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There have been no large comparisons of the clinical and laboratory features of familial neonatal hemophagocytosis (f-nHLH) and infectious neonatal hemophagocytosis (i-nHLH). The objectives of this study were the following: (1) Describe the demographic, diagnostic, and clinical features of patients with familial nHLH (F-nHLH) and infectious HLH (i-nHLH). (2) Compare key variables between f-nHLH and i-nHLH. (3) Compare the clinical outcomes of f-nHLH and i-nHLH. (4) Summarize literature on cytokine levels in patients with nHLH. Data from a previously published nHLH meta-analysis report were used to describe and compare features of infants with f-nHLH versus i-nHLH. Variables were tested with the χ 2 test or Fisher exact test, Cochran-Armitage test, independent 2-sample t test, or Wilcoxon rank-sum test as appropriate. Odds ratios were calculated for any comparison with a P -value of <0.05. Data extracted from 99 cases of f-nHLH and 54 cases of i-nHLH were included in this analysis. Infants with f-HLH met HLH criteria at the following rates: fever (84%); organomegaly (100%); pancytopenia (75%); hypofibrinogenemia (84%); hypertriglyceridemia (48%); hypofibrinogenemia or hypertriglyceridemia (82%); hemophagocytosis (81%); hyperferritinemia (99%); low or absent NK cell activity (91%); and elevated soluble CCD25 (91%). Infants with i-nHLH had higher median ferritin levels (22,537 ng/mL) than infants with f-nHLH (7587 ng/mL) ( P =0.072). Infants with f-nHLH had higher rates of symptoms in utero, preterm birth, family history of HLH, and family history of infant death. The overall survival among infants with familial nHLH was lower than infectious nHLH ( P =0.037). Management of nHLH requires rapid diagnosis and prompt treatment, as current literature suggests nHLH has high mortality rates. Distinguishing between familial and infectious causes of nHLH can aid in determining the correct treatment of choice.

Glutathione synthetase (GSS) deficiency is an extremely rare autosomal recessive inborn error of metabolism. This metabolic disorder is caused by mutations in the GSS gene, which encodes GSS—an enzyme that catalyses the ATP-dependent conversion of γ-glutamyl-cysteine and glycine to glutathione. Low glutathione impairs the cellular antioxidant defence mechanism, leaving cells susceptible to oxidative stress and damage.

Abstract Introduction: Inherited & acquired bone marrow failure syndromes (BMFS) have “stress erythropoiesis” with macrocytic anemia, elevated fetal hemoglobin (HbF) & erythropoietin (EPO) levels. The degree of HbF elevation & its capacity to discriminate between patients with inherited & acquired BMFS needs to be systemically studied. Genetic testing is often delayed & it is important to establish an early clinical diagnosis to make clinical decisions such as initiation of immunosuppressive therapy. Methods: After institutional review board approval, we compiled a clinically & genetically well-annotated cohort of patients with BMFS evaluated at Mayo Clinic. All patients were required to have at least cytopenia(s) & evidence of low or variable bone marrow cellularity upon a bone marrow evaluation. Patients with pre-clonal or malignant disorders were excluded. Clinical diagnoses were independently verified for accuracy. Detailed clinical & laboratory features were recorded. Germline genetic testing was performed as clinically appropriate on peripheral blood or bone marrow samples through targeted panels. Distribution of continuous variables was statistically compared using nonparametric (Mann-Whitney or Kruskal-Wallis) tests, while nominal variables were compared using the Chi-Square test. Kaplan-Meier estimate of overall survival (OS) was computed from the date of diagnosis to date of death or last follow-up (also censored at the time of allogeneic hematopoietic stem cell transplant). Results: Between years 1998 - 2023, 129 patients met criteria for inclusion in the study. Among these, clinical diagnoses included immune-mediated aplastic anemia (AA, n=56, 43%, 21% severe or very severe as per the Camitta criteria), telomere biology disorders (TBD, n=37, 29%), Fanconi anemia (n=10, 8%), GATA2 haploinsufficiency (n=8, 6%), Diamond-Blackfan anemia (DBA, n=2, 2%), deficiency of adenosine deaminase-2 (DADA2, n=2, 2%), congenital dyserythropoietic anemia (CDA, n=1, 1%), congential amegakaryocytic thrombocytopenia (CAMT, n=1, 1%), Schwachman-Diamond syndrome (n=1, 1%) & undefined (n=11, 9%). Among the inherited group, 63% had an identifiable germline pathogenic variant (most commonly, TERT/TERC 30%, FANC group 25% & GATA2 15%) with the rest diagnosed on a clinical basis. Elevated HbF &gt;1% was noted in 79% of all BMFS patients; 83% AA, 70% TBD, 50% in DADA2 & 67% in undefined patients (no data was available for other inherited subtypes). In patients with an elevated HbF, absolute monocyte count (p=0.04) was significantly higher; however, there were no other significant associations with variables at diagnosis such as hemoglobin (p=0.5), white blood cell count (WBC, p=0.14), absolute neutrophil count (p=0.5), platelet count (p=0.7), mean corpuscular volume (MCV, p=0.2), absolute lymphocyte count (p=0.1), absolute reticulocyte count (p=0.4), EPO level (p=0.3), presence of a PNH clone (p=0.2), or presence of a germline variant (p=0.3). When diseases were grouped into inherited & acquired (AA) subgroups, median HbF was not significantly different (median%, 4.5 versus 2.3, p=0.4), with elevated HbF (&gt;1%) in 75% versus 83% (p=0.6) patients respectively. On the other hand, minor PNH clone (&gt;0.1% in at least two cell types) was detectable in the acquired group only (0 versus 55%, p&lt;0.0001). Similarly, acquired group had a shorter (&lt;3 months) onset of cytopenias preceding diagnosis (P&lt;0.0001), with no significant differences in MCV (p=0.2), marrow dysplasia (p=0.09) or atypia (p=0.6), & splenomegaly (p=0.9). At median follow-up of 7 years, Kaplan-Meier estimate of transplant-censored median OS was lower in inherited versus acquired group (16 years versus median not reached, p=0.02). Elevated HbF did not significantly predict adverse OS in either group. Conclusions: Fetal hemoglobin is elevated in both patients with inherited & acquired (aplastic anemia) BMFS. When compared to established variables, elevated HbF has neither diagnostic utility nor prognostic relevance in predicting adverse outcomes. On the other hand, onset of cytopenias and presence of a minor PNH clone are both useful clinical variables in differentiating patients with inherited from acquired BMFS. Our data offers practical clinical utility in making early treatment decisions for patients with BMFS.

Abstract Introduction: Sexual health is an important part of overall well-being for adolescents and young adults (AYAs) after hematopoietic stem cell transplantation (HCT). AYAs have unique sexual health needs as they navigate development, relationships, and identity formation. AYA patients may experience sexual dysfunction due to conditioning chemotherapy/radiation therapy, graft-versus-host disease (GVHD), changes in body image, mental health effects, relationship shifts, and the challenges of dating with a serious illness. We surveyed both pediatric and adult HCT providers at our institution to assess current practices of discussing sexual health needs with AYAs as well as barriers to these discussions in order to guide interventions to improve communication. Methods: Adult and pediatric HCT physicians, advanced practice providers, and nurse coordinators in the Mayo Clinic Rochester HCT program completed an online survey to understand their perspectives about addressing sexual health needs in AYA HCT survivors. This survey covered current practice patterns in discussing sexual health and managing sexual health needs, barriers to providing sexual health care, and recommendations for provider education. Results: This survey included responses from 25 HCT providers (35% response rate): 22 adult providers and 3 pediatric providers. The respondents comprised of 10 physicians (40%), 8 advanced practice providers (32%), and 7 nurses (28%). Most of the providers saw 6-10 AYA patients per month (48%), while others reported: 1-5 AYAs (36%), 11-15 AYAs (12%), and 16-20 AYAs (4%); no provider saw 21 or more. While all respondents felt sexual health was an important topic for AYA HCT patients, most (80%) also reported rarely (44%) or only sometimes (36%) discussing sexual health with AYA patients. Primary barriers included inadequate knowledge of resources for referrals (72%), insufficient training on this topic (60%), limited time for discussion (56%), discomfort discussing sexual health with AYAs (32%), and concern about patient discomfort (28%). When it came to screening for GVHD, 28% of respondents reported not regularly screening for genitourinary GVHD and 40% indicated feeling uncomfortable or very uncomfortable managing it. Frequently discussed topics included fertility (64%) and contraception (52%). Almost all respondents (96%) expressed interest in further education. Topics of interest included an overview of common sexual health issues in AYA HCT survivors (88%), medical management of sexual health concerns such as erectile dysfunction, low libido, and vaginal dryness (72%), management of psychosocial concerns impacting body image and relationships (64%), cultural considerations for addressing sexual health (56%), providing inclusive care for lesbian, gay, bisexual, trans, queer or questioning (LGBTQ) AYAs (56%), genitourinary GVHD (56%), and safer sex practices during and after transplant (52%). Discussion: Although regular sexual health assessment in HCT survivors is recommended, most providers at our institution did not routinely discuss sexual health with AYAs. While genitourinary GVHD is an important HCT-specific sexual health topic, screening for this condition is not consistently performed. Providers were eager for further education and identified several topic areas for future educational interventions. Our data will aid in the development of an educational intervention for providers covering key sexual health issues in AYA HCT survivors, including medical and psychosocial management of sexual health concerns, as well as inclusive care for intercultural and LGBTQ AYAs, with the aim of improving frequency of sexual health discussions and provider confidence. Time constraints were identified as a key barrier, so patient-focused educational interventions that can occur outside of the clinical appointment may be an opportunity to deliver information and empower patients to raise specific concerns during their visits. In combination with healthcare provider-focused education, this may promote critical sexual health-related discussions during appointments.

345 Background: Pediatric febrile neutropenia (PFN) requires emergent evaluation due to risk of invasive bacterial infection. In the management of PFN, there are varying, accepted definitions for fever requiring emergency evaluation and neutropenia requiring admission. Problem statement: From September 1, 2022 - May 31, 2023, 15.1% (n = 11/73) of emergency department (ED) visits and 17.1% (n = 6/35) of admissions for PFN at Mayo Clinic Rochester may be considered unnecessary due to patients not meeting updated clinical criteria. Aim: Decrease unnecessary ED visits and hospitalizations for PFN by 50% from 15.1% to 7.5% (for ED visits) and from 17.1% to 8.6% (for hospitalizations) by 02/29/2024 without adversely impacting mortality from invasive bacterial infection. Methods: We used the DMAIC framework for process improvement. Interventions included (1) adoption of a higher fever definition for PFN, (2) adoption of a risk-stratified neutropenia definition for hospital admission, (3) provided electronic fever plans with definitions to all families, (4) re-iterated that parents call on-call provider with any concern for fever, (5) educated pediatric oncology staff on definition and management of fevers in pediatric oncology patients, and (6) educated pediatric emergency department staff on definition and management of fevers in pediatric oncology patients. Interventions were tested with rapid tests of change. Relevant clinical characteristics, variables, and outcomes for all patients from pediatric oncology were tracked for all encounters of pediatric oncology patients presenting to the ED for acute illnesses. Results: At baseline,15.1% (n = 11/73) of ED visits for PFN were considered unnecessary due to patients not meeting clinical criteria for emergency evaluation. Post-interventions, unnecessary ED visits for PFN had decreased to 3.4% (n = 1/32). At baseline, 17.1% (n = 6/35) of hospitalizations were considered unnecessary due to patients not meeting clinical criteria for admission. Post-interventions, 7.7% (n = 2/26) of hospitalizations were considered unnecessary. There were no patient deaths from invasive bacterial infection among this cohort at baseline or after interventions. Conclusions: Multiple interventions including adoption of a higher, accepted fever threshold and risk stratified neutropenia definition for PFN was associated with a reduction of unnecessary ED visits and hospitalizations for PFN without an increase in mortality from invasive bacterial infection. The projected medical expense savings of approximately $144,000-$210,000 per year.

Summary Recipients of haploidentical and unrelated haematopoietic cell transplants (HCTs) historically had a higher risk for graft‐versus‐host disease (GvHD). However, with improved GvHD prophylaxis, recent data suggest adult patients undergoing transplantation from unrelated or mismatched donors now experience the rates of GvHD similar to those receiving matched related donor grafts. This finding is not yet explored in paediatric patients. The objectives of this study were to: (1) compare acute and chronic GvHD incidence, mortality and GvHD‐free relapse‐free survival (GRFS) among matched related donor (MRD), matched unrelated donor (MUD) and haploidentical paediatric HCT recipients in the era of enhanced GvHD prophylaxis for high‐risk patients, (2) identify independent risk factors for GvHD and (3) evaluate the efficacy of various GvHD prophylactic regimens in our cohort. We conducted a retrospective, single‐centre medical record abstraction among patients aged 0–25 years who underwent allogeneic HCT for any indication. The results demonstrated that 5‐year cumulative incidence rates of any GvHD, all‐cause mortality and GRFS are similar across the haploidentical, MRD and MUD groups. Tacrolimus‐containing doublet/triplet regimens were associated with decreased GvHD, as compared to ciclosporin. Adding alemtuzumab also decreased risk for GvHD, without increasing relapse rates. Prospective studies with larger cohorts are warranted to further optimize outcomes for paediatric allogeneic HCT patients.

Post-transplant lymphoproliferative disorder is a rare and serious complication of organ and stem cell transplant secondary to immunosuppressive therapies, most commonly of monomorphic B-cell subtype. Here we describe the first reported case of a pediatric heart transplant patient who developed both monomorphic B-cell and nondestructive PTLD with plasmacytic hyperplasia followed by an unrelated case of monomorphic T-cell and nondestructive PTLD with plasmacytic hyperplasia, which later relapsed. We detail the patient’s risk factors for development of PTLD and her successful treatment regimens. This case highlights the potential relationship between Epstein-Barr virus and/or cytomegalovirus and PTLD.

ABSTRACT Background Patients at high risk for cytomegalovirus (CMV) infection after allogeneic hematopoietic stem cell transplant (HCT) should receive CMV prophylaxis. Historically, ganciclovir has been the preferred agent. However, its side effect profile, particularly myelosuppression, is undesirable. Letermovir is a newer agent that is not myelosuppressive and has replaced ganciclovir as the preferred agent for CMV prophylaxis in high‐risk adult patients. Methods The primary objective was to compare the incidence of dose modifications or discontinuation of CMV prophylaxis between pediatric patients who received ganciclovir versus letermovir. Secondary objectives included comparing the use of granulocyte colony‐stimulating factor (G‐CSF) support and the incidence of CMV DNAemia. We reviewed records of all pediatric patients who received an HCT at our institution between 2000 and 2024 and received either ganciclovir/valganciclovir or letermovir for CMV prophylaxis. Results Between 2000 and 2024, 65 pediatric patients receiving prophylactic ganciclovir, valganciclovir, or letermovir were evaluated. The median age at transplant was 12.2 years. No patients receiving letermovir required dose modification or discontinuation as opposed to 14 (29.2%) patients receiving ganciclovir ( p = 0.014). After engraftment, 12 (25%) patients receiving ganciclovir required G‐CSF support compared to seven (41.2%) patients receiving letermovir ( p = 0.23). In the ganciclovir group, 10 (20.8%) patients experienced CMV infection versus one (5.9%) patient receiving letermovir ( p = 0.26). Conclusion Compared with those receiving letermovir, a significantly higher proportion of patients in the ganciclovir/valganciclovir group experienced dose modifications or discontinuation of CMV prophylaxis due to adverse effects. Letermovir shows great promise as a CMV prophylactic agent in pediatric HCT patients due to its favorable side effect profile.

Abstract Southeast Minnesota is home to a significant population of Anuak individuals who seek care within the Mayo Clinic Health Systems. The city of Austin, MN is home to a population numbering around 450 Anuak individuals who are seen at the Mayo Clinic Austin location as well as the Rochester main campus of Mayo Clinic. In total, more than 3000 Anuak individuals live in Minnesota in what is considered to be the largest Anuak population outside of East Africa. For pediatric patients with SCD, 15 of 20 (75%) are Anuak. The majority of these patients have severe SCD with chronic anemia, frequent pain crises, cardiac ventricular enlargement, acute chest pain, and multiple hospital admissions. The objective of this review is to understand what is known about SCD, the severity of phenotype, and outcomes in the published literature regarding this special population. A scoping review was conducted using primarily OVID databases. Only 2 studies met established criteria. Unfortunately, both sources of literature were dated and not consistent with current trends. Despite communicating with colleagues in Ethiopia, there does not exist accurate or robust data about the incidence or prevalence of SCD among the Anuak people. The local Anuak diaspora in Southeast Minnesota likely represents the best current data and representation in this patient population. There is a need for further research regarding SCD outcomes in this special population.

This Viewpoint summarizes recent progress in gene therapy for hemoglobinopathies.