Pediatric Hematopoietic Stem Cell Transplantation Research Articles

Linking gastrointestinal microbiota and metabolome dynamics to clinical outcomes in paediatric haematopoietic stem cell transplantation

BackgroundHaematopoietic stem cell transplantation is a curative procedure for a variety of conditions. Despite major advances, a plethora of adverse clinical outcomes can develop post-transplantation including graft-versus-host disease and infections, which remain the major causes of morbidity and mortality. There is increasing evidence that the gastrointestinal microbiota is associated with clinical outcomes post-haematopoietic stem cell transplantation. Herein, we investigated the longitudinal dynamics of the gut microbiota and metabolome and potential associations to clinical outcomes in paediatric haematopoietic stem cell transplantation at a single centre.ResultsOn admission (baseline), the majority of patients presented with a different gut microbial composition in comparison with healthy control children with a significantly lower alpha diversity. A further, marked decrease in alpha diversity was observed immediately post-transplantation and in most microbial diversity, and composition did not return to baseline status whilst hospitalised. Longitudinal trajectories identified continuous fluctuations in microbial composition, with the dominance of a single taxon in a significant proportion of patients. Using pam clustering, three clusters were observed in the dataset. Cluster 1 was common pre-transplantation, characterised by a higher abundance of Clostridium XIVa, Bacteroides and Lachnospiraceae; cluster 2 and cluster 3 were more common post-transplantation with a higher abundance of Streptococcus and Staphylococcus in the former whilst Enterococcus, Enterobacteriaceae and Escherichia predominated in the latter. Cluster 3 was also associated with a higher risk of viraemia. Likewise, further multivariate analysis reveals Enterobacteriaceae, viraemia, use of total parenteral nutrition and various antimicrobials contributing towards cluster 3, Streptococcaceae, Staphylococcaceae, Neisseriaceae, vancomycin and metronidazole contributing towards cluster 2. Lachnospiraceae, Ruminococcaceae, Bifidobacteriaceae and not being on total parenteral nutrition contributed to cluster 1. Untargeted metabolomic analyses revealed changes that paralleled fluctuations in microbiota composition; importantly, low faecal butyrate was associated with a higher risk of viraemia.ConclusionsThese findings highlight the frequent shifts and dominations in the gut microbiota of paediatric patients undergoing haematopoietic stem cell transplantation. The study reveals associations between the faecal microbiota, metabolome and viraemia. To identify and explore the potential of microbial biomarkers that may predict the risk of complications post-HSCT, larger multi-centre studies investigating the longitudinal microbial profiling in paediatric haematopoietic stem cell transplantation are warranted.3ijjxzWkyLUsL7DWLJaC9PVideo abstract.

Outcomes and risk factors of hemorrhagic cystitis in pediatric allogeneic hematopoietic stem cell transplantation recipients using different graft source and condition with severe aplastic anemia

ABSTRACT Background Hemorrhagic cystitis (HC) is a severe complication of allo-HSCT, characterized by irritative symptoms of the urinary tract and a higher morbidity rate. The risk factors and prognosis of HC are still unclear. Objective The objective of this study is to identify risk factors and outcomes to improve treatment in pediatric SAA patients undergoing HSCTs in the Children's Hospital of Soochow University. Methods A total of 97 SAA patients as a cohort were enrolled from 2010 to 2019 in the Children's Hospital of Soochow University and a number of factors related to HC and outcomes were analysed. In all transplants (except UCBT), patients received a combination of G-CSF stimulated bone marrow (BM) and peripheral blood stem cell (PBSC). The minimum number of CD34 + cells is 5 × 106 cells/kg. Results Mononuclear cells dose (MNC, cut off: 8.53 × 108/kg) and grade II–IV acute graft versus host disease (aGVHD) were identified as independent risk factors for HC. Patients without HC had better overall survival (OS) than with HC (No HC: 98.6%±1.4% vs HC: 87.4% ± 6.8%, p = 0.03). Conclusion We concluded that aGVHD and MNC dose in graft might play an important role in the development of HC in pediatric SAA patients undergoing allo-HSCT. HC is also a key complication affecting the prognosis of children with SAA after allo-HSCT.

Thyroid Disorders Following Hematopoietic Stem Cell Transplantation in Childhood: Impact of Conditioning Regimen on Thyroid Dysfunction, Volume Changes, and Occurrence of Nodules

Thyroid late effects are among the most frequent sequelae reported after pediatric hematopoietic stem cell transplantation (HSCT). Although the detrimental effects of radiotherapy on the developing thyroid gland have been extensively assessed, the role of chemotherapy-only conditioning regimens remains controversial. We aimed to describe the occurrence, monitoring, and management of thyroid function disorders (ie, Graves disease, Hashimoto thyroiditis, and nonautoimmune hypothyroidism), nodules, and volumetric changes over a 20-year observation period in a single pediatric transplantation unit. In addition, we assessed the impact of different conditioning regimens on thyroid health. The study population for this retrospective observational analysis comprised 244 pediatric patients who underwent HSCT for malignant or nonmalignant diseases between 1999 and 2018 and for whom at least 4 thyroid function tests and 1 or more thyroid ultrasound(s) assessed sequentially after HSCT were available. The 15-year cumulative incidence of either autoimmune or nonautoimmune thyroid dysfunctions (34%, SE 5.3%) did not differ statistically between total body irradiation (TBI)-based and chemotherapy-based regimens (P = .23). Indeed, the cumulative incidence after busulfan (Bu)-based conditioning was overall superimposable to that recorded after TBI (10-year cumulative incidence, 22.2% versus 25.9%, respectively). Nevertheless, the cumulative incidence of nonautoimmune hypothyroidism was statistically higher after Bu-based conditioning (12.4%, SE 3.7%) than after other chemotherapy-only-based conditioning regimens (3.1%, SE 3.1%; P = .02, 5-year cumulative incidence), treosulfan (Treo) included. The overall cumulative incidence of nodules was low for the first 5 years after HSCT (1.9%, SE .9%) but subsequently increased steeply over time, with a 15-year cumulative incidence as high as 52.1% (SE 7.5%). TBI-conditioned patients had a higher 15-year cumulative incidence of nodules (66.8%, SE 9.1%) compared with patients receiving chemotherapy-only regimens (33.6%, SE 9.5%; P = .02), whereas age >10 years at transplantation showed a protective effect (hazard ratio, .42, 95% confidence interval, .2 to .88). Finally, a systematic sonographic follow-up highlighted a progressive statistically significant reduction in thyroid anteroposterior diameter among patients conditioned with TBI (P=.005), but not in those who received chemotherapy-only regimens. TBI and younger age at HSCT have a statistically significant detrimental effect on the occurrence of thyroid nodules, both benign and malignant. TBI and Bu expose patients to a higher cumulative incidence of thyroid dysfunction compared with other chemotherapy-only regimens, Treo included. Accordingly, Bu can be considered the most thyrotoxic agent among those administered as a part of a chemotherapy-only conditioning regimen. Finally, patients conditioned with TBI, but not those with other regimens, show a progressive decrease in thyroid volume over time, as assessed by sequential ultrasound examinations.

Male Gonadal Function After Pediatric Hematopoietic Stem Cell Transplantation: A Systematic Review

Male gonadal dysfunction is a frequent late effect after pediatric hematopoietic stem cell transplantation (HSCT) that can lead to disturbances in pubertal development, sexual dysfunction, and infertility. However, no systematic review exists regarding prevalence and risk factors in relation to different treatment regimens. We aimed to systematically evaluate the current evidence regarding the prevalence of male gonadal dysfunction after pediatric HSCT, related risk factors, and the diagnostic value of surrogate markers of spermatogenesis in this patient group. We searched PubMed and Embase using a combination of text words and subject terms. The eligibility screening was conducted using predefined criteria. Data were extracted corresponding to the Leydig cell compartment involved in testosterone production and the germ cell compartment involved in spermatogenesis, respectively. Subsequently, data synthesis was performed. Of 2369 identified records, 25 studies were eligible. The studies were heterogeneous in terms of included diagnoses, gonadotoxic therapy, follow-up time, and definitions of gonadal dysfunction. The data synthesis revealed a preserved Leydig cell function in patients treated with non-total body irradiation (TBI) regimens, whereas the evidence regarding the impact of TBI conditioning on Leydig cell function was conflicting. Based on surrogate markers of spermatogenesis and only limited data on semen quality, the germ cell compartment was affected in half of the patients treated with non-TBI regimens and in nearly all patients treated with TBI conditioning. Testicular irradiation as part of front-line therapy before referral to HSCT led to complete Leydig cell failure and germ cell failure. Evidence regarding the impact of diagnosis, pubertal stage at HSCT, and chronic graft-versus-host disease is limited, as is the evidence of the diagnostic value of surrogate markers of spermatogenesis. Testicular irradiation as part of front-line therapy and TBI conditioning are the main risk factors associated with male gonadal dysfunction after pediatric HSCT; however, impaired spermatogenesis is also observed in half of the patients treated with non-TBI regimens. Methodological shortcomings limit existing evidence, and future studies should include semen quality analyses, follow-up into late adulthood, and evaluation of the cumulative exposure to gonadotoxic therapy.

Impact of Adequate Day 30 Post-Pediatric Hematopoietic Stem Cell Transplantation Vitamin D Level on Clinical Outcome: An Observational Cohort Study

This prospective observational study evaluated the impact of adequate vitamin D levels by day +30 after vitamin D supplementation on early post-HSCT outcomes, including acute graft-versus-host disease (aGVHD), immune recovery, infection rates, and overall survival. Forty children (age 2 to 16 years) undergoing hematopoietic stem cell transplantation (HSCT) were given vitamin D supplementation, were followed prospectively from day +30 post-transplantation, and had day +30 vitamin D levels measured. Thirty patients with normal vitamin D levels (≥30 ng/mL) were compared with 10 patients with low day +30 vitamin D levels (<30 ng/mL). The times to neutrophil and platelet engraftment was similar in both day +30 vitamin D groups (P=.13 and .32, respectively). At day +100, slower immune recovery in CD4+ cells (P=.027), CD19+ cells (P=.024), and natural killer cells (P=.042) was observed in the patients with a low vitamin D level (<30 ng/mL), and no between-group differences were detected in the incidence of infection (P=.72) or grade II-IV aGVHD (P=.46). Our findings show that patients with adequate vitamin D levels during transplantation had faster immune recovery and better overall survival. Vitamin D deficiency does not appear to impact engraftment or the risk of aGVHD and infection in pediatric HSCT.

Predictors of kidney complications and analysis of hypertension in children with allogeneic hematopoietic stem cell transplantation.

This study aimed to determine incidence of kidney complications in pediatric allogeneic hematopoietic stem cell transplantation (HSCT) patients. Pediatric allogeneic HSCT patients were included. Post-transplantation urinary system complications were collected from medical records and glomerular filtration rates at last visit compared with clinical parameters. Additionally, 24-h ambulatory blood pressure monitoring was performed. The study included 165 pediatric patients. Acute kidney injury (AKI) developed in 125 (75.8%) patients of whom 54 (43.2%) had stage 1, 36 (28.8%) stage 2, and 35 (28%) stage 3 AKI. Primary malignant disease and viral infection post-HSCT were associated with increased risk of AKI (OR: 4; 95%CI: 1.2-13, p = 0.022 and OR: 2.9; 95%CI: 1.2-6.8, p = 0.014, respectively). Mean duration of post-HSCT follow-up was 4.4 ± 2.5 years, during which time 8 patients had chronic kidney disease (CKD) (stage 1, 4 patients; stage 2, 3 patients; stage 3, 1 patient). CKD incidence was higher in patients in whom stem cell product was bone marrow + cord blood and mobilized peripheral blood, compared to bone marrow alone (40-37.5% versus 5.1%, p = 0.002). Based on 24-h ABPM, 14.7% and 7.4% of patients with normal office blood pressure had pre-hypertension and hypertension, respectively. In patients with albuminuria/severe albuminuria, daytime and nighttime systolic SDS scores were higher than those without albuminuria/severe albuminuria (p = 0.010 and p = 0.004, respectively). Incidence of AKI is higher in pediatric HSCT patients with primary malignant disease and those with documented viral infection. Our study highlights the beneficial role of 24-h ABPM as a routine part of standard care of pediatric HSCT recipients.

Pain, Depressive Symptoms, and Global Health among Survivors of Pediatric Hematopoietic Stem Cell Transplant

Pain, Depressive Symptoms, and Global Health among Survivors of Pediatric Hematopoietic Stem Cell Transplant

Threshold of Quantitative Cytomegalovirus DNA PCR for Preemptive Treatment in Pediatric Hematopoietic Stem Cell Transplant Recipients.

Consensus cytomegalovirus (CMV) DNA viral load thresholds for intervention in hematopoietic stem cell transplant (HSCT) recipients have not been established, especially in children. This study aimed at obtaining viral load thresholds of CMV DNA to guide preemptive management in pediatric HSCT recipients. A total of 465 blood samples from 177 children who received HSCT between 2015 and 2019 were included in a single center in Korea. The samples were analyzed for CMV infection by both antigenemia assay and quantitative DNA polymerase chain reaction. The 2 assay results were compared for the 233 samples which were collected when antiviral treatment has not been initiated. We determined the viral loads corresponding to the antigenemia of 5 pp65-positive cells/2×10 5 white blood cells (WBCs) as the level for initiating preemptive therapy. Sixty percent of the samples were collected within 100 days (39.7% in 0 to 50 d, 60.2% in 0 to 100 d) from the graft infusion. The correlation between CMV DNA viral load and CMV antigenemia level increased significantly after 50 days from the graft infusion ( r =0.71 vs. r =0.93, P <0.0001). The correlation was greater in the antiviral treatment-naive group than the treatment group ( r =0.75 vs. r =0.66, P <0.0001). Under receiver operating characteristic curve analysis of the treatment-naive group, the estimated threshold CMV DNA viral loads corresponding to 5 pp65-positive cells/2×10 5 WBCs was 898 IU/mL. The CMV DNA levels that corresponded to 5 pp65-positive cells/2×10 5 WBCs was 900 IU/mL in the HSCT group. The proposed viral load thresholds can be used to guide preemptive therapy in pediatric HSCT recipients, especially in the preengraftment period.

The significance of mixed chimaerism and cell lineage chimaerism monitoring in paediatric patients post haematopoietic stem cell transplant.

Haematopoietic stem cell transplants (HSCTs) are carried out across the world to treat haematological and immunological diseases which would otherwise prove fatal. Certain diseases are predominantly encountered in paediatric patients, such severe primary immunodeficiencies (PID) and diseases of inborn errors of metabolism (IEM). Chimaerism testing for these disorders has different considerations compared to adult diseases. This review focuses on the importance of cell-lineage-specific chimaerism testing and examines the appropriate cell populations to be assessed in individual paediatric patient groups. By analysing disease-associated subpopulations, abnormalities are identified significantly earlier than in whole samples and targeted clinical decisions can be made. Chimaerism methods have evolved over time and lead to an ever-increasing level of sensitivity and biomarker arrays to distinguish between recipient and donor cells. Short tandem repeat (STR) is still the gold standard for routine chimaerism assessment, and hypersensitive methods such as quantitative and digital polymerase chain reaction (PCR) are leading the forefront of microchimaerism testing. The rise of molecular methods operating with minute DNA amounts has been hugely beneficial to chimaerism testing of paediatric samples. As HSCTs are becoming increasingly personalised and risk-adjusted towards a child's individual needs, chimaerism testing needs to adapt alongside these medical advances ensuring the best possible care.

Target Enrichment Metagenomics Reveals Human Pegivirus-1 in Pediatric Hematopoietic Stem Cell Transplantation Recipients.

Human pegivirus-1 (HPgV-1) is a lymphotropic human virus, typically considered nonpathogenic, but its infection can sometimes cause persistent viremia both in immunocompetent and immunosuppressed individuals. In a viral discovery research program in hematopoietic stem cell transplant (HSCT) pediatric patients, HPgV-1 was detected in 3 out of 14 patients (21.4%) using a target enrichment next-generation sequencing method, and the presence of the viruses was confirmed by agent-specific qRT-PCR assays. For the first time in this patient cohort, complete genomes of HPgV-1 were acquired and characterized. Phylogenetic analyses indicated that two patients had HPgV-1 genotype 2 and one had HPgV-1 genotype 3. Intra-host genomic variations were described and discussed. Our results highlight the necessity to screen HSCT patients and blood and stem cell donors to reduce the potential risk of HPgV-1 transmission.

Febrile Neutropenia Duration Is Associated with the Severity of Gut Microbiota Dysbiosis in Pediatric Allogeneic Hematopoietic Stem Cell Transplantation Recipients.

Simple SummaryFebrile neutropenia is a common complication in pediatric patients undergoing allogeneic hematopoietic stem cell transplantation. Its genesis is often attributed to infections; however, a specific cause frequently cannot be defined. We hypothesize that the composition of the intestinal flora may contribute to the genesis of the neutropenic fever. We analyzed the microbial composition of stool samples from pediatric patients from three European centers and assessed the relationship with the duration of the fever during neutropenia. We found that a more stable composition of the microbiota during the transplantation course is associated with a shorter duration of fever. Moreover, patients with a higher duration of fever presented higher levels of Collinsella, Megasphaera, Prevotella, Roseburia, Eggerthella and Akkermansia in the stool.Febrile neutropenia (FN) is a common complication in pediatric patients receiving allogeneic hematopoietic stem cell transplantation (HSCT). Frequently, a precise cause cannot be identified, and many factors can contribute to its genesis. Gut microbiota (GM) has been recently linked to many transplant-related complications, and may also play a role in the pathogenesis of FN. Here, we conducted a longitudinal study in pediatric patients receiving HSCT from three centers in Europe profiling their GM during the transplant course, particularly at FN onset. We found that a more stable GM configuration over time is associated with a shorter duration of fever. Moreover, patients with longer lasting fever exhibited higher pre-HSCT levels of Collinsella, Megasphaera, Prevotella and Roseburia and increased proportions of Eggerthella and Akkermansia at the engraftment. These results suggest a possible association of the GM with the genesis and course of FN. Data seem consistent with previous reports on the relationship of a so-called “healthy” GM and the reduction of transplant complications. To our knowledge, this is the first report in the pediatric HSCT setting. Future studies are warranted to define the underling biological mechanisms and possible clinical implications.

Two Different Transplant Preconditioning Regimens Combined with Irradiation and Chemotherapy in the Treatment of Childhood Leukemia: Systematic Review and Meta-Analysis.

Objective To observe the therapeutic effect and the incidence of adverse reactions of total body irradiation plus cyclophosphamide (TBI/CY) and busulfan plus cyclophosphamide (BU/CY) in the treatment of pediatric hematopoietic stem cell transplantation. Methods By searching the Cochrane Library, PubMed, Web of Knowledge, Embase, Chinese Biomedical Literature Database (CBM), and screening randomized controlled trials (RCTs), quality evaluation and data extraction were performed for the included literature, and meta-analysis was performed for RCTs included at using Review Manager 5.2 software. Results A total of 10160 patients were enrolled in 15 RCTs, including 5211 patients in the TBI/CY group and 4949 patients in the BU/CY group. Meta-analysis showed that there was a statistical difference in transplant failure rate (OR = 1.56, 95% CI (1.23, 1.97), P = 0.0002, I2 = 56%, Z = 3.69), transplant mortality (OR = 1.45, 95% CI (1.24, 1.68), P < 0.00001, I2 = 76%, Z = 4.80), transplantation long-term disease-free survival rate (OR = 1.52, 95% CI (1.09, 2.12), P = 0.01, I2 = 0%, Z = 2.50), and transplantation adverse reactions (OR = 1.28, 95% CI (1.08, 1.52), P = 0.004, I2 = 0%, Z = 2.85). Conclusion Meta-analysis showed that TBI/CY combined pretreatment regimen was more effective than BU/CY regimen alone in the treatment of pediatric hematologic transplantation, with a lower incidence of adverse reactions and significant long-term survival efficacy.

Therapeutic Drug Monitoring of Conditioning Agents in Pediatric Allogeneic Stem Cell Transplantation; Where do We Stand?

Allogeneic hematopoietic stem cell transplantation (HSCT) is an established curative treatment that has significantly improved clinical outcome of pediatric patients with malignant and non-malignant disorders. This is partly because of the use of safer and more effective combinations of chemo- and serotherapy prior to HSCT. Still, complications due to the toxicity of these conditioning regimens remains a major cause of transplant-related mortality (TRM). One of the most difficult challenges to further improve HSCT outcome is reducing toxicity while maintaining efficacy. The use of personalized dosing of the various components of the conditioning regimen by means of therapeutic drug monitoring (TDM) has been the topic of interest in the last decade. TDM could play an important role, especially in children who tend to show greater pharmacokinetic variability. However, TDM should only be performed when it has clear added value to improve clinical outcome or reduce toxicity. In this review, we provide an overview of the available evidence for the relationship between pharmacokinetic parameters and clinical outcome or toxicities of the most commonly used conditioning agents in pediatric HSCT.

477 - Availability of Donor Derived Patient Specific Virus-Specific T-Cells (VSTs) Is Not Associated with Differences in Outcomes As Compared to Frontline Administration of Third Party Vsts for the Management of Viral Infections after Pediatric Hematopoietic Stem Cell Transplant

477 - Availability of Donor Derived Patient Specific Virus-Specific T-Cells (VSTs) Is Not Associated with Differences in Outcomes As Compared to Frontline Administration of Third Party Vsts for the Management of Viral Infections after Pediatric Hematopoietic Stem Cell Transplant

LBA6 - A Retrospective Comparison of Tacrolimus Intrapatient Variablity Measures and Outcomes in Pediatric Hematopoietic Stem Cell Transplant Patients

LBA6 - A Retrospective Comparison of Tacrolimus Intrapatient Variablity Measures and Outcomes in Pediatric Hematopoietic Stem Cell Transplant Patients

444 - Sharing Best Practice: Establishing a National Vietnamese Pediatric Hematopoietic Stem Cell Transplant and Cellular Therapy Consortium

444 - Sharing Best Practice: Establishing a National Vietnamese Pediatric Hematopoietic Stem Cell Transplant and Cellular Therapy Consortium

193 - Transplant Associated Risk Factors, Intensive Care Utilization and Outcomes Following Pediatric Hematopoietic Stem Cell Transplants: A Single Center Retrospective Analysis

193 - Transplant Associated Risk Factors, Intensive Care Utilization and Outcomes Following Pediatric Hematopoietic Stem Cell Transplants: A Single Center Retrospective Analysis

172 - Incidence and Outcomes from Transplant-Associated Thrombotic Microangiopathy in Allogeneic Pediatric Hematopoietic Stem Cell Transplant Recipients before and after the Introduction of Eculizumab: A Single Institution Experience from Oregon Health & Science University

172 - Incidence and Outcomes from Transplant-Associated Thrombotic Microangiopathy in Allogeneic Pediatric Hematopoietic Stem Cell Transplant Recipients before and after the Introduction of Eculizumab: A Single Institution Experience from Oregon Health & Science University

192 - Xylitol in the Pediatric Hematopoietic Stem Cell Transplant Population: Quality Initiative to Decrease Bloodstream Infections

192 - Xylitol in the Pediatric Hematopoietic Stem Cell Transplant Population: Quality Initiative to Decrease Bloodstream Infections

132 - Implementation of Preemptive Pharmacogenomics Testing in Pediatric Hematopoietic Stem Cell Transplant and Cellular Therapy Patients

132 - Implementation of Preemptive Pharmacogenomics Testing in Pediatric Hematopoietic Stem Cell Transplant and Cellular Therapy Patients