Risk factors predicting need for the pediatric intensive care unit (PICU) post-hematopoietic cell transplant, PICU utilization, and outcomes following HCT: a single center retrospective analysis.

Hematopoietic cell transplant (HCT) is a curative treatment for multiple malignant and non-malignant disorders. While morbidity and mortality have decreased significantly over the years, some patients still require management in the pediatric intensive care unit (PICU) during their HCT course for additional respiratory, cardiovascular, and/or renal support. We retrospectively reviewed pediatric patients (0-18 years) who underwent HCT from January 2015-December 2020 at our institution to determine risk factors for PICU care and evaluate PICU utilization and outcomes. We also assessed pulmonary function testing (PFT) data to determine if differences were noted between PICU and non-PICU patients as well as potential evolution of pulmonary dysfunction over time. Risk factors of needing PICU care were lower age, lower weight, having an underlying inborn error of metabolism, and receiving busulfan-based conditioning. Nearly half of PICU encounters involved use of each of respiratory support types including high-flow nasal cannula, non-invasive positive pressure ventilation, and mechanical ventilation. Approximately one-fifth of PICU encounters involved renal replacement therapy. Pulmonary function test results largely did not differ between PICU and non-PICU patients at any timepoint aside from individuals who required PICU care having lower DLCO scores at one-year post-HCT. Future directions include consideration of combining our data with other centers for a multi-center retrospective analysis with the goal of gathering and reporting additional multi-center data to work toward continuing to decrease morbidity and mortality for patients undergoing HCT.

Natural history of craniovertebral abnormalities in a single-center study in 54 patients with Hurler syndrome.

OBJECTIVE: Craniovertebral junction (CVJ) abnormalities are common and well documented in mucopolysaccharidosis type I-Hurler syndrome (MPS IH), often causing severe spinal canal narrowing. However, the requirement for surgical decompression and/or fusion is uncommon. Although hematopoietic cell transplant (HCT) has been shown to prolong the lives of patients with MPS IH, its effect in halting or reversing musculoskeletal abnormalities is less clear. Unfortunately, there are currently no universal guidelines for imaging or indication for surgical interventions in these patients. The goal of this study was to track the progression of the CVJ anatomy in patients with MPS IH following HCT, and to examine radiographic features in patients who needed surgical intervention. METHODS: Patients with MPS IH treated at the University of Minnesota with allogeneic HCT between 2008 and 2020 were retrospectively reviewed. Patients who underwent CVJ surgery were identified with chart review. All MPS IH cervical scans were examined, and the odontoid retroflexion angle, clivoaxial angle (CXA), canal width, and Grabb-Oakes distance (pB-C2) were measured yearly for up to 7 years after HCT. Longitudinal models based on the measurements were made. An intraclass correlation coefficient was used to measure interrater reliability. Nine children without MPS IH were examined for control CVJ measurements. RESULTS: A total of 253 cervical spine MRI scans were reviewed in 54 patients with MPS IH. Only 4 (7.4%) patients in the study cohort required surgery. Three of them had posterior fossa and C1 decompression, and 1 had a C1-2 fusion. There was no statistically significant difference in the spinal parameters that were examined between surgery and nonsurgery groups. Among the measurements, canal width and CXA varied drastically in patients with different neck positions. Odontoid retroflexion angle and CXA tended to decrease with age. Canal width and pB-C2 tended to increase with age. CONCLUSIONS: Based on the data, the authors observed an increase in canal width and pB-C2, whereas the CXA and odontoid retroflexion angle became more acute as the patients aged after HCT. The longitudinal models derived from these data mirrored the development in children without MPS IH. Spinal measurements obtained on MR images alone are not sufficient in identifying patients who require surgical intervention. Symptom monitoring and clinical examination, as well as pathological spinal cord changes on MRI, are more crucial in assessing the need for surgery than is obtaining serial imaging.

Hurler Syndrome Glycosaminoglycans Decrease in Cerebrospinal Fluid without Brain-Targeted Therapy.

Novel therapies for Hurler syndrome aim to cross the blood-brain barrier (BBB) to target neurodegeneration by degrading glycosaminoglycans (GAG). BBB penetration has been assumed with decreased cerebrospinal fluid (CSF) GAG, yet little is known about CSF GAG without brain-targeting therapies. We compared pre-transplant CSF GAG in patients who were treatment naïve (n = 19) versus receiving standard non-BBB penetrating enzyme replacement therapy (ERT, n = 12). In the ERT versus treatment naïve groups, CSF GAG was significantly lower across all content assayed, raising questions about using CSF GAG decrements to show BBB penetration. Future studies should compare GAG reduction in standard versus novel therapies. ANN NEUROL 2023;94:1182-1186.

Hematopoietic cell transplantation for Mucopolysaccharidosis I in the presence of decreased cardiac function.

BACKGROUND: Severe mucopolysaccharidosis type I, (MPS IH) is a rare inherited lysosomal disorder resulting in progressive storage of proteoglycans (GAGs) in central nervous system and somatic tissues and, if left untreated, causing death within the first decade of life. Hematopoietic cell transplantation (HCT) arrests many of the features of MPS IH but carries a 10-15% risk of mortality. Decreased cardiac function can occur in MPS IH and increase the risk of HCT. METHODS: Retrospective chart review was performed to determine the long-term outcome of individuals evaluated for HCT with MPS IH who had decreased cardiac function as measured by cardiac echocardiogram (echo) and ejection fraction (EF) of <50% at the time of initial evaluation. RESULTS: Six patients ranging in age from 1 week to 21 months (median: 4 months) had EFs ranging from 25 to 47% (median: 32%) at diagnosis and were initiated on enzyme replacement therapy (ERT) with improvement in EF in three patients by 5 months. The remaining three patients continued to have EFs <50% and continuous milrinone infusion was added in the pre-HCT period. On average, milrinone infusion was able to be discontinued post-HCT, prior to hospital discharge, within a mean of 37 days. Five patients survived HCT and are alive today with normal EFs. One patient receiving milrinone died of sepsis during HCT with a normal EF. CONCLUSION: Decreased cardiac systolic function in infants with MPS IH that fails to normalize with ERT alone may benefit from the addition of continuous milrinone infusion during HCT.

A case series of adrenoleukodystrophy in children conceived through in vitro fertilization with an egg donor.

Objective: To report 3 cases of adrenoleukodystrophy (ALD) in children conceived by in vitro fertilization (IVF) and egg donation. Design: A case report. Patients: Patients aged 4-5 years old, evaluated by the University of Minnesota Leukodystrophy Center, who were diagnosed with ALD after being conceived by IVF with oocytes provided by the same donor. Interventions: One patient received a hematopoietic stem cell transplant from a human leukocyte antigen-matched donor, and 1 patient received autologous lentiviral corrected hematopoietic cells. The disease state in 1 patient was unfortunately too advanced for effective treatment to be administered. Main Outcome Measures: Progression of disease after diagnosis or treatment was observed by cerebral magnetic resonance imaging and monitoring the development or advancement of any cognitive, adaptive, and motor deficits. Results: Patients who received a transplant for ALD successfully experienced little to no disease progression at least 6 months to 1 year after treatment. Conclusions: These 3 cases of transmission of ALD through oocyte donation and IVF highlight the potential need to implement more comprehensive genetic screening of gamete donors to prevent the transfer of rare but severe genetic diseases through IVF. Further, these cases highlight limitations in carrier screening guidelines that limit reportable variants to pathogenic and likely pathogenic variants.

Heinz body hemolysis following extended use phenazopyridine in a post-HCT patient with hemorrhagic cystitis: An old problem for a new generation.

Hemorrhagic cystitis is a common complication following the use of cyclophosphamide. Associated dysuria can be painful and there are few good options to relieve pain. Phenazopyridine has historically been utilized for dysuria and is available over the counter. However, it is associated with hematologic side effects with prolonged use. Here we present a case of a patient who developed Heinz body hemolysis following prolonged administration of phenazopyridine to treat cyclophosphamide-induced hemorrhagic cystitis following hematopoietic stem cell transplant.

Neurocognitive and mental health impact of adrenoleukodystrophy across the lifespan: Insights for the era of newborn screening.

X-linked adrenoleukodystrophy (ALD) is a rare inherited neurological disorder that poses considerable challenges for clinical management throughout the lifespan. Although males are generally more severely affected than females, the time course and presentation of clinical symptoms are otherwise difficult to predict. Opportunities to improve outcomes for individuals with ALD are rapidly expanding due to the introduction of newborn screening programs for this condition and an evolving treatment landscape. The aim of this comprehensive review is to synthesize current knowledge regarding the neurocognitive and mental health effects of ALD. This review provides investigators and clinicians with context to improve case conceptualization, inform prognostic counseling, and optimize neuropsychological and mental health care for patients and their families. Results highlight key predictive factors and brain-behavior relationships associated with the diverse manifestations of ALD. The review also discusses considerations for endpoints within clinical trials and identifies gaps to address in future research.

Prospective Validation and Refinement of a Population Pharmacokinetic Model of Fludarabine in Children and Young Adults Undergoing Hematopoietic Cell Transplantation.

Fludarabine is a nucleoside analog with antileukemic and immunosuppressive activity commonly used in allogeneic hematopoietic cell transplantation (HCT). Several fludarabine population pharmacokinetic (popPK) and pharmacodynamic models have been published enabling the movement towards precision dosing of fludarabine in pediatric HCT; however, developed models have not been validated in a prospective cohort of patients. In this multicenter pharmacokinetic study, fludarabine plasma concentrations were collected via a sparse-sampling strategy. A fludarabine popPK model was evaluated and refined using standard nonlinear mixed effects modelling techniques. The previously described fludarabine popPK model well-predicted the prospective fludarabine plasma concentrations. Individuals who received model-based dosing (MBD) of fludarabine achieved significantly more precise overall exposure of fludarabine. The fludarabine popPK model was further improved by both the inclusion of fat-free mass instead of total body weight and a maturation function on fludarabine clearance. The refined popPK model is expected to improve dosing recommendations for children younger than 2 years and patients with higher body mass index. Given the consistency of fludarabine clearance and exposure across its multiple days of administration, therapeutic drug monitoring is not likely to improve targeted exposure attainment.

Treatment of cerebral adrenoleukodystrophy: allogeneic transplantation and lentiviral gene therapy.

INTRODUCTION: Adrenoleukodystrophy (ALD) is an X-linked peroxisomal disorder with an incidence of 1 in 14-17,000 male births, caused by pathogenic variants within the ABCD1 gene. By adulthood, approximately 40% of the patients develop cerebral ALD, a severe, neuroinflammatory condition that is generally progressive and fatal without intervention. AREAS COVERED: Historically, only allogeneic hematopoietic stem cell transplantation (HSCT) has been shown to halt progression of cerebral ALD, with superior outcomes obtained when HSCT is performed early in the disease process. More recently, a lentiviral-based gene therapy approach has been investigated as therapy for cerebral ALD as an alternative to allogeneic transplantation. A focused literature review was performed using the terms 'hematopoietic stem cell transplantation,' 'gene therapy' and 'adrenoleukodystrophy' to include relevant literature, especially comparing the experience with gene therapy and HSCT outcomes. We review the history and experience with HSCT in cerebral ALD and its limitations, as well as the information currently available in association with the gene therapy trials for cerebral ALD. EXPERT OPINION: The data regarding this lentiviral-based gene therapy approach and its relative risks and benefits is still being evaluated. This information is explored in the context of the experience with allogeneic HSCT for cerebral ALD.

Glycoprotein nonmetastatic melanoma protein B (GNMPB) as a novel biomarker for cerebral adrenoleukodystrophy.

Adrenoleukodystrophy (ALD) is an X-linked peroxisomal disease caused by a mutation in the ABCD1 gene, producing mutations in the very long chain fatty acid transporter, ALD protein. Cerebral ALD (cALD) is a severe phenotype of ALD with neuroinflammation and neurodegeneration. Elevated levels of Glycoprotein Nonmetastatic Melanoma Protein B (GNMPB) have been recently documented in neurodegenerative diseases such as Alzheimer's disease, Multiple Sclerosis and Amyotrophic Lateral Sclerosis. Our objective was to measure the levels cerebral spinal fluid (CSF) GNMPB in cALD patients to determine if GNMPB could be a potential biomarker in tracking cALD disease progression. CSF GNMPB levels were significantly higher in cALD patients versus controls (2407 ± 1672 pg/mL vs. 639.5 ± 404 pg/mL, p = 0.0009). We found a positive correlation between CSF GNMPB and MRI disease severity score levels (R2 = 0.3225, p < 0.0001) as well as the gadolinium intensity score (p = 0.0204). Boys with more severe neurologic deficits also had higher levels of CSF GNMPB (p < 0.0001). A positive correlation was shown between CSF GNMPB and another biomarker, chitotriosidase (R2 = 0.2512, p = 0.0244). These data show that GNMPB could be a potential biomarker of cALD disease state and further studies should evaluate it as a predictor of the disease progression.

Primary Adrenal Insufficiency in a Boy with Type I Diabetes: The Importance of Considering X-linked Adrenoleukodystrophy.

Primary adrenal insufficiency (PAI) is often the first clinical sign of X-linked adrenoleukodystrophy (X-ALD), a rare genetic disorder that can present with various clinical phenotypes. A subset of boys with X-ALD develop cerebral ALD (cALD), characterized by progressive central demyelination, neurocognitive decline, and ultimately death. Timely intervention with hematopoietic cell transplant (HCT) can be a life-saving therapy by stopping progression of cerebral disease. We report the case of an 11-year-old boy with type 1 diabetes mellitus who presented with PAI, growth delay, and symptoms of attention deficit hyperactivity disorder. Given his history of T1DM, his PAI was presumed to be autoimmune and he was started on hydrocortisone and fludrocortisone. Eleven months later brain magnetic resonance imaging revealed white matter hyperintensity consistent with advanced cALD. The degree of disease progression at the time of diagnosis rendered the patient ineligible for transplant and he has continued to experience progressive neurologic decline. Initial symptoms of cALD are often subtle but should not be overlooked, as early identification of X-ALD is critical to allow early intervention with lifesaving HCT. PAI typically presents prior to the onset of neurologic symptoms. All boys who present with PAI should undergo workup for X-ALD with plasma very long chain fatty acid testing, even in the setting of underlying autoimmune disease.

Evaluation of Neurofilament Light Chain as a Biomarker of Neurodegeneration in X-Linked Childhood Cerebral Adrenoleukodystrophy.

Cerebral adrenoleukodystrophy (CALD) is a devastating, demyelinating neuroinflammatory manifestation found in up to 40% of young males with an inherited mutation in ABCD1, the causative gene in adrenoleukodystrophy. The search for biomarkers which correlate to CALD disease burden and respond to intervention has long been sought after. We used the Olink Proximity Extension Assay (Uppsala, Sweden) to explore the cerebral spinal fluid (CSF) of young males with CALD followed by correlative analysis with plasma. Using the Target 96 Neuro Exploratory panel, we found that, of the five proteins significantly increased in CSF, only neurofilament light chain (NfL) showed a significant correlation between CSF and plasma levels. Young males with CALD had a 11.3-fold increase in plasma NfL compared with controls. Importantly, 9 of 11 young males with CALD who underwent HCT showed a mean decrease in plasma NfL of 50% at 1 year after HCT compared with pre-HCT levels. In conclusion, plasma NfL could be a great value in determining outcomes in CALD and should be scrutinized in future studies in patients prior to CALD development and after therapeutic intervention.

Hematopoietic cell transplantation for sialidosis type I.

We report the clinical and laboratory follow-up data of an adolescent female with Type I Sialidosis who underwent bone marrow transplant (BMT). After BMT, plasma and urine biomarkers responded concurrently with engraftment. Neuropsychiatry data showed preservation in some domains, but she did have overall decline in motor performance. Sialidosis is a very rare lysosomal condition, and we believe this to be the first report of a case of Type I Sialidosis undergoing BMT.

Busulfan dose Recommendation in Inherited Metabolic Disorders: Population Pharmacokinetic Analysis.

Busulfan is a commonly used alkylating agent in the conditioning regimens of hematopoietic cell transplantation (HCT). Population pharmacokinetic (popPK) models enable description of busulfan PK and optimization of exposure, which leads to improvement of event-free survival after HCT. Prior busulfan popPK analysis has been limited by small numbers in patients with inherited metabolic disorders (IMD). The primary objective was to characterize population PK of busulfan in a large cohort of children and young adults undergoing HCT for IMD. PopPK analysis of busulfan drug concentrations was performed using data from 78 patients with IMD who received intravenous busulfan (every 24 hours, 4 doses) as part of pretransplantation combination chemotherapy. The final model for busulfan drug clearance was used to estimate individual doses aimed to achieve a target cumulative area under the curve (cAUC) of 80 to 100 mg · h/L. We then compared the probability of cAUC within the range of 80 to 100 mg · h/L by the developed dosing regimen versus conventional regimen. A 1-compartment, linear elimination model best described the PK of busulfan. Significant covariates demonstrated to affect busulfan clearance included total body weight and the time (in days) from busulfan infusion start. The probability of target cAUC attainment by the developed dosing versus the conventional dosing were 47% versus 43% for body weight <12 kg, and 48% versus 36% for body weight ≥12 kg. We described population PK of intravenous busulfan in a large IMD cohort. The proposed dosing regimen based on the developed model can improve the target cAUC attainment of busulfan for IMD.

Differential outcomes for frontal versus posterior demyelination in childhood cerebral adrenoleukodystrophy.

In the most common variant of childhood cerebral adrenoleukodystrophy (cALD), demyelinating brain lesions are distributed predominately in parieto-occipital white matter. Less frequently, lesions first develop in frontal white matter. This matched cohort study examined whether outcomes after standard treatment with hematopoietic cell transplantation (HCT) differ in patients with early stage frontal lesions as compared to parieto-occipital lesions. Retrospective chart review identified seven pediatric patients with frontal cALD lesions and MRI severity score < 10 who underwent a single HCT at our center between 1990 and 2019. Concurrent MRI, neurocognitive and psychiatric outcomes at last comprehensive follow-up (mean 1.2 years; range 0.5-2.1 years) were compared with a group of seven boys with the parieto-occipital variant matched on pre-HCT MRI severity score. Both groups showed similar rates of transplant complications and radiographic disease advancement. Neurocognitive outcomes were broadly similar, with more frequent working memory deficits among individuals with frontal lesions. Psychiatric problems (hyperactivity, aggression, and atypical behavior) were considerably more common and severe among patients with frontal lesions. Aligned with the critical role of the frontal lobes in emotional and behavioral regulation, functional disruption of self-regulation skills is widely observed among patients with frontal lesions. Comprehensive care for cALD should address needs for psychiatric care and management.

A Guidance for Concomitant Drug Reconciliation Prior to Allogeneic Hematopoietic Cell Transplantation in Children and Young Adults.

Pediatric diseases treated by allogeneic hematopoietic stem cell transplantation (alloHCT) are complex and associated with significant comorbidities and medication requirements that can complicate the transplant process. It is critical to reconcile pre-transplant concomitant medications (pcon-meds) in the weeks prior to alloHCT and to consider the potential for pcon-meds to cause harmful drug-drug interactions (DDIs) or overlapping toxicities with conditioning agents. In this perspective, we describe a systematic process to review pcon-meds and determine the drug modifications needed to avoid DDIs with conditioning regimens. We provide an extensive appendix with timelines for discontinuation or modification of common pcon-meds that patients are taking when presenting to the HCT medical team. The timelines are based on the pharmacokinetic (PK) properties of both the pcon-meds and the planned conditioning medications, as well as anticipated DDIs. They also account for the ages seen at pediatric transplant centers (0-30 years old). Common scenarios, such as when pcon-med discontinuation is not an option, are discussed. Since alloHCT patients are often dependent upon psychiatric medications with problematic DDIs, a table of alternative, non-interacting psychiatric medications is also presented. The appendix provides details regarding how to adjust pcon-meds prior to the start of chemotherapy for children and young adults undergoing alloHCT, however patient-specific circumstances always need to be taken into account. Careful attentiveness to pcon-meds at the time the decision is made to pursue transplant will result in more consistent HCT outcomes, with lower toxicity and increased efficacy of conditioning agents.

Consensus opinion on immune-mediated cytopenias after hematopoietic cell transplant for inherited metabolic disorders.

Hematopoietic stem cell transplantation (HCT) has been increasingly used for patients with inherited metabolic disorders (IMD). Immune mediated cytopenias (IMCs) after HCT, manifesting as hemolytic anemia, thrombocytopenia, and/or neutropenia, are recognized as a significant complication in this patient population, yet our understanding of the incidence, risk factors, and pathophysiology is currently limited. Review of the published literature demonstrates a higher incidence in younger patients who undergo HCT for a nonmalignant disease indication. However, a few reports suggest that the incidence is even higher among those with IMD (incidence ranging from 10 to 56%). This review summarizes the literature, provides an approach to better understanding of the possible etiology of IMCs, and proposes a diagnostic and management plan for patients with IMD who develop single or multi-lineage cytopenias after HCT.

Umbilical Cord Blood Transplants: Current Status and Evolving Therapies.

Hematopoietic cell transplants using stem cells from umbilical cord blood are used worldwide for the treatment of malignant and non-malignant disorders. Transplant procedures from this stem cell source have shown promising outcomes in successfully treating various hematologic, immunologic, malignant, and inherited metabolic disorders. Rapid availability of these stem cells is an important advantage over other unrelated donor transplants, especially in situations where waiting can adversely affect the prognosis. The umbilical cord blood is rich in CD34+ stem cells, though with a limited cell dose and usually takes longer to engraft. Limitations around this have been addressed by in vivo and ex vivo expansion techniques as well as enhanced engraftment kinetics. Development of adoptive immunotherapy using other components of umbilical cord blood such as regulatory T cells, virus-specific T cells, and natural killer cells has further transformed the field and enhanced the utility of umbilical cord blood unit.