Introduction Data integrity is critical for reporting outcomes and quality improvement initiatives. However, blood and marrow transplant (BMT) center data is often stored in multiple silos, which presents challenges in consistency, accuracy, and accessibility. Our aim was to analyze critical data elements across all stakeholders at a single center to identify gaps and redundancies, with the goal of streamlining critical BMT data into a unified and accurate repository integrated within the Epic Electronic Health Record (EHR)1. Methods We performed a requirements analysis of critical BMT data elements at Children’s Healthcare of Atlanta (CHOA). This analysis involved various stakeholders, including operational leaders, clinicians, quality managers, Center for International Blood and Marrow Transplant Research (CIBMTR) data managers, researchers and research support staff (Figure 1). We extracted all data elements used in existing data capture tools and systematically mapped them to CIBMTR Transplant Essential Data (TED) forms. We harmonized, annotated, and prioritized data elements based on their relevance to clinical outcomes, reporting requirements, and research objectives. We mapped required data elements to discrete fields within the EHR and identified missing fields for future custom EHR builds. Results We identified 661 discrete data elements stored across 4 Microsoft Excel spreadsheets and 7 other distinct reports (Figure 2). Amongst discrete data elements, 402 (61%) elements are reportable to CIBMTR and 95 (14%) are used in quality reporting. 136 (21%) elements were determined to be redundant, and an exploratory analysis of data quality revealed 9% discordance in one critical data field (vital status). Only 281 (43%) elements are mappable to discrete data fields within Epic EHR. We identified an additional 84 priority data elements needed for future custom EHR builds. Our complete requirement analysis document is available upon request. Conclusion BMT programs have significant operational, clinical, quality, reporting and research data needs. However, existing data systems and processes are inadequate and inefficient. Our comprehensive requirements analysis uncovered opportunities to streamline data management by reducing duplicative work while enhancing data accuracy, consistency, and accessibility. This analysis serves as a roadmap for the development of a custom, unified BMT data repository integrated within Epic EHR, currently underway at our institution. Our requirements analysis may be useful at other transplant centers.

Background Children with sickle cell disease (SCD) remain at risk for invasive pneumococcal disease (IPD) because of impaired splenic function and increased susceptibility to encapsulated bacteria. Data describing IPD after allogeneic hematopoietic cell transplantation (HCT) for SCD are limited.Methods We conducted a multicenter retrospective cohort study of children and young adults with SCD undergoing first allogeneic HCT at two participating Sickle Cell Transplant Advocacy and Research (STAR) centers. IPD occurring within 365 days after HCT was identified through registry data, microbiologic culture review, and supplemental chart review.Results Among 182 patients undergoing HCT, three developed IPD within the first year after transplant. All cases presented with sepsis and bacteremia; one patient also developed meningitis and died of septic shock. IPD occurred between 7 and 365 days after HCT. None of the patients had received post-transplant pneumococcal vaccination before IPD diagnosis. Serotype data were unavailable for all cases.Conclusion In this multicenter cohort of patients with SCD undergoing allogeneic HCT, IPD was uncommon but clinically severe, including late infections occurring nearly one year after transplantation. Prospective studies evaluating immune recovery, splenic function, pneumococcal vaccination practices, and long-term infectious outcomes are needed to better define persistent susceptibility to invasive pneumococcal disease after HCT in patients with SCD.

Background Infections are a major driver of morbidity and mortality after pediatric hematopoietic cell transplantation (HCT) in part due to unidentified or delayed identification of pathogens, precluding targeted therapy. Emerging data suggest plasma microbial cell–free DNA sequencing (mcfDNA) identifies more pathogens, though data in pediatric HCT is limited. We hypothesized that mcfDNA would reveal more pathogens than standard of care (SOC) testing and that these would be interpreted as clinically meaningful in pediatric HCT patients by HCT and infectious disease specialists (HCTs, IDs). Methods All pediatric HCT recipients who had mcfDNA testing for suspected high-risk infections from August 2019 to June 2024 were included in a retrospective, single-center, IRB-approved study. Our aim was to determine: i) the rate and result of positive mcfDNA tests as compared to SOC and ii) the clinical impact adjudicated by independent chart review by 2 HCTs and 2 IDs, and then an intra-group consensus meeting. The impact could be: positive (e.g. initiating targeted treatment or narrowing therapy), no impact (e.g. confirming SOC results or negative without therapy change), or negative (e.g. leading to unnecessary treatment or withdrawal of agents after false negative). Results 73 mcfDNA tests were obtained in 46 patients with an average age of 9.1 years (range, 0.7-19 years). The mcfDNA identified pathogens in 61.6 % of testsconsistent with SOC, 8.9% of these identified earlier by mcfDNA than SOC. . Of the 38.4% negative mcfDNA tests, 11.1% were positive by SOC test. Overall, positive McfDNA identified: viruses in 57.8%, gram negative bacteria in 46.6%, gram positive bacteria in 37.8%, mycobacteria in 4.4%, and fungus in 2.2%. Multiple pathogens were identified in 23 (51.1%) of positive tests.McfDNA results were interpreted as leading to a negative clinical impact, in 13.7% (n=10) and 0% of patients ascribed by IDs and HCTs respectively (Figure). Most mcfDNA testing, 65.8% (n=48) perceived by IDs and 58.9% (n=43) by HCTs, resulted in no impact. McfDNA results were deemed to have a positive clinical impact in 16.4% (n=12) and 38.4% (n=28) of tests by IDs and HCTs respectively. Indeterminant impact was rare, in 4% (n=3) by IDs and 2.7% (n=2) by HCTs. Discussion Our data show that mcfDNA and that both ID and HCT physicians concluded that the results had a positive or no impact in most cases. McfDNA identified pathogens that are difficult to capture expediently such as mucor and extramedullary mycobacteria, and expedited therapy for life-threatening pathogens. Future studies are warranted to determine optimal timing of testing, the sensitivity for focal infections, and data to inform the interpretation of results.

Due to limited published data assessing pediatric hematopoietic cell donor experiences, we previously conducted one of the largest quantitative investigations of pediatric donor experiences and health-related quality-of-life (HRQoL) at the time (RDSafe). Findings from RDSafe demonstrated that a subset of pediatric HC donors experienced very poor HRQoL; unfortunately, that dataset addressed only a limited number of factors, and key associations explaining this poor HRQoL were not found. In this study, our goal was to address that deficit by describing pre-donation donor HRQoL in detail and identifying factors across five key domains that were associated with donor HRQoL. We conducted a prospective study involving 29 centers in the US (31 enrolled, 29 contributed data). After consent at the local center, data were collected via telephone interviews with donors, recipients, other siblings, and parents, and via a web-based survey from transplant centers. Family data (donors, recipients, sibling, parents) were collected before donation and at four weeks, six months, and one-year post-donation. Domains assessed included sociodemographics, general and donation-related psychosocial, clinical, and transplant center characteristics. Data presented here are from the 133 donor-parent pairs who completed the pre-donation interview, 64 recipients, 59 non-donor/non-recipient siblings in these related donor families, and 78 comparison siblings of patients receiving unrelated marrow, PBSC, or cord blood transplantation. Important percentages of pediatric donors reported very poor psychosocial (20%) and overall (13%) HRQoL and parents overestimated their donor child's HRQoL. Donors had significantly better HRQoL than recipients and worse HRQoL than parent proxy reports. Multiple donor, recipient, parent and transplant center characteristics were associated with HRQoL in bivariate analyses. Multivariable analyses by donor age group suggested that donor HRQoL was significantly negatively associated with donor self-reported anxiety, depression and parental education and significantly positively associated with family cohesion, understanding of donation and proxy reports of donor HRQoL. The link between donor HRQoL and recipient and parent health and well-being suggests that variations in donor HRQoL do not occur in isolation but affect and/or are affected by the overall functioning and well-being of other family members and the family as a whole. Particularly striking is the association of donor HRQoL with perceived understanding of the donation process-improved donor education is a potential pathway to improving donor HRQoL. Assessment of-and Interventions to mitigate-risks to donors should involve the functioning of the family as a whole and not just the donor.

BACKGROUND:Gene therapy (GT) is a transformative therapy for sickle cell disease (SCD) that requires transfusion support to suppress hemoglobin S (HbS) for hematopoietic progenitor cell (HPC) mobilization and autologous hematopoietic cell transplantation (HCT). Given the prevalence of red blood cell (RBC) alloimmunization in patients with SCD and recommendations to provide prophylactic minor antigen matching, knowledge of transfusion utilization and duration during the GT process is necessary for transfusion management. STUDY DESIGN AND METHODS:We performed a retrospective review of transfusion utilization of all patients with SCD who received GT at our center through 2024. Transfusions were recorded for three time periods: (1) ≤120 days before first HPC collection, (2) time from first collection to HPC infusion, (3) HPC infusion to transfusion independence. RESULTS:Nine patients received GT, 4 (44%) with RBC alloimmunization. One patient became alloimmunized (ant-Jka) during pre-HPC transfusion management. Four patients had 1 mobilization cycle, 5 patients had 2 cycles, with a median of 3 collection days (1-5). Median RBC transfusion utilization was 38 units (range 27-55): 15 units (9-27) for Period 1, 20 units (10-30) for Period 2, 6 units (4-9) for Period 3. Median platelet utilization was 13 units (7-31) in Period 3. DISCUSSION:The transfusion support of patients with SCD during GT has unique considerations due to RBC transfusion requirements for HPC mobilization cycles. This single institution report will help support transfusion planning and decision making about the feasibility of transfusion support for patients with extensive RBC alloimmunization.

Sickle cell disease (SCD) is an inherited red blood cell disorder leading to life-long, life-threatening complications. Hematopoietic cell transplant (HCT) is the only curative option, and with increasing patients opting for HCT, the number of survivors at risk for late effects and in need of life-long monitoring is increasing. Recognizing the complexity of survivorship in these patients, a dedicated multidisciplinary late effects clinic provides a comprehensive model of care, supporting long-term health and quality of life in survivors.In this single center, retrospective quality assessment, we identified SCD patients who underwent HCT from 2010-2023 at Children’s Healthcare of Atlanta (CHOA) using our Aflac Sickle Cell Registry. Epic Slicer Dicer was used to identify post-HCT follow up, and patients were excluded if <1 post-HCT visit or age ≤20 yrs. In our final cohort (Figure 1), outpatient visits were manually reviewed to categorize as multidisciplinary clinic (“ex sickle”) vs routine HCT clinic. Data were summarized as median (IQR) or N (%). Fisher’s exact test was used to compare consults and studies performed between clinic types. All data was transformed and analyzed in RStudio.Of 101 SCD patients post-HCT, baseline characteristics and select outcomes are shown (Table). One patient (1%) died 10 yrs post-HCT. Following HCT, SCD patients had 450 visits, 4.0 (3.0, 6.0) visits/person with yr 1 attendance of 99% (Figure 2). Of those with yr 1 visit, most (77%) attended ex sickle clinic. Of the 23 patients not seen in ex sickle clinic for yr 1 visit, 20 (87%) returned for yr 2 visit (e.g. 3 lost to follow up), 12 (60%) of whom converted to ex sickle clinic. Nutrition and psychology consults occurred significantly more frequently in HCT clinic, however pulmonary function testing (PFT) and echocardiogram (echo) were significantly more likely to be performed in ex sickle clinic (Figure 3).Our multidisciplinary clinic model demonstrated greater follow up for organ function compared to standard clinic; while nutrition and psychology consults occurred more frequently in HCT clinic, this may be due to greater accessibility. While most patients completed 1 yr post-HCT follow up, rates declined by 4.5 years post-HCT highlighting the gap in long-term late effects care. Ongoing efforts are needed to promote engagement beyond 5 years, efforts of which are ongoing as part of a quality improvement initiative.

Hematopoietic cell transplantation (HCT) for sickle cell disease (SCD) is an established cure, but mixed donor chimerism is common even with myeloablative conditioning regimens. With many North American centers using less intensive conditioning regimens, rates of mixed donor chimerism may increase. The clinical long-term outcomes of these patients are not well described in combination with laboratory markers of hemolysis and hemoglobin S percentage. The objective of this study was to describe long-term graft integrity and clinical outcomes in survivors of HCT for SCD with mixed donor chimerism at 1-year post-HCT. A retrospective multi-center observational analysis of 33 children and adolescents with sickle cell disease and mixed donor chimerism at 1-year post-HCT and at least 2 years of follow-up was performed. Descriptive statistics and a linear mixed-effects model (LMM) were used. Longer time to follow-up was predictive of lower myeloid chimerism but not lymphoid chimerism. Higher chimerism at 1-year post-HCT were associated with higher chimerism at last follow-up (myeloid and lymphoid). Hemolysis was noted when donor myeloid chimerism was 25% or less. No secondary neoplasms were noted. In this cohort of children and adolescents who have undergone HCT for SCD with mostly reduced intensity or nonmyeloablative conditioning, lower myeloid chimerism was seen with longer follow-up, highlighting the need for lifetime surveillance of chimerism and clinical outcomes. A higher donor myeloid chimerism at one year is preferable and associated with higher long-term values. No secondary malignancies were observed.

High-dose chemotherapy with tandem autologous stem cell transplantation (ASCT) is a standard approach for pediatric high-risk neuroblastoma (HR-NB); however, data on acute regimen-related toxicities are limited. This study evaluated treatment-related toxicities and day +180 outcomes following tandem ASCT in children with HR-NB. We conducted a multi-institutional (n = 13) retrospective review including pediatric patients with HR-NB scheduled for tandem ASCT between January 2014 and June 2021. Descriptive analyses were performed to evaluate organ toxicities and transplantation-related outcomes, focusing on endothelial injury. A total of 255 patients underwent ASCT 1 with thiotepa/cyclophosphamide (TT/Cy). Fourteen patients were unable to proceed to ASCT 2, owing to death in 9, with underlying disease relapse the cause of death in 7 of these 9 (78%). Severe endothelial toxicities, including veno-occlusive disease (VOD) and transplantation-associated thrombotic microangiopathy (TA-TMA) in 3 patients, prevented progression to tandem ASCT. The remaining 241 patients (94.5%) completed tandem ASCT with TT/Cy and carboplatin/etoposide/melphalan. Post-ASCT 2 complications included bloodstream infections (17%), intensive care unit admission (20%), respiratory failure requiring intubation (12%), pulmonary hypertension (4%), and acute kidney injury (18%), with 5% requiring dialysis. VOD occurred in 9% of patients, and TA-TMA occurred in 16% of patients completing tandem ASCT. Six-month survival was 94% for the tandem ASCT recipients. This study highlights the impact of regimen-related toxicities in pediatric HR-NB patients undergoing tandem ASCT. Despite a modest 6-month mortality rate, the burden of endotheliopathies contributed to morbidity and mortality post-ASCT 2. Improved screening and early intervention strategies may help mitigate transplantation-related morbidity.

We prospectively collected PROMIS©25 and PROMIS©29 surveys in the Sickle Cell Transplant Evaluation of Long Term and Late Effects Registry (STELLAR). Mobility and social participation T-scores were decreased; all other domains were within the norm.

HLA-matched sibling donor transplantation accounts for the majority of transplants performed for sickle cell disease (SCD). However, only about 18% of patients in the United States with SCD will have unaffected human leukocyte antigen (HLA)-matched siblings or one with sickle trait, limiting applicability. A Blood and Marrow Transplant Clinical Trials Network phase II trial of HLA-matched unrelated donor bone marrow transplantation (URD BMT) for severe SCD was conducted between 2008 and 2014 and enrolled patients aged 3–19 years (BMT CTN 0601, NCT00745420).1 A reduced intensity immunosuppressive conditioning regimen (RIC) of alemtuzumab (45 mg; days −22 to −19), fludarabine (150 mg/m2; day −8 to −4), and melphalan (140 mg/m2; day −3) was employed using alemtuzumab early to provide recipient immune suppression to overcome a higher risk of graft rejection (GR) with URD BMT in SCD patients while also limiting toxicities associated with myeloablative agents.1 The trial met a pre-specified primary endpoint of 75% 1-year event-free survival (EFS). However, as previously reported, the incidence of 1-year acute and extensive chronic graft-versus-host disease (GVHD) were unacceptably high at 17% and 38%, respectively. This report details long-term outcomes in this previously reported cohort as an important consideration for therapeutic trials as follow-up is usually limited to early time points. Follow-up information beyond 2 years post-BMT was available for 20 of 21 survivors described in the initial report through the Center for International Blood and Marrow Transplant Research (CIBMTR) database, which collects patient-level data from transplant centers annually for 5 years and then every 2 years for as long the center maintains contact with the patient (www.cibmtr.org). Median follow-up was 97 months (range 11–144). Six patients were lost to follow-up at 11 months, 4.0, 4.5, 5.5, 5.5, and 6 years after transplantation. For this report, GR, GVHD, EFS, and overall survival (OS) were examined similar to the initial report.1 The incidence of GR and chronic GVHD was calculated using the cumulative incidence estimator to accommodate competing risks. Probabilities of EFS and OS were calculated using the Kaplan–Meier estimator. Surviving patients were censored at the last follow-up or death. Analyses were performed using SAS version 9.4 (SAS Institute, Cary, NC). The median age of this cohort at transplant was 13 years (range: 6–18); 5 were 6–9 years old, 10 were 10–15 years old, and 6 were 16–19 years old (Table S1). Median donor age was 34 years (range: 21–53). Indications included stroke (N = 11), vaso-occlusive episodes (N = 5), acute chest syndrome (N = 3), and high transcranial Doppler velocity (>200 cm/s) (N = 2). The median age of recipients at the current time is 21 years (range: 11–25). Eighteen (86%) had ≥5 years of follow-up. Three patients died beyond 2 years post-transplant. Two deaths were secondary to complications of chronic GVHD at 2.6 and 3.9 years. A third patient who had primary GR (reported in the initial report), underwent a second myeloablative URD umbilical cord blood transplant 27 months after the first and died at 2.5 years after the first transplant of grade IV acute GVHD that developed following the second transplant. Consequently, the 5- and 8-year probabilities of OS were 68% (95% CI: 48%–82%) (Figure 1A). With a single secondary GR 5 years after transplantation, the 5- and 8-year probabilities of EFS were 61% (95% CI: 41%–76%) and 57% (95% CI: 37%–73%), respectively (Figure 1B). The 8-year GR rate is 14%, similar to that previously reported after myeloablative or reduced intensity alternative donor transplantation.2 At last follow-up, performance scores for 19 of 20 patients were reported as 90–100 (n = 13) and 70–80 (n = 6). There were no central nervous system (CNS), pulmonary, or vaso-occlusive events reported after successful donor engraftment. No patient reported pulmonary, cardiac, hepatic, renal, or CNS toxicity beyond a year post-transplant. Details of immune reconstitution were available in 12 patients, and all reported normalization of CD4+ and CD8+ T cell numbers at 2 years. Four patients reported gonadal dysfunction of which two patients (male aged 13 years and female aged 18 years at transplantation) were receiving hormone replacement therapy. Two others did not (male aged 10 years and female aged 15 years but now deceased). Fifteen patients are ≥18 years of age and none have reported pregnancies or history of having fathered children. However, the cohort is still young at a median age of 21 years (range: 18–25) and longer follow-up will be necessary to report on fertility. Apart from the conditioning agents, additional disease-related factors that impede fertility in SCD patients include vascular complications affecting the gonads, transfusional iron-overload and related toxicity, and hydroxyurea use.3 The level of contribution of each of these factors is difficult to evaluate unless future trials incorporate such data collection. Other complications beyond 1 year after transplantation were reported in nine patients. New-onset avascular necrosis was reported in 4 patients, 1.3, 2.4, 2.9, and 3.4 years post-transplantation. Two patients had pancreatitis 1.7 and 2.2 years post-transplant, adrenal insufficiency was reported at 3 years in one patient, and severe depression and anxiety in one patient each, 1.8 and 5 years post-transplant. Patients with SCD and progressive age-related vasculopathy are predisposed to all these complications that could have been exacerbated by GVHD prophylaxis or therapy with corticosteroids.4-6 Four patients were lost to follow-up 4–6 years after transplantation and one declined consent for data collection upon age of maturity. The reasons for loss of follow-up are not known but previous reports have noted obstacles to transition of care, perceived discrimination and consequent nonadherence to physician recommendations, communication barriers regarding the impact of participation in clinical trials, and concerns regarding maintenance of privacy. We have also experienced limitations that impact outcomes such as medication compliance especially in adolescent patients. The small sample size was inadequate to formally examine risk factors for late mortality. The two deaths beyond 2 years after transplantation occurred in patients aged 15 and 19 years at the time of transplant and was GVHD associated. This extends the observation reported in the primary manuscript1 that all GVHD-associated deaths occurred in patients who were transplanted beyond 13 years of age. A higher mortality in SCD patients transplanted beyond the first decade of life (presumably with more advanced disease) and an increasing GVHD risk with age and associated mortality have been previously reported.7 Calcineurin inhibitor and short-course methotrexate-based GVHD prophylaxis that was used in this trial is a common regimen that is used with T-depleting antibody-based conditioning where the latter helps provide additional GVHD prophylaxis. In this study, however, in vivo T-cell depletion with alemtuzumab was used 3 weeks prior to transplant targeted immune ablation of the recipient while sparing donor cells to facilitate engraftment due to the higher risk for GR in this non-malignant disorder. As hoped, this supported sustained engraftment despite the RIC regimen. The alemtuzumab however was unable to provide a GVHD sparing benefit. The regimen had previously been used in other non-malignant disorders and in HLA-matched sibling donor transplantation for SCD with EFS and OS rates of 90% and 93%, respectively.8 In that setting, chronic GVHD again occurred only in recipients >13 years of age and GVHD-related mortality was noted only in patients >17 years of age at the time of transplant similar to GVHD patterns previously described and encountered in the current study.1, 9 Safety was compromised by the high rate of GVHD and associated mortality in older recipients drawing attention to the need for more effective GVHD prophylaxis for this transplant approach. In summary, extended follow-up demonstrated that engraftment and cure were achievable with a RIC regimen following unrelated donor transplantation. The GVHD prophylaxis, however, was inadequate especially in recipients over 13 years of age, compromising outcomes and increasing mortality. Since completion of BMT CTN 0601 and the recognition of the GVHD-related complications, successful application of novel GVHD prophylaxis, including extended duration abatacept, has been reported with this conditioning regimen in HLA matched and minimally mismatched unrelated transplants.10 This progress has paralleled with the successful use of RIC regimens in haploidentical transplantation with post-transplantation cyclophosphamide to offset chronic GVHD in older recipients thus helping advance alternate donor transplantation for SCD.11 These efforts are proceeding in parallel with gene therapy efforts that have successfully achieved engraftment of gene-modified autologous cells following myeloablative conditioning. It is encouraging that the results from these collective curative efforts are now approaching those previously described only after HLA-matched sibling donor transplantation and serve to expand curative options for SCD patients over a wide age and therapeutic range. Importantly, these curative therapies require long-term follow-up via registries as described here to ensure that short-term success is sustained and pros and cons are tracked. Mary Eapen and Shalini Shenoy designed the study, interpreted the data, and drafted the manuscript. Mary Eapen and Jianqun Kou assembled and prepared the data set and analyzed the data. All remaining authors critically reviewed the manuscript. All authors approved the final manuscript. Support for this study was provided by grant #U10HL069294 to the Blood and Marrow Transplant Clinical Trials Network from the National Heart, Lung, and Blood Institute and the National Cancer Institute, along with funding by the National Marrow Donor Program, the Sickle Cell Disease Clinical Research Network, and the National Center on Minority Health and Health Disparities. The Center for International Blood and Marrow Transplant Research is supported primarily by grant #U24-CA76518 from the National Cancer Institute, the National Heart, Lung, and Blood Institute, and the National Institute of Allergy and Infectious Diseases and contract HHSH234200637015C with Health Resources and Services Administration (HRSA/DHHS). The content is solely the responsibility of the authors and does not necessarily represent the official views of the above mentioned parties. Authors declare none for this study. Data available on request due to privacy/ethical restrictions. Table S1. Patient and donor characteristics at transplantation. Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.

Background: Endothelial dysfunction is a key driver of transplant associated thrombotic microangiopathy (TA-TMA) and sinusoidal obstructive syndrome (SOS)- early syndromes post hematopoietic cell transplantation, which are associated with non-relapse related mortality (NRM). Circulating endothelial cells (CEC), a marker of endothelial damage, are a diagnostic and prognostic biomarker in other TMAs, with scant data in TA-TMA and SOS. Non-invasive imaging modalities of endothelial health are also untested in both diseases. The primary objective of this pilot study was to determine the feasibility of routine hyperemia arterial tonometry (RH-PAT) and measuring circulating endothelial cells (CEC). Secondary objectives included determining the diagnostic, prognostic, and predictive performance of RH-PAT, CEC and endothelial markers and the development of TA-TMA, SOS and NRM. Methods: In this prospective IRB approved study, patients were serially enrolled from April 2020- December 2022. Imaging and blood were obtained pre-HCT, day 0, day 14 and day 30. All ages were eligible for the blood sample component, but the RH-PAT arm was restricted to those >10 years. CEC were measured using flow cytometry (Farinacci et al. Res Pracr Thromb Haemost. 2019). ST2 and VCAM-1 were measured by ELISAs per manufacturing recommendations. RH-PAT is an FDA approved, non-invasive technique to measure endothelial health and calculates a reactive hyperemic index (lnRHI), lower lnRHI values are indicative or poor endothelial function. Descriptive statistics were used to compare groups. Results: Fifty-one patients enrolled in the study, 21 participated in the RH-PAT arm, 43 in the blood sample arm, and 17 in both. Attrition rates were high in the RH-PAT arm, 4 people tolerated 1 study then declined additional tests, 5 underwent 2, and 12 tolerated 3 or more measurements. The median age at HCT was 10.1 years, 24 (49%) were female and 47 (96%) underwent allogeneic HCT. Ten (25%) were Black and 13 (27%) Hispanic. Nineteen (37.2%) developed TA-TMA a median of 35 days post HCT (range 24.5 to 59). There were no significant differences in CEC at any time points in patients with TA-TMA compared to those without. LnRHI values were significantly lower pre-HCT in those who later developed TA-TMA compared to those who did not develop TA-TMA (mean 0.32, 95% CI 0.25-0.39 vs 0.61, 95% CI 0.44-0.78 respectively), though there were no differences on day 0, 14 or at the time of TA-TMA diagnosis. Eleven patients developed SOS a median of 13 days post HCT (range 9.5 to 23). Seven patients experienced NRM a median of 134 days post HCT (range 69 to 353.5). CEC were not different among patients with SOS or those who died of NRM at any time point. Throughout the HCT process, CEC were present in very small amounts and peaked on day 14 (median of 0.04). LnRHI was significantly lower on day 30 in those who ultimately died of NRM versus those who did not (mean 0.25, 95% CI 0.13 to 0.36 vs 0.50, 95% CI 0.41 to 0.58 respectively). Day 30 lnRHI predicted NRM with an AUC of 0.81 (95% CI 0.59 to 1). However, there were no differences in lnRHI at other time points, nor were there any differences in lnRHI in those with SOS compared to no SOS at any time points. ST2 and sVCAM-1 were significantly elevated on day 14 and 30 in patients with TA-TMA, SOS and NRM. While endothelial markers ST2 and VCAM-1 had a significant positive correlation with each other, there were no significant correlations of these markers with CEC nor lnRHI, nor were CEC or lnRHI associated with each other. Discussion: In this pilot study, we tested new imaging and blood biomarkers in children post HCT. CEC were low at all time points, difficult to isolate, and not different in those with endothelial disorders, SOS and TA-TMA. While small numbers, RH-PAT lnRHI was significantly lower pre-HCT preparative regimen in those who developed TA-TMA, which could suggest these patients had pre-existing endothelial injury, a potential risk factor for subsequent disease. At day 30, the RH-PAT lnRHI was associated with NRM, perhaps suggesting that endothelial dysfunction of any etiology is a risk factor for death. While noninvasive, RH-PAT was poorly tolerated, limiting feasibility for future studies. While ST2 and sVCAM-1 were elevated on day 14 and day 30 in TA-TMA, SOS and NRM, they were non-specific. Additional studies are needed to identify alternative approaches of measuring endothelial dysfunction to predict and prognose TA-TMA and SOS.

Fever is common in children undergoing hematopoietic cell transplantation (HCT). Empiric antibiotic (EA) therapy is initiated and often continued until neutrophil engraftment. Prolonged antibiotic exposure reduces microbiome diversity and causes overgrowth of pathogenic organisms, leading to such complications as infections from antibiotic-resistant organisms and Clostridium difficile colitis. Shorter courses of EA therapy have been studied in adults undergoing HCT without significant safety concerns, but data in children are lacking. We instituted a single-center preintervention/ postintervention quality improvement (QI) project to assess the feasibility of short-course EA therapy for first fever in patients undergoing HCT. We aimed to reduce the median duration of broad-spectrum antibiotic use in eligible patients from 20 days in 2020 to 10 days in 2021. Patients were eligible for the intervention, limiting EAs to 7 days for first fever, if they were admitted for their first allogeneic HCT, were afebrile for >24 hours, had no infection requiring systemic treatment, and were hemodynamically stable. Outcome measures included days of EA therapy for first fever and total broad-spectrum antibiotic use during the period of hospitalization, defined as the time from the start of conditioning to 30 days after HCT or hospital discharge, whichever occurred first. Balancing measures included bloodstream infection (BSI), fever, and intensive care (ICU) admission within 3 days of stopping EA therapy. Project criteria were applied retrospectively to patients who underwent HCT in 2020 to construct a preintervention short-course-eligible cohort. During the intervention period, 41 patients underwent allogeneic HCT, of whom 17 (41%) were eligible for short-course EA therapy. Among eligible patients, the median age was 5.3 years, 47% had an underlying malignancy, and 88% received myeloablative conditioning. There were no differences in demographic or HCT characteristics between patients eligible for shortcourse EA during the intervention and preintervention period (n = 24). The short-course EA schedule was adhered to by 14 of the 17 eligible patients (82%). The duration of EA for first fever and total broad-spectrum antibiotic use was significantly decreased in the short-course EA-eligible patients compared to the preintervention cohort, from a median of 17 days to 8 days and from 20 days to 10 days, respectively (P < .01). Of the 14 patients adhering to short-course EA, 2 experienced a balancing measure of recurrent fever requiring resumption of EA, but no infection was identified. There were no BSIs, ICU admissions, or deaths during the hospitalization period in patients who received short-course EA. In this single-center QI project, short-course EA for initial fever was successfully applied to children undergoing allogeneic HCT using strict criteria and led to a significant decrease in broad-spectrum antibiotic use during hospitalization. These results should be validated in a prospective clinical trial to include the impact of short-course EA on antibiotic-resistant organisms, the intestinal microbiome, and HCT outcomes.(c) 2023 The American Society for Transplantation and Cellular Therapy. Published by Elsevier Inc. All rights reserved.

Hematopoietic cell transplantation (HCT) is the only readily available cure for many life-threatening pediatric nonmalignant diseases (NMD), but most patients lack a matched related donor and are at higher risk for graft-versus-host disease (GVHD). Use of abatacept (Aba) to target donor T-cell activation has been safe and effective in preventing GVHD after unrelated donor (URD) HCT for malignant diseases (Aba2 trial). Our primary objective was to evaluate the tolerability of Aba added to standard GVHD prophylaxis (cyclosporine and mycophenolate mofetil) in pediatric patients with NMD undergoing URD HCT. In this single-arm, single-center phase 1 trial, 10 patients receiving reduced intensity or nonmyeloablative conditioning underwent URD HCT. Immune reconstitution was assessed longitudinally via flow cytometry and compared to pediatric patients on Aba2. Nine patients successfully engrafted, with 1 primary graft rejection in the setting of inadequate cell dose; secondary graft rejection occurred in 1 patient with concurrent cytomegalovirus viremia. Two deaths occurred, both unrelated to Aba. One patient developed probable posttransplant lymphoproliferative disease, responsive to rituximab and immune suppression withdrawal. No patients developed severe acute or chronic GVHD, and 8 patients were off systemic immunosuppression at 1 year. Immune reconstitution did not appear to be impacted by Aba, and preservation of naive relative to effector memory CD4+ T cells was seen akin to Aba2. Thus, 4 doses of Aba were deemed tolerable in pediatric patients with NMD following URD HCT, with encouraging preliminary efficacy and supportive immune correlatives in this NMD cohort.

Curative therapy for sickle cell disease (SCD) through hematopoietic cell transplantation (HCT) is associated with a high level of risk for treatment-related gonadal dysfunction and future infertility. Both the myeloablative conditioning (MAC) and reduced-intensity conditioning (RIC) regimens used for SCD HCT are considered to carry a high risk for ovarian damage. Cyclophosphamide equivalent doses (CEDs) are thought to correlate with the degree of gonadal damage in pediatric oncology patients. We aimed to evaluate ovarian outcomes previously reported from our center, characterize the conditioning regimens as MAC or RIC, and calculate the CED for each regimen. The ovarian outcomes diminished ovarian reserve (DOR), as determined by an anti-Müllerian hormone (AMH) below the normal limits for age and assay or <5%, and premature ovarian insufficiency (POI), defined as a follicle-stimulating hormone (FSH) level >40 mIU/ML, are presented by conditioning regimen from 3 clinical studies from our center (2 published and 1 presented as an abstract in 2022). The studies were not mutually exclusive of patients. CEDs were calculated for each regimen. The CED ranged from 3388 to 9705 mg/m2 for MAC regimens and from 5600 to 18,750 mg/m2 for RIC regimens. DOR was observed in all regimens; however, in one study 2 patients had normal AMH levels after a fludarabine/melphalan regimen, and 1 patient had a normal AMH level after a fludarabine/melphalan/thiotepa regimen. Rates of POI were more variable and ranged from 40% to 100% after MAC regimens and from 0 to 100% after RIC regimens. Female patients with SCD who undergo HCT have very high rates of DOR after both MAC HCT and RIC HCT. Two of the 3 RIC regimens evaluated had higher CEDs than were seen in any of the MAC regimens evaluated. Rates of POI were more variable but may increase with time from transplantation. All SCD patients need to be counseled about the risk of infertility and provided information about fertility preservation.