Pediatric Allogeneic Hematopoietic Cell Transplantation Research Articles

CD38brightCD8+ T Cells Associated with the Development of Acute GVHD Are Activated, Proliferating, and Cytotoxic Trafficking Cells.

We have previously reported that a peripheral blood absolute CD38brightCD8+ effector memory T cell (TEM) population expansion of >35 cells/µL predicts the development of acute graft-versus-host disease (GVHD). We hypothesized that these T cells are activated, proliferating, and cytotoxic trafficking cells that are not a response to viral reactivation and may be involved in acute GVHD. We characterized peripheral blood T cell populations at the time of maximum CD38brightCD8+ TEM expansion in patients from our originally reported pediatric allogeneic hematopoietic cell transplantation recipient cohort. Samples were incubated with fluorochrome-conjugated antibodies directed against CD3, CD8, CD38, HLA-DR (T cell activation), Ki-67 (T cell proliferation), granzyme B (marker of cytotoxic T cells), CLA (skin trafficking), CCR5 (visceral trafficking), and CXCR6 (liver trafficking). We also incubated samples with Epstein-Barr virus (EBV) and cytomegalovirus (CMV) peptide pools and measured IFN-γ production by flow cytometry and performed EBV and CMV tetramer staining. Higher median proportions of cell expression of HLA-DR, Ki-67, granzyme B, CLA, CCR5, and CXCR6 were observed for CD38brightCD8+ T cells compared with CD38nonbrightCD8+ T cells in patients with acute GVHD (P < .05) but not in patients without acute GVHD (P not significant). No IFN-γ production was observed after incubation with CMV and EBV peptide pools. EBV-specific tetramer populations of 6.85% and 3.17% were detected in 2 patients with acute GVHD, whereas a CMV-specific tetramer population of 3.77% was detected in 1 patient with acute GVHD. No EBV- or CMV-specific tetramer populations were detected in any patient without acute GVHD. We conclude that CD38brightCD8+ T cells associated with the development of acute GVHD are activated, proliferating, and cytotoxic trafficking cells that do not appear to respond to CMV or EBV reactivation. Further studies are needed to determine whether these cells are directly involved in acute GVHD pathogenesis.

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

Population Pharmacokinetics of Alemtuzumab (Campath) in Pediatric Hematopoietic Cell Transplantation: Towards Individualized Dosing to Improve Outcome.

Background and ObjectiveAlemtuzumab (Campath®) is used to prevent graft-versus-host disease and graft failure following pediatric allogeneic hematopoietic cell transplantation. The main toxicity includes delayed immune reconstitution, subsequent viral reactivations, and leukemia relapse. Exposure to alemtuzumab is highly variable upon empirical milligram/kilogram dosing.MethodsA population pharmacokinetic (PK) model for alemtuzumab was developed based on a total of 1146 concentration samples from 206 patients, aged 0.2–19 years, receiving a cumulative intravenous dose of 0.2–1.5 mg/kg, and treated between 2003 and 2015 in two centers.ResultsAlemtuzumab PK were best described using a two-compartment model with a parallel saturable and linear elimination pathway. The linear clearance pathway, central volume of distribution, and intercompartmental distribution increased with body weight. Blood lymphocyte counts, a potential substrate for alemtuzumab, did not impact clearance.ConclusionThe current practice with uniform milligram/kilogram doses leads to highly variable exposures in children due to the non-linear relationship between body weight and alemtuzumab PK. This model may be used for individualized dosing of alemtuzumab.Electronic supplementary materialThe online version of this article (10.1007/s40262-019-00782-0) contains supplementary material, which is available to authorized users.

Transplant Energize Me Patient Outcome (TEMPO): A Quality Improvement Project that Maintains Functional Mobility in Pediatric Patients Admitted for Allogeneic Hematopoietic Cell Transplantation.

Allogeneic hematopoietic cell transplantation (HCT) remains the definite cure for many pediatric hematologic diseases but causes profound deconditioning, which impairs daily physical functioning and may lead to further health complications. The Transplant Energize Me Patient Outcome (TEMPO) project is a standard-of-care, quality improvement (QI) project whose primary objective is to maintain physical functional mobility and strength throughout admission for pediatric allogeneic HCT patients. Specifically, TEMPO incorporates individualized and developmentally appropriate exercises and activities that are administered by a multidisciplinary team, who objectively measure and record a patient's physical stamina at predetermined frequencies. Discipline-specific metrics at admission, at weekly intervals, at discharge, and at 100 days after graft infusion (D100) are recorded in templated flowsheets in the electronic medical record. As a secondary objective, resource utilization as measured by length of stay, duration of parenteral feeds and narcotics, readmission by D100, and infections was compared between TEMPO and historical control (pre-TEMPO) allogeneic HCT patients. TEMPO participation maintained physical endurance and functional strength throughout hospitalization, an effect that was significantly sustained or improved at D100. Resource utilization did not significantly differ between patient cohorts. Taken together, the TEMPO QI Project maintains physical functional mobility, strength, and endurance, thereby decreasing physical deconditioning in pediatric allogeneic HCT patients, an effect that is objectively sustained at D100.

Prevalence of Secondary Adrenal Insufficiency in Recipients of Pediatric Hematopoietic Stem Cell Transplant: A Single Center Study

Background Data on adrenal function following pediatric allogeneic hematopoietic cell transplantation (HCT) is limited. Therefore, a single-institution retrospective study was performed to determine the prevalence of secondary adrenal insufficiency (AI) and identify associated risk factors in pediatric HCT recipients. Methods All allogeneic HCT patients from January 2007 through December 2014, with a minimum of two years of post-HCT follow up were included. AI was diagnosed when testing done at either clinical presentation of AI or routine yearly screening in the long term follow up clinic, revealed a morning cortisol level Results Eighty patients (48 male, 32 female) with malignant (n=38) and non-malignant diagnoses (n=42) were included. Median age at HCT and length of follow up were 7.6 years (range 0.1- 20.5 years) and 4.1 years (range 2-10 years), respectively. Twelve (12, 15%) patients developed secondary AI at a median of 16 months post-HCT (range 2-61 months), with an equal number presenting with clinical AI (n=6) and biochemical AI (n=6) respectively. In univariate analysis (Table 1), occurrence of graft-versus-host disease (GvHD), and post-HCT corticosteroid exposure were significant risk factors for development of secondary AI. Age, gender, type of diagnosis, total body irradiation (TBI)-containing and myeloablative conditioning were not. Conclusion: GvHD, and post-HCT steroid exposure were significant risk factors for AI, with one-third patients with post-HCT corticosteroid exposure diagnosed with AI. As half of patients with AI in this cohort were asymptomatic, routine screening for AI should be performed in pediatric allogeneic HCT recipients for timely diagnosis of AI to prevent morbidity associated with this complication.

Pre-Transplant Predictors of Cost of First Hospitalization for Pediatric Allogeneic Hematopoietic Cell Transplantation (alloHCT)

Background AlloHCT is associated with significant cost, owing to prolonged hospitalization and potential complications. With increasing concern about healthcare utilization in the US, having accurate information on treatment costs is crucial for making informed decisions in our healthcare system. There is little data on predictors of cost in pediatric alloHCT. Methods Primary endpoint was cost of first hospitalization for alloHCT. We analyzed pre-HCT variables for their effect on cost by simple linear regression – age, race, sex, donor, HLA match, graft source, disease, conditioning intensity, TBI use, performance status, Campath/ATG use, recipient CMV status, HCT-CI, and weight; those found to be significant were included in a final multivariable linear regression model. The same variables were analyzed for their association with higher transplant costs (>$150,000) by multivariable logistic regression. Significance was defined as p Results 240 children underwent alloHCT from 2005-16. Median age was 9.5y (0.2-21y). Patients were primarily male (61%), CMV risk (75%), malignancies (52%), and received myeloablative conditioning (78%). Donors were HLA-matched in 53% and were alternative donors in 60%. Bone marrow was the most common graft source (48%). Median cost of first hospitalization was $158,896 (range 13,126-1,471,698). Sex, donor, and graft source were linearly associated with cost (Table 1); an equation to predict cost of first hospitalization can be described as: $126,165 + $51,164(female) + $106,055(alternative donor) – $11,445(unmanipulated PBSC) + $117,238(cord) – $62,351(CD34 selected PBSC). Variables associated with higher cost (>$150,000) of initial hospitalization included alternative donors (OR 2.9, 95% CI 1.4-6.1, p=0.003), cord blood (OR 7.6, 95% CI 2.8-20.6, p Conclusion Cost of first hospitalization for pediatric alloHCT is primarily related to sex, donor and graft source and can be used to predict expected hospital costs. Although this estimation does not consider cost of complications, it can help define a cost index to predict baseline hospital costs. Validation of this model can help guide center with negotiation of contracts with insurance companies and ultimately lead to policy change.

Healthcare Utilization and Cost Associated with Cytomegalovirus Infection Among Pediatric Allogeneic Hematopoietic Cell Transplant Recipients.

Understanding the cost and healthcare utilization associated with cytomegalovirus (CMV) treatment is particularly important as new alternative agents for CMV prevention and treatment such as letermovir and anti-CMV cytotoxic T lymphocytes become available. Literature on the impact of CMV-related hospitalization in allogeneic hematopoietic cell transplant (alloHCT) pediatric patients is limited. We hypothesized that CMV infections post-alloHCT will result in increased length of stay (LOS) in hospital and higher healthcare costs. The aim of this study was to determine healthcare utilization and outcomes of CMV-related hospitalization in alloHCT patients using a single-center clinical database. This was a retrospective study of 240 children ages 3 months to 21 years old who were transplanted between 2005 and 2016. Impact of CMV-related length of stay and total healthcare costs were quantified. Factors associated with prolonged CMV viremia (>25 days) were also examined. The median age of patients was 9.5 years old. In at risk CMV patients, the incidence of CMV viremia was 38%, the median time to onset was 33 days (range 0-292 days), and the median time to resolution was 25 days (range 3-148 days). The median LOS in the first year post-alloHCT for patients with viremia was higher compared to those without viremia (101 days [range 25-319 days] vs 72 days [range 26-354 days], p In the regression analyses, the unadjusted association between CMV infection and LOS was 27.4 days (p=0.003). In multivariable analysis, patients with CMV infection had an average of 23.3 days (p=0.004) longer LOS compared to patients without infection [Table] and added hospital costs of US$45,443 (p=0.162) compared to patients without CMV infection. In multivariable analysis, alemtuzumab was associated with CMV viremia >25 days (p=0.027). In conclusion, CMV viremia is associated with prolonged LOS and higher healthcare costs and indicates a need for improved and cost-effective CMV prevention strategies. Further study into patient outcomes and costs in alloHCT pediatric populations is needed.

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.

Screening and Treatment of Adenovirus Infection in Pediatric and Adult Allogeneic Hematopoietic Cell Transplant Recipients: Multicenter Survey of Transplant Centers in the United States

Introduction Allogeneic hematopoietic cell transplant (allo-HCT) recipients are at risk of life-threatening viral infections. Objective The objective of the AdVance US practice patterns survey was to characterize current practices in screening and treatment of adenovirus (AdV) infection in the United States (US). Methods Physicians at participating centers were provided with a link to access an online survey. The survey questions addressed current practices around management of AdV infections in allo-HCT recipients at their center, and classified patients with regard to known risks for AdV infection (e.g., T-cell depletion, cord blood, haploidentical, mismatched, GVHD). When necessary, respondents consulted with other physicians in their center to ensure consensus before submitting responses. Results 62 centers were approached, of which 15 (24%) agreed to participate in this survey prior to the first deadline for response. 11 of the participating centers treat pediatric patients and 4 treat adult patients (Figure). According to CIBMTR data and physician interview responses, the pediatric and adult centers conduct an average of 36 and 142 allo HCTs per year, respectively. Almost all (91%) pediatric centers conduct weekly routine screening for AdV after allo-HCT among higher-risk patients, and around half (55%) conduct routine screening for AdV among lower-risk patients. Routine AdV screening is conducted by 25% of adult centers for higher-risk patients, and none routinely screen lower-risk patients. Among those screening higher-risk patients for AdV, all pediatric and adult centers screen blood samples at least once weekly and the majority (90%) of pediatric centers screen blood for at least 3 months post allo-HCT; the one adult center that screens blood does so weekly for up to 6 months post-HCT. Most pediatric centers have a pre-emptive AdV treatment approach for higher-risk patients (91%) and lower-risk patients (82%), using positive blood PCR as the treatment trigger. All adult centers that screen higher-risk patients use a pre-emptive approach. The pre-emptive AdV treatment most frequently reported by pediatric and adult centers is off-label IV cidofovir in spite of well-known toxicity concerns including renal injury. Conclusions The AdVance US practice patterns survey suggests that pediatric centers are more likely than adult centers to screen for AdV, and are also more likely to have a pre-emptive AdV treatment approach compared to adult centers. Perceived risk of AdV infection is a determining factor for whether routine screening and pre-emptive treatment are implemented. For both pediatric and adult centers, AdV viremia was the most common pre-emptive treatment trigger, with off-label IV cidofovir commonly utilized for treatment in spite of toxicity concerns. Treatment practices in the centers surveyed are generally consistent with ASBMT guidelines.

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.

Lost to Follow-up Rates Are Higher in Pediatric Than Adult Survivors, but Not By Transplant Type: A Report from the Center for International Blood and Marrow Transplant Research

IntroductionFollow-up is an integral part of hematopoietic cell transplant (HCT) care which ensures accurate characterization of HCT-related outcomes as well as surveillance and intervention for complications. Despite the importance of follow-up of all HCT recipients at transplant centers, they may be lost to follow-up (LTFU). HCT recipients who are LTFU may be demographically or clinically distinct from HCT recipients who maintain regular center follow-up. Using population-based data from 17,550 adult and 4,279 pediatric HCT recipients from United States centers reported to the Center for International Blood and Marrow Transplant Research (CIBMTR), we characterize the incidence of, and predictors for, becoming LTFU.MethodsThe study included 2-year (yr) survivors of first allogeneic (10,367 adults and 3,865 children) or autologous (7,183 adults and 414 children) HCT for malignant and non-malignant disorders in the United States from 2002-2013 reported to the CIBMTR. LTFU was defined as a patient having missed 2 consecutive follow-up reporting periods. CIBMTR follow-up forms are collected annually for the first 6 yrs post-HCT and bi-annually thereafter. The cumulative incidence of LTFU HCT recipients was calculated. Marginal Cox models allowing adjustment for center effect were fit to evaluate risk factors for becoming LTFU among adults and pediatric allogeneic and autologous HCT survivors. Risk factors evaluated included: sociodemographic (age at HCT, sex, performance status, race, distance to center, income, health insurance, marital status) and disease/HCT-related (disease type, yr of HCT) factors.ResultsAmong 2-yr allogeneic HCT survivors, the median age at the time of HCT was 49 yrs (range, 18-81) and 7 yrs (range, <1-18) for adult and pediatric recipients, respectively. Corresponding median follow-up was 75 months (mos) (range, 12-173) and 74 mos (range, 3-173). Health insurance coverage was public (23%) or private (64%) for adult recipients, and public (40%) or private (43%) for pediatric recipients. For 2-yr autologous HCT survivors, the median age at the time of HCT was 58 yrs (range, 18-82) and 4 yrs (range, <1-18) for the adult and pediatric recipients, respectively. Corresponding median follow-up was 76 mos (range, 3-174) and 73 mos (range, 6-173). Health insurance coverage was public (27%) or private (57%) for adult recipients, and public (48%) or private (39%) for pediatric recipients. The 10-year cumulative incidence of becoming LTFU among adult and pediatric allogeneic HCT recipients was 13% (95% CI, 12-14) and 25% (95% CI, 24-27), respectively. Among autologous HCT recipients, the 10-year cumulative incidence of becoming LTFU among adults and children was 15% (95% CI, 14-16) and 23% (95% CI, 19-28), respectively. (Figure 1) Among pediatric allogeneic HCT survivors, older age, non-white race, public or no insurance (referent: private), and earlier yr of HCT were significantly associated with increased LTFU risk. However, in adult allogeneic HCT survivors, younger age, non-malignant disease, public or no insurance (referent: private), living farther from the HCT center, and unmarried were significantly associated with higher risk of LTFU (Table 1). In pediatric autologous HCT survivors, males and Non-Hodgkin lymphoma (NHL)/Hodgkin lymphoma patients (referent: central nervous system tumors) were significantly associated with higher risk of becoming LTFU (Table 1), whereas for adult autologous HCT survivors, older age and multiple myeloma (referent: NHL) were significantly associated with decreased risk of LTFU.ConclusionsThe incidence of LTFU is significantly higher in pediatric than adult patients, with no difference between autologous and allogeneic HCT patients, regardless of age. We identified risk factors for LTFU that differed by age and HCT donor type. A national, comprehensive, risk-based approach to long-term follow-up focusing on minimizing the attrition in high-risk groups such as adolescent and young adult-aged HCT survivors and HCT survivors with non-private health insurance is needed. Future studies incorporating patient reported outcomes may help describe reasons for lack of long-term follow-up. Collection of accurate and meaningful epidemiologic and clinical data from all survivors can help develop and refine strategies to improve long-term outcomes of this population. [Display omitted] DisclosuresParsons:Seattle Genetics: Research Funding.

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.

Clinical and Economic Impact of Cytomegalovirus Infection among Children Undergoing Allogeneic Hematopoietic Cell Transplantation.

The literature on the impact of cytomegalovirus (CMV)-related hospitalization in pediatric allogeneic hematopoietic cell transplantation (alloHCT) recipients is limited. The aim of this study was to determine utilization and outcomes of CMV-related hospitalization in alloHCT recipients using a single-center clinical database. This was a retrospective study of 240 children aged 3 months to 21 years (median age, 9.5 years) who underwent alloHCT between 2005 and 2016. The impacts of CMV-related length of stay (LOS) and total healthcare costs were quantified. Factors associated with prolonged CMV viremia (>25 days' duration) were also examined. In at-risk patients with CMV infection, the incidence of CMV viremia was 38% (59 of 155), the median time to onset was 33 days (range, 0 to 292 days), and the median time to resolution was 25 days (range, 3 to 48 days; n = 53). CMV infection was associated with a 23.3-day increase in LOS (P = .004) and added hospital costs of $45,443 (P = .162) compared with patients without CMV infection. In multivariable analysis, receipt of alemtuzumab (P = .027) was associated with CMV viremia of >25 days' duration. Our data show that CMV viremia is associated with prolonged LOS and higher hospital costs and indicate the need for improved and cost-effective CMV prevention strategies. Further studies of patient outcomes and costs in pediatric alloHCT recipients is needed.

1732. Adenovirus Load Dynamics Are Consistently Correlated With Risk of Mortality in Pediatric Allogeneic Hematopoietic Cell Transplant Recipients: Findings From the Landmark AdVance Study

BackgroundAdenovirus (AdV) infection is an important cause of mortality among allogeneic hematopoietic cell transplant (allo-HCT) recipients. Current European Conference of Infections in Leukemia (ECIL-4) guidelines support weekly AdV screening for those at-risk and pre-emptive antiviral treatment with off-label cidofovir when adenoviremia is detected. However, there is limited understanding of the relative prognostic strength of different dynamic AdV viral load measures. We examined the association between adenovirus viral load dynamics and mortality in pediatric allo-HCT recipients managed under the current standard of care.MethodsAdVance was a multinational, multicenter study characterizing the current screening and treatment practices for AdV infection in allo-HCT recipients between January 2013 and September 2015. This analysis focused on pediatric (<18 years) patients who experienced AdV viremia ≥1,000 copies/mL within 6 months of HCT. Multivariate Cox Proportional Hazard models, controlling for factors including immune reconstitution, were used to examine the relationship between AdV viral load dynamics (Figure 1) and all-cause mortality in the 6 months after first AdV viremia ≥1,000 copies/mL.ResultsA total of 241 pediatric allo-HCT recipients had AdV viremia ≥1,000 copies/mL in the 6 months following allo-HCT. Among these, 43/241 (18%) died within 6 months of first AdV ≥1,000 copies/mL. AdV viral load dynamics; whether measured by AdV AAUC0–16, peak viremia, 2-week change in viremia, or days of viremia >1,000 copies/mL, were consistently correlated with all-cause mortality (Figure 2; hazard ratio [HR] range: 1.3–2.3). Most notably, patients with AdV AAUC0–16 in the highest quartile had an HR of 11.6 relative to those in the lowest (confidence interval: 4.7–24.0; Figure 3).ConclusionAdV infection is a significant risk for allo-HCT recipients. The AdVance study has identified several dynamic measures of AdV viral load that correlate with the risk of mortality in pediatric allo-HCT recipients. Results show for the first time, that AdV AAUC0–16 provides the optimal correlation with mortality in this population and serves as a clinically useful indicator of outcome in patients with AdV infection. Disclosures F. Galaverna, Chimerix, Inc.: Investigator, Research support. R. Wynn, Chimerix, Inc.: Scientific Advisor, Grant recipient and Speaker honorarium. Orchard Therapeutics: Scientific Advisor and Shareholder, Consulting fee and Licensing agreement or royalty. Genzyme: Scientific Advisor, Speaker honorarium. P. Comoli, Chimerix, Inc.: Investigator, Research support. A. Chandak, Chimerix, Inc.: Research Contractor, Research support. Analytica Laser: Employee, Salary. E. Vainorius, Chimerix, Inc.: Employee and Shareholder, Salary. T. Brundage, Chimerix, Inc.: Employee and Shareholder, Salary. E. Mozaffari, Chimerix, Inc.: Employee and Shareholder, Salary. G. Nichols, Chimerix, Inc.: Employee and Shareholder, Salary.

1896. A Retrospective Cohort Analysis to Determine the Incidence of CMV Viremia and Progression to CMV Disease in Pediatric Patients Receiving Allogeneic Hematopoietic Cell Transplantation at an Academic Children’s Hospital

BackgroundThere are limited data on incidence of CMV reactivation and safety of anti-CMV prophylaxis in pediatric allogeneic hematopoietic cell transplant (HCT) recipients. We aimed to describe the rate of CMV viremia in patients receiving two different prophylaxis regimens based on risk assessment. The frequency of toxicity from prophylaxis is also reported.MethodsWe assembled a single-center cohort of allogeneic HCT recipients undergoing CMV surveillance testing between January 1, 2014 to June 30, 2017. Subjects were excluded if they were CMV PCR positive in the 30 days prior to HCT. Patients were categorized as high-risk (HR) if the donor product was from a CMV positive patient and they met one of the following criteria: T cell depleted graft, cord blood transplant, or receipt of anti-thymocyte globulin or alemtuzumab. The local CMV prophylaxis pathway recommends all patients initiate standard dose acyclovir on day −7. HR patients transition to foscarnet in the first week post-transplant which is continued until enteral therapy is tolerated. They are then transitioned to valganciclovir, which is continued through day +100. Standard-risk (SR) patients continue acyclovir through day +100. Patients were followed until day +180 for these outcomes: CMV viremia, CMV disease, and CMV prophylaxis related-toxicity.ResultsThe cohort included 147 subjects with 44 developing CMV viremia (29.9%). CMV viremia was more common in HR (18/35) as compared with SR (26/112) patients (51.4 vs. 23.2%, P < 0.01). The median time to reactivation was also earlier in HR patients (9 vs. 33.5 days, P = 0.01). Only two (4.5%) patients with CMV viremia progressed to CMV disease. Toxicity requiring a therapeutic change of an antiviral prophylactic agent was more common in HR (25.7%) vs. SR (8.9%) patients. Renal insufficiency was the most common reported toxicity, followed by electrolyte wasting (figure). ConclusionHR HCT recipients had a CMV viremia rate nearly triple the SR group despite a more comprehensive prophylaxis regimen. Few subjects with CMV viremia progressed to CMV disease but toxicities from antiviral prophylaxis were common. Further investigations of novel CMV prophylaxis agents with improved toxicity profile are needed to justify CMV prophylaxis in pediatric HCT patients.Disclosures M. Hayes, Merck: Grant Investigator, Research grant. A. Newman, Merck: Grant Investigator, Research grant. C. L. K. Boge, Merck: Grant Investigator, Research grant. B. T. Fisher, Merck: Grant Investigator, Grant recipient and Research grant.

Acute Respiratory Failure in Pediatric Hematopoietic Cell Transplantation: A Multicenter Study.

Acute respiratory failure is common in pediatric hematopoietic cell transplant recipients and has a high mortality. However, respiratory prognostic markers have not been adequately evaluated for this population. Our objectives are to assess respiratory support strategies and indices of oxygenation and ventilation in pediatric allogeneic hematopoietic cell transplant patients receiving invasive mechanical ventilation and investigate how these strategies are associated with mortality. Retrospective, multicenter investigation. Twelve U.S. pediatric centers. Pediatric allogeneic hematopoietic cell transplant recipients with respiratory failure. None. Two-hundred twenty-two subjects were identified. PICU mortality was 60.4%. Nonsurvivors had higher peak oxygenation index (38.3 [21.3-57.6] vs 15.0 [7.0-30.7]; p < 0.0001) and oxygen saturation index (24.7 [13.8-38.7] vs 10.3 [4.6-21.6]; p < 0.0001), greater days with FIO2 greater than or equal to 0.6 (2.4 [1.0-8.5] vs 0.8 [0.3-1.6]; p < 0.0001), and more days with oxygenation index greater than 18 (1.4 [0-6.0] vs 0 [0-0.3]; p < 0.0001) and oxygen saturation index greater than 11 (2.0 [0.5-8.8] vs 0 [0-1.0]; p < 0.0001). Nonsurvivors had higher maximum peak inspiratory pressures (36.0 cm H2O [32.0-41.0 cm H2O] vs 30.0 cm H2O [27.0-35.0 cm H2O]; p < 0.0001) and more days with peak inspiratory pressure greater than 31 cm H2O (1.0 d [0-4.0 d] vs 0 d [0-1.0 d]; p < 0.0001). Tidal volume per kilogram was not different between survivors and nonsurvivors. In this cohort of pediatric hematopoietic cell transplant recipients with respiratory failure in the PICU, impaired oxygenation and use of elevated ventilator pressures were common and associated with increased mortality.

PIN71 - ADENOVIRUS VIREMIA IS AN INDEPENDENT PREDICTOR OF PROLONGED TRANSPLANTATION HOSPITALIZATION IN PEDIATRIC ALLOGENEIC HEMATOPOIETIC CELL TRANSPLANT RECIPIENTS: FINDINGS FROM ADVANCE

To identify prognostic factors associated with longer transplant hospitalization in pediatric allogeneic hematopoietic cell transplant (allo-HCT) recipients with adenovirus (AdV) infection. AdVance is a retrospective, European multinational study into allo-HCT recipients who develop AdV infection. Here we focus on predictors of increased length of hospitalization. Review of medical chart data for the six months following allo-HCT identified patients with AdV infection. Fine-Gray multivariate regression models were utilized to identify prognostic factors associated with longer transplant hospitalization in pediatric patients who developed AdV infection following allo-HCT. Models accounted for death as a competing risk and data were censored at one year after allo-HCT. Transplant hospitalization was defined as the time from allo-HCT procedure until hospital discharge. For the transplant hospitalization, median length of stay was 50 days for patients with AdV viremia during the hospitalization (n=263) versus 34 days for those without AdV viremia (n=295). Multivariate regression analysis, controlling for age, race, and center effect as a fixed factor, revealed factors independently associated with risk of longer transplant hospitalization: AdV viremia ≥10,000 copies/mL (HR=5.26; 95% CI: 3.13-8.33; p<0.0001) or from 1000 to 10,000 copies/mL (HR=2.08; 95%CI: 1.32-3.33; p=0.0017); lymphocyte counts <300 cells/mL (HR=1.67; 95% CI: 1.15-2.38; p=0.0062); and graft versus host disease (GvHD) grade 3 (HR=2.86; 95% CI: 1.89-4.35; p<0.0001) or grade 4 (HR=6.25; 95% CI: 3.33-11.11; p<0.0001). AdV viremia in pediatric allo-HCT recipients is a strong independent predictor of longer hospital stay following allo-HCT. Higher viral burden is associated with increased risk of prolonged transplant hospitalization, independent of other confirmed risk factors such as low lymphocyte counts or GvHD. Approaches that prevent or mitigate high-level AdV viremia could therefore reduce the healthcare resource burden associated with allo-HCT.

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.