Pediatric Allogeneic Hematopoietic Stem Cell Research Articles

Antithymocyte globulin in pediatric allogeneic hematopoietic stem cell transplantation: Infusion time and tolerability.

Antithymocyte globulin is a major drug in transplantation. rATG has been successfully used to prevent graft-versus-host disease in allogeneic HSCT. However, its first infusion is associated with reactions ranging from simple fevers to distributive shocks and may interfere with the transplant conditioning. To evaluate the impact of rATG infusion rate on clinical tolerability, we conducted a retrospective study of all pediatric allogeneic HSCT patients who received rATG (Thymoglobulin®) as part of their conditioning at Lille University Hospital from 2003 to 2018. Until 2012, patients received rATG with a theoretical infusion time of 12hours (12H group, n=33). From 2012, they had a theoretical infusion time of 4hours (4H group, n=43). Patients from the 12H arm presented more≥grade 3 infusion-related reactions at first dose (70% versus 44%, P=.027), had significantly higher fever (median of 39.6°C versus 39.2°C, P=.002), and needed a greater use of symptomatic treatments. However, they received a slightly higher first dose of rATG (median of 2.7 versus 2.3mg/kg, P=.042). In view of these results, a rATG infusion time of 4hours can be a relevant option for pediatric transplant centers to avoid interference with the conditioning regimen and facilitate medical surveillance.

Acute toxicity and outcome among pediatric allogeneic hematopoietic transplant patients conditioned with treosulfan-based regimens

Treosulfan-based regimens constitute a feasible and increasingly used, but still myeloablative, conditioning in pediatric allogeneic hematopoietic stem cell transplantation (HSCT). We retrospectively analyzed the acute toxicity and outcome of all consecutive (2004–2015) pediatric HSCT patients prepared for HSCT with treosulfan in a single-center setting. We included HSCTs performed for both nonmalignant (n = 23) and malignant diseases (n = 11). The controls were patients with nonmalignant diseases or hematological malignancies conditioned with cyclophosphamide (Cy)-total body irradiation (TBI)-based (39 patients) or busulfan-based regimens (11 patients). The major toxicities of the treosulfan-based regimens were limited to oral mucosa and skin. 50% of the patients needed IV morphine for severe mucositis compared to 31% in patients conditioned with Cy-TBI (P = 0.02). Other toxicities were rare. The disease-free survival (DFS) of patients transplanted for nonmalignant disorders was 88.9 ± 7.5% at 2 years. The event-free survival (EFS) at 2 years in this small cohort for those with a malignant disease and a treosulfan-based conditioning was 54.5 ± 1.5%. We conclude that a treosulfan-based conditioning regimen gives excellent DFS in pediatric HSCT performed for a nonmalignant disorder but with substantial mucosal toxicity. In a malignant disorder a treosulfan-based regimen looks promising but larger, preferably randomized, studies are needed to prove efficacy.

Anxiety, depression, and mental health-related quality of life in survivors of pediatric allogeneic hematopoietic stem cell transplantation: a systematic review.

Allogeneic hematopoietic stem cell transplantation (allo-HSCT) has become increasingly used as a therapeutic treatment for several pediatric conditions, however the long-term mental health sequelae remain understudied among these survivors. Our objective was to conduct a systematic literature review to determine the association between allo-HSCT and anxiety, depression, and psychological health-related quality of life (HRQOL) in pediatric allo-HSCT recipients compared to survivors of pediatric cancer or healthy children. A literature search of peer-reviewed databases was conducted. Data extraction was conducted using a standardized form. Due to the heterogeneity in studies, populations, and measurement instruments, only a qualitative synthesis was performed. A total of 24 studies met eligibility criteria. Rates of anxiety and depression were higher among survivors of pediatric allo-HSCT compared to population normal values or children treated for health conditions without allo-HSCT. Most allo-HSCT survivors self-reported psychological HRQOL within normal levels, although some studies in leukemia patients identified poorer psychological HRQOL. The presence of multiple chronic health conditions, chronic graft-versus-host-disease, and patient sex were important risk factors for worse mental health. Patients who receive allo-HSCT during childhood experience subsequent anxiety, depression, and poorer psychological HRQOL after transplant and several clinical characteristics contribute to these mental health sequelae.

Targeted Sequence Capture Metagenomics (ViroCap) to Detect Viruses in Stool Samples of Hematopoietic Stem Cell Transplantation Patients

Introduction Gastro-intestinal (GI) symptoms in pediatric allogeneic hematopoietic stem cell transplantation (HSCT) patients are common and may be caused by viruses, Graft-Versus-Host-Disease (GVHD) or both. Currently, little is known about the GI viriome in SCT patients, hindering the study of the pathogenicity and role in GVHD. We used ViroCap, a viral target enrichment method, in combination with Next Generation Sequencing (NGS) to detect viruses in stool samples of HSCT patients and compared to PCR results. Methods Using ViroCap, nucleic acid of a broad range of RNA and DNA viruses infecting vertebrate hosts was enriched in banked stool samples of HSCT patients. Upon enrichment, samples were sequenced by NGS on an Illumina MiSeq system and detected viral sequences were analyzed using the automated Genome Detective pipeline (GD) and/or directly aligned (DA) to a reference sequence of a specific virus, using Genious software. Where possible, presence of newly detected viral pathogens was confirmed by virus-specific qPCR. Results Stool samples of 11 patients, age range 1-17, that had undergone HSCT for a variety of indications were selected for ViroCap analysis. All selected patients suffered from GI-symptoms. Ten were diagnosed with grade I-IV GI-GVHD according to consensus guidelines. In 6 samples adenovirus (ADV), norovirus or both had been previously detected by clinical diagnostic qPCRs (Diagnosis D), while in 5 samples no viral GI pathogens were found (No diagnosis ND). In all D samples the presence of the initially found virus could be confirmed upon ViroCap analysis. ADV was most commonly found and Ct values grossly correlated with the number of sequence specific reads upon ViroCap GD and DA analysis. In addition, ViroCap led to the detection of multiple, possibly clinically relevant viral pathogens in D samples, including human herpesvirus-6B (HHV6B) (n=1), BK polyomavirus (BKV) (n=2), ADV (n=1) and human rhinovirus (HRV) (n=1). Presence of BKV and HRV was confirmed by qPCR. Furthermore, in 4/5 ND samples viral pathogens were detected. These included human herpes Virus 7 (HHV7) (n=1), BKV (n=1), HRV (n=2) and Astrovirus (AV) (n=1). HRV presence was confirmed by qPCR, HHV7 was not tested. BKV could not be confirmed, but other clinical samples from the same patient taken closely before/after the specific stool sample were BKV positive. Further analysis of the AV sequences revealed that the routine PCR failed to detect this virus due to extensive sequence mismatches in the primer/probe binding regions. This AV clade was classified as an AV VA3 (JX857868.1). Conclusion In summary, application of viral target enrichment strategies with limited pathogen detection bias, such as ViroCap, increase the sensitivity of NGS for virus detection and can lead to discovery of novel variants. As such, it might be a useful screening tool to study associations of viral pathogens with GI-symptoms and GVHD.

Epidemiology, utilisation of healthcare resources and outcome of invasive fungal diseases following paediatric allogeneic haematopoietic stem cell transplantation.

Epidemiology and management practices of invasive fungal diseases (IFD) after allogeneic haematopoietic stem cell transplantation (HSCT) are a subject of constant change. We investigated the contemporary incidence, diagnostics, antifungal management and outcome at a major paediatric transplant centre in Germany. The single-centre retrospective observational study included all paediatric allogeneic HSCT patients (pts) transplanted between 2005 and 2015. Patient-related data were assessed up to 365days post-transplant. The primary endpoint was the incidence of possible, probable and proven IFDs. Secondary endpoints included diagnostics and antifungal treatment; analysis of risk factors; and overall survival with the last follow-up in January 2017. A total of 221 first (196), second (21) or third (4) procedures were performed in 200 pts (median age: 9years, range, 0.5-22) for leukaemia/lymphoma (149) and non-malignant disorders (72). Prophylaxis was administered in 208 HSCT procedures (94%; fluconazole, 116, mould-active agents, 92). At least one computed tomography scan of the chest was performed in 146, and at least one galactomannan antigen assay in 60 procedures. There were 15 cases of proven (candidemia, 4; aspergillosis, 4) or probable (aspergillosis, 7) IFDs, accounting for an incidence rate of 6.8%. Overall mortality at last follow-up was 30%; the occurrence of proven/probable IFDs was associated with a reduced survival probability (P<.001). Morbidity and mortality from IFDs at our institution were consistent with data reported from other centres. Utilisation of healthcare resources for prevention, diagnosis and management of IFDs was considerable.

Management of growth failure and growth hormone deficiency after pediatric allogeneic HSCT: Endocrinologists are of importance for further guidelines and studies

Growth failure (GF) is a frequent problem after pediatric allogeneic hematopoietic stem cell transplantation (HSCT). Growth hormone deficiency (GHD) occurs in 20 to 85%, but published data on the efficacy of growth hormone treatment (GHT) are conflicting. Currently, there are no recommendations on screening for and treatment of GHD after HSCT. We aimed to describe the management of endocrine follow-up (FU)and details of GHT within European Society for Blood and Marrow Transplantation (EBMT) centers.In a retrospective questionnaire study, all EBMT centers performing pediatric HSCT were invited. Results were evaluated in correlation with the structure of endocrine aftercare (HSCT-clinicians and endocrinologists).The majority of centers (80%) reported endocrine FU by an endocrinologist – either within the HSCT-center or in a separate endocrine clinic. Fifty-four percent reported FU outside of the HSCT-center. As diagnostic tests the insulin-like growth factor IGF-I and insulin-like growth factor binding protein IGFBP3, insulin tolerance test and arginine stimulation test were most frequently used. Sixty-four percent of centers performed GHT and endocrinologists were more likely to prescribe GH (74%) compared to HSCT-clinicians (33%). The most frequent indication for GHT was GHD in 60%, with a distinct different approach of endocrinologists in comparison with HSCT-clinicians.Our study reveals substantial variation in practice and emphasizes the need for endocrine aftercare performed by dedicated endocrinologists in close collaboration with the HSCT-center. Our results indicate that the management of GHT depends on the structure of endocrine aftercare, which is important for the future development and distribution of studies and guidelines.

Specific gut microbiome members are associated with distinct immune markers in pediatric allogeneic hematopoietic stem cell transplantation

BackgroundIncreasing evidence reveals the importance of the microbiome in health and disease and inseparable host-microbial dependencies. Host-microbe interactions are highly relevant in patients receiving allogeneic hematopoietic stem cell transplantation (HSCT), i.e., a replacement of the cellular components of the patients’ immune system with that of a foreign donor. HSCT is employed as curative immunotherapy for a number of non-malignant and malignant hematologic conditions, including cancers such as acute lymphoblastic leukemia. The procedure can be accompanied by severe side effects such as infections, acute graft-versus-host disease (aGvHD), and death. Here, we performed a longitudinal analysis of immunological markers, immune reconstitution and gut microbiota composition in relation to clinical outcomes in children undergoing HSCT. Such an analysis could reveal biomarkers, e.g., at the time point prior to HSCT, that in the future could be used to predict which patients are of high risk in relation to side effects and clinical outcomes and guide treatment strategies accordingly.ResultsIn two multivariate analyses (sparse partial least squares regression and canonical correspondence analysis), we identified three consistent clusters: (1) high concentrations of the antimicrobial peptide human beta-defensin 2 (hBD2) prior to the transplantation in patients with high abundances of Lactobacillaceae, who later developed moderate or severe aGvHD and exhibited high mortality. (2) Rapid reconstitution of NK and B cells in patients with high abundances of obligate anaerobes such as Ruminococcaceae, who developed no or mild aGvHD and exhibited low mortality. (3) High inflammation, indicated by high levels of C-reactive protein, in patients with high abundances of facultative anaerobic bacteria such as Enterobacteriaceae. Furthermore, we observed that antibiotic treatment influenced the bacterial community state.ConclusionsWe identify multivariate associations between specific microbial taxa, host immune markers, immune cell reconstitution, and clinical outcomes in relation to HSCT. Our findings encourage further investigations into establishing longitudinal surveillance of the intestinal microbiome and relevant immune markers, such as hBD2, in HSCT patients. Profiling of the microbiome may prove useful as a prognostic tool that could help identify patients at risk of poor immune reconstitution and adverse outcomes, such as aGvHD and death, upon HSCT, providing actionable information in guiding precision medicine.

Lung evaluation in 10year survivors of pediatric allogeneic hematopoietic stem cell transplantation.

There is little data on the long-term respiratory development of children after allogeneic hematopoietic stem cell transplantation (allo-HSCT). We describe the respiratory assessment 10years after allo-HSCT of 35 children transplanted between 2000 and 2004. During this period, 90 children were transplanted at our center. Twenty-five children died, thirty were lost to follow-up, and thirty-five came to have a pulmonary investigation. The thirty-five participants answered a questionnaire asking if they had pulmonary symptoms, and pulmonary function tests (PFTs) were performed. The median age of these children 10years after the transplant was 16years old. Just over a third of them had pulmonary symptoms. Among them, 5/13 (38%) had bronchiolitis obliterans syndrome (BOS). The majority of children (62.8%) did not have respiratory symptoms. PFTs were abnormal in one-third of asymptomatic children, revealing restrictive lung disease that was always mild to moderate (p = 0.02).Conclusion: In the long term, research at the time of the medical examination for the presence of chronic cough, shortness of breath on exertion, or wheezing helps to guide the clinician as to the need for further lung exploration. Similarly, informing patients and their families about these symptoms, which can be underestimated, should allow for more specific management.What is Known:• Pulmonary complications are a major cause of hematopoietic stem cell transplantation (HSCT) morbidity and mortality.• A long time after allogeneic HSCT, pulmonary function tests abnormalities may occur in children, but it is not always related to symptoms.What is New:• The occurrence of respiratory symptoms: cough, dyspnea on exertion, chronic bronchitis, and wheezing should be systematically investigated in the follow-up of allografted patients, even at a distance.• The presence of respiratory symptoms should lead to a respiratory functional investigation to detect the presence of an obstructive syndrome.

Cognitive and psychological outcomes of pediatric allogeneic hematopoietic stem cell transplantation survivors in a single center in China.

To investigate the cognitive and psychological outcomes of pediatric allogeneic HSCT survivors in China.A total of 135 3 to 18 years old children and adolescents who underwent allo-HSCT and survived at least 3 months post-HSCT were recruited and completed the assessments. Cognitive and psychological functions were assessed via age-appropriate standardized measures. Clinical information was extracted from the medical records.Forty one 3 to 6 years old children completed Psychological Questionnaires for 3 to 6 years Children. The scores of 21(51.2%) children in cognitive development dimension, 18(43.9%) in motor development dimension, 16(39.0%) in language development and social development dimension, 15(36.6%) in emotion and will dimension and 14(34.1%) in living habits dimension were less than the standard. Fifty six 8 to 16 years old children and adolescents completed the Depression Self-rating Scale for Children and 9 (16.1%) of these met the criteria of depression. Sixty nine 7 to 16 years old children and adolescents completed the screening for Child Anxiety Related Disorders and 7 (10.1%) of these met the criteria of anxiety, especially social phobia and school phobia. Eighty nine 6 to 18 years old children and adolescents completed the Symptom Checklist-90 and 43.8% to 77.5% of these experienced mild symptoms like obsession-compulsion (77.5%), hostility (64%), and interpersonal sensitivity (60.7%). Children treated with total body irradiation (TBI) showed more cognitive impairments like motor deficits than those without TBI. Also older children and adolescents had more symptoms like psychoticism.These findings demonstrated cognitive and psychological late effects of pediatric allo-HSCT survivors in a single center in China and highlighted that the survivors conditioned with TBI had more cognitive impairments and older children and adolescents had more symptoms. Early intervention in these children and adolescents might minimize the cognitive losses and psychological effects.

PB2349 EXTRACORPOREAL PHOTOPHERESIS FOR PEDIATRIC PATIENTS WITH GRAFT‐VS‐HOST DISEASE AFTER HAEMATOPOIETIC STEM CELL TRANSPLANTATION: AN AUSTRALIAN EXPERIENCE

Background:Graft‐versus‐host disease (GVHD) remains a major cause of morbidity and mortality following pediatric allogeneic hematopoietic stem cell transplant (HSCT). Extracorporeal photopheresis (ECP) is a cellular immuno‐modulatory therapy licensed for the treatment of steroid‐dependent or refractory GVHD. ECP has been shown to be effective in the treatment of GVHD in the adult population, however there is little data in the pediatric setting. Here we present our Australian experience in paediatric patients with GVHD.Aims:To assess the outcome and feasibility of ECP as a treatment modality for GVHD in the pediatric allograft patients in Australia.Methods:A retrospective case note analysis of all patients receiving ECP for the treatment of GVHD between August 2010 and December 2018 at the Royal Children's Hospital and Peter MacCallum Cancer Centre, Victoria.Results:14 patients were identified, with a median age of 4.4 years (range 0.5‐14.8). Demographic and transplant characteristics are summarised in Table 1. ECP was used to treat both acute (aGVHD, n = 7) and chronic (cGVHD, n = 8) GVHD. One patient required two treatment episodes for acute and subsequently chronic GVHD. All patients were refractory to prior immunosuppressive therapy, with a median of 3 agents used (range 2‐5). Median steroid dose was 0.8 mg/kg/day methylprednisolone equivalent (range 0‐2). An overall response was obtained in 6 of 7 (86%) acute and 6 of 8 (75%) chronic GVHD patients. Overall survival was 79% (11 of 14 patients).Of those treated for aGVHD varying from grade II – IV, 86% (n = 6) showed a partial response or better, with 43% (n = 3) achieving a complete response. Median steroid dose was reduced by 94% from 1.8 mg/kg/day methylprednisolone equivalent to 0.1 mg/kg/day from beginning to end of ECP. ECP duration was a median of 1.9 months (range 1.4‐5.7), with a median of 16 treatments (range 12‐25).The majority of cGVHD patients had extensive disease (n = 7, 88%), with 75% (n = 6) achieving at least a partial response, with a complete response in 37.5% (n = 3). Median steroid dose was reduced by 88% from 0.18 mg/kg/day methylprednisolone equivalent to 0.02 mg/kg/day from beginning to end of ECP. ECP was used for a median period of 7.1 months (range 1.9‐39.1) with a median of 25 treatments (range 7‐61).Catheter‐related sepsis was the most common reason for premature discontinuation of ECP in our cohort, occurring in 6 patients (43%). Other noted complications included haemodynamic instability requiring admission, occurring in 3 patients (21%). This caused discontinuation of ECP in one patient weighing 7.5 kg. Of the 3 patients who died, two had grade IV aGVHD with progressive disease post‐ECP, and one with refractory extensive cGVHD. The causes of death were sepsis (n = 2) and relapsed primary malignancy (n = 1).Summary/Conclusion:This is the first report of ECP therapy in Australia for pediatric patients with GVHD. Our results demonstrate that ECP is an effective and feasible treatment modality for both acute and chronic GVHD post‐HSCT. In our cohort, ECP allowed for tapering of corticosteroids, which has been shown to be associated with improved survival. Although ECP was well tolerated overall, specific consideration should be given when used in the pediatric population, especially with regard to the risk of haemodynamic instability, the use of blood prime of the circuit and catheter‐related sepsis.image

Outcomes Using Narrow Band UVB Phototherapy for Acute Skin Graft Versus Host Disease (GVHD) in Pediatric Allogeneic Hematopoietic Stem Cell Transplant Recipients

Acute graft-versus-host-disease (aGVHD) is a significant complication of pediatric allo- BMT. Narrow band UVB (nbUVB) therapy allows targeted treatment without systemic immunosuppression, but data is limited for pediatric patients. We retrospectively reviewed the charts of all pediatric allo-BMT patients from July 1, 2007- July 1, 2018. Seven patients (1 female, 6 male) with a median age of 12.9 years (range 3-20) received nbUVB therapy. Diagnoses included ALL (4), MDS (2), and NHL (1). Preparative regimens were TBI-based (5) or Bu/Cy (2). Donor sources included MSD (1), MUD (1), MMUD (4), and haplo (1). Three of the patients had unrelated female donors. All patients failed topical steroids prior to nbUVB. Treatment with nbUVB was initiated at a median of 48 days (range 44-77) post-BMT, requiring a median of 26 treatments (range 4-36) over a median of 11.5 weeks (range 3 – 17). One patient underwent a second trial of nbUVB due to recurrence. Complete response was noted in 75% of the 8 total nbUVB treatment courses with a mean cumulative dose of 364.5 J•cm−2 (range 234 – 1557). Partial response and no response each occurred in one treatment course (12.5%). Only two patients had aGVHD of other organs prior to nbUVB; however, all seven received IV/PO steroids during a portion of nbUVB treatment. Five patients remain alive without cGVHD at a median of 7 years (range 0.8-10) post-BMT. One patient with a TBI-based preparative regimen developed poikilodermatous radiation dermatitis 4 years post-BMT. No other additional treatment-related skin complications to date. Two patients developed overlap syndrome and cGVHD and died. There is scant published data regarding nbUVB use in pediatric aGVHD treatment. These results suggest that nbUVB is a highly effective second-line therapy for treatment of pediatric cutaneous aGVHD, and further research should be completed to elucidate its efficacy.

Improving Microbiological Diagnostic Yield of Bronchoalveolar Lavage (BAL) Specimens in Pediatric Allogeneic Hematopoietic Stem Cell Transplant (AlloHSCT) Recipients

Background Pulmonary complications, including both infectious and noninfectious etiologies, are a frequent cause of morbidity and mortality in pediatric alloHSCT patients from the immediate post-transplant period to 5 years post-transplant. Early detection and initiation of appropriate antimicrobial therapy improve survival. However, present techniques for identifying infectious organisms are limited by pretreatment with antimicrobial therapies and the need for a priori knowledge of likely viral pathogens, greatly decreasing the yield of BAL. Our group has published the results of 193 pediatric HSCT patients and found a 43% probability of need for BAL in the year following stem cell transplant with only a 40% yield of identifying an infectious organism. Massively parallel sequencing (MPS) has the potential to mitigate these limitations, by identifying the genetic sequence of all DNA or RNA in a sample without the need for viable organisms or microbe specificity. Methods Pediatric alloHSCT patients with new pulmonary findings on imaging underwent BAL by the pediatric pulmonary service at MFCH as a pilot study (NYMC-181). BAL was performed per standard WMC clinical practice methods and lavage fluid sent for bacterial, fungal, and viral cultures, aspergillus galactomannan, βD-glucan, and PCRs for CMV, EBV, and adenovirus, and other tests as indicated. Excess BAL fluid was preserved in Trizol prior to RNA isolation. cDNA libraries were generated from each sample and sequenced on the Illumina NextSeq platform. Sequence reads were de novo assembled using the Trinity assembler and classified using Kraken and a custom-built database. Results from MPS and clinical testing were compared. Results 9 patients underwent 10 BALs (1 patient underwent 2 BALs) from July 2016 through December 2017 and had sufficient BAL fluid for inclusion in this study (Figure 1). Clinical microbiological testing identified infections in 6 patients (60%), 3 with bacterial infections (2 Staphylococcus haemolyticus & 1 Streptococcus viridans), 3 with viral pathogens (1 CMV, 1 EBV, and 1 RSV), and 1 fungal infection (Candida). MPS identified infections in 5 patients, one fewer than the clinical testing. Results were wholly concordant in 2 patients (Staph haemolyticus and RSV) and partly concordant in 1 patient (Candida detected, but different viruses found on clinical and sequencing testing). CMV, EBV, S. haemolyticus, and S. viridans (1 patient each) were detected on clinical testing, but not using sequencing. Haemophilus influenza, rhinovirus, and enterovirus (1 patient each) were detected using sequencing, but not clinical testing. Conclusions RNA based massively parallel sequencing techniques can serve as an adjunct to standard clinical testing of BAL fluid for improved detection of infections (especially polymicrobial) in pediatric recipients of alloHSCT.

Pediatric Outcomes in Transplant: PersOnaliSing Immunosuppression To ImproVe Efficacy (POSITIVE Study): The Collaboration and Design of a National Transplant Precision Medicine Program.

BackgroundDespite age-related differences in biology, physiology, and behavior, transplant immunosuppression is not tailored by age. This likely contributes to high graft failure and posttransplant complications. We present the aims, design, and methods of the Pediatric Outcomes in Transplant: PersOnaliSing Immunosuppression To ImproVe Efficacy Study aimed at personalizing posttransplant immunosuppression in children and young adults.MethodsIn this prospective observational cohort study, we recruited pediatric and young adult solid organ transplant, pediatric allogeneic hematopoietic stem cell transplant recipients, and matched living and deceased organ donors from 14 transplant centers across Canada. Clinical data, questionnaires, biospecimens, and pharmacy records were collected at serial time points: (1) to identify genetic and host immune factors that influence immunosuppression dose requirements across different ages and transplant types, (2) to identify viral-host interactions that increase susceptibility to Epstein-Barr virus infection, and (3) to define care processes and structures associated with medication adherence in adolescents and young adults.ResultsFrom 2015 to 2018, 1662 new and prevalent transplant recipients were screened, 1166 were recruited for the various aims, including 370 liver, 445 kidney, 277 heart, 19 lung, 19 multiple, and 36 hematopoietic stem cell transplant transplants. Twelve percent were younger than 2 years, 30% were 2 to 10 years, 42% were 10 to 18 years, and 16% were 18 to 24 years at enrollment. Nine hundred thirty-one consented to participation in aims 1 and 2 (90% consent rate), 287 to aim 3 (82% consent rate). Biospecimens collected included 898 for DNA, 276 for immunoassays, and 717 for biomarker studies. Seventy percent participants have completed follow-up; 30% are pending study completion.ConclusionsThe design of this national multicenter cross-organ network helped maximize recruitment of a large patient cohort for studying age and organ-related differences in immunosuppression needs that would not otherwise be feasible. Leveraging the unique clinical, biological, environmental, and behavioral characteristics of this cohort will help develop precision medicine strategies for individualizing posttransplant immunosuppression.

Area-Based Socioeconomic Status and Pediatric Allogeneic Hematopoietic Stem Cell Transplantation Outcomes: A CIBMTR Analysis

▪Introduction: Outcome disparities related to race and area-based socioeconomic status (SES) following allogeneic hematopoietic stem cell transplantation (allo-HCT) have been identified in adult patients [Baker et al. 2009]. The relationship between SES and outcomes in pediatric allo-HCT has not been previously described. Among a large cohort of pediatric allo-HCT recipients we sought to determine the impact of area-based poverty on 5-year outcomes of overall survival (OS), acute and chronic graft-versus-host-disease (aGVHD, cGVHD); as well as the short-term outcome of infection through day 100 .Methods: We utilized the Center for International Blood and Marrow Transplant Research (CIBMTR) database to examine the association of sociodemographic variables with outcomes in two cohorts of pediatric transplant recipients aged <=18 years who received allo-HCT at U.S. centers between 2006-2015. Cohort 1 (malignant) included 2053 children who received myeloablative conditioning for any malignancy. Cohort 2 (non-malignant) included 1696 children who received myeloablative or reduced-intensity conditioning for any non-malignant disease. Zip codes of child's residence were categorized as high-poverty area (>=20% households living below 100% federal poverty level (FPL)) versus low-poverty area (<20% households below 100% FPL) by linkage to U.S. Census data [Krieger et al. 2002]. Individual-level sociodemographic variables including insurance (Medicaid-only vs Other), race (Caucasian vs Black vs Other) and ethnicity (non-Hispanic vs Hispanic) were included as covariates. Cox regression was used to examine the effect of patient-related (age, performance status, insurance, race, and ethnicity), disease-related (disease type and status), and HCT-related (donor/graft type, CMV status, stem cell source, HLA match, donor age and gender, conditioning regimen and intensity, GVHD prophylaxis, year of HCT) variables on the outcomes of interest between the two area-based poverty groups.Results: Fifteen percent (N=299) of children in Cohort 1 lived in a high-poverty area; 35% (N=711) were insured by Medicaid-only; 11% (N=227) were African-American and 20% (N=417) Hispanic. Median follow-up of survivors was 74 months. In multivariable analysis, there was no association between area-based poverty and OS; however, OS was inferior in children with Medicaid-only insurance compared to those with private insurance (HR 1.22 (95% CI 1.06-1.40), p=0.0037) and in Black children compared to Caucasian (HR 2.02 (95% CI 1.10-3.73), p=0.0234). For the secondary outcomes of aGVHD, cGVHD or infection through day 100, there were no associations between area-based poverty, insurance, race, or ethnicity in multivariable analysis. To further explore the independent association of insurance with OS, we performed an ad hoc univariate analysis that demonstrated that insurance-related differences in OS for malignant disease appear to be driven by differences in treatment-related mortality (TRM) (5-year TRM: Medicaid-only 25% (95% CI 22-28) versus 18% (95% CI 16-21) other).Thirteen percent (N=228) of children in Cohort 2 lived in a high-poverty zip code; 35% were insured by Medicaid-only (N=597); 20% (N=332) were African-American and 20% (N=344) Hispanic. Median follow-up of survivors was 74 months. In multivariable analyses, there was no association between area-based poverty, insurance, race or ethnicity and any outcome.Conclusion: Area-based poverty is not associated with disparate outcomes in pediatric allo-HCT for malignant or non-malignant disease. In the setting of malignant disease, insurance-a household-level measure of socioeconomic status-and Black race are independently associated with inferior OS. These results suggest that future prospective investigation of more refined measures of household-level socioeconomic status may identify risk-factors for treatment-related mortality in this population. DisclosuresNo relevant conflicts of interest to declare.

Post-transplant Replication of Torque Teno Virus in Granulocytes.

Torque Teno virus (TTV) in humans is characterized by ubiquitous occurrence in peripheral blood (PB), without any related disease described to date. Several studies reported a significant increase of TTV plasma DNA levels in allogeneic transplant recipients, and suggested a correlation of elevated virus titers with immunosuppression and transplant-related complications. However, the site of viral replication in this setting has remained unclear. We have studied TTV in serial plasma specimens derived from 43 pediatric allogeneic hematopoietic stem cell transplantation (HSCT) recipients by RQ-PCR, and found increasing TTV-DNA levels in all patients post-transplant, with a peak around day +100 and maximum virus copy numbers reaching 4 × 10E9/ml. To assess whether the virus replicates in PB-cells, leukocyte subsets including granulocytes, monocytes, NK-cells, T- and B-lymphocytes were serially isolated by flow-sorting for TTV analysis in 19 patients. The virus was undetectable in most cell types, but was identified in granulocytes in all instances, revealing a median DNA copy number increase of 1.8 logs between days +30–100 post-transplant. Our data therefore provide evidence for TTV replication in granulocytes in this setting. In a control cohort of immunocompetent children and in HSCT recipients before day +30, TTV positivity in granulocytes was less common (33%), and the copy numbers were considerably lower. However, rising TTV replication about 2 weeks after granulocyte engraftment (>500 cells/μl) was observed suggesting that granulocyte recovery might be required for TTV expansion in severely immunosuppressed transplant recipients.

Utility of Autopsy among Pediatric Allogeneic Hematopoietic Stem Cell Transplant Recipients: One Last Chance to Learn?

Autopsy may confirm clinical diagnoses or identify conditions that were not suspected prior to a patient's death. Previous studies evaluating the utility of autopsy in hematopoietic stem cell transplant (HSCT) recipients yielded conflicting results.We conducted a retrospective cohort study of children (<18 years of age) undergoing allogeneic HSCT at Duke University who died of any cause between January 1, 1995, and December 31, 2016. We evaluated associations between patient characteristics and autopsy performance using chi-square or Fisher exact tests. We reviewed autopsy reports to determine the concordance between preautopsy causes of death and pathological diagnoses identified on autopsy. We classified unexpected diagnoses on autopsy using criteria developed by Goldman et al. We evaluated for temporal changes in the autopsy consent rate and the frequency of unexpected diagnoses on autopsy using Cochran-Armitage tests.During the 22-year study period, 475 patients died and had data available on autopsy performance, and 130 (27%) of these patients underwent autopsy. The autopsy consent rate declined over time (P < .0001), with autopsies being performed for 40% of deaths in 1995 to 1999 and 17% of deaths in 2009 to 2016. White patients were more likely to undergo autopsy than nonwhite patients (P = .03). There were no associations between autopsy performance and patient age, sex, HSCT indication, or HSCT donor. Unexpected diagnoses were identified in 31 (24%) autopsies. The proportion of autopsies with an unexpected diagnosis did not change during the study period (P = .45). However, infectious diagnoses that would have led to a change in management were more frequently identified on autopsies in 1995 to 2003 than in 2004 to 2016 (20% versus 0%; P = .001).The autopsy consent rate for pediatric HSCT recipients at our institution has declined substantially over the past several decades. The utility of autopsy in this patient population remains high despite a reduction in the identification of unexpected infections.

Donor cell chimerism evaluation in cerebrospinal fluid by short tandem repeat analysis following allogeneic hematopoietic stem cell transplantation

Cerebrospinal fluid (CSF) cell count, morphology and flow cytometric evaluations are used to investigate central nervous system (CNS) involvement in leukemia/lymphoma. We performed CSF short tandem repeat (STR) analysis to monitor CSF chimerism status and evaluate for disease involvement in 11 asymptomatic pediatric allogeneic hematopoietic stem cell transplantation (HSCT) recipients with hemato-lymphoid neoplasms and high risk for or history of CNS involvement. Eighteen (64%) of the samples with median CSF cell count of 1/mm3 with 90% lymphocytes gave conclusive STR results, suggesting that this DNA-based method can be used in monitoring CSF chimerism status after HSCT with an acceptable yield.

Impaired Bone Mineral Density in Pediatric Patients with Chronic Graft-versus-Host Disease

Pediatric allogeneic hematopoietic stem cell transplantation (AHSCT) recipients with chronic graft-versus-host disease (cGVHD) are at high risk for endocrinopathies, particularly impaired bone mineral density (BMD). However, rates of BMD impairment in pediatric AHSCT recipients with cGVHD have not been well documented. We report 33 patients with cGVHD who were referred to the National Institutes of Health (NIH) for the Natural History of Clinical and Biological Factors Determining Outcomes in Chronic Graft-versus-Host Disease Study (NCT 0092235) and underwent formal BMD assessment via dual-energy X-ray absorptiometry (DEXA). Not surprisingly, we found much higher rates of BMD impairment than previously reported for pediatric AHSCT recipients who were not stratified by the presence or absence of cGVHD. Most of these patients (73%) had a z-score ≤−2 in at least 1 anatomic site. Although we expected the rate to be higher than that observed for pediatric AHSCT recipients in studies that did not analyze patients with cGVHD separately, this rate is nonetheless extremely high. Furthermore, the overall rate of occult vertebral compression fractures (VCFs) in our cohort was 17%, and the rate was 23% in patients with at least 1 z-score of ≤−2. The rates of BMD impairment and VCF in our pediatric cohort were significantly higher than those seen in the adult AHSCT recipients who were concurrently enrolled on the same study at the NIH and had similar cGVHD severity. We found that older age at cGVHD diagnosis and a greater number of systemic therapies were associated with occult VCF. Moreover, the intensity of current immunosuppression negatively impacted lumbar spine and total hip BMD in this cohort. Our study, although limited by small patient numbers and lack of a control AHSCT recipient group without cGVHD, indicates that children with cGVHD are at a greater risk for BMD impairment than previously appreciated. Given the rising incidence of cGVHD in AHSCT recipients and our findings, we recommend that pre-AHSCT DEXA be incorporated into routine pediatric pretransplantation screening studies. A baseline DEXA study could facilitate longitudinal monitoring of BMD in children, who may be more susceptible than adults to the negative effects of AHSCT on BMD. In addition, given the high risk of BMD impairment in pediatric AHSCT recipients with cGVHD, such patients should undergo BMD evaluation upon developing cGVHD, with continued monitoring thereafter to allow intervention before progression of the BMD impairment to its severe manifestation, VCF.

558 - Reactivation of Human Herpesvirus 6 (HHV6) in Pediatric Allogeneic Hematopoietic Stem Cell Transplant (HSCT) Recipients

558 - Reactivation of Human Herpesvirus 6 (HHV6) in Pediatric Allogeneic Hematopoietic Stem Cell Transplant (HSCT) Recipients

612 - Donor Lymphocyte Experience in Pediatric Allogeneic Hematopoietic Stem Cell Transplant Patients

612 - Donor Lymphocyte Experience in Pediatric Allogeneic Hematopoietic Stem Cell Transplant Patients