Pediatric Hemophagocytic Lymphohistiocytosis: Formation of an Interdisciplinary HLH Working Group at a Single Institution.

Fever of unknown origin is a common presentation in children with an extensive differential diagnosis that encompasses multiple specialties. From a hematologic standpoint, the differential includes hyperinflammatory syndrome, such as hemophagocytic lymphohistiocytosis (HLH), among others. Due to the rarity of HLH and nonspecific symptoms at initial presentation, specialists are often consulted later in the disease progression, which complicates disease evaluation further. Cook Children's Medical Center (CCMC) has recently developed a multidisciplinary histiocytic disorder group that is often consulted on cases presenting with fever of unknown origin to increase awareness and potentially not miss new HLH cases. In this study, we examine the clinical presentation and workup of 13 patients consulted by the HLH work group at a single institution and describe the clinical course of 2 patients diagnosed with HLH. The goal of this project was to describe the formation of a disease-specific team and the development of a stepwise diagnostic approach to HLH. A review of the current diagnostic criteria for HLH may be warranted given findings of markers such as soluble IL2 receptor and ferritin as nonspecific and spanning multiple disciplines including rheumatology, infectious disease, and hematology/oncology.

Implementing a Disease-specific Multidisciplinary Team and Order Set for Hemophagocytic Lymphohistiocytosis in a Pediatric Hospital.

OBJECTIVE: To improve outcomes of hemophagocytic lymphohistiocytosis (HLH), prompt recognition and treatment are necessary. A HLH multidisciplinary team was implemented at our institution, and we established an electronic order set to foster uniformity in the diagnostic approach. The goal of this study is to capture the impact of this diagnostic tool. METHODS: This is a retrospective study analyzing the utilization of a HLH-specific order set since time of implementation in June 2019 through December 2022. The trends in the utilization of the order set by providers were analyzed to evaluate the awareness and effectiveness of this tool. RESULTS: The order set was utilized 50 times, most commonly by hematology/oncology (50%) and infectious disease (26%). Utilization by providers on newly presenting patients included 4 times in the year 2019, 12 times in 2020, 16 times in 2021, and 18 times in 2022. Utilization was associated with the diagnosis of HLH in 9 patients (18%). CONCLUSION: Implementation of an HLH-specific order set facilitated a systematic method to approach patients with suspected HLH. The utilization of the order set displayed an upward trend over time, indicating support of this tool among these providers. This tool can increase awareness and early identification of HLH.

Haematopoietic stem cell transplantation for refractory Langerhans cell histiocytosis: outcome by intensity of conditioning.

Patients with Langerhans cell histiocytosis (LCH) refractory to conventional chemotherapy have a poor outcome. There are currently two promising treatment strategies for high-risk patients: the first involves the combination of 2-chlorodeoxyadenosine and cytarabine; the other approach is allogeneic haematopoietic stem cell transplantation (HSCT). Here we evaluated 87 patients with high-risk LCH who were transplanted between 1990 and 2013. Prior to the year 2000, most patients underwent HSCT following myeloablative conditioning (MAC): only 5 of 20 patients (25%) survived with a high rate (55%) of transplant-related mortality (TRM). After the year 2000 an increasing number of patients underwent HSCT with reduced intensity conditioning (RIC): 49/67 (73%) patients survived, however, the improved survival was not overtly achieved by the introduction of RIC regimens with similar 3-year probability of survival after MAC (77%) and RIC transplantation (71%). There was no significant difference in TRM by conditioning regimen intensity but relapse rates were higher after RIC compared to MAC regimens (28% vs. 8%, P = 0·02), although most patients relapsing after RIC transplantation could be salvaged with further chemotherapy. HSCT may be a curative approach in 3 out of 4 patients with high risk LCH refractory to chemotherapy: the optimal choice of HSCT conditioning remains uncertain.

Outcomes after hematopoietic stem cell transplantation for children with I-cell disease.

Mucolipidosis type II (MLII), or I-cell disease, is a rare but severe disorder affecting localization of enzymes to the lysosome, generally resulting in death before the 10th birthday. Although hematopoietic stem cell transplantation (HSCT) has been used to successfully treat some lysosomal storage diseases, only 2 cases have been reported on the use of HSCT to treat MLII. For the first time, we describe the combined international experience in the use of HSCT for MLII in 22 patients. Although 95% of the patients engrafted, overall survival was low, with only 6 patients (27%) alive at last follow-up. The most common cause of death post-transplant was cardiovascular complications, most likely due to disease progression. Survivors were globally delayed in development and often required complex medical support, such as gastrostomy tubes for nutrition and tracheostomy with mechanical ventilation. Although HSCT has demonstrated efficacy in treating some lysosomal storage disorders, the neurologic outcome and survival for patents with MLII were poor. Therefore, new medical and cellular therapies should be sought for these patients.

Exercise is Medicine: Implementing a New Initiative to Increase Patients' Activity and Functional Mobility in Pediatric Stem-Cell Transplant Unit.

PURPOSE: Patients undergoing stem-cell transplants endure prolonged hospitalizations and aggressive medical treatments. This combination can quickly evolve into loss of functional strength and physical debilitation. We aimed to promote independent patient activity during hospitalizations, to improve compliance with prescribed physical therapy (PT) sessions, and to focus those sessions on resistance and endurance exercises. METHODS: We used the Institute for Healthcare Improvement Model of Improvement as our quality improvement (QI) framework, and we implemented an initiative called Exercise is Medicine. The initiative included three key components: (1) educating staff and caregivers about the importance of early ambulation, (2) incorporating the Miles in Motion (MiM) program to encourage patients' daily activity, and (3) eliminating barriers to allow for higher completion rates of prescribed PT sessions. Data were collected for the completion rate of PT sessions, rate of high-frequency PT sessions, participation in the MiM program, and 1-minute sit-to-stand test scores on admission and discharge. RESULTS: Before intervention, 42% of patients required high-frequency PT because of significant debilitation, which decreased to 17% after intervention. The completion rate of PT sessions increased from 71% to 87%. By discharge, 79% of patients improved their 1-minute sit-to-stand test scores and 21% returned to baseline score, indicating stable or improved functional strength, and 92% of patients participated in MiM. CONCLUSION: The Exercise is Medicine initiative facilitated positive changes with patients showing stable or improved functional strength and endurance and increased participation in independent activity during inpatient stays.

Sickle Cell Transplantation Evaluation of Long-term and Late Effects Registry (STELLAR) to Compare Long-term Outcomes After Hematopoietic Cell Transplantation to Those in Siblings Without Sickle Cell Disease and in Nontransplanted Individuals With Sickle Cell Disease: Design and Feasibility Study.

BACKGROUND: There are sparse data on the long-term and late effects of hematopoietic cell transplantation (HCT) for sickle cell disease (SCD). OBJECTIVE: This study aims to establish an international registry of long-term outcomes post-HCT for SCD and demonstrate the feasibility of recruitment at a single site in the United States. METHODS: The Sickle Cell Transplantation Evaluation of Long-Term and Late Effects Registry (STELLAR) was designed to enroll patients with SCD ≥1 year post-HCT, their siblings without SCD, and nontransplanted controls with SCD to collect web-based participant self-reports of health status and practices by using the Bone Marrow Transplant Survivor Study (BMTSS) surveys, health-related quality of life (HRQOL) using the Patient-Reported Outcomes Measurement Information System (PROMIS) Pediatric Profile-25 or Pediatric Profile-29 survey, chronic graft-versus-host disease (cGVHD) using the symptom scale survey, daily pain using an electronic pain diary, the economic impact of HCT using the financial hardship survey, sexual function using the PROMIS Sexual Function SexFSv2.0 survey, and economic productivity using the American Time Use Survey (ATUS). We also piloted retrieval of clinical data previously submitted to the Center for International Blood and Marrow Transplant Research (CIBMTR); recorded demographics, height, weight, blood pressure, waist and hip circumferences, timed up and go (TUG) test, and handgrip test; and obtained blood for metabolic screening, gonadal function, fertility potential, and biorepository of plasma, serum, RNA, and DNA. RESULTS: Of 100 eligible post-HCT patients, we enrolled 72 (72%) participants aged 9-38 (median 17) years. We also enrolled 19 siblings aged 5-32 (median 10) years and 28 nontransplanted controls with SCD aged 4-46 (median 22) years. Of the total 119 participants, 73 (61%) completed 85 sets of surveys and 41 (35%) contributed samples to the biorepository. We completed ATUS interviews of 28 (24%) participants. We successfully piloted retrieval of data submitted to the CIBMTR and expanded recruitment to multiple sites in the United States, Canada, the United Kingdom, and Nigeria. CONCLUSIONS: It is feasible to recruit subjects and conduct study procedures for STELLAR in order to determine the long-term and late effects of HCT for SCD. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): DERR1-10.2196/36780.

Cyclophosphamide conditioning in patients with severe aplastic anaemia given unrelated marrow transplantation: a phase 1-2 dose de-escalation study.

BACKGROUND: The optimum preparative regimen for unrelated donor marrow transplantation in patients with severe aplastic anaemia remains to be established. We investigated whether the combination of fludarabine, anti-thymocyte globulin, and total body irradiation (TBI) would enable reduction of the cyclophosphamide dose to less than 200 mg/kg while maintaining engraftment and having a survival similar to or better than that with standard regimens using a cyclophosphamide dose of 200 mg/kg (known to be associated with significant organ toxicity) for unrelated donor transplantation for severe aplastic anaemia. We have previously shown that cyclophosphamide at 150 mg/kg resulted in excess toxicity and its omission (0 mg/kg) resulted in unacceptable graft failure (three of three patients had secondary graft failure). Here we report results for the 50 mg/kg and 100 mg/kg cohorts. METHODS: In a multicentre phase 1-2 study, patients (aged ≤65 years) with severe aplastic anaemia, adequate organ function, and an unrelated adult marrow donor HLA matched at the allele level for HLA A, B, C, and DRB1 or mismatched at a single HLA locus received bone marrow grafts from unrelated donors. All patients received anti-thymocyte globulin (rabbit derived 3 mg/kg per day, intravenously, on days -4 to -2, or equine derived 30 mg/kg per day, intravenously, on days -4 to -2), fludarabine (30 mg/m(2) per day, intravenously, on days -5 to -2), and TBI (2 Gy). Cyclophosphamide dosing started at 150 mg/kg and was de-escalated in steps of 50 mg/kg (to 100 mg/kg, 50 mg/kg, and 0 mg/kg). The primary endpoint was the selection of the optimum cyclophosphamide dose based on assessments of graft failure (primary or secondary), toxicity, and early death during 100 days of follow-up after the transplant; this is the planned final analysis for the primary endpoint. This trial is registered with ClinicalTrials.gov, number NCT00326417. FINDINGS: 96 patients had bone marrow transplant. At day 100, 35 (92%) of 38 patients were engrafted and alive in the cyclophosphamide 50 mg/kg cohort and 35 (85%) of 41 in the 100 mg/kg cohort. Cyclophosphamide 50 mg/kg and 100 mg/kg resulted in posterior means for fatality without graft failure of 0·7% (credible interval 0-3·3) and 1·4% (0-4·9), respectively. Three patients (8%) had graft failure with cyclophosphamide 50 mg/kg and six (15%) with cyclophosphamide 100 mg/kg. Four (11%) patients had major regimen-related toxicity with cyclophosphamide 50 mg/kg and nine (22%) with cyclophosphamide 100 mg/kg. The most common organ toxicity was pulmonary (grade 3 or 4 dyspnoea or hypoxia including mechanical ventilation), and occurred in three (8%) and four (10%) patients given cyclophosphamide 50 mg/kg and 100 mg/kg, respectively. INTERPRETATION: Cyclophosphamide at 50 mg/kg and 100 mg/kg with TBI 2 Gy, fludarabine, and anti-thymocyte globulin results in effective conditioning and few early deaths after unrelated donor transplantation for severe aplastic anaemia. These doses of cyclophosphamide provide a framework for further regimen optimisation strategies. FUNDING: US National Heart, Lung, and Blood Institute and National Cancer Institute.

Treatment of Epstein-Barr virus lymphoproliferative disease after hematopoietic stem-cell transplantation with hydroxyurea and cytotoxic T-cell lymphocytes.

Epstein-Barr virus (EBV) lymphoproliferative disease (LPD) is a potentially fatal complication that may follow allogeneic hematopoietic stem-cell transplantation (HSCT). In this article, the authors report a 2-year-old girl with Hurler's syndrome who developed multiple central nervous system (CNS) EBV LPD lesions 1 year after unrelated donor HSCT. Before this CNS occurrence, the patient had a complete response to rituximab treatment for EBV LPD of the spleen and lymph nodes; however, treatment of the CNS disease with rituximab proved ineffective. Because of reported favorable response of primary CNS EBV LPD in two human immunodeficiency virus-positive patients, the authors treated this patient with low-dose oral hydroxyurea. The patient improved clinically, with a decrease in size of multiple EBV LPD brain lesions. Subsequently, the patient received EBV-specific cytotoxic T-cell lymphocytes and remains well. The benefit and limited toxicity of hydroxyurea therapy merit its further consideration as treatment for EBV LPD.

Allogeneic hematopoietic stem-cell transplantation for leukocyte adhesion deficiency.

OBJECTIVES: Leukocyte adhesion deficiency is a rare primary immune disorder caused by defects of the CD18 beta-integrin molecule on immune cells. The condition usually presents in early infancy and is characterized by deep tissue infections, leukocytosis with impaired formation of pus, and delayed wound healing. Allogeneic hematopoietic stem-cell transplantation offers the possibility of curative therapy, and with patient numbers at any individual center being limited, we surveyed the transplant experience at 14 centers worldwide. METHODS: The course of 36 children with a confirmed diagnosis of leukocyte adhesion deficiency who underwent hematopoietic stem-cell transplantation between 1993 and 2007 was retrospectively analyzed. Data were collected by the registries of the European Society for Immunodeficiencies/European Group for Blood and Marrow Transplantation, and the Center for International Blood and Marrow Transplant Research. RESULTS: At a median follow-up of 62 months (extending to 14 years), the overall survival rate was 75%. Myeloablative conditioning regimens were used in 28 patients, and reduced-intensity conditioning in 8 patients, with no deaths in this subgroup. Survival rates after matched family donor and unrelated donor transplants were similar, with 11 of 14 matched family donor and 12 of 14 unrelated donor recipients alive; mortality was greatest after haploidentical transplants, after which 4 of 8 children did not survive. Twenty-seven transplant recipients were alive, with full donor engraftment in 17 cases, mixed multilineage chimerism in 7 patients, and mononuclear cell-restricted chimerism in an additional 3 cases. CONCLUSIONS: Hematopoietic stem-cell transplantation offers long-term benefit in leukocyte adhesion deficiency and should be considered as an early therapeutic option if a suitable HLA-matched stem-cell donation is available. Reduced-intensity conditioning was particularly safe, and mixed-donor chimerism seems sufficient to prevent significant symptoms, although careful long-term monitoring will be required for these patients.