Children's Oncology Group's 2023 blueprint for research: Cellular therapy and stem cell transplantation.

Since the publication of the last Cellular Therapy and Stem Cell Transplant blueprint in 2013, Children's Oncology Group cellular therapy-based trials advanced the field and created new standards of care across a wide spectrum of pediatric cancer diagnoses. Key findings include that tandem autologous transplant improved survival for patients with neuroblastoma and atypical teratoid/rhabdoid brain tumors, one umbilical cord blood (UCB) donor was safer than two UCB donors, killer immunoglobulin receptor (KIR) mismatched donors did not improve survival for pediatric acute myeloid leukemia when in vivo T-cell depletion is used, and the depth of remission as measured by next-generation sequencing-based minimal residual disease assessment pretransplant was the best predictor of relapse for acute lymphoblastic leukemia. Plans for the next decade include optimizing donor selection for transplants for acute leukemia/myelodysplastic syndrome, using novel engineered cellular therapies to target a wide array of malignancies, and developing better treatments for cellular therapy toxicities such as viral infections and graft-vs-host disease.

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). Forty-four patients developed cGVHD. Mixed and fixed effect regression analyses were performed on diagnostic cGVHD onset blood samples for cellular and plasma biomarkers, with individual markers declared relevant if they met 3 criteria: an effect ratio ≥1.3 or ≤0.75; an area under the curve (AUC) of ≥0.60; and a P value <5.814 × 10-4 (Bonferroni correction) (mixed effect) or <.05 (fixed effect). To address the complexity of cGVHD diagnosis in children, we built a machine learning-based classifier that combined multiple cellular and plasma biomarkers with clinical factors. Decreases in regulatory natural killer cells, naïve CD4 T helper cells, and naïve regulatory T cells, and elevated levels of CXCL9, CXCL10, CXCL11, ST2, ICAM-1, and soluble CD13 (sCD13) characterize the onset of cGVHD. Evaluation of the time dependence revealed that sCD13, ST2, and ICAM-1 levels varied with the timing of cGVHD onset. The cGVHD diagnostic classifier achieved an AUC of 0.89, with a positive predictive value of 82% and a negative predictive value of 80% for diagnosing cGVHD. Our polyomic approach to building a diagnostic classifier could help improve the diagnosis of cGVHD in children but requires validation in future prospective studies. This trial was registered at www.clinicaltrials.gov as #NCT02067832.

Hematopoietic Cell Transplantation in the Treatment of Pediatric Acute Myelogenous Leukemia and Myelodysplastic Syndromes: Guidelines from the American Society of Transplantation and Cellular Therapy.

The role of allogeneic hematopoietic stem cell transplantation (HCT) in the treatment of acute myelogenous leukemia (AML) in children is reviewed and critically evaluated in this evidence-based review. Specific criteria were used for searching the published literature, grading the quality and strength of evidence, and assigning the strength of treatment recommendations. Genomic characterization and response to therapy have been critical in the risk stratification of pediatric AML. Although some children are cured with chemotherapy alone, allogeneic HCT offers a survival benefit in selected patients with certain unfavorable risk features and is the standard of care for children who relapse following initial treatment with chemotherapy. Important aspects of HCT include recipient characteristics, donor source, and preparative regimen. The goals of HCT are to reduce incidence of relapse, enhance graft-versus-leukemia (GVL) effects, and minimize graft-versus-host disease. Relapse following HCT remains a significant cause of treatment failure, and interventions pre- and post-HCT, especially those that may augment GVL, are an important focus of ongoing investigations.

Retrospective Application of Sinusoidal Obstruction Syndrome/Veno-occlusive Disease Diagnostic Criteria in a Pediatric Hematopoietic Stem Cell Transplant Cohort.

Sinusoidal obstruction syndrome/veno-occlusive disease (SOS/VOD) posthematopoietic stem cell transplantation (HSCT) is often diagnosed using the modified Seattle (MS) or European Society for Blood and Marrow Transplantation (EBMT) criteria. We hypothesized that strict application of these criteria could affect the timing of diagnosis and incidence of SOS/VOD. We collected data on 215 transplants performed in 184 patients at a single pediatric hematopoietic stem cell transplantation center, which were divided into 3 cohorts. Clinical diagnosis and treatment of SOS/VOD was documented in 13% of transplants (cohort 1). On retrospective review, 49% of transplant events met either MS and/or EBMT criteria, however, were not diagnosed with SOS/VOD (cohort 2); remaining 38% of transplant events did not meet MS or EBMT criteria and were not diagnosed with SOS/VOD (cohort 3). Day+100 overall survival was significantly inferior for cohort 1 (78%) compared with cohorts 2 or 3 (92% and 95%, P=0.01) with no difference between cohorts 2 and 3 (P=0.5). Patients diagnosed with SOS/VOD >day+13 had worse day+100 overall survival when compared with those diagnosed ≤day13 (64.3% and 100%, respectively, P=0.02). This study highlights the value of careful clinical assessment to guide diagnosis and the need to refine diagnostic criteria for SOS/VOD in children.

Metabolomic identification of α-ketoglutaric acid elevation in pediatric chronic graft-versus-host disease.

Chronic graft-versus-host disease (cGVHD) is the most common cause for non-relapse mortality postallogeneic hematopoietic stem cell transplant (HSCT). However, there are no well-defined biomarkers for cGVHD or late acute GVHD (aGVHD). This study is a longitudinal evaluation of metabolomic patterns of cGVHD and late aGVHD in pediatric HSCT recipients. A quantitative analysis of plasma metabolites was performed on 222 evaluable pediatric subjects from the ABLE/PBMTC1202 study. We performed a risk-assignment analysis at day + 100 (D100) on subjects who later developed either cGVHD or late aGVHD after day 114 to non-cGVHD controls. A second analysis at diagnosis used fixed and mixed multiple regression to compare cGVHD at onset to time-matched non-cGVHD controls. A metabolomic biomarker was considered biologically relevant only if it met all 3 selection criteria: (1) P ≤ .05; (2) effect ratio of ≥1.3 or ≤0.75; and (3) receiver operator characteristic AUC ≥0.60. We found a consistent elevation in plasma α-ketoglutaric acid before (D100) and at the onset of cGVHD, not impacted by cGVHD severity, pubertal status, or previous aGVHD. In addition, late aGVHD had a unique metabolomic pattern at D100 compared with cGVHD. Additional metabolomic correlation patterns were seen with the clinical presentation of pulmonary, de novo, and progressive cGVHD. α-ketoglutaric acid emerged as the single most significant metabolite associated with cGVHD, both in the D100 risk-assignment and later diagnostic onset analysis. These distinctive metabolic patterns may lead to improved subclassification of cGVHD. Future validation of these exploratory results is needed. This trial was registered at www.clinicaltrials.gov as #NCT02067832.

Reduction of Central-line-Associated Bloodstream Infections in a Tertiary Neonatal Intensive Care Unit through Simulation Education.

Introduction: Critically ill neonates and those with complex medical conditions frequently require the use of central venous lines. Unfortunately, central line-associated bloodstream infections (CLABSIs) result in significant morbidity and mortality, and the cost and increased length of stay burden the healthcare system. Previous studies have demonstrated that standardized care bundles can decrease CLABSI rates, but achieving sustained improvement has proven difficult. Methods: All patients admitted to the Neonatal Intensive Care Unit between 2014 and 2020 who had a CVL were included in this study. First, we recorded all CLABSI events and total CVL days according to defined criteria. Then, in late 2016, we instituted simulation-based nursing training for CVL care. Results: Job Instruction Sheets were initially introduced to Neonatal Intensive Care Unit nursing staff simultaneously with one-on-one teaching sessions between instructors and bedside nurses. Intermittent performance audits and re-education for identified deficiencies did not improve the CLABSI rate per 1000 line days. After instituting simulation-based CVL training in 2016, there was a decreased rate of CLABSI events per 1000 line days sustained over time (x = 0.692). Conclusions: Standardized care bundles and Hospital-acquired Condition interactor audits were insufficient to reduce the CLABSI rate. However, combining care bundles and education with simulation-based training significantly decreased CLABSI rates. One-on-one intensive training and continued ongoing monitoring were critical to producing a sustained reduction. This experience demonstrates that supervised, interactive education combined with simulation can significantly impact patient outcomes.

Comparison of total body irradiation versus non-total body irradiation containing regimens for de novo acute myeloid leukemia in children.

With limited data comparing hematopoietic cell transplant outcomes between myeloablative total body irradiation (TBI) containing and non-TBI regimens in children with de novo acute myeloid leukemia, the aim of this study was to compare transplant-outcomes between these regimens. Cox regression models were used to compare transplant-outcomes after TBI and non-TBI regimens in 624 children transplanted between 2008 and 2016. Thirty two percent (n=199) received TBI regimens whereas 68% (n=425) received non-TBI regimens. Five-year non-relapse mortality was higher with TBI regimens (22% vs. 11%, p<0.0001) but relapse was lower (23% vs. 37%, p<0.0001) compared to non-TBI regimens. Consequently, overall (62% vs. 60%, p=1.00) and leukemia-free survival (55% vs. 52%, p=0.42) did not differ between treatment groups. Grade II-IV acute GVHD was higher with TBI regimens (56% vs. 27%, p<0.0001) but not chronic GVHD. The 3-year incidence of gonadal or growth hormone deficiency was higher with TBI regimens (24% vs. 8%, p<0.001) but there were no differences in late pulmonary, cardiac or renal impairment. In the absence of a survival advantage, the choice of TBI or non-TBI regimen merits careful consideration with the data favoring non-TBI regimens to limit the burden of morbidity associated with endocrine dysfunction.

A validated pediatric disease risk index for allogeneic hematopoietic cell transplantation.

A disease risk index (DRI) that was developed for adults with hematologic malignancy who were undergoing hematopoietic cell transplantation is also being used to stratify children and adolescents by disease risk. Therefore, to develop and validate a DRI that can be used to stratify those with AML and ALL by their disease risk, we analyzed 2569 patients aged <18 years with acute myeloid (AML; n = 1224) or lymphoblastic (ALL; n = 1345) leukemia who underwent hematopoietic cell transplantation. Training and validation subsets for each disease were generated randomly with 1:1 assignment to the subsets, and separate prognostic models were derived for each disease. For AML, 4 risk groups were identified based on age, cytogenetic risk, and disease status, including minimal residual disease status at transplantation. The 5-year leukemia-free survival for low (0 points), intermediate (2, 3, 5), high (7, 8), and very high (>8) risk groups was 78%, 53%, 40%, and 25%, respectively (P < .0001). For ALL, 3 risk groups were identified based on age and disease status, including minimal residual disease status at transplantation. The 5-year leukemia-free survival for low (0 points), intermediate (2-4), and high (≥5) risk groups was 68%, 51%, and 33%, respectively (P < .0001). We confirmed that the risk groups could be applied to overall survival, with 5-year survival ranging from 80% to 33% and 73% to 42% for AML and ALL, respectively (P < .0001). This validated pediatric DRI, which includes age and residual disease status, can be used to facilitate prognostication and stratification of children with AML and ALL for allogeneic transplantation.

Infection prophylaxis patterns following pediatric autologous hematopoietic stem cell transplantation: A survey of Pediatric Transplant and Cell Therapy Consortium centers.

No standardized guidelines exist for infectious prophylaxis following pediatric auto-HSCT. We hypothesized significant variation in clinical practice. Thirty-three Pediatric Transplant and Cell Therapy Consortium centers completed a survey to assess institutional management. The majority utilize viral (91%) and fungal prophylaxis (94%), but duration varies. Bacterial prophylaxis during neutropenia is instituted by 42%. Our study demonstrates marked practice variability in infectious prophylaxis across centers. Additional research is needed to address patterns of infectious complications and to develop meaningful clinical practice guidelines for pediatric auto-HSCT.

Immune profile differences between chronic GVHD and late acute GVHD: results of the ABLE/PBMTC 1202 studies.

Human graft-versus-host disease (GVHD) biology beyond 3 months after hematopoietic stem cell transplantation (HSCT) is complex. The Applied Biomarker in Late Effects of Childhood Cancer study (ABLE/PBMTC1202, NCT02067832) evaluated the immune profiles in chronic GVHD (cGVHD) and late acute GVHD (L-aGVHD). Peripheral blood immune cell and plasma markers were analyzed at day 100 post-HSCT and correlated with GVHD diagnosed according to the National Institutes of Health consensus criteria (NIH-CC) for cGVHD. Of 302 children enrolled, 241 were evaluable as L-aGVHD, cGVHD, active L-aGVHD or cGVHD, and no cGVHD/L-aGVHD. Significant marker differences, adjusted for major clinical factors, were defined as meeting all 3 criteria: receiver-operating characteristic area under the curve ≥0.60, P ≤ .05, and effect ratio ≥1.3 or ≤0.75. Patients with only distinctive features but determined as cGVHD by the adjudication committee (non-NIH-CC) had immune profiles similar to NIH-CC. Both cGVHD and L-aGVHD had decreased transitional B cells and increased cytolytic natural killer (NK) cells. cGVHD had additional abnormalities, with increased activated T cells, naive helper T (Th) and cytotoxic T cells, loss of CD56bright regulatory NK cells, and increased ST2 and soluble CD13. Active L-aGVHD before day 114 had additional abnormalities in naive Th, naive regulatory T (Treg) cell populations, and cytokines, and active cGVHD had an increase in PD-1- and a decrease in PD-1+ memory Treg cells. Unsupervised analysis appeared to show a progression of immune abnormalities from no cGVHD/L-aGVHD to L-aGVHD, with the most complex pattern in cGVHD. Comprehensive immune profiling will allow us to better understand how to minimize L-aGVHD and cGVHD. Further confirmation in adult and pediatric cohorts is needed.

A psychosocial clinical care pathway for pediatric hematopoietic stem cell transplantation.

OBJECTIVE: Currently, no evidence-based psychosocial clinical care pathways (PCCP) exist to triage psychosocial risk levels and guide delivery of psychosocial care to youth receiving a hematopoietic stem cell transplantation (HCT) and their families. The purpose of this paper is to describe the use of qualitative research methodologies to develop PCCP in pediatric HCT consistent with the Standards for Psychosocial Care developed for children with cancer. METHODS: We previously used qualitative methodologies to interview parents to identify four principles to inform the development of PCCPs. Then in this study a focus group with parents and multidisciplinary clinicians was conducted to assess the acceptability of the PCCP, suggest modifications, and provide input on its use. RESULTS: The PCCP is six-step pathway, starting with a standardized screening assessment with the Psychosocial Assessment Tool (PAT-HCT) that identifies the family's specific care needs. The focus group data support overall assessment with the PAT-HCT and the care principles underlying this approach. CONCLUSIONS: This PCCP is a systemic multidisciplinary model for providing psychosocial care that is ready for the next stage of development and evaluation in clinical care.

Benefits and challenges with diagnosing chronic and late acute GVHD in children using the NIH consensus criteria.

Chronic graft-versus-host disease (cGVHD) and late acute graft-versus-host disease (L-aGVHD) are understudied complications of allogeneic hematopoietic stem cell transplantation in children. The National Institutes of Health Consensus Criteria (NIH-CC) were designed to improve the diagnostic accuracy of cGVHD and to better classify graft-versus-host disease (GVHD) syndromes but have not been validated in patients <18 years of age. The objectives of this prospective multi-institution study were to determine: (1) whether the NIH-CC could be used to diagnose pediatric cGVHD and whether the criteria operationalize well in a multi-institution study; (2) the frequency of cGVHD and L-aGVHD in children using the NIH-CC; and (3) the clinical features and risk factors for cGVHD and L-aGVHD using the NIH-CC. Twenty-seven transplant centers enrolled 302 patients <18 years of age before conditioning and prospectively followed them for 1 year posttransplant for development of cGVHD. Centers justified their cGVHD diagnosis according to the NIH-CC using central review and a study adjudication committee. A total of 28.2% of reported cGVHD cases was reclassified, usually as L-aGVHD, following study committee review. Similar incidence of cGVHD and L-aGVHD was found (21% and 24.7%, respectively). The most common organs involved with diagnostic or distinctive manifestations of cGVHD in children include the mouth, skin, eyes, and lungs. Importantly, the 2014 NIH-CC for bronchiolitis obliterans syndrome perform poorly in children. Past acute GVHD and peripheral blood grafts are major risk factors for cGVHD and L-aGVHD, with recipients ≥12 years of age being at risk for cGVHD. Applying the NIH-CC in pediatrics is feasible and reliable; however, further refinement of the criteria specifically for children is needed.

Screening for Family Psychosocial Risk in Pediatric Hematopoietic Stem Cell Transplantation with the Psychosocial Assessment Tool.

Family psychosocial risk screening is an important initial step in delivering evidence-based care in hematopoietic stem cell transplantation (HCT). Establishing an evidence-based screening approach that is acceptable, reliable, and valid is an essential step in psychosocial care delivery. This is a 3-institution multimethod study. In part 1, caregivers of children about to undergo HCT (n = 140) completed the Psychosocial Assessment Tool-Hematopoietic Cell Transplantation (PAT-HCT), a brief parent report screener adapted for HCT, and validating questionnaires. Families received feedback on their risks identified on the PAT-HCT. In part 2, 12 caregivers completed a semistructured interview about their perceptions of the PAT and the feedback process. The reliability and validity of the PAT-HCT total and subscale scores were tested using Kuder-Richardson-20 (KR-20) and Pearson correlations. Thematic content analysis was used to analyze the qualitative interview data. Internal consistency for the total score (KR-20 = .88) and the Child Problems, Sibling Problems, Family Problems, and Stress Reactions subscales were strong (KR-20 >.70). Family Structure, Social Support, and Family Beliefs subscales were adequate (KR-20 = .55 to .63). Moderate to strong correlations with the criteria measures provided validation for the total and subscale scores. Feedback was provided to 97.14% of the families who completed the PAT-HCT, and the mean rating of acceptability was >4.00 (on a 5-point scale). The qualitative data indicate that families appreciate the effort to provide screening and feedback. The PAT-HCT is a psychometrically sound screener for use in HCT. Feedback can be given to families. Both the screener and the feedback process are acceptable to caregivers.

Treosulfan, Fludarabine, and Low-Dose Total Body Irradiation for Children and Young Adults with Acute Myeloid Leukemia or Myelodysplastic Syndrome Undergoing Allogeneic Hematopoietic Cell Transplantation: Prospective Phase II Trial of the Pediatric Blood and Marrow Transplant Consortium.

This multicenter study evaluated a treosulfan-based regimen in children and young adults with acute myeloid leukemia (AML) or myelodysplastic syndrome (MDS) undergoing allogeneic hematopoietic cell transplant (HCT). Forty patients with median age 11 years (range, 1 to 19) underwent allogeneic HCT for AML in first (n = 18), second (n = 11), and third or greater remission (n = 3) or MDS (n = 8) using bone marrow (n = 25), peripheral blood stem cells (n = 5), or cord blood (n = 9). The regimen consisted of body surface area (BSA)-based treosulfan 10 g/m2/day (BSA ≤ .5 m2), 12 g/m2/day (BSA > .5 to 1.0 m2), or 14 g/m2/day (BSA > 1.0 m2) on days -6 to -4; fludarabine 30 mg/m2/day on days -6 to -2; and a single fraction of 200 cGy total body irradiation on day -1. Graft-versus-host disease (GVHD) prophylaxis included tacrolimus and methotrexate for marrow and peripheral blood stem cell and cyclosporine/mycophenolate mofetil for cord blood. One-year overall survival, disease-free survival, and nonrelapse mortality were 80%, 73%, and 3%, respectively. One-year relapse was 38% for AML and 13% for MDS. No serious organ toxicities were observed. All 37 assessable patients engrafted. Cumulative incidences of grades II to IV acute GVHD and chronic GVHD were 22% and 40%, respectively. BSA-based treosulfan dosing resulted in predictable area under the curve and maximum concentration, which is required for dosing without measuring individual pharmacokinetic parameters. Observed differences in pharmacokinetics did not impact disease control or regimen toxicity. This BSA-based treosulfan regimen resulted in excellent engraftment and disease-free survival and minimal toxicity and transplant-related mortality (3%) in children and young adults with AML and MDS.

Extramedullary Relapse of Acute Lymphoblastic Leukemia Presenting as Abnormal Uterine Bleeding: A Case Report.

BACKGROUND: Acute lymphoblastic leukemia (ALL) is the most common childhood malignancy. Relapse of ALL occurs in 15%-20% of patients, with 2%-6% occurring exclusively in extramedullary sites. Relapse of ALL in gynecologic organs is extremely rare. CASE: We present a case of a 12-year-old girl with a history of ALL who was referred to the pediatric gynecology clinic with abnormal uterine bleeding. She was determined to have an extramedullary uterine relapse of her ALL. SUMMARY AND CONCLUSION: Abnormal uterine bleeding in the setting of childhood malignancy is a frequent reason for consultation to pediatric and adolescent gynecology services. This bleeding is commonly attributed to thrombocytopenia due to bone marrow suppressive chemotherapeutic agents. However, as shown in this report, abnormal uterine bleeding might be a manifestation of an extramedullary relapse.

Inferior outcomes for black children with high risk acute lymphoblastic leukemia and the impact of socioeconomic variables.

BACKGROUND: While significant improvements have been made for children with acute lymphoblastic leukemia (ALL) in the United States over the past 20 years, black patients continue to have inferior outcomes. The full impact of socioeconomic variables on outcomes in this minority population is not entirely understood. PROCEDURE: Disease characteristics, demographic, and socioeconomic status (SES) variables were collected on black (n = 44) and white (n = 178) patients diagnosed at the University of Alabama at Birmingham. Cox proportional hazard regression was used to evaluate the influence of SES and insurance status on survival. RESULTS: As a cohort, 5-year overall survival (OS) was 87% (82-91%), with a median follow-up of 99 months. In univariable analysis, black race was not significantly associated with a higher risk of death or relapse and death. White and black patients with standard-risk leukemia had excellent outcomes, with 97% (91-99%) and 96% (75-99%) 5-year OS, respectively. In contrast, for high-risk disease, white patients had a statistically significant improved 5-year OS rates compared with black patients (79% [68-87%] vs. 52% [28-72%]). Black children were more likely to have public insurance, and, in multivariable analysis, this was associated with a trend toward an improved outcome. Black patients also had poorer census tract-level SES parameters, but these variables were not associated with survival. CONCLUSION: Our study demonstrates significantly inferior outcomes for black children with high-risk leukemia. These outcome disparities were not related to SES variables, including poverty or private insurance coverage, suggesting the involvement of other factors and highlighting the need for a prospective investigative analysis.

Development and survival of Th17 cells within the intestines: the influence of microbiome- and diet-derived signals.

Th17 cells have emerged as important mediators of host defense and homeostasis at barrier sites, particularly the intestines, where the greatest number and diversity of the microbiota reside. A critical balance exists between protection of the host from its own microbiota and pathogens and the development of immune-mediated disease. Breaches of local innate immune defenses provide critical stimuli for the induction of Th17 cell development, and additional cues within these tissues promote Th17 cell survival and/or plasticity. Normally, this results in eradication of the microbial threat and restitution of homeostasis. When dysregulated, however, Th17 cells can cause a range of immune-mediated diseases, whether directed against Ags derived from the microbiota, such as in inflammatory bowel disease, or against self-Ags in a range of autoimmune diseases. This review highlights recent discoveries that provide new insights into ways in which environmental signals impact Th17 cell development and function in the intestines.