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Allogeneic hematopoietic stem cell transplantation (HSCT) is the gold standard curative therapy for infants and children with many inborn errors of immunity (IEI), but adolescents and adults with IEI are rarely referred for transplant. Lack of published HSCT outcome data outside small, single-center studies and perceived high risk of transplant-related mortality have delayed the adoption of HSCT for IEI patients presenting or developing significant organ damage later in life. This large retrospective, multicenter HSCT outcome study reports on 329 IEI patients (age range, 15-62.5 years at HSCT). Patients underwent first HSCT between 2000 and 2019. Primary endpoints were overall survival (OS) and event-free survival (EFS). We also evaluated the influence of IEI-subgroup and IEI-specific risk factors at HSCT, including infections, bronchiectasis, colitis, malignancy, inflammatory lung disease, splenectomy, hepatic dysfunction, and systemic immunosuppression. At a median follow-up of 44.3 months, the estimated OS at 1 and 5 years post-HSCT for all patients was 78% and 71%, and EFS was 65% and 62%, respectively, with low rates of severe acute (8%) or extensive chronic (7%) graft-versus-host disease. On univariate analysis, OS and EFS were inferior in patients with primary antibody deficiency, bronchiectasis, prior splenectomy, hepatic comorbidity, and higher hematopoietic cell transplant comorbidity index scores. On multivariable analysis, EFS was inferior in those with a higher number of IEI-associated complications. Neither age nor donor had a significant effect on OS or EFS. We have identified age-independent risk factors for adverse outcome, providing much needed evidence to identify which patients are most likely to benefit from HSCT. ispartof: BLOOD vol:140 issue:14 pages:1635-1649 ispartof: location:United States status: published

MHC class II deficiency is a rare, but life-threatening, primary combined immunodeficiency. Hematopoietic cell transplantation (HCT) remains the only curative treatment for this condition, but transplant survival in the previously published result was poor. We analyzed the outcome of 25 patients with MHC class II deficiency undergoing first HCT at Great North Children's Hospital between 1995 and 2018. Median age at diagnosis was 6.5 months (birth to 7.5 years). Median age at transplant was 21.4 months (0.1-7.8 years). Donors were matched family donors (MFDs; n = 6), unrelated donors (UDs; n = 12), and haploidentical donors (HIDs; n = 7). Peripheral blood stem cells were the stem cell source in 68% of patients. Conditioning was treosulfanbased in 84% of patients; 84% received alemtuzumab (n = 14) or anti-thymocyte globulin (n = 8) as serotherapy. With a 2.9-year median follow-up, OS improved from 33% (46-68%) for HCT before 2008 (n = 6) to 94% (66-99%) for HCT after 2008 (n = 19; P = .003). For HCT after 2008, OS according to donor was 100% for MFDs and UDs and 85% for HIDs (P = .40). None had grade III-IV acute or chronic graft-versus-host disease. Latest median donor myeloid and lymphocyte chimerism were 100% (range, 0-100) and 100% (range, 64-100), respectively. Latest CD4+ T-lymphocyte number was significantly lower in transplant survivors (n = 14) compared with posttransplant disease controls (P = .01). All survivors were off immunoglobulin replacement and had protective vaccine responses to tetanus and Haemophilus influenzae. None had any significant infection or autoimmunity. Changing transplant strategy in Great North Children's Hospital has significantly improved outcomes for MHC class II deficiency.

Cidofovir is preemptively used for controlling adenoviremia and preventing disseminated viral disease in hematopoietic cell transplant (HCT) recipients but does not lead to resolution of viremia without T-cell immune-reconstitution. The lipid-conjugated prodrug of cidofovir, brincidofovir, has improved oral bioavailability and achieves higher intracellular concentrations of active drug. We present retrospective multicenter data comparing the kinetics of viremia and toxicities following preemptive treatment with and brincidofovir in children and adolescents diagnosed with HCT-related adenoviremia. Forty-one episodes (18 = brincidofovir; 23 = cidofovir) of antiviral therapy were observed in 27 patients. The 2 groups had comparable immune-reconstitution and viral burden. Major (≥2 log-reduction in 2 weeks; n = 13) and minor (≥1 to ≤2 log-reduction in 2 weeks; n = 2) virological responses were observed in 15 (83%) brincidofovir episodes compared to only 2 (9%) major virological responses with cidofovir (P < .0001). Brincidofovir mediated major responses in 9 of 11 cidofovir-unresponsive patients and resulted in complete responses (CR) despite significant lymphopenia (Brincidofovir vs cidofovir; CR = 13 (80%) vs 8 (35%); median lymphocyte count = 320/μl vs 910/μl; P < .05). One patient experienced abdominal cramps and diarrhea necessitating interruption of brincidofovir and none developed nephrotoxicity with brincidofovir. Thus, brincidofovir is well-tolerated and highly efficacious in controlling adenoviremia during the lymphopenic phase of HCT.

Introduction: Hurler syndrome (HS), the most severe phenotype of mucopolysaccharidosis type I, is characterized by α-L-iduronidase (IDUA) deficiency. Without therapy, most affected children die of cardiac complications in the first decade. Haematopoietic stem cell transplantation (HSCT) is the standard of care in children with HS as it is the only therapy that can arrest disease progression. One of the challenges in HSCT for HS is graft failure. Here, we examined the evolving pattern of graft failure over the past three decades. Methods: Retrospective review of all children with HS undergoing first HSCT at the Royal Manchester Children's Hospital or the University of Minnesota Children's Hospital over a thirty-four-year period (1983 - 2016). The diagnosis of HS was confirmed by an increase in urinary GAG excretion, a deficiency or absence of IDUA in peripheral blood leukocytes, and the clinical phenotype. A full-intensity Busulfan-based myeloablative conditioning regimen (MAC) with pharmacokinetic-guided dosing was started from 2004 (post Bu-pK era). Conditioning regimen used prior to Bu-pK era was variable. Graft failure was classified into 4 types: 1. Primary aplasia, (no neutrophil engraftment by Day +42) 2. Primary autologous reconstitution (neutrophil engrafted by Day +42 but with Results: A total of 240 children with HS were enrolled (131 pre-Bu-pK; 109 post-Bu-pK). The median age at HSCT was 16.3 months (range 4.9-72.2 months) in pre-Bu-pK era and 14.0 months (range 3.8-65.1 months) in post-Bu-pK era (p = 0.002) ). In pre-Bu-pK era, the graft source was predominately marrow/peripheral blood (n=109, 83.2%). The use of cord blood (CB) increased from 16.8% (n=22) in pre-Bu-pk era to 63.3% (n=69) in post-Bu-pK era (p Conclusions: The transplant outcomes have improved. All deaths due to infection, graft failure and pulmonary failure have significantly reduced a better transplant care. The pattern of graft failure has changed from primarily marrow reconstitution likely secondary to inadequate myelosuppression in pre-Bu-pk era, to graft rejection likely secondary to inadequate immunosuppression in post-Bu-pk era. Disclosures Jones: Genzyme: Consultancy, Research Funding, Speakers Bureau; BioMarin: Consultancy, Research Funding, Speakers Bureau.