transplantation (HSCT) is a successful treatment for chronic granulomatous disease (CGD), but the safety and efficacy of HSCT from unrelated donors is less certain., Objective: We evaluated the outcomes and overall survival in patients with CGD after HSCT., Methods: We report the outcomes for 11 children undergoing HSCT from an MRD (n = 4) or an HLA-matched unrelated donor (MUD) (n = 7); 9 children were boys, and the median age was 3.8 years (range, 1-13 years). We treated both X-linked (n = 9) and autosomal recessive (n = 2) disease. Nine children had serious clinical infections before transplantation. The conditioning regimens contained busulfan, cyclophosphamide, cytarabine, or fludarabine according to the donor used. All patients received alemtuzumab (anti-CD52 antibody). Additional graft-versus-host disease (GvHD) prophylaxis included cyclosporine and methotrexate for MUD recipients and cyclosporine and prednisone for MRD recipients., Results: Neutrophil recovery took a median of 16 days (range, 12-40 days) and 18 days (range, 13-24 days) for MRD and MUD recipients, respectively. Full donor neutrophil engraftment occurred in 9 patients, and 2 had stable mixed chimerism; all patients had sustained correction of neutrophil oxidative burst defect. Four patients had grade I skin acute GVHD responding to topical treatment. No patient had grade II to IV acute GvHD or chronic GvHD. All patients are alive between 1 and 8 years after HSCT., Conclusion: For CGD, equivalent outcomes can be obtained with MRD or MUD stem cells, and HSCT should be considered an early treatment option., (Copyright © 2011 American Academy of Allergy, Asthma & Immunology. Published by Mosby, Inc. All rights reserved.)

Primary Immune Regulatory Disorders (PIRD) are an expanding group of diseases caused by gene defects in several different immune pathways, such as regulatory T cell function. Patients with PIRD develop clinical manifestations associated with diminished and exaggerated immune responses. Management of these patients is complicated; oftentimes immunosuppressive therapies are insufficient, and patients may require hematopoietic cell transplant (HCT) for treatment. Analysis of HCT data in PIRD patients have previously focused on a single gene defect. This study surveyed transplanted patients with a phenotypic clinical picture consistent with PIRD treated in 33 Primary Immune Deficiency Treatment Consortium centers and European centers. Our data showed that PIRD patients often had immunodeficient and autoimmune features affecting multiple organ systems. Transplantation resulted in resolution of disease manifestations in more than half of the patients with an overall 5-years survival of 67%. This study, the first to encompass disorders across the PIRD spectrum, highlights the need for further research in PIRD management.

BackgroundImmunodysregulation polyendocrinopathy enteropathy x-linked (IPEX) syndrome is a monogenic autoimmune disease caused by FOXP3 mutations. Because it is a rare disease, the natural history and response to treatments, including allogeneic hematopoietic stem cell transplantation (HSCT) and immunosuppression (IS), have not been thoroughly examined.ObjectiveThis analysis sought to evaluate disease onset, progression, and long-term outcome of the 2 main treatments in long-term IPEX survivors.MethodsClinical histories of 96 patients with a genetically proven IPEX syndrome were collected from 38 institutions worldwide and retrospectively analyzed. To investigate possible factors suitable to predict the outcome, an organ involvement (OI) scoring system was developed.ResultsWe confirm neonatal onset with enteropathy, type 1 diabetes, and eczema. In addition, we found less common manifestations in delayed onset patients or during disease evolution. There is no correlation between the site of mutation and the disease course or outcome, and the same genotype can present with variable phenotypes. HSCT patients (n = 58) had a median follow-up of 2.7 years (range, 1 week-15 years). Patients receiving chronic IS (n = 34) had a median follow-up of 4 years (range, 2 months-25 years). The overall survival after HSCT was 73.2% (95% CI, 59.4-83.0) and after IS was 65.1% (95% CI, 62.8-95.8). The pretreatment OI score was the only significant predictor of overall survival after transplant (P = .035) but not under IS.ConclusionsPatients receiving chronic IS were hampered by disease recurrence or complications, impacting long-term disease-free survival. When performed in patients with a low OI score, HSCT resulted in disease resolution with better quality of life, independent of age, donor source, or conditioning regimen.

While matched related donor (MRD) allogeneic hematopoietic stem cell transplantation (HSCT) is a curative option for transfusion-dependent beta-thalassemia (TDT), the use of alternative sources has increased, resulting in the exploration of novel transplant-conditioning regimens to reduce the contribution of graft-versus-host disease (GVHD) and graft failure (GF) to transplant-related morbidity and mortality. Alemtuzumab is a CD52 monoclonal antibody that has been successfully incorporated into myeloablative conditioning regimens for other hematologic conditions, yet there have been limited studies regarding the use of alemtuzumab in HSCT for TDT. The purpose of this study was to evaluate engraftment, incidence of GVHD, and transplant related morbidity and mortality in patients with TDT who received alemtuzumab in addition to standard busulfan-based conditioning. The primary endpoint was severe GVHD-free, event-free survival (GEFS). Our cohort included 24 patients with a median age of 6.8 years (range 1.5-14.9). Eleven patients received a 10/10 MRD HSCT, eleven 10/10 unrelated donor (UD), and two mismatched UD. All patients achieved primary engraftment. For all patients, 5-year GEFS was 77.4% and 5-year overall survival (OS) was 91%. The 5-year cumulative incidence of GF (attributed to poor graft function) without loss of donor chimerism was 13.8% (95% CI: 4.5, 35.3). We report low rates of significant acute GVHD grade II–IV (12.5%) and chronic GVHD (4.4%). Younger age and MRD were associated with significantly improved GEFS, OS and EFS. Our results show that the use of alemtuzumab promotes stable engraftment, may reduce rates of severe GVHD, and results in acceptable GEFS, OS, and EFS. [ABSTRACT FROM AUTHOR]

Chronic granulomatous disease (CGD) is a primary immune deficiency due to defects in phagocyte respiratory burst leading to severe and life-threatening infections. Patients with CGD also suffer from disorders of inflammation and immune dysregulation including colitis and granulomatous lung disease, among others. Additionally, patients with CGD may be at increased risk of systemic inflammatory disorders such as hemophagocytic lymphohistiocytosis (HLH). The presentation of HLH often overlaps with symptoms of systemic inflammatory response syndrome (SIRS) or sepsis and therefore can be difficult to identify, especially in patients with a primary immune deficiency in which incidence of infection is increased. Thorough evaluation and empiric treatment for bacterial and fungal infections is necessary as HLH in CGD is almost always secondary to infection. Simultaneous treatment of infection with anti-microbials and inflammation with immunosuppression may be needed to blunt the hyperinflammatory response in secondary HLH. Herein, we present a series of X-linked CGD patients who developed HLH secondary to or with concurrent disseminated CGD-related infection. In two patients, CGD was a known diagnosis prior to development of HLH and in the other two CGD was diagnosed as part of the evaluation for HLH. Concurrent infection and HLH were fatal in three; one case was successfully treated, ultimately receiving hematopoietic stem cell transplantation. The current literature on presentation, diagnosis, and treatment of HLH in CGD is reviewed. [ABSTRACT FROM AUTHOR]

Haematopoietic stem cell transplantation (HSCT) for patients with haemophagocytic lymphohistiocytosis (HLH) following myeloablative conditioning regimens (MAC) is associated with high rates of non-relapse mortality (Baker I et al. i , [2]). Of these seven patients, two received additional cytokine-directed therapy, and one of these patients also received alemtuzumab as HLH salvage therapy. At initial testing for donor engraftment, eight patients were 100% donor and one patient had 99% donor chimerism. Three patients developed GVHD: one patient had Grade IV gut GVHD as described above and two patients developed Grade II GVHD which resolved with therapy. [Extracted from the article]

Abstract: Relapsed ALK‐positive ALCL often is responsive to CRZ monotherapy. The subsequent role of allogeneic HCT after achieving second remission is poorly understood. We report 6 children who underwent allogeneic HCT for relapsed ALCL after CRZ. Age at transplant ranged from 10.7 to 22.6 years. Follow‐up ranged from 0.9 to 4.5 years. All patients engrafted. Three of 4 patients that received a reduced‐toxicity conditioning regimen containing fludarabine, alemtuzumab, and low‐dose irradiation showed progressive mixed chimerism. Five patients remain in remission. One patient developed isolated CNS relapse 3.6 years after HCT despite a lack of previous CNS involvement. No acute transplant‐related complications were experienced. One patient developed chronic renal disease secondary to transplant‐associated microangiopathy and one patient chronic GVHD secondary to DLI. Ultimately, allogeneic HCT appears safe and potentially curative after remission induction with CRZ. The role of conditioning therapy, ablative or reduced intensity, remains uncertain for patients’ post‐CRZ monotherapy, and further studies may be warranted. [ABSTRACT FROM AUTHOR]

Abstract: BK virus hemorrhagic cystitis is a complication of HCST. Response to IV cidofovir is unpredictable, and treatment carries risk of toxicity. We report the largest series of pediatric patients with BKHC after HSCT successfully treated with intravesicular cidofovir. There was no significant decrease in urine or plasma BK PCR. There was significant decrease in pain score on days 3 and 7, with associated decrease in morphine use. No patients experienced toxicities associated with IV cidofovir. Intravesicular cidofovir appears to be safe and effective for symptomatic treatment of BKHC in pediatric patients after HSCT. [ABSTRACT FROM AUTHOR]

Human metapneumovirus (hMPV) is a respiratory virus detected in ≥9% of allogeneic hematopoietic stem cell transplant (HSCT) recipients, in whom it can cause significant morbidity and mortality. Given the lack of effective antivirals, we investigated the potential for immunotherapeutic intervention, using adoptively transferred T cells. Thus, we characterized the cellular immune response to the virus and identified F, N, M2-1, M, and P as immunodominant target antigens. Reactive T cells were polyclonal (ie, they expressed CD4 and CD8), T-helper type 1 polarized, and polyfunctional (ie, they produced interferon γ, tumor necrosis factor α, granulocyte-macrophage colony-stimulating factor, and granzyme B), and they were able to kill autologous antigen-loaded targets. The detection of hMPV-specific T cells in HSCT recipients who endogenously controlled active infections support the clinical importance of T-cell immunity in mediating protective antiviral effects. Our results demonstrate the feasibility of developing an immunotherapy for immunocompromised patients with uncontrolled infections. [ABSTRACT FROM AUTHOR]

Relapse of hematological malignancies after hematopoietic stem cell transplantation (HCT) is associated with poor prognosis. A second HCT represents one of the few therapeutic options for these high-risk patients. For children undergoing second HCT, the outcome data are particularly limited. We, therefore, conducted a retrospective single-institution study and report the outcomes and prognostic variables associated with overall survival (OS) and relapse in 43 pediatric patients who underwent a second HCT between 2000 and 2013. Eleven of the 43 patients who underwent transplantation remain alive and disease-free at a median follow-up of 49 months (range, 5 to 127 months). The 5-year probability of OS for the entire cohort was 24%. Patients who had early relapse (<6 months) after first HCT had significantly worse OS than those who relapsed late (>6 months), with 5-year OS at 11% versus 34%, respectively (hazard ratio [HR], 2.24; 95% confidence interval [CI], 1.21 to 4.93; P = .013). Active disease at time of second HCT was also associated with a significantly increased risk of relapse (subdistribution hazard ratio [SHR], 2.36; P = .049) for the entire cohort and relapse was the most frequent cause of death (23 of 32; 72%). On subgroup analysis for the 34 patients with leukemia alone, presence of active disease was associated both with a significant decrease in OS (SHR, 2.28; 95% CI, 1.02 to 5.09; P = .044) and significant increase in the rate of relapse (SHR, 2.46; P = .046). By contrast, underlying disease, donor source, conditioning regimen, or development of GVHD did not modify OS or rate of relapse. Hence, a second HCT appears to be a useful therapeutic option in children with relapsed hematological malignancies that is most likely to benefit those individuals with late onset of relapse and with low disease burden at the time of transplantation. [ABSTRACT FROM AUTHOR]

• A combination of phenotypic and functional immune assays enables risk stratification of patients with viral infections after transplant. • Functional immune monitoring can help identify patients in need of additional antiviral intervention. Serious viral infections, due to delayed immune reconstitution, are a leading cause of morbidity and mortality after allogeneic hematopoietic stem cell transplantation (HSCT). Thus, many transplant centers prospectively track cellular immune recovery by evaluating absolute cell numbers and the phenotypic profile of reconstituting T cell subsets to identify individuals who are at highest risk of infection. Conventional assessments, however, fail to measure either the antigen specificity or functional capacity of reconstituting cells—both factors that correlate with endogenous antiviral protection. In this pilot study, we sought to address this limitation by prospectively investigating the tempo of endogenous immune reconstitution in a cohort of 23 pediatric HSCT patients using both quantitative (flow cytometry) and qualitative (IFNγ ELISpot) measures, which we correlated with either the presence or absence of infections associated with cytomegalovirus, adenovirus, Epstein-Barr virus, BK virus, human herpes virus 6, respiratory syncytial virus, parainfluenza, influenza, and human metapneumovirus. We present data spanning 12 months post-transplant demonstrating the influence of conditioning on immune recovery and highlighting the differential impact of active viral replication on the quantity and quality of reconstituting cells. Judicious use of standard (phenotypic) and novel (functional) monitoring strategies can help guide the clinical care and personalized management of allogenic HSCT recipients with infections. [ABSTRACT FROM AUTHOR]

Highlights • Ninety-three percent of patients treated with plasma exchange developed chronic kidney disease. • The cumulative incidence of severe chronic kidney disease development was 33%. • Therapeutic plasma exchange was not effective in preventing chronic kidney disease. Abstract Transplantation-associated thrombotic microangiopathy (TA-TMA) is a complication of hematopoietic stem cell transplant (HSCT) that causes severe multiorgan injury. The kidneys are almost universally affected. There is no proven therapy, but therapeutic plasma exchange (TPE) is commonly used to treat TA-TMA at Texas Children's Hospital (TCH). To date, there have been no studies assessing the long-term efficacy of TPE in preventing the development of chronic kidney disease (CKD) in TA-TMA patients. In this study we retrospectively analyzed the incidence of CKD in TA-TMA pediatric patients treated with TPE to determine if this treatment modality improves renal morbidity. We reviewed records between January 2007 and June 2017 of pediatric HSCT patients diagnosed with TA-TMA, identified through an internal database maintained at TCH. To be included patients must have completed a course of TPE per the "TPE in TA-TMA" institutional protocol at TCH. CKD was defined as kidney damage for at least 3 months and stratified into stages 1 through 5 according to estimated glomerular filtration rate. Stages 4 and 5 were considered "severe CKD." In the 10-year timeframe 15 patients with TA-TMA completed a course of TPE per our institutional protocol and were subsequently followed for a median of 963 days. Fourteen patients developed CKD, and 5 of these 14 patients developed severe CKD. The cumulative incidence of severe CKD development was 33% (95% confidence interval. 11% to 57%). 6 patients required dialysis, and 2 patients received a renal transplant. 5 patients received eculizumab in addition to TPE. In our patients a TPE course of at least 7 weeks (and up to 25 weeks) was not effective in the prevention of CKD. Our data indicate a need for alternative therapeutic measures to prevent the development of CKD in TA-TMA patients. [ABSTRACT FROM AUTHOR]

The Primary Immune Deficiency Treatment Consortium (PIDTC) performed a retrospective analysis of 662 patients with severe combined immunodeficiency (SCID) who received a hematopoietic cell transplantation (HCT) as first-line treatment between 1982 and 2012 in 33 North American institutions. Overall survival was higher after HCT from matched-sibling donors (MSDs). Among recipients of non-MSD HCT, multivariate analysis showed that the SCID genotype strongly influenced survival and immune reconstitution. Overall survival was similar for patients with RAG, IL2RG, or JAK3 defects and was significantly better compared with patients with ADA or DCLRE1C mutations. Patients with RAG or DCLRE1C mutations had poorer immune reconstitution than other genotypes. Although survival did not correlate with the type of conditioning regimen, recipients of reduced-intensity or myeloablative conditioning had a lower incidence of treatment failure and better T- and B-cell reconstitution, but a higher risk for graft-versus-host disease, compared with those receiving no conditioning or immunosuppression only. Infection-free status and younger age at HCT were associated with improved survival. Typical SCID, leaky SCID, and Omenn syndrome had similar outcomes. Landmark analysis identified CD4+ and CD4+CD45RA+ cell counts at 6 and 12 months post-HCT as biomarkers predictive of overall survival and long-term T-cell reconstitution. Our data emphasize the need for patient-tailored treatment strategies depending upon the underlying SCID genotype. The prognostic significance of CD4+ cell counts as early as 6 months after HCT emphasizes the importance of close follow-up of immune reconstitution to identify patients who may need additional intervention to prevent poor long-term outcome. [ABSTRACT FROM AUTHOR]

The Primary Immune Deficiency Treatment Consortium (PIDTC) is enrolling children with severe combined immunodeficiency (SCID) to a prospective natural history study. We analyzed patients treatedwith allogeneic hematopoietic cell transplantation (HCT) from 2010 to 2014, including 68 patientswith typical SCID and 32 with leaky SCID, Omenn syndrome, or reticular dysgenesis. Most (59%) patients were diagnosed by newborn screening or family history. The 2-year overall survivalwas 90%, but was 95%for thosewhowere infection-free at HCTvs 81%for those withactive infection (P5.009). Other factors, including thediagnosis of typical vs leaky SCID/Omenn syndrome, diagnosis via family history or newborn screening, useofpreparative chemotherapy, or thetypeof donorused, did not impact survival. Although 1-year post-HCT median CD4 counts and freedom from IV immunoglobulin were improved after the use of preparative chemotherapy, other immunologic reconstitution parameters were not affected, and the potential for late sequelae in extremely young infants requires additional evaluation. After a T-cell-replete graft, landmark analysis at day 1100 post-HCT revealed that CD3 < 300 cells/μL, CD8 < 50 cells/μL, CD45RA < 10%, or a restricted Vb T-cell receptor repertoire (<13 of 24 families) were associated with the need for a second HCT or death. In the modern era, active infection continues to pose the greatest threat to survival for SCID patients. Although newborn screening has been effective in diagnosing SCID patients early in life, there is an urgent need to identify validated approaches through prospective trials to ensure that patients proceed to HCT infection free. [ABSTRACT FROM AUTHOR]

High risk or relapsed pediatric acute myeloid leukemia (AML) is potentially curable with allogeneic hematopoietic stem cell transplantation (HSCT). Significant improvements have been made with supportive care practices, but there are limited HSCT outcome data for pediatric AML patients in the contemporary era. We report retrospective data in 87 pediatric patients with high risk or relapsed AML, who underwent HSCT at a single institution between 2008 and 2018. The median age at time of HSCT was 8 years (range: 0.6-20 years). Forty three patients (49%) were transplanted in CR1, 18 (21%) in CR2, and 26 (30%) with active disease (defined as any evidence of disease at the time of HSCT). Patients were transplanted using matched related (MRD, n=21), matched unrelated (MUD, n=25), mismatched unrelated (MMUD, n=15), haplo-identical (haplo, n=12) or umbilical cord blood (UCB, n=14) grafts. The majority of patients (78/87, 90%) received myeloablative conditioning. MRD and UCB graft recipients did not receive serotherapy. All other graft recipients (n=52) received serotherapy, the majority using an alemtuzumab-based conditioning regimen, 42/52 (81%). Haplo-identical transplants were performed using CD34+ selected grafts. Three-year overall survival (OS) and disease free survival (DFS) for the entire cohort were 52% (95% CI: 41-62%) and 49% (95% CI: 38-59%) respectively. OS differed significantly according to disease status at time of transplant (p=0.018), with 3 year OS: 60%, (95% CI: 43-74%) for those in CR1, 56%, (95% CI: 31-75%) for those in CR2 and 34% (95% CI: 17-52%) for those with active disease. OS differed by donor type (p=0.058). OS was comparable for patients with MRD (71%, 95% CI: 46-86%) and 10/10 MUD (59%, 95% CI: 37-75%) (p=0.67). Patients with alternate donor sources had worse outcomes (MMUD 33%, 95% CI: 10-59%; UCB 43%, 95% CI: 18-66%; Haplo 33%, 95% CI: 10-59%) as compared to MRD (MMUD vs MRD, p=0.042, UCB vs MRD, p=0.046, haplo vs MRD p=0.017). There was a low incidence of Grade III-IV acute GVHD (8%, n=7) and extensive chronic GVHD (9%, n=7) likely secondary to the use of alemtuzumab-based conditioning regimens. The 3-year non-relapse mortality was low at 11% (95% CI: 5-19%). The primary cause of death was relapse, with a 3-year cumulative incidence of relapse of 40%, (95% CI: 30-50%). Patients with active disease at HSCT had significantly higher cumulative incidence of relapse (sHR: 2.42, 95% CI: 1.18-4.95, p=0.016) compared to patients in remission. In the contemporary era, outcomes after allogeneic HSCT are comparable for MRD and 10/10 MUD for pediatric AML. Myeloablative and alemtuzumab based conditioning regimens were well tolerated with low rates of NRM and GVHD. Relapse remains the major cause of treatment failure. Future trials evaluating use of cellular therapies and targeted agents post-HSCT will be needed. [ABSTRACT FROM AUTHOR]

Allogeneic hematopoietic stem cell transplantation (HSCT) is a curative treatment for transfusion-dependent b-thalassemia (TDT). Application of alternative donor HSCT for TDT is more accepted as rates of graft failure (GF) and GVHD decline. Alemtuzumab is a CD52 monoclonal antibody with potent lymphocytic activity that can reduce GVHD risk, though infectious associations have limited its use. We hypothesize that the addition of alemtuzumab to standard myeloablative conditioning in HSCT for TDT will reduce rates of GVHD without affecting engraftment or transplant-related mortality (TRM). We retrospectively reviewed engraftment, GVHD, and survival for TDT patients (pts) who underwent HSCT at Texas Children's Hospital between 2004-2018. All pts received myeloablative conditioning with IV targeted busulfan (AUC of 800-1200 μM per minute), cyclophosphamide 50 mg/kg daily for 4 days, and IV alemtuzumab (5-15kg= 3mg; 15-30kg=5mg; >30kg=10mg) from d -5 through d -2. Pts receiving MUD/MMUD HSCT additionally received fludarabine 30 mg/m2 for 4 days. GVHD prophylaxis included methotrexate (d +1,3,6,11) and a calcineurin inhibitor. Twenty-one consecutive pts underwent MRD (10), MUD (9), or MMUD (2) HSCT with a median age at HSCT of 6.5 yrs (range: 1.5-14.9). Stem cell source consisted of bone marrow (17), peripheral blood (3), MRD umbilical cord and marrow (1). Neutrophil engraftment (ANC>500/ml x 3 d) was achieved in all patients at a median of 19 d (range: 13-29). Median platelet engraftment (platelet > 20,000 × 7 d without transfusion) was 35.5 d (range: 15-123). Median RBC engraftment (Hb >8 g/dL x 7 d without transfusion) was 24 d (range: 10-115). No GF was observed. Poor graft function (PGF) was seen in 2 pts (9.5%) requiring stem cell boost or 2nd HSCT. Overall incidence of acute (grade II-IV) and chronic GVHD (all limited) of 9.5% and 14.2%, respectively. Five-year overall survival was 89.9% with a median follow-up of 3.6 yrs (range: 0-14.4). Two deaths occurred secondary to infections complications in the setting of PGF and GVHD, respectively. Myeloablative conditioning with alemtuzumab minimized the incidence of severe GVHD with good overall survival. GF, GVHD, and TRM rates were improved from previous reports in TDT. PGF in our UD cohort was comparable to previous reports of engraftment complications. The addition of Alemtuzumab is a reasonable strategy to reduce GVHD risk in MRD and UD HSCT for TDT, though durability of engraftment after UD HSCT requires further investigation. [ABSTRACT FROM AUTHOR]

Introduction Many HSCT patients experience severe vital sign changes during their hospital stay often requiring a higher level of service. Treatment historically uses fluid boluses, antibiotics, and vasopressors. However, inflammation places HSCT patients at risk of third spacing and fluid overload, prompting the need for targeted resuscitative efforts dependent on the etiology of the patientÕs vital sign abnormalities. Objective We propose a novel treatment algorithm for patients receiving HSCT created in collaboration with the pediatric intensive care unit (PICU) at Texas ChildrenÕs Hospital to provide targeted resuscitation for HSCT patients. The overarching goal is to limit morbidities associated with resuscitation and minimize differences in management across PICU and HSCT teams. Methods Our center is employing a grading system from 1 to 4 based on hemodynamics at various phases of HSCT (Figure A). This system will identify what we are characterizing as cytokine shock syndrome (CSS). Once they reach a grade of 1, they will receive antibiotics, albumin, hydrocortisone, and blood products as needed. There will be a maximum of 20 ml/kg of colloids given before starting pressors to avoid further fluid overload. Blood transfusions and albumin will be used as the fluids of choice. For worsening scores, they will receive additional targeted cardiac and respiratory interventions (Figure B). Echocardiogram and central venous pressure will provide additional resources for targeted management. Results Four patients to date have been managed according to this algorithm. All patients responded to therapy and received antibiotics, albumin, hydrocortisone, and TNF antibody without the need of further escalation of care. Conclusions We demonstrate that providing targeted therapy to HSCT patients has the potential to identify and treat HSCT patients early and prevent morbidity and mortality due to aggressive nonspecific treatment efforts when rapidly deteriorating. With further validation, this poses a promising alternative to existing supportive care measures. [ABSTRACT FROM AUTHOR]

Introduction Matched related donor (MRD) hematopoietic cell transplant (HCT) is an accepted treatment for sickle cell disease (SCD). Alemtuzumab is a lymphocytic medication that can reduce the risk of GVHD; however, it is associated with mixed donor chimerism (MDC) and graft loss when used with submyeloablative conditioning. We explored the use of myeloablative chemotherapy with alemtuzumab in MRD HCT for SCD to concurrently prevent GVHD and promote durable engraftment. Methods We retrospectively reviewed outcomes for patients that underwent MRD HCT for SCD at Texas Children's Hospital between 2003-2017. All patients received busulfan intravenously every 6 hours for 4 days (target AUC: 800-1200 μM per minute) and cyclophosphamide 50 mg/kg daily for 4 days. GVHD prophylaxis included intravenous alemtuzumab daily for 3-4 doses starting on day -5 (5-15 kg=3 mg, 15-30 kg=5 mg, >30 kg= 10 mg daily), methotrexate and a calcineurin inhibitor. Donor chimerism was evaluated periodically via short tandem repeats or fluorescent-in-situ hybridization of nucleated cells from the peripheral blood. Persistent MDC was defined by the presence of recipient cells on 2 consecutive evaluations without return to full donor chimerism at last follow-up. Results Thirty-eight consecutive patients underwent MRD transplant (3 non-sibling and 35 sibling) with a median age at transplant of 8.6 yrs (range: 2.9-18.4 yr). Stem cell source consisted of bone marrow grafts for all patients. Two patients concurrently received cord blood from the same donor. Neutrophil engraftment was achieved in all patients at a median time of 19 days (range: 13-24 days). Incidence of persistent MDC was 60.5% with a median last chimerism of 94% donor cells (range: 24-100%). Three of 23 patients (13.0%) with persistent MDC had <50% donor cells. The single patient with severe MDC <25% stabilized at 24% at 2 yrs post-HCT with concurrent Hgb S <50% on electrophoresis reflective of sickle cell trait in the donor. Graft rejection and recurrence of SCD related symptoms were not observed in any patient. No additional cell products were given to manage mixed chimerism. Overall incidence of significant acute GVHD (grade II-IV) was 5.3%. One patient developed limited chronic GVHD. Overall survival was 94.7% with a median time to last follow-up of 2.9 yrs (range: 90-4627 days). Two deaths occurred secondary to transplant-related complications including 1 death <100 days from HCT due to disseminated Mycobacterium tuberculosis and 1 secondary to hemophagocytic syndrome on day +318. Conclusions Myeloablative conditioning was well tolerated, and the addition of alemtuzumab minimized occurrence of significant GVHD. Chimerism stabilized at >50% donor cells in most patients and no graft rejection or recurrence of SCD occurred. This regimen may be a promising approach for patients with SCD that can tolerate myeloablative chemotherapy. [ABSTRACT FROM AUTHOR]