Case Report: Unmanipulated Matched Sibling Donor Hematopoietic Cell Transplantation In TBX1 Congenital Athymia: A Lifesaving Therapeutic Approach When Facing a Systemic Viral Infection

Congenital athymia can present with severe T cell lymphopenia (TCL) in the newborn period, which can be detected by decreased T cell receptor excision circles (TRECs) on newborn screening (NBS). The most common thymic stromal defect causing selective TCL is 22q11.2 deletion syndrome (22q11.2DS). T-box transcription factor 1 (TBX1), present on chromosome 22, is responsible for thymic epithelial development. Single variants in TBX1 causing haploinsufficiency cause a clinical syndrome that mimics 22q11.2DS. Definitive therapy for congenital athymia is allogeneic thymic transplantation. However, universal availability of such therapy is limited. We present a patient with early diagnosis of congenital athymia due to TBX1 haploinsufficiency. While evaluating for thymic transplantation, she developed Omenn Syndrome (OS) and life-threatening adenoviremia. Despite treatment with anti-virals and cytotoxic T lymphocytes (CTLs), life threatening adenoviremia persisted. Given the imminent need for rapid establishment of T cell immunity and viral clearance, the patient underwent an unmanipulated matched sibling donor (MSD) hematopoietic cell transplant (HCT), ultimately achieving post-thymic donor-derived engraftment, viral clearance, and immune reconstitution. This case illustrates that because of the slower immune recovery that occurs following thymus transplantation and the restricted availability of thymus transplantation globally, clinicians may consider CTL therapy and HCT to treat congenital athymia patients with severe infections.

Longitudinal study of stool-associated microbial taxa in sibling pairs with and without autism spectrum disorder

Autism Spectrum Disorder (ASD) is a complex neurodevelopmental disorder influenced by both genetic and environmental factors. Recently, gut dysbiosis has emerged as a powerful contributor to ASD symptoms. In this study, we recruited over 100 age-matched sibling pairs (between 2 and 8 years old) where one had an Autism ASD diagnosis and the other was developing typically (TD) (432 samples total). We collected stool samples over four weeks, tracked over 100 lifestyle and dietary variables, and surveyed behavior measures related to ASD symptoms. We identified 117 amplicon sequencing variants (ASVs) that were significantly different in abundance between sibling pairs across all three timepoints, 11 of which were supported by at least two contrast methods. We additionally identified dietary and lifestyle variables that differ significantly between cohorts, and further linked those variables to the ASVs they statistically relate to. Overall, dietary and lifestyle features were explanatory of ASD phenotype using logistic regression, however, global compositional microbiome features were not. Leveraging our longitudinal behavior questionnaires, we additionally identified 11 ASVs associated with changes in reported anxiety over time within and across all individuals. Lastly, we find that overall microbiome composition (beta-diversity) is associated with specific ASD-related behavioral characteristics.

Comparable Outcomes Among Adult Patients Allotransplanted for Myelodysplastic Syndrome Using Haploidentical, Matched Unrelated or Matched Sibling Donors: A Single-Center Study

Introduction: Allogeneic stem cell transplantation (allo-SCT) remains the only curative option for patients with myelodysplastic syndrome (MDS). If recent data have shown encouraging results with haploidentical (haplo) donors in this context, no comparison with allo-SCT using other source of graft (matched sibling [MSD] or unrelated [MUD] donors) has been reported so far. Methods: We retrospectively considered 102 consecutive adults transplanted for MDS between March 2010 and August 2020 in our Department, comparing outcomes between those receiving a graft from a MSD, a MUD or a haplo-donor. Results : Thirty-three, 48 and 21 patients respectively received a graft from a MSD, MUD or haplo donor. Peripheral blood stem cells (PBSC) were the source of graft for all patients. The median age of the whole cohort was 63 years old (range: 20-74) and the median follow-up was 23 months (range: 0-125). The three groups shared similar characteristics (gender, type of MDS, disease status, disease risk index, CMV status, ABO compatibility, peripheral blood stem cells graft count, conditioning regimen) except median recipient age which was younger in matched patients ( 61 vs 65 MUD vs 65 Haplo, p=0,04) and median donor age which was older in matched transplant ( 61 vs 34 MUD vs 42 Haplo, p< 0,001) (Table 1). With a median follow-up of 46,4 months, the 4-year OS (Figure 1) was comparable between the three groups (haplo: 60.1 % ± 11,0 % , MSD: 59,0 % ±9,4 % and MUD: 61.2 % ± 7,2 %, p = 0.88) as well as the 4-year DFS (Figure 2) (55.9 % ± 11,1 % vs 51,2 % ±9,2 % vs 59.6 % ± 7,2 %, p = 0.78) and the cumulative incidence (CI) of NRM (34.6 % ±12,4 % , 15,4% ± 6,4% and 23.8 % ± 6,4 %, p = 0.21). Also, the 4-year CI of acute grade 3-4 GVHD (14,3% vs 15,2% vs 20,8%, p=0.79) and of moderate/severe chronic GVHD (14,3% vs 24.2% vs 27,1%, p=0.56) were not significantly different. The 4-year GRFS seemed better with haplo (Figure 3) but this was not statistically significant (56,1 % ± 11,0% vs 28,1% ±9,2 % vs 32,8 % ± 7,4%,p=0 .41). Conclusions: These data suggest that haplo-identical donors represent a valid alternative in MDS patients lacking a MSD or a MUD for allo-SCT. Figure 1 Figure 1. Disclosures Moreau: Oncopeptides: Honoraria; Amgen: Honoraria; Celgene BMS: Honoraria; Janssen: Honoraria; Sanofi: Honoraria; Abbvie: Honoraria.

Nonmyeloablative Transplant for Sickle Cell Disease Does Not Lead to Kidney Dysfunction Post-HSCT

Hematopoietic stem cell transplantation (HSCT) is a potentially curative therapy for patients with sickle cell disease (SCD). Though HSCT can reverse the SCD phenotype, both acute kidney injury (AKI) and chronic kidney disease (CKD) have been associated with HSCT. SCD alters renal function thus the impact of HSCT on renal function in SCD patients is a critical area of exploration. Here, we report the effect of HSCT on renal function in people with SCD. This study analyzes data from 195 patients who received HLA-matched sibling or haploidentical HSCT for SCD at Imperial College London (ICL), National Institutes of Health (NIH), and University of Illinois Chicago (UIC). The former is a pediatric cohort and all sites employed a nonmyeloablative conditioning. Patients' renal function was assessed at baseline and annually thereafter for up to 3-years. We examined the prevalence of CKD before and after HSCT, estimated glomerular filtration rate (eGFR) and urine albumin to creatinine ratio (UACR) trends after HSCT, and the incidence of AKI within 100 days of HSCT. We defined and staged AKI according to Kidney Disease: Improving Global Outcomes (KDIGO) criteria; we calculated eGFR with the CKD- epidemiology collaboration (CKD-EPI) equation for adults and Bedside Schwartz for children. The median eGFR declined annually but remained within the normal range throughout the follow-up period: the baseline median eGFR was 138 ml/min/1.73m 2 and declined by 7 in the first year of follow-up and by additional decreases of 5 and 3.6 ml/min/1.73m 2 in subsequent years (p-values of 0.07, 0.0002, and 0.0002 for years 1, 2, and 3 for comparison to baseline from regression model of eGFR). No differences in eGFR were seen for covariates in the model: haploidentical vs. matched sibling, engraftment status, gender, or site. The downward eGFR trend may represent an improvement in renal function toward normal as hyperfiltration (eGFR ≥150 ml/min/1.73m 2) was present in 28% of patients at baseline and steadily declined to 7% by 3 years post-HSCT. There was a corresponding increase in patients with normal eGFR (60-149 ml/min/1.73m 2) from 59% at baseline to 88% at 3 years post-HSCT. Among the ICL and NIH cohorts (UIC excluded due to use of a different AKI determination strategy), 58% of patients developed AKI in the early post-HSCT period. 67% of AKI cases were mild, stage 1; 25% were moderate, stage 2; and 8% were severe, stage 3 AKI. This study demonstrates that HSCT in patients with SCD is associated with a transient increase in UACR but not associated with a significant increase in CKD prevalence by 3-years post-HSCT. The stability of UACR compared to baseline by the 3-year time point suggests that even more mild renal damage may stabilize after HSCT. While there is a substantial decline in eGFR from baseline to each annual follow-up, the proportion of patients whose eGFR was in the normal range increased as the prevalence of hyperfiltration decreased. Finally, while AKI occurred in more than half the patients in our cohort, the preponderance developed only mild AKI. Therefore, our data indicate that nonmyeloablative HSCT for SCD does not lead to significant kidney dysfunction post-HSCT. Disclosures Saraf: Pfizer: Research Funding; Global Blood Therapeutics: Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding. Diamantidis: United Health Group: Consultancy.