Pediatric Allogeneic Hematopoietic Cell Transplantation Research Articles

Nature's endless wonder: unexpected motherhood after pediatric allogeneic stem cell transplantation and severe late effects.

SummaryInfertility and endocrine late effects (LE) are common sequelae after pediatric allogeneic hematopoietic stem cell transplantation (HSCT) after myeloablative conditioning. Nevertheless, the individual risk for these LE is not always easy to predict and therefore these issues are of ongoing interest to the clinical research community dealing with HSCT aftercare. This article describes the case of a young woman who received polychemotherapy and total body irradiation (TBI) containing conditioning for HSCT for a relapsed anaplastic large cell lymphoma (ALCL). She developed severe sclerotic chronic graft-versus-host disease (GVHD) with irreversible joint contractures and multiorgan involvement, requiring long-term multimodal immunosuppressive treatment. Subsequently showing a considerable number of LE including hypergonadotropic hypogonadism, she accepted that infertility would be quite likely. Her courageous personal life planning included part-time working and a partnership but not motherhood. This article reports the unexpected and spontaneous pregnancy and the extreme preterm birth of a surprisingly adequately developing child.

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.

Risk Factors, Clinical Outcomes, and Cost-of-Care Related to Graft Failure in Pediatric Allogeneic Hematopoietic Cell Transplant Recipients

Allogeneic hematopoietic cell transplantation (HCT) has the capacity to cure numerous malignant and nonmalignant disorders. A dreaded complication is graft failure (GF), as it puts patients at high risk of infection and disease relapse. There are few contemporary data on the risks, outcomes, and economic burden of GF in pediatric patients. In this study, we address this gap by focusing on 14 years of transplant at our single center, for which data are compared in 2 time periods: 2005 to 2010 (n=146) and 2011 to 2018 (n=144). In the 290 patients studied, the median age was 9.33 years, and 50.3% had malignant versus nonmalignant disease. Cell source included bone marrow (51%), cord blood (19.7%), unmanipulated peripheral blood stem cells (PBSCs; 12.1%), and CD34-selected PBSCs (17.2%). Twenty-one percent of patients had reduced-intensity conditioning (RIC), and 54.8% of transplants were fully HLA matched. Most patients received serotherapy with rabbit anti-thymocyte globulin (39.3%) or alemtuzumab (42.8%). The incidence of neutropenic and non-neutropenic GF (NGF and NNGF) was 6.6% and 3.8%, respectively. Multivariate analysis demonstrated alemtuzumab (odds ratio [OR], 6.256, P < .001) was the main variable associated with a higher rate of GF in both time periods, whereas RIC (OR, 11.8, P < .001) and cell source (CD34-selected PBSCs; OR, 4.22, P=.04) showed period-specific effects. Specifically, from time periods 1 to 2, cord blood transplants were discontinued at our center, with a concomitant increase in CD34-selected grafts and a shift from more episodes of NGF to NNGF. Overall survival was 69% in the entire HCT cohort and 50% among patients with GF. Survival among GF patients improved from time periods 1 to 2 (20% versus 80%, P=.001), potentially due to a higher incidence of NNGF and increased ability to perform stem cell boosts from the same donor once cord blood transplants were phased out. Inpatient length of stay was consistently higher for patients with GF. Similar trends were seen for inpatient costs, although improvements were seen in our entire HCT population over time. In summary, GF remains a significant challenge in pediatric HCT and poses an economic burden on the health care system.

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.

Race/Ethnicity and Socioeconomic Status in Pediatric Allogeneic Hematopoietic Cell Transplantation for Non-Malignant Conditions

<h3>Introduction</h3> Survival disparities by race/ethnicity and socioeconomic status (SES) have been observed in a wide range of pediatric treatment settings. Few studies have examined the effects of ethnicity and SES in pediatric allogeneic hematopoietic cell transplantation (alloHCT). <h3>Objectives</h3> We explored whether survival differed by ethnicity or SES in children receiving alloHCT for non-malignant conditions at a single institution serving a diverse patient population. <h3>Methods</h3> The Kaplan-Meier method was used to estimate overall survival (OS) with the logrank test for between-group comparisons. Cox proportional hazards models were used for adjusted analyses of OS. <h3>Results</h3> Of 133 subjects from <1-21yrs, 19% were non-Hispanic white (NHW), 34% were non-Hispanic black (NHB), 40% were Hispanic, and 7% were Asian. 67% had public insurance and 47% of patients lived in neighborhoods where median family income was ≤$44,100/yr. Indications for alloHCT were hemoglobinopathy (56%), bone marrow failure (22%), and other (22%). Mean follow up was 6.5yrs (SD=4.4) and did not differ by ethnicity. Overall survival for the entire cohort was 88% (SE=3.3) at 5.8yrs. On univariable analysis, hazard of mortality did not differ by race/ethnicity or insurance, and hazard of mortality was lower in patients from lower income neighborhoods (Table). In multivariable analysis, only aGVHD was associated with inferior OS (HR 6.7, CI95% 2.3-19.5 p<0.001). <h3>Conclusion</h3> Our findings suggest that in patients undergoing alloHCT for non-malignant conditions, treatment at a tertiary care center with a multidisciplinary approach may mitigate the health disparities seen in other treatment settings. Future research should include larger multicenter studies investigating the complex interrelationships among race/ethnicity, SES, and clinical outcomes in this understudied patient population. Occurrence of aGVHD was the only factor associated with inferior OS, emphasizing a need for better prevention and treatment strategies in children with non-malignant diseases.

Timing of Induction Treatment for Reactivation of Cytomegalovirus Impacts Overall Survival in Pediatric Allogeneic Hematopoietic Cell Transplant

Background Despite significant advances in viral detection and treatment, reactivation of cytomegalovirus (CMV) remains a major complication following allogeneic hematopoietic cell transplant (allo-HCT). Methods to decrease the risk of CMV reactivation and long-term sequelae of CMV disease include controlling for known risk factors and administering appropriate antiviral treatments. Although they are shown to be effective, these treatments carry considerable adverse effects that may limit their use. The optimal timing to initiate induction treatment remains unclear, especially in the pediatric population. Design We performed a retrospective analysis of patients who received initial conventional or ex-vivo T-cell depleted (TCD) allo-HCT on the pediatric service from January 2010 – June 2018 at Memorial Sloan Kettering Cancer Center. CMV reactivation was defined as ≥ 1 CMV PCR >500 in whole blood or >137 in plasma within 180 days post-transplant. Induction treatment was typically initiated for CMV PCR ≥ 1000 in whole blood, ≥ 300 in plasma, or rising viremia from baseline. Hospital databases and medical records were utilized to identify patients and collect clinical data. Time-dependent Cox models and multi-state models to account for competing risks were used. This study was approved by Institutional Review Board. Results Our study consisted of 227 patients (54 days - 27 years old) who underwent allo-HCT for malignant (N=143) and non-malignant (N=84) diseases. TCD represented 76% of all allografts. CMV donor (D) and recipient (R) serostatus were: D+/R+ N=90, D+/R- N=29, D-/R+ N=38, D-/R- N=70. Cumulative incidence of CMV reactivation was 24.8% and 15 patients (27%) developed CMV disease. Median time to CMV reactivation was 24 days (IQR 14-33). Of the 56 patients who reactivated, 41 (73%) patients received induction treatment. The median time from CMV reactivation to induction treatment was 6 days (IQR 1-15). D+/R+ serostatus was a predictor for CMV reactivation when compared to D-/R+ (HR=2.1, [95% CI 1.1 - 4, P Conclusions A short interval between CMV reactivation and initiation of induction treatment was significantly associated with improved OS in TCD HCT. Earlier treatment did not translate into improved outcomes, which may be confounded by high-risk patients receiving induction therapies earlier. Further evaluation into CMV prophylaxis and prompt initiation of induction treatment on additional CMV outcomes will help optimize treatment options and improve clinical outcomes.

Prospective Open-Label Phase II Trial of Individualized Anti-Thymocyte Globulin for Improved T-Cell Reconstitution after Pediatric Allogeneic Hematopoietic Cell Transplantation: The Parachute-Study

Introduction Rabbit anti-thymocyte globulin (ATG) is used in allogeneic hematopoietic cell transplantation (HCT) to prevent graft-versus-host-disease (GvHD) and graft failure (GF). Its main and unpredictable toxicity includes poor immune reconstitution associated with increased relapse, viral reactivations and subsequently higher mortality. Early ( Methods We performed an open label, phase II historically controlled non-randomized prospective clinical trial investigating individualized versus fixed dosing of ATG (Thymoglobulin). Individualized dosing was based on the results from a previous validated population PKPD model1,2 with cumulative doses varying between 2 to 10 mg/kg starting based on weight, recipient lymphocyte counts before first dose of ATG and stem cell source, starting day -9. Primary endpoint was successful CD4+ T-cell reconstitution (CD4+ >50/mm3 at 2 consecutive timepoints within 100 days after HCT1) in patients alive without relapse or graft failure Results We included 58 patients between 2015-2018, and compared to 112 historical controls (table 1). CD4+ reconstitution was significantly better in the individualized dosing group: 83% versus 54% in the fixed dosing group; HR 2.4 (95% CI 1.6-3.6), p Conclusions Individualized ATG dosing significantly increases the chance of rapid immune reconstitution without affecting the incidence of aGvHD and graft failure. Together, this is an important step towards predictable CD4+ T cell reconstitution and improved survival changes.

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.

Low seroprevalence and low incidence of infection with Toxoplasma gondii (Nicolle et Manceaux, 1908) in pediatric hematopoietic cell transplantation donors and recipients: Polish nationwide study.

Toxoplasmosis is a potentially fatal complication after hematopoietic cell transplantation (HCT). Pre-transplant seropositivity of graft recipient to Toxoplasma gondii (Nicolle et Manceaux, 1908) is an important factor for disease reactivation after HCT. As toxoplasmosis epidemiology varies all over the world, we performed a Polish nationwide retrospective cohort study to determine the seroprevalence of toxoplasmosis in donors and pediatric allogeneic and autologous HCT recipients and the incidence of clinically evident toxoplasmosis in this patient group. Polish adult donors had higher anti-T. gondii seroprevalence than Polish pediatric donors (28% vs 8%; OR = 4.4; p = 0.02) and allo-HCT recipients (28% vs 17%; OR = 1.9; p = 0.01). Clinically apparent disease occurred in 1% of allo-HCT recipients: it was diagnosed by PCR as cerebral and/or ocular toxoplasmosis and successfully treated with antiprotozoal therapy. Regarding current practice, no prospective screening for infection of T. gondii in pediatric HCT centres is being performed, but, vast majority of HCT pediatric patients are receiving anti-T. gondii active prophylaxis. Since pre-HCT T. gondii serology was not assessed in all HCT; recipients, we propose this test should be a standard practice. Standardisation of management with infection of T. gondii in children after HCT is needed.

Predictors of Loss to Follow-Up Among Pediatric and Adult Hematopoietic Cell Transplantation Survivors: A Report from the Center for International Blood and Marrow Transplant Research.

Follow-up is integral for hematopoietic cell transplantation (HCT) care to ensure surveillance and intervention for complications. We characterized the incidence of and predictors for being lost to follow-up. Two-year survivors of first allogeneic HCT (10,367 adults and 3865 children) or autologous HCT (7291 adults and 467 children) for malignant/nonmalignant disorders between 2002 and 2013 reported to the Center for International Blood and Marrow Transplant Research were selected. The cumulative incidence of being lost to follow-up (defined as having missed 2 consecutive follow-up reporting periods) was calculated. Marginal Cox models (adjusted for center effect) were fit to evaluate predictors. The 10-year cumulative incidence of being lost to follow-up was 13% (95% confidence interval [CI], 12% to 14%) in adult allogeneic HCT survivors, 15% (95% CI, 14% to 16%) in adult autologous HCT survivors, 25% (95% CI, 24% to 27%) in pediatric allogeneic HCT survivors, and 24% (95% CI, 20% to 29%) in pediatric autologous HCT survivors. Factors associated with being lost to follow-up include younger age, nonmalignant disease, public/no insurance (reference: private), residence farther from the tranplantation center, and being unmarried in adult allogeneic HCT survivors; older age and testicular/germ cell tumor (reference: non-Hodgkin lymphoma) in adult autologous HCT survivors; older age, public/no insurance (reference: private), and nonmalignant disease in pediatric allogeneic HCT survivors; and older age in pediatric autologous HCT survivors. Follow-up focusing on minimizing attrition in high-risk groups is needed to ensure surveillance for late effects.

1753. Adherence and Immunogenicity of Early Vaccination in Pediatric Allogeneic Hematopoietic Cell Transplantation (allo-HCT) Recipients

BackgroundAllo-HCT recipients are at increased risk for vaccine-preventable infections. Early vaccination (EV) beginning at 3–6 months (mo) post-HCT has been shown to be safe, immunogenic, and is recommended. We assessed adherence and immunogenicity to EV in children post-allo-HCT.MethodsRetrospective analysis of allo-HCT performed 1/1/10–6/30/18 at NCH. Children who died, relapsed, or received anti-CD20 biologics in the 6 mo preceding intended vaccination were excluded. Institutional guidelines recommend EV starting at 6 (+1) mo post-HCT with: 3 PCV13 + 1 PPSV23, IPV, HBV, DTaP and HIB. Vaccination rates were analyzed at 6(+1), 8(+1) and 10(+1) mo post-HCT and serologies were obtained pre- and ≥ 4 weeks post vaccination. Immunogenicity was defined as antibody (Ab) concentrations ≥ 1.3 µg/mL or a 4 fold rise ≥ 70% of 10 PCV13 serotypes, tetanus (T) and diphtheria (D) Ab ≥ 0.1 IU/mL, and HBs Ab ≥ 10 IU/mL. Non-parametric statistics were applied; correlations between T&B cell subsets and IgG pre-vaccination and specific Ab post-vaccination were performed.ResultsDuring the 8-year study period, 171 allo-HCT were performed: 131 children were eligible for EV (Table 1); however, EV occurred in only 49.6% (65/131) and was completed in 37.5% (45/120) of children at 10(+1) mo post-HCT. Vaccine immunogenicity of PCV13, HBV, T and D was achieved in 40/45, 34/36, 63/64, and 18/18 of evaluable children, respectively. Protective Ab response after EV for PCV13, HBV, T and D was found in 21/24 (87.5%), 14/16 (87.5%), 35/36 (97.2%), and 8/8 (100%) children, respectively. Specific IgG geometric mean concentration pre- and post-vaccination was similar in children whether they received early or delayed vaccination (median 9.8 mo post-HCT, IQR 8–14) (Figures 1 and 2). No correlations were found between absolute CD4, CD8, CD19 and IgG pre-vaccination and vaccines specific Abs post-vaccination (Figure 3).ConclusionDespite recommendations, adherence to EV was low among our cohort of allo-HCT recipients and identified opportunities for improvement. Overall, vaccines were immunogenic with no significant differences in Ab concentrations among patients receiving early vs. delayed vaccination. No robust correlations were found between number of T&B cells or total IgG and Ab titers. Disclosures All authors: No reported disclosures.

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.

Comprehensive Prognostication in Critically Ill Pediatric Hematopoietic Cell Transplant Patients: Results from Merging the Center for International Blood and Marrow Transplant Research (CIBMTR) and Virtual Pediatric Systems (VPS) Registries.

Critically ill pediatric allogeneic hematopoietic cell transplant (HCT) patients may benefit from early and aggressive interventions aimed at reversing the progression of multiorgan dysfunction. Therefore, we evaluated 25 early risk factors for pediatric intensive care unit (PICU) mortality to improve mortality prognostication. We merged the Virtual Pediatric Systems and Center for International Blood and Marrow Transplant Research databases and analyzed 936 critically ill patients ≤21 years of age who had undergone allogeneic HCT and subsequently required PICU admission between January 1, 2009, and December 31, 2014. Of 1532 PICU admissions, the overall PICU mortality rate was 17.4% (95% confidence interval [CI], 15.6% to 19.4%) but was significantly higher for patients requiring mechanical ventilation (44.0%), renal replacement therapy (56.1%), or extracorporeal life support (77.8%). Mortality estimates increased significantly the longer that patients remained in the PICU. Of 25 HCT- and PICU-specific characteristics available at or near the time of PICU admission, moderate/severe pre-HCT renal injury, pre-HCT recipient cytomegalovirus seropositivity, <100-day interval between HCT and PICU admission, HCT for underlying acute myeloid leukemia, and greater admission organ dysfunction as approximated by the Pediatric Risk of Mortality 3 score were each independently associated with PICU mortality. A multivariable model using these components identified that patients in the top quartile of risk had 3 times greater mortality than other patients (35.1% versus 11.5%, P < .001, classification accuracy 75.2%; 95% CI, 73.0% to 77.4%). These data improve our working knowledge of the factors influencing the progression of critical illness in pediatric allogeneic HCT patients. Future investigation aimed at mitigating the effect of these risk factors is warranted.

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.

Late cardiovascular morbidity and mortality following pediatric allogeneic hematopoietic cell transplantation

Early cardiovascular disease is relatively common among childhood cancer survivors (CCS). A high risk of accelerated atherosclerosis and a 8.2-fold higher cardiac mortality rate have been reported (1). Arterial stiffness, an independent risk factor for cardiovascular morbidity and mortality in adults, seems to increase in young adult CCS (2). In hematopoietic cell transplantation (HCT) survivors, the risk of cardiovascular death is 2–4 fold higher than the general population, and cardiovascular adverse events occur earlier than average (3).

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.

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