Impact of Abatacept Inclusive Graft-Versus-Host Disease Prophylaxis in Pediatric Stem Cell Transplantation for Hemoglobinopathy.

Allogeneic hematopoietic cell transplantation (HCT) provides a curative option for patients with hemoglobinopathies by establishing donor-derived hematopoiesis. However, outcomes are compromised by toxicities and graft-versus-host disease (GVHD), particularly in patients older than 13 years undergoing HCT from unrelated donors. To evaluate the safety and benefit of extended duration (until day +365) abatacept incorporated into GVHD prophylaxis compared to standard prophylaxis that included prednisone in children and adolescents with hemoglobinopathy undergoing HCT from related and unrelated donors.

NIH Chronic Graft-Versus-Host Disease Consensus Conference 2025 Update.

In 2020, the third NIH Consensus Development Project on Criteria for Chronic Graft-versus-Host Disease (GVHD) Clinical Trials was held with the goals of identifying gaps in understanding, prevention and treatment of chronic graft-versus-host disease (GVHD) and making actionable recommendations that would advance the field. An interim meeting was held in October 2024 to review progress on the 2020 recommendations. Each group was charged with reviewing their previous recommendations, assessing whether the field is on track to eventually achieve the goals, and considering whether recommendations should be modified in light of new data or insufficient progress.

Integrating Pulmonary and Systemic Transcriptomic Profiles to Characterize Lung Injury after Pediatric Hematopoietic Stem Cell Transplant.

Hematopoietic stem cell transplantation (HCT) is potentially curative for numerous malignant and non-malignant diseases but can lead to lung injury due to chemoradiation toxicity, infection, and immune dysregulation. Bronchoalveolar lavage (BAL) is the most commonly used procedure for diagnostic sampling of the lung but is invasive, cannot be performed in medically fragile patients, and is challenging to perform serially. We previously showed that BAL transcriptomes representing pulmonary inflammation and cellular injury can phenotype post-HCT lung injury and predict mortality outcomes.

Inborn errors of immunity in Canadian First Nations and Nunavut Inuit Children: the tip of the iceberg.

Objectives: Inborn errors of immunity (IEI) are a heterogeneous group of genetic diseases that impact normal immune development and function. Individual IEI are rare, but collectively, can represent an important health burden. Little is known about the types of IEI seen in Canadian First Nations (FN) and Inuit populations.

Pediatric Transplant and Cellular Therapy Consortium RESILIENT Conference on Pediatric Chronic Graft-versus-Host Disease Survivorship after Hematopoietic Cell Transplantation: Part III. Long-Term Impact of Chronic Graft-versus-Host Disease on Endocrinologic, Cardiovascular, and Metabolic Outcomes in Survivors of Pediatric Hematopoietic Cell Transplantation.

Chronic graft-versus-host disease (cGVHD) has a profound impact on the endocrinologic and cardiovascular health of survivors of transplantation performed in childhood. The impact of cGVHD is long-lasting and contributes to morbidity and early mortality through multiple mechanisms. Organs and tissues may be direct targets of alloreactive donor-derived immune cells.

Pediatric Transplant and Cellular Therapy Consortium RESILIENT Conference on Pediatric Chronic Graft-versus-Host Disease Survivorship after Hematopoietic Cell Transplantation: Part II. Organ Dysfunction and Immune Reconstitution Considerations for Children with Chronic Graft-versus-Host Disease after Hematopoietic Cell Transplantation.

While highly morbid forms of chronic graft versus host disease (cGVHD) and severe late effects of allogeneic hematopoietic cell transplantation (HCT) can impact children and adults alike, unique considerations arise in pediatric cases regarding diagnosis, monitoring, treatment, and likelihood of resolution. As children can present with atypical features of cGVHD and with more significant disease due to inability to communicate symptoms, they may be at increased risk for highly morbid forms of cGVHD and incur greater subsequent late effects, which may be more pronounced in those with underlying chromosomal breakage syndromes, with higher prevalence in pediatric HCT recipients. The long-term effects of cGVHD and its therapies include impaired immune reconstitution, leading to increased risks of infection and secondary malignant neoplasms.

Pediatric Transplant and Cellular Therapy Consortium RESILIENT Conference on Pediatric Chronic Graft-Versus-Host Disease Survivorship After Hematopoietic Cell Transplantation: Part IV. Patient Important Outcomes.

Chronic graft-versus-host disease (cGVHD) occurs in approximately 1 in 5 pediatric allogeneic HCT patients and is a leading cause of late morbidity and mortality. Late effects of hematopoietic cell transplantation (HCT) may lead to long-term chronic health conditions and shortened life expectancy. In addition to direct physiologic challenges from cGVHD and other late effects, numerous patient-important outcomes impact the quality of life (QOL) of patients and their families.

Pediatric Transplant and Cellular Therapy Consortium RESILIENT Conference on Pediatric Chronic Graft-Versus-Host Disease Survivorship After Hematopoietic Cell Transplantation: Part I. Phases of Chronic GVHD, Supportive Care, and Systemic Therapy Discontinuation.

Current literature lacks details on the impact of pediatric chronic graft-versus-host disease (cGVHD) on long-term survivorship after allogeneic hematopoietic cell transplantation (HCT). Nonetheless, cGVHD remains a leading cause of post-transplant morbidity and mortality in children and adolescents, which is particularly relevant given the longer life-expectancy after HCT (measured in decades) compared to older adults. To address this knowledge gap, leaders of the Pediatric Transplant and Cellular Therapy Consortium convened a multidisciplinary taskforce of experts in pediatric cGVHD and HCT late effects known as RESILIENT after Chronic GVHD (Research and Education towards Solutions for Late effects to Innovate, Excel, and Nurture after cGVHD).

Pathobiological signatures of dysbiotic lung injury in pediatric patients undergoing stem cell transplantation.

Hematopoietic cell transplantation (HCT) uses cytotoxic chemotherapy and/or radiation followed by intravenous infusion of stem cells to cure malignancies, bone marrow failure and inborn errors of immunity, hemoglobin and metabolism. Lung injury is a known complication of the process, due in part to disruption in the pulmonary microenvironment by insults such as infection, alloreactive inflammation and cellular toxicity. How microorganisms, immunity and the respiratory epithelium interact to contribute to lung injury is uncertain, limiting the development of prevention and treatment strategies.

Tubular Injury Biomarkers to Predict CKD and Hypertension at 3 Months Post-Cisplatin in Children.

Key Points: Tubular injury biomarkers are not individually strong predictors of 3-month post-cisplatin CKD. When combined with clinical measures, tubular injury biomarkers can predict post-therapy hypertension and identify high-risk patients.

Background: Urine kidney injury biomarkers measured during cisplatin therapy may identify patients at risk of adverse subsequent kidney outcomes.

Relevance of lymphocyte proliferation to PHA in severe combined immunodeficiency (SCID) and T cell lymphopenia.

Severe combined immunodeficiency (SCID) is characterized by a severe deficiency in T cell numbers. We analyzed data collected (n = 307) for PHA-based T cell proliferation from the PIDTC SCID protocol 6901, using either a radioactive or flow cytometry method. In comparing the two groups, a smaller number of the patients tested by flow cytometry had <10% of the lower limit of normal proliferation as compared to the radioactive method (p = 0.

Urinary TIMP-2*IGFBP-7 to diagnose acute kidney injury in children receiving cisplatin.

Background: Cisplatin is associated with acute kidney injury (AKI) and electrolyte abnormalities. Urine tissue inhibitor of metalloproteinase 2 (TIMP-2) and insulin-like growth factor-binding protein 7 (IGFBP-7) may be early cisplatin-AKI biomarkers.

Methods: We conducted a 12-site prospective cohort study with pediatric patients treated with cisplatin (May 2013-December 2017).

Measuring the effect of newborn screening on survival after haematopoietic cell transplantation for severe combined immunodeficiency: a 36-year longitudinal study from the Primary Immune Deficiency Treatment Consortium.

Background: Severe combined immunodeficiency (SCID) is fatal unless durable adaptive immunity is established, most commonly through allogeneic haematopoietic cell transplantation (HCT). The Primary Immune Deficiency Treatment Consortium (PIDTC) explored factors affecting the survival of individuals with SCID over almost four decades, focusing on the effects of population-based newborn screening for SCID that was initiated in 2008 and expanded during 2010-18.

Methods: We analysed transplantation-related data from children with SCID treated at 34 PIDTC sites in the USA and Canada, using the calendar time intervals 1982-89, 1990-99, 2000-09, and 2010-18.

Circulating cell-free mitochondrial DNA as a diagnostic and prognostic biomarker in chronic and late acute graft-versus-host disease in children.

In an earlier study, we found that mitochondrial DNA (mtDNA) concentration is elevated in adults with chronic graft-versus-host disease (cGvHD), acting as an endogenous source of TLR9 agonists to augment B-cell responses. To validate this in children, we evaluated mtDNA plasma expression in a large pediatric cohort (ABLE/PBMTC 1202 study). Plasma cell-free mtDNA (cf-mtDNA) copy numbers were measured in 202 pediatric patients using quantitative Droplet Digital polymerase chain reaction (ddPCR).

Elevated ADA2 Enzyme Activity at the Onset of Chronic Graft-versus-Host Disease in Children.

Adenosinergic signaling has potent, context-specific effects on immune cells, particularly on the dysregulation of lymphocytes. This in turn may have a role in immune activation and loss of tolerance in such diseases as chronic graft-versus-host disease (chronic GVHD). We assessed whether changes in the enzymatic activity of adenosine deaminase 2 (ADA2), an enzyme that depletes adenosine in the extracellular space via conversion to inosine, may be associated with the onset of chronic GVHD.

Updated Management Guidelines for Adenosine Deaminase Deficiency.

Inherited defects in the adenosine deaminase (ADA) gene typically cause severe combined immunodeficiency. In addition to infections, ADA-deficient patients can present with neurodevelopmental, behavioral, hearing, skeletal, lung, heart, skin, kidney, urogenital, and liver abnormalities. Some patients also suffer from autoimmunity and malignancies.

The diagnosis of severe combined immunodeficiency (SCID): The Primary Immune Deficiency Treatment Consortium (PIDTC) 2022 Definitions.

Severe combined immunodeficiency (SCID) results from defects in the differentiation of hematopoietic stem cells into mature T lymphocytes, with additional lymphoid lineages affected in particular genotypes. In 2014, the Primary Immune Deficiency Treatment Consortium published criteria for diagnosing SCID, which are now revised to incorporate contemporary approaches. Patients with typical SCID must have less than 0.

The diagnosis of severe combined immunodeficiency: Implementation of the PIDTC 2022 Definitions.

Background: Shearer et al in 2014 articulated well-defined criteria for the diagnosis and classification of severe combined immunodeficiency (SCID) as part of the Primary Immune Deficiency Treatment Consortium's (PIDTC's) prospective and retrospective studies of SCID.

Objective: Because of the advent of newborn screening for SCID and expanded availability of genetic sequencing, revision of the PIDTC 2014 Criteria was needed.

Methods: We developed and tested updated PIDTC 2022 SCID Definitions by analyzing 379 patients proposed for prospective enrollment into Protocol 6901, focusing on the ability to distinguish patients with various SCID subtypes.

Acute kidney injury during cisplatin therapy and associations with kidney outcomes 2 to 6 months post-cisplatin in children: a multi-centre, prospective observational study.

Background: Few studies describe acute kidney injury (AKI) burden during paediatric cisplatin therapy and post-cisplatin kidney outcomes. We determined risk factors for and rate of (1) AKI during cisplatin therapy, (2) chronic kidney disease (CKD) and hypertension 2-6 months post-cisplatin, and (3) whether AKI is associated with 2-6-month outcomes.

Methods: This prospective cohort study enrolled children (aged < 18 years at cancer diagnosis) treated with cisplatin from twelve Canadian hospitals.

A diagnostic classifier for pediatric chronic graft-versus-host disease: results of the ABLE/PBMTC 1202 study.

The National Institutes of Health Consensus criteria for chronic graft-versus-host disease (cGVHD) diagnosis can be challenging to apply in children, making pediatric cGVHD diagnosis difficult. We aimed to identify diagnostic pediatric cGVHD biomarkers that would complement the current clinical criteria and help differentiate cGVHD from non-cGVHD. The Applied Biomarkers of Late Effects of Childhood Cancer (ABLE) study, open at 27 transplant centers, prospectively evaluated 302 pediatric patients after hematopoietic cell transplant (234 evaluable).

CD56bright CD16- natural killer cells as an important regulatory mechanism in chronic graft--host disease.

Chronic graft-versus-host disease (cGvHD) is a major cause of morbidity after hematopoietic stem cell transplantation (HSCT). In large patient populations, we have shown a CD56bright natural killer (NK) population to strongly associate with a lack of cGvHD and we hypothesize that these cells function to suppress cGvHD. We aimed to isolate and define the characteristics of regulatory NK (NKreg) cells associated with suppression of cGvHD.