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Key Points Standard chemotherapy can still be used for new diagnosis of acute lymphoblastic leukemia in patients with SARS-CoV-2. Corticosteroid can be given safely to patients with SARS-CoV-2 presenting with acute respiratory distress syndrome and ALL.

While there are increasing reports of acute kidney injury among hospitalized adults with COVID-19, there is still limited information on renal complications associated with COVID-19 in children. The cause of kidney involvement in COVID-19 is likely multifactorial, and appears to involve a complex process, including complement dysregulation and thrombotic microangiopathy. We present a pediatric case of COVID-19 and renal failure due to thombotic microangiopathy, successfully treated with eculizumab.

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.

Complications following allogeneic hematopoietic cell transplantation (alloHCT) continue to be a significant challenge that often result in significant morbidity/mortality and increased healthcare utilization and cost. In this study, we analyzed the impact of post-alloHCT complications on healthcare utilization and cost during first year post-transplant. We analyzed data on 240 pediatric patients. Complications analyzed included kidney injury, liver injury, lung injury, viral infections, bacterial infections, fungal infections, and acute graft-versus-host disease (GVHD). Patients were divided into three groups based on the number of complications (0–1, 2–3, and >3). Cost was estimated from charges recorded in the Pediatric Health Information System database and hospital accounting records. Patients with >3 complications had higher healthcare utilization and cost, primarily driven by inpatient hospitalization and intensive care unit admissions. Multivariable analysis of risk factors identified bacteremia ($90,166, SE = 26,636, p

Although organizations such as Centers for Disease Control and Prevention and American Academy of Pediatrics have published guidelines favoring the resumption of in-person schooling during the coronavirus disease 19 (COVID-19) pandemic, there is no specific guidance on hematopoietic cell transplantation (HCT) recipients' safe return to school. We conducted a cross-sectional survey of pediatric HCT physician members of the Pediatric Transplantation and Cellular Therapy Consortium practicing in the United States to describe current return-to-school practices during the COVID-19 pandemic for HCT recipients. A total of 122 respondents (response rate, 30.6%) from 60 transplant centers in 32 US states completed the survey. Most of the respondents (76%) recommended that HCT recipients consider a remote or hybrid school option at this time if possible. If not possible, the respondents recommended a return to in-person school if the patient is at least 12 months post-transplantation or off immune suppression, while taking school safety measures and local COVID-19 cases into account. These results provide valuable guidance for the HCT community, patients, and caregivers on important topics to consider while making return-to-school decisions.

The North American Pediatric Aplastic Anemia Consortium (NAPAAC) is a group of pediatric hematologist-oncologists, hematopathologists, and bone marrow transplant physicians from 46 institutions in North America with interest and expertise in aplastic anemia, inherited bone marrow failure syndromes, and myelodysplastic syndromes. The NAPAAC Bone Marrow Failure Diagnosis and Care Guidelines Working Group was established with the charge of harmonizing the approach to the diagnostic workup of aplastic anemia in an effort to standardize best practices in the field. This document outlines the rationale for initial evaluations in pediatric patients presenting with signs and symptoms concerning for severe aplastic anemia.

The impact of AGVHD on healthcare utilization and cost is not well described. In this retrospective single center cohort study of 240 pediatric patients, we analyzed cost, healthcare utilization and patient outcomes for the first year post-alloHCT. Costs were estimated from charges recorded in the Pediatric Health Information System database and the hospital’s accounting system. The overall incidence of grade I–IV aGVHD was 40.4%. The incidence of grade I, grade II, and grade III–IV aGVHD was 6.6%, 16.2%, and 17.5%, respectively. The overall incidence of steroid refractory (SR)-aGVHD was 10.8%. The median number of days of hospitalization in the first year post-alloHCT was significantly higher for patients with aGVHD vs. no aGVHD: 113 days (range: 35–354 days) vs. 63 days (range: 25–298 days), p

Hemophagocytic lymphohistiocytosis (HLH) is a potentially fatal illness characterized by impaired natural killer (NK) cell and cytotoxic T-cell function. Patients develop systemic inflammation, multisystem organ dysfunction, and if untreated, death. Patients who present in the neonatal period often have atypical presentations with evidence of liver dysfunction and cholestasis; this has a broad differential diagnosis including neonatal infection, congenital liver defects, or other causes of liver dysfunction, such as neonatal hemochromatosis. Here, we present an infant whose diagnosis of familial HLH was confounded by the history of a stillborn sibling with suspected neonatal hemochromatosis, ultimately delaying diagnosis and initiation of curative treatment. This highlights the need to maintain a low threshold for sending HLH work-up concurrently with evaluation of liver diseases in infants with liver dysfunction, to ensure timely diagnosis and initiation of treatment. Clinicians should maintain a high index of suspicion for HLH and be aware that HLH may mimic the findings on liver biopsy seen in neonatal hemochromatosis.

CD19 chimeric antigen receptor T-cell (CART) therapy has revolutionized the treatment of patients with relapsed/refractory hematologic malignancies, especially B-cell acute lymphoblastic leukemia. As CART immunotherapy expands from clinical trials to FDA-approved treatments, a consensus among oncologists and hematopoietic cell transplant (HCT) physicians is needed to identify which patients may benefit from consolidative HCT post-CART therapy. Here, we review CD19 CART therapy and the outcomes of published clinical trials, highlighting the use of post-CART HCT and the pattern of relapse after CD19 CART. At this time, the limited available long-term data from clinical trials precludes us from making definitive HCT recommendations. However, based on currently available data, we propose that consolidative HCT post-CART therapy be considered for all HCT-eligible patients and especially for pediatric patients with KMT2A-rearranged B-cell acute lymphoblastic leukemia.

Despite improvements, mortality after allogeneic hematopoietic cell transplantation (HCT) for nonmalignant diseases remains a significant problem. We evaluated whether pre-HCT conditions defined by the HCT Comorbidity Index (HCT-CI) predict probability of posttransplant survival. Using the Center for International Blood and Marrow Transplant Research database, we identified 4083 patients with nonmalignant diseases transplanted between 2007 and 2014. Primary outcome was overall survival (OS) using the Kaplan-Meier method. Hazard ratios (HRs) were estimated by multivariable Cox regression models. Increasing HCT-CI scores translated to decreased 2-year OS of 82.7%, 80.3%, 74%, and 55.8% for patients with HCT-CI scores of 0, 1 to 2, 3 to 4, and ≥5, respectively, regardless of conditioning intensity. HCT-CI scores of 1 to 2 did not differ relative to scores of 0 (HR, 1.12 [95% CI, 0.93-1.34]), but HCT-CI of 3 to 4 and ≥5 posed significantly greater risks of mortality (HR, 1.33 [95% CI, 1.09-1.63]; and HR, 2.31 [95% CI, 1.79-2.96], respectively). The effect of HCT-CI differed by disease indication. Patients with acquired aplastic anemia, primary immune deficiencies, and congenital bone marrow failure syndromes with scores ≥3 had increased risk of death after HCT. However, higher HCT-CI scores among hemoglobinopathy patients did not increase mortality risk. In conclusion, this is the largest study to date reporting on patients with nonmalignant diseases demonstrating HCT-CI scores ≥3 that had inferior survival after HCT, except for patients with hemoglobinopathies. Our findings suggest that using the HCT-CI score, in addition to disease-specific factors, could be useful when developing treatment plans for nonmalignant diseases.

Renal dysfunction is a recognized risk factor for mortality after allogeneic hematopoietic cell transplantation (alloHCT), yet our understanding of the effect of different levels of renal dysfunction at time of transplantation on outcomes remains limited. This study explores the impact of different degrees of renal dysfunction on HCT outcomes and examines whether the utilization of incremental degrees of renal dysfunction based on estimated glomerular filtration rate (eGFR) improve the predictability of the hematopoietic cell transplantation comorbidity index (HCT-CI). The study population included 2 cohorts: cohort 1, comprising patients age ≥40 years who underwent alloHCT for treatment of hematologic malignancies between 2008 and 2016 (n = 13,505; cohort selected given a very low incidence of renal dysfunction in individuals age40 years), and cohort 2, comprising patients on dialysis at the time of HCT (n = 46). eGFR was measured using the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) method. The patients in cohort 1 were assigned into 4 categories-eGFR ≥90 mL/min (n = 7062), eGFR 60 to 89 mL/min (n = 5264), eGFR 45 to 59 mL/min (n = 897), and eGFR45 mL/min (n=282)-to assess the impact of degree of renal dysfunction on transplantation outcomes. Transplantation outcomes in patients on dialysis at the time of alloHCT were analyzed separately. eGFR60 mL/min was associated with an increased risk for nonrelapse mortality (NRM) and requirement for dialysis post-HCT. Compared with the eGFR ≥90 group, the hazard ratio (HR) for NRM was 1.46 (P = .0001) for the eGFR 45 to 59 mL/min group and 1.74 (P = .004) for the eGFR45 mL/min group. Compared with the eGFR ≥90 mL/min group, the eGFR 45 to 59 mL/min group (HR, 2.45; P.0001) and the eGFR45 mL/min group (HR, 3.09; P.0001) had a higher risk of renal failure necessitating dialysis after alloHCT. In addition, eGFR45 mL/min was associated with an increased overall mortality (HR, 1.63; P.0001). An eGFR-based revised HCT-CI was also developed and shown to be predictive of overall survival (OS) and NRM, with predictive performance similar to the original HCT-CI. Among 46 patients on dialysis at alloHCT, the 1-year probability of OS was 20%, and that of NRM was 67%. The degree of pretransplantation renal dysfunction is an independent predictor of OS, NRM, and probability of needing dialysis after alloHCT. An eGFR-based HCT-CI is a validated index for predicting outcomes in adults with hematologic malignancies undergoing alloHCT. The outcomes of alloHCT recipients on dialysis are dismal; therefore, one should strongly weigh the significant risks of being on hemodialysis as a factor in determining alloHCT candidacy.

Introduction: Delirium occurs frequently in adults undergoing hematopoietic cell transplantation, with significant associated morbidity. Little is known about the burden of delirium in children in the peri-transplant period. This study was designed to determine delirium rates, define risk factors (demographic and treatment related), and establish feasibility of multi-institutional bedside screening for delirium in children undergoing hematopoietic cell transplant.Methods: This is a multi-institutional point prevalence study. All subjects were prospectively screened for delirium twice daily using the Cornell Assessment of Pediatric Delirium over a 10-day period. De-identified data, including basic demographics and daily characteristics, were extracted from the electronic medical record.Results: Eleven North American institutions were included, 106 children were enrolled, and 883 hospital days were captured. Delirium screening was successfully completed on more than 98% of the study days. Forty-eight children (45%) developed delirium over the course of the 10-day study. Children were diagnosed with delirium on 161/883 study days, for an overall delirium rate of 18% per day. Higher delirium rates were noted in children Conclusion: Delirium was a frequent occurrence in our study cohort, with identifiable risk factors. Delirium screening is highly feasible in the pediatric hematopoietic cell transplant patient population. A large-scale prospective longitudinal study following children throughout their transplant course is urgently needed to fully describe the epidemiology of pediatric delirium, explore the effects of delirium on patient outcomes, and establish guidelines to prevent and treat delirium in the peri-transplant period.

Supplemental Digital Content is available in the text., Objectives: The disease caused by severe acute respiratory syndrome coronavirus 2, known as coronavirus disease 2019, has resulted in a global pandemic. Reports are emerging of a new severe hyperinflammatory syndrome related to coronavirus disease 2019 in children and adolescents. The Centers for Disease Control and Prevention has designated this disease multisystem inflammatory syndrome in children. Our objective was to develop a clinical inpatient protocol for the evaluation, management, and follow-up of patients with this syndrome. Data Sources: The protocol was developed by a multidisciplinary team based on relevant literature related to coronavirus disease 2019, multisystem inflammatory syndrome in children, and related inflammatory syndromes, as well as our experience caring for children with multisystem inflammatory syndrome in children. Data were obtained on patients with multisystem inflammatory syndrome in children at our institution from the pre-protocol and post-protocol periods. Data Synthesis: Our protocol was developed in order to identify cases of multisystem inflammatory syndrome in children with high sensitivity, stratify risk to guide treatment, recognize co-infectious or co-inflammatory processes, mitigate coronary artery abnormalities, and manage hyperinflammatory shock. Key elements of evaluation include case identification using broad clinical characteristics and comprehensive laboratory and imaging investigations. Treatment centers around glucocorticoids and IV immunoglobulin with biologic immunomodulators as adjuncts. Multidisciplinary follow-up after discharge is indicated to manage continued outpatient therapy and evaluate for disease sequelae. In nearly 2 months, we admitted 54 patients with multisystem inflammatory syndrome in children, all of whom survived without the need for invasive ventilatory or mechanical circulatory support. After institution of this protocol, patients received earlier treatment and had shorter lengths of hospital stay. Conclusions: This report provides guidance to clinicians on evaluation, management, and follow-up of patients with a novel hyperinflammatory syndrome related to coronavirus disease 2019 known as multisystem inflammatory syndrome in children. It is based on the relevant literature and our experience. Instituting such a protocol during a global pandemic is feasible and is associated with patients receiving treatment and returning home more quickly.

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

Identifying which patients are at high risk for transplant-related mortality, prior to allogeneic hematopoietic cell transplantation (alloHCT), is crucial both to guide decision making with patients and families and to inform the alloHCT approach. There is a paucity of data evaluating the utility of the HCT comorbidity index (HCT-CI) in pediatric patients. We performed a retrospective cohort study of 188 patients who underwent alloHCT between January 2008 and October 2016 and assessed pretransplant comorbidities defined and weighted by the HCT-CI. The primary endpoint of our study was overall survival (OS). Kaplan-Meier method was used to assess survival estimates at 1-year post-transplant and did not differ based on HCT-CI scores: 78.7% (SE 6.69%) for HCT-CI = 0, 74.7% (SE 6.33%) for HCT-CI = 1 to 2, and 77.3% (SE 4.17%) for HCT-CI ≥3. Multivariable Cox proportional hazards analysis did not show HCT-CI having an effect on OS: hazard ratio (HR) of 0.633 (95% confidence interval [CI], 0.297 to 1.347) for HCT-CI scores 1 to 2 and HR of 0.935 (95% CI, 0.456 to 1.918) for HCT-CI scores ≥3 compared to scores of 0. The most frequent comorbidities observed were hepatic disease (mild in 29%, severe in 23%) and pulmonary disease (moderate in 15% and severe in 29%). However, only 55% were able to complete pulmonary function testing. Hepatic disease was based on transaminitis in 48% and by bilirubin alone in 26% of patients; 46% of patients with hepatic dysfunction had an underlying hemoglobinopathy and hyperbilirubinemia related to ongoing hemolysis. This study evaluates HCT-CI comorbidities in greater detail than has been performed previously in children undergoing alloHCT. We identify challenges with the HCT-CI in the pediatric population and highlight the comorbidities that may benefit from adjustments to their definition to create an improved risk assessment tool for children.

We examined the risk of subsequent neoplasms (SNs) and late mortality in children and adolescents undergoing allogeneic hematopoietic cell transplantation (HCT) for nonmalignant diseases (NMDs). We included 6028 patients (median age, 6 years; interquartile range, 1-11; range

Background: Little is known about the effect of COVID-19 disease on pediatric hematology, oncology and hematopoietic stem cell transplant (HCT) patients brbr

Background: Acute graft versus host disease (aGVHD) affects approximately 30–60% of patients after allogeneic hematopoietic stem cell transplantation (HCT) and our ability to predict who develops this complication and their response to treatment is limited. Fecal calprotectin has recently gained popularity as an effective marker of GI inflammation in patients with Inflammatory Bowel Disease (IBD). Methods: Fecal calprotectin and albumin were evaluated as prognostic and predictive markers of aGVHD in 60 adult and pediatric HCT patients. Stool samples were sent for calprotectin quantification prior to starting conditioning, at day 14 post-HCT, at day 28 post-HCT, and at onset of aGVHD ± 2 days. Results: Fecal calprotectin did not differentiate patients with GI-GVHD and non-GI GVHD and did not vary based on severity. However, in patients with steroid-refractory GI aGVHD, significantly higher fecal calprotectin levels were noted. At onset of lower-GI symptoms, steroid refractory patients (n = 3) had a mean fecal calprotectin level of 449 ug/g (range 116–1111 ug/g) and a mean albumin of 1.93 g/dL (range 1.6–2.3 g/dL) compared with a mean fecal calprotectin of 24 ug/g (range 16–31 ug/g) and a mean albumin of 3.3 g/dL (range 2.3–3.9 g/dL) in steroid responsive patients (n = 9) (fecal calprotectin p = 0.032, albumin p = 0.027). Conclusion: Patients with steroid-refractory GI aGVHD had higher fecal calprotectin levels and lower albumin levels than patients with steroid-responsive disease. We recommend further studies to evaluate non-invasive tests with fecal calprotectin in combination with albumin in predicting steroid refractory disease at onset of symptoms to potentially identify patients that may benefit from upfront escalation in GVHD treatment. Keywords: GVHD, Calprotectin, Albumin

Hematopoietic stem cell transplantation (HCT) offers a potential cure for patients with high-risk malignancies but carries a risk of death from transplant-related complications. Extracorporeal membrane oxygenation (ECMO) is often considered a contraindication to transplant with the assumption that lung injury puts the patient at risk for pulmonary complications post-HCT. Although patients who have required prolonged intubation show gradual improvement in pulmonary function over time, there is little data on pulmonary functional recovery after ECMO which makes assessment pre-HCT difficult. We present a case series of two patients with high-risk hematologic malignancies, who had previously received ECMO and then underwent reduced-intensity HCT. Although both patients had complications post-HCT, neither patient suffered significant pulmonary toxicity related to their prior ECMO exposure. We conclude that, although patients who have previously been treated with ECMO remain at high risk for complications after transplant, but they should not be excluded from consideration for reduced intensity transplantation.

Background: Umbilical cord blood hematopoietic stem cell transplant (UCBT) has been practiced as an alternative source of hematopoietic stem cells for patients in need of transplantation. Double-units UCBT has been established as a means of achieving a cell dose of at least 2.5x10 7 nucleated cells per kilogram of body weight in adult recipients. The advantages of UCBT include its rapid availability, reduced stringency in terms of human leukocyte antigen (HLA) match requirements, and subsequent increase in access to transplants for racial minorities. Both related and unrelated UCBTs with single or double units have been performed with high rates of success in both pediatric and adult settings to treat a variety of medical conditions. Prior to undergoing UCBT, recipients must undergo a conditioning regimen to create space in the bone marrow, suppress the immune system to allow for donor stem cell engraftment, and reduce the tumor burden in cases of neoplastic disease. Total body irradiation (TBI) is commonly incorporated into conditioning regimens to enforce these efforts. Although intense myeloablation in general is associated with a lower risk of relapse and graft rejection, greater regimen intensity also leads to a higher rate of transplant related morbidity and mortality (TRM). Inclusion of TBI specifically in conditioning regimens has been shown to result in organ toxicity and subsequent malignant neoplasm. To help mitigate the risks of myeloablative conditioning (MAC) regimens, non-TBI and reduced-intensity conditioning (RIC) regimens have been investigated as a means of reducing TRM and increasing access of transplantation to patients with age disadvantages or significant comorbidities. Despite ongoing investigation, studies comparing conditioning regimens of UCBT, with and without TBI, remain limited. This study, using real-world data collected from 4 institutions, retrospectively analyzed the impact of TBI as part of MAC or RIC conditioning regimens in patients undergoing UCBT. Methods: This is a retrospective study that analyzed the outcomes of 136 patients receiving umbilical cord blood transplants at four institutions. Seventy-nine patients received myeloablative condition (MAC), in which 36 underwent TBI and 33 did not; 67 patients received reduced-intensity condition (RIC), in which 24 underwent TBI and 43 did not. Univariate and multivariate analyses were conducted to compare the outcomes and the post-transplant complications between patients who did and did not undergo TBI in MAC subgroup and RIC subgroup, respectively. Results: Characteristics of UCBT recipients who did and did not undergo TBI, stratified by conditioning regimen were compared with both multivariate and univariate analyses and didn't see significant difference. We didn't observe significant difference in GVHD and transplant-related infection incidence rates between patient subgroup that did and did not undergo TBI as part of their pre-UCBT conditioning regimen via both multivariate and univariate analyses. In RIC subgroup, the patients who underwent TBI appeared to have superior overall survival (adjusted hazard ratio [aHR]=0.25, 95% confidence interval [CI]: 0.09-0.66, p=0.005) (Figure 1), progression-free survival (aHR=0.26, 95% CI: 0.10-0.66, p=0.005) (Figure 2), and shorter time to neutrophil engraftment (aHR=6.26, 95% CI: 2.27 - 17.31, p=0.0004) (Figure 3). However, in MAC subgroup, there were no statistically significant difference between using and not using TBI. There were also no differences between the patients who either underwent or not underwent TBI in terms of acute or chronic GVHD rates or rates of transplant-related infections in both subgroups. Conclusion: Combining with RIC, TBI may improve OS, PFS, and neutrophil engraftment time. However, the incidences of other post-transplant complication were comparable between patients who underwent and did not undergo TBI as part of conditioning regimens during umbilical cord blood transplant. Figure 1 Figure 1. Disclosures No relevant conflicts of interest to declare.

Autologous hematopoietic cell transplantation (autoHCT) has become a critical component in the treatment of pediatric malignancies, allowing for high-dose chemotherapy to be given safely and with greater efficacy in a subset of children at high risk for relapse. Risk factors associated with hospital length of stay (LOS) in adults undergoing autoHCT have been studied extensively; however, there is a paucity of studies describing risk factors associated with LOS and health care cost in children undergoing autoHCT. This study sought to identify factors influencing LOS and cost in pediatric autoHCT. We assessed LOS from autologous stem cell infusion from day 0 (D0) in 100 autoHCT admissions in 73 patients with malignant disease between 2007 and 2019. We evaluated demographic, pre-transplantation, post-transplantation, and socioeconomic variables to identify potential risk factors associated with LOS and cost. AutoHCT cost data were provided by the Pediatric Health Information System database. Indications for autoHCT included neuroblastoma (35.6%), brain tumor (27.4%), and relapsed lymphoma (24.7%). The median patient age was 4.88 years (range, 0.72 to 22 years), with 71% age12 years, and the cohort was 63% male, 77% white, and 41% Hispanic. The median LOS from D0 was 19 days (range, 13 to 100 days). On multivariable analysis, age12 years compared with 2 to 12 years (estimate, -8.9 days; 95% confidence interval [CI], -15.1 to -2.8; P = .004) and complete remission/very good partial response disease status (estimate, -5.0 days; 95% CI, -9.6 to -0.4 days; P = .031) were associated with a significantly decreased median LOS, whereas Hispanic ethnicity (estimate, +6.8 days; 95% CI, 1.1 to 12.6 days; P = .019),5 days of fever (estimate, +7.3 days; 95% CI, 1.4 to 13.2 days; P = .015), and pediatric intensive care unit (PICU) LOS (estimate, +14.9 days; 95% CI, 1.8 to 28.0 days; P = .025) were associated with a significant increase in median LOS. The median cost per transplantation admission was $96,850 (range, $39,833 to $587,321). Multivariable analysis showed that age12 years (estimate, -$6,776; 95% CI, -$71,787 to -$11,402; P = .007) or2 years (estimate, -$32,426; 95% CI, -$53,507 to -$11,345; P = .003), and complete remission/very good partial response disease status (estimate, -$20,266; 95% CI, -$40,211 to -$322; P = .046) were associated with significantly decreased median cost, whereas5 days of fever (estimate, +$58,886; 95% CI, $30,667 to $87,105; P.001) and PICU admission (estimate, +$102,458; 95% CI, $23,843 to $181,076; P = .011) were associated with significantly increased median cost. In summary, fever and PICU stay were found to be risk factors for increased LOS and cost. Age12 years and Hispanic ethnicity were risk factors for increased LOS, whereas age2 years and12 years and female sex were associated with decreased cost. Further investigation to determine specific factors influencing LOS and cost is warranted to identify potentially modifiable risks within these patient populations.

Introduction: Allogeneic hematopoietic cell transplantation (HCT) is curative for children &young adults with hematologic malignancies but is associated with a significant risk of morbidity and mortality. The HCT-comorbidity index (HCT-CI) is a prognostic tool that can predict non-relapse mortality (NRM) based on pre-HCT risk factors; however, it is less applicable for pediatric and young adult patients as some comorbidities are age-related while others are defined differently in this younger population. The objective of this study was to test each component of HCT-CI and additional pediatric-specific comorbidity definitions on NRM in children, adolescents, and young adults with hematologic malignancies, with the aim of supplementing the HCT-CI to create a broader risk score for this younger population. Methods: Using the Center for International Blood and Marrow Transplant Research (CIBMTR) registry, patients 95th percentile, ≥18yo: >35kg/m2) and underweight ( Results: 5,790 patients were included in this study. The median age was 22 (0-39)yo. HCT indications were primarily acute myeloid leukemia (43%) and acute lymphoblastic leukemia (31%). Conditioning was mostly myeloablative (85%). Most common donor types were cord blood (35%), matched unrelated (28%) and matched sibling (18%). Donor source was peripheral blood stem cells (41%), umbilical cord blood (35%), or bone marrow (24%). Using the HCT-CI resulted in scores of 0, 1-2, and ≥3 for 45%, 26%, and 29% of the patient population, respectively. By adding pediatric-specific definitions to the HCT-CI, we developed the Expanded HCT-CI, with scores of 0, 1-2, and ≥3 translating to 31%, 28%, and 33% of the patients, respectively. Further, comorbidities with HR The Expanded HCT-CI discriminated risk of NRM, with scores of 1-2 and ≥3 demonstrating hazard ratios (HR) of 1.02 (95%CI 0.75-1.38) and 1.52 (95%CI 1.16-1.99), respectively, vs. score of 0 (p Conclusion: The Expanded HCT-CI is a more comprehensive and practical pre-HCT risk score to predict NRM in children, adolescents, and young adults with hematologic malignancies, improving the sensitivity of the original HCT-CI while retaining the same level of specificity. This novel model can be widely used by transplant physicians to better assess HCT risks when counseling patients and improve study designs targeting the younger patient population. Disclosures Schiller: Agios: Consultancy, Research Funding, Speakers Bureau; Amgen: Consultancy, Current equity holder in publicly-traded company, Research Funding, Speakers Bureau; Abbvie: Research Funding; Karyopharm: Research Funding; Jazz Pharmaceuticals: Research Funding; AstraZeneca: Consultancy; Incyte: Consultancy, Research Funding, Speakers Bureau; Novartis: Consultancy, Research Funding; Stemline: Speakers Bureau; Celgene: Research Funding, Speakers Bureau; Sanofi: Speakers Bureau; Ono Pharma: Consultancy; Gilead: Speakers Bureau; Constellation: Research Funding; Cyclacel: Research Funding; Celator: Research Funding; Pfizer: Current equity holder in publicly-traded company, Research Funding; Regimmune: Research Funding; Johnson & Johnson: Current equity holder in publicly-traded company; Onconova: Research Funding; Daiichi Sankyo: Research Funding; Samus: Research Funding; Kite Pharma: Research Funding; Geron: Research Funding; FujiFilm: Research Funding; Forma: Research Funding; Bristol-Myers Squibb: Current equity holder in publicly-traded company, Research Funding; DeltaFly: Research Funding; Deciphera: Research Funding; Astellas Pharma: Honoraria, Research Funding; Ariad: Research Funding; Actinium: Research Funding; Mateon: Research Funding; Genentech-Roche: Research Funding; Gamida: Research Funding; Tolero: Research Funding; Kaiser Permanente: Consultancy; Trovagene: Research Funding; Sangamo: Research Funding; MedImmune: Research Funding. Stadtmauer:Bristol Myers Squibb: Consultancy, Research Funding; Takeda: Consultancy; AbbVie: Research Funding; Sanofi: Consultancy. Pasquini:Bristol Myers Squibb: Consultancy; BMS: Membership on an entity's Board of Directors or advisory committees, Research Funding; Amgen: Other; Novartis: Research Funding; Kite: Research Funding. Thakar:Infectious Disease Research Institute: Consultancy. Sorror:Jazz Pharmaceutical: Other: Honorarium for Advisory role. .

Introduction: Allogeneic hematopoietic cell transplantation (HCT) can be employed as curative therapy for many non-malignant diseases but there is risk of transplant related complications. Pre-HCT, patient-specific factors can help inform risk using the HCT comorbidity index (HCT-CI); however, it can be difficult to apply in children and young adults, where assessment of organ function differs from those defined by the HCT-CI. We aimed to supplement the HCT-CI with pediatric-specific comorbidity definitions to broaden the use of the HCT-CI for pediatric & young adult patients with non-malignant diseases. Methods: Patients 95th percentile for Results: 2,815 patients received allogeneic HCT for non-malignant diseases (25.8% aplastic anemia, 26.5% immune deficiency, 18.2% hemoglobinopathies, 29.5% other) at a median age of 6 ( In multivariable analysis, comorbidities with pediatric-specific definitions demonstrated increased hazards of death, including in underweight patients (HR 1.55, 95% confidence interval (CI) 1.18-2.04), those with history of mechanical ventilation (HR 1.85, 95%CI 1.39-2.48), mild renal disease by eGFR (HR 1.49, 95%CI 1.11-2.0), or moderate/severe renal disease by eGFR (HR 2.04, 95%CI 1.1-3.26). Therefore, comorbidities were expanded to include these definitions in the Expanded HCT-CI. Expanding the comorbidity definitions increased the number of patients identified as having pre-HCT comorbidities: 35% were categorized with scores of 0, 32% with scores of 1-2, and 33% with scores of ≥3. Figure 1 shows the expanded comorbidity definitions and effect on OS. Arrhythmia and Psychiatric diseases were noted to have HR Conclusion: Modifications to definitions in the HCT-CI can create a pre-HCT risk tool that more broadly classifies organ dysfunction for children & young adults. By expanding the comorbidity definitions, 24% more patients were re-categorized as having at least 1 comorbidity, allowing for better assessment of pre-HCT risk. This expanded HCT-CI performs as well as the HCT-CI but is more broadly applicable to children & young adults with non-malignant diseases and can aid physicians in pre-HCT counseling. Disclosures Schiller: Johnson & Johnson: Current equity holder in publicly-traded company; Karyopharm: Research Funding; Sangamo: Research Funding; AstraZeneca: Consultancy; Amgen: Consultancy, Current equity holder in publicly-traded company, Research Funding, Speakers Bureau; Agios: Consultancy, Research Funding, Speakers Bureau; Incyte: Consultancy, Research Funding, Speakers Bureau; Novartis: Consultancy, Research Funding; Ono Pharma: Consultancy; Celgene: Research Funding, Speakers Bureau; Sanofi: Speakers Bureau; Gilead: Speakers Bureau; Stemline: Speakers Bureau; Onconova: Research Funding; Samus: Research Funding; Regimmune: Research Funding; Pfizer: Current equity holder in publicly-traded company, Research Funding; Cyclacel: Research Funding; Daiichi Sankyo: Research Funding; Deciphera: Research Funding; DeltaFly: Research Funding; Bristol-Myers Squibb: Current equity holder in publicly-traded company, Research Funding; Forma: Research Funding; FujiFilm: Research Funding; Gamida: Research Funding; Genentech-Roche: Research Funding; Geron: Research Funding; Jazz Pharmaceuticals: Research Funding; Kite Pharma: Research Funding; Mateon: Research Funding; MedImmune: Research Funding; Tolero: Research Funding; Trovagene: Research Funding; Kaiser Permanente: Consultancy; Celator: Research Funding; Constellation: Research Funding; Astellas Pharma: Honoraria, Research Funding; Ariad: Research Funding; Actinium: Research Funding; Abbvie: Research Funding. Stadtmauer:Amgen Inc, Celgene Corporation, Janssen Biotech Inc, Novartis, Onyx Pharmaceuticals, an Amgen subsidiary, Takeda Oncology: Consultancy. Pasquini:Bristol Myers Squibb: Consultancy; BMS: Membership on an entity's Board of Directors or advisory committees, Research Funding; Amgen: Other; Novartis: Research Funding; Kite: Research Funding. Thakar:Infectious Disease Research Institute: Consultancy. Sorror:Jazz Pharmaceutical: Other: Honorarium for Advisory role. .

Introduction 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). Objectives 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. Methods 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. Results Of 133 subjects from Conclusion 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.

Children with acute leukemia who relapse after hematopoietic cell transplantation (HCT) have few therapeutic options. We studied 251 children and young adults with acute myelogenous or lymphoblastic leukemia who underwent a second HCT for relapse after their first HCT. The median age at second HCT was 11 years, and the median interval between first and second HCT was 17 months. Most of the patients (n = 187; 75%) were in remission, received a myeloablative conditioning regimen (n = 157; 63%), and underwent unrelated donor HCT (n = 230; 92%). The 2-year probability of leukemia-free survival (LFS) was 33% after transplantation in patients in remission, compared with 19% after transplantation in patients not in remission (P = .02). The corresponding 8-year probabilities were 24% and 10% (P = .003). A higher rate of relapse contributed to the difference in LFS. The 2-year probability of relapse after transplantation was 42% in patients in remission and 56% in those in relapse (P = .05). The corresponding 8-year probabilities were 49% and 64% (P = .04). These data extend the findings of others showing that patients with a low disease burden are more likely to benefit from a second transplantation. Late relapse led to a 10% decrement in LFS beyond the second year after second HCT. This differs from first HCT, in which most relapses occur within 2 years after HCT.

Emergency (stress) granulopoiesis is an episodic process for the production of granulocytes in response to infectious challenge. We previously determined that Fanconi C, a component of the Fanconi DNA-repair pathway, is necessary for successful emergency granulopoiesis. Fanconi anemia results from mutation of any gene in this pathway and is characterized by bone marrow failure (BMF) in childhood and clonal progression in adolescence. Although murine Fanconi anemia models exhibit relatively normal steady-state hematopoiesis, FANCC−/− mice are unable to mount an emergency granulopoiesis response. Instead, these mice develop BMF and die during repeated unsuccessful emergency granulopoiesis attempts. In FANCC−/− mice, BMF is associated with extensive apoptosis of hematopoietic stem and progenitor cells through an undefined mechanism. In this study, we find that TP53 haploinsufficiency completely rescues emergency granulopoiesis in FANCC−/− mice and protects them from BMF during repeated emergency granulopoiesis episodes. Instead, such recurrent challenges accelerated clonal progression in FANCC−/−TP53+/− mice. In FANCC−/− mice, BMF during multiple emergency granulopoiesis attempts was associated with increased ataxia telangiectasia and Rad3-related protein (Atr) and p53 activation with each attempt. In contrast, we found progressive attenuation of expression and activity of Atr, and consequent p53 activation and apoptosis, in the bone marrow of FANCC−/−TP53+/− mice during this process. Therefore, activation of Atr—with consequent Fanconi-mediated DNA repair or p53-dependent apoptosis—is an essential component of emergency granulopoiesis and it protects the bone marrow from genotoxic stress during this process.

Acquired aplastic anemia (AA) is a bone marrow failure syndrome characterized by peripheral cytopenias and bone marrow hypoplasia. It is ultimately fatal without treatment, most commonly from infection or hemorrhage. Current treatments focus on suppressing immune-mediated destruction of bone marrow stem cells or replacing hematopoietic stem cells (HSCs) by transplantation. Our incomplete understanding of the pathogenesis of AA has limited development of targeted treatment options. Mesenchymal stem cells (MSCs) play a vital role in HSC proliferation; they also modulate immune responses and maintain an environment supportive of hematopoiesis. Some of the observed clinical manifestations of AA can be explained by mesenchymal dysfunction. MSC infusions have been shown to be safe and may offer new approaches for the treatment of this disorder. Indeed, infusions of MSCs may help suppress auto-reactive, T-cell mediated HSC destruction and help restore an environment that supports hematopoiesis. Small pilot studies using MSCs as monotherapy or as adjuncts to HSC transplantation have been attempted as treatments for AA. Here we review the current understanding of the pathogenesis of AA and the function of MSCs, and suggest that MSCs should be a target for further research and clinical trials in this disorder.

Key Points Optimal salvage therapy for refractory HLH is unknown. In our patient, ruxolitinib treatment led to clinical remission of refractory HLH.

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.

Children with multiple relapsed or refractory leukemia have dismal survival. Research has identified engagement of immune checkpoint receptors (e.g., PD-1, PD-L1 and CTLA-4) as a mechanism for treatment resistance. For adult cancer, inhibitors of PD-1 (nivolumab) and CTLA-4 (ipilimumab) have shown promise with response rates ranging from 7 to 40%. In vitro studies using acute myeloid leukemia cell lines have shown that acute myeloid leukemia blasts may similarly utilize the PD-1/PD-L1 axis to evade an anticancer immune response. We report the first case of a pediatric patient with multiple relapsed/refractory leukemia treated with nivolumab, ipilimumab and 5-azacytidine who tolerated therapy with brief improvement of symptoms.

Patients with acute myeloid leukemia (AML) who relapse after hematopoietic stem cell transplantation (HCT) have dismal outcomes. Our ability to predict those at risk for relapse is limited. We examined chimerism trends post-HCT in 63 children who underwent HCT for AML or myelodysplastic syndrome (MDS). Mixed T-cell chimerism at engraftment and absence of chronic graft versus host disease (cGVHD) were associated with relapse (P = 0.04 and P = 0.02, respectively). Mixed T-cell chimerism at engraftment was predictive in patients without cGVHD (P = 0.03). Patients with engraftment mixed T-cell chimerism may warrant closer disease monitoring and consideration for early intervention.