Ferdjallah, Asmaa

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.

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.

Background: Hematopoietic stem cell transplant (HSCT) based gene therapies (GT) have successfully demonstrated significant reduction in vasocclusive crises (VOCs) associated with sickle cell disease (SCD). The efficacy and safety of these products is well established across multiple clinical trials (Kanter et al. NEJM 2022, Frangoul et al. NEJM 2024). This led to the Food and Drug Administration (FDA) approval of the lentiviral-based gene addition product (lovotibeglogene autotemcel) and CRISPR-Cas9 based gene editing product (exagamglogene autotemcel) for patients with SCD above 12 years of age. As these therapies have a different logistical process compared to a standard allogeneic HSCT, there is a need to develop a collaborative transition of care plan for these patients and families prior to and long after completion of transformative therapies. Methods: Upper Midwest Sickle Cell Curative Therapies Consortium is a collaborative model including multiple stakeholders between 7 centers across the upper Midwest United States, the regional community-based organization (CBO) and National Marrow Donors Program (NMDP). The structure and workflow for this model was presented previously (Blaylark et al. ASH 2023). With the advent of commercial GTs, we developed a multi-specialty care model in collaboration with community stakeholders to address diverse patient and logistical needs for smoother transition to and from these therapies. Discussion: The initial transition is a period of potential gaps in medical care and often high anxiety for patients and families. Thus, when patients and families are considering GT, our care model engages a multidisciplinary team. As part of the comprehensive evaluation prior to gene therapy, an initial shared collaborative checklist includes an extensive medical history, assessment of treatment plan, an individualized pain plan and adherence, transfusion planning (simple or exchange) with setting of target hemoglobin and hemoglobin S% targets, and coordination of multi-specialty consults including apheresis, fertility preservation, child life, and social work. Additionally, pain, psychology, and integrative medicine specialists address not only ongoing concerns, but also help develop a plan for future transition back to the primary site of SCD care (“re-transition”) after GT. Patients undergo neuropsychological evaluations to establish baseline functioning and the role of chronic pain and fatigue, as GT can significantly impact long term cognitive functioning, emotional coping with transitions, and overall daily functioning. When appropriate and available, warm handoffs are encouraged between centers within each of these specialties. Our team also reviews available resources for education and ongoing support through the process and after from national and regional CBOs. Similarly, the post-GT transition is also a period of potential medical care gaps and high anticipated anxiety and concern, as patients go through significant unfamiliar adverse effects followed by the potential for persistent freedom from VOCs. In the post-GT transition, ongoing psychology, integrative medicine, and pain team support; peer mentoring; and support groups are critical for a smooth re-transition to post-GT care and further successful re-transition back into the community. Using this interdisciplinary approach across GT clinical trials, we successfully weaned opioids in 83% of patients (5/6) by day 60 post-GT infusion and successful re-transition of these patients, further highlighting the role of interdisciplinary care. Our team's collaborative approach to SCD care with sickle cell specialists, transplant team and other care providers and CBO continues into the long term follow up period, including ongoing supportive services for both patients and their families. Conclusion: As newer therapies are developed and approved for transformative SCD care, development of a transitional model with early engagement of an interdisciplinary team is critical for empowering sickle cell warriors and for their successful transition back into the community.