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.

Posttransplantation late complications increase over time for patients with SCID: A Primary Immune Deficiency Treatment Consortium (PIDTC) landmark study.

Background: The Primary Immune Deficiency Treatment Consortium (PIDTC) enrolled children in the United States and Canada onto a retrospective multicenter natural history study of hematopoietic cell transplantation (HCT).

Objective: We investigated outcomes of HCT for severe combined immunodeficiency (SCID).

Methods: We evaluated the chronic and late effects (CLE) after HCT for SCID in 399 patients transplanted from 1982 to 2012 at 32 PIDTC centers.

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.

Evaluation of hymenal adhesions resection in the treatment of recurrent post-coital cystitis.

Objective: To describe and evaluate the technique of hymenal adhesions resection in the treatment of recurrent post-coital cystitis.

Materials And Methods: Monocentric retrospective observational study including patients operated for hymenal adhesions resection between 2013 and 2020. The indication was based on the association of 4 conditions: at least 3 episodes of documented cystitis per year, a post-coital rhythm, a failure of preventing hygienic and dietary rules, a negative etiological assessment except for the existence of hymenal adhesions.

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.

Outcomes following treatment for ADA-deficient severe combined immunodeficiency: a report from the PIDTC.

Adenosine deaminase (ADA) deficiency causes ∼13% of cases of severe combined immune deficiency (SCID). Treatments include enzyme replacement therapy (ERT), hematopoietic cell transplant (HCT), and gene therapy (GT). We evaluated 131 patients with ADA-SCID diagnosed between 1982 and 2017 who were enrolled in the Primary Immune Deficiency Treatment Consortium SCID studies.

Toward a Better Understanding of the Atypical Features of Chronic Graft-Versus-Host Disease: A Report from the 2020 National Institutes of Health Consensus Project Task Force.

Alloreactive and autoimmune responses after allogeneic hematopoietic cell transplantation can occur in nonclassical chronic graft-versus-host disease (chronic GVHD) tissues and organ systems or manifest in atypical ways in classical organs commonly affected by chronic GVHD. The National Institutes of Health (NIH) consensus projects were developed to improve understanding and classification of the clinical features and diagnostic criteria for chronic GVHD. Although still speculative whether atypical manifestations are entirely due to chronic GVHD, these manifestations remain poorly captured by the current NIH consensus project criteria.