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PURPOSE Nonresponse and relapse after CD19-chimeric antigen receptor (CAR) T-cell therapy continue to challenge survival outcomes. Phase II landmark data from the ELIANA trial demonstrated nonresponse and relapse rates of 14.5% and 28%, respectively, whereas use in the real-world setting showed nonresponse and relapse rates of 15% and 37%. Outcome analyses describing fate after post-CAR nonresponse and relapse remain limited. Here, we aim to establish survival outcomes after nonresponse and both CD19+ and CD19– relapses and explore treatment variables associated with inferior survival. METHODS We conducted a retrospective multi-institutional study of 80 children and young adults with B-cell acute lymphoblastic leukemia experiencing nonresponse (n = 23) or relapse (n = 57) after tisagenlecleucel. We analyze associations between baseline characteristics and these outcomes and establish survival rates and salvage approaches. RESULTS The overall survival (OS) at 12 months was 19% across nonresponders (n = 23; 95% CI, 7 to 50). Ninety-five percent of patients with nonresponse had high preinfusion disease burden. Among 156 morphologic responders, the cumulative incidence of relapse was 37% (95% CI, 30 to 47) at 12 months (CD19+; 21% [15 to 29], CD19–; 16% [11 to 24], median follow-up; 380 days). Across 57 patients experiencing relapse, the OS was 52% (95% CI, 38 to 71) at 12 months after time of relapse. Notably, CD19– relapse was associated with significantly decreased OS as compared with patients who relapsed with conserved CD19 expression (CD19– 12-month OS; 30% [14 to 66], CD19+ 12-month OS; 68% [49 to 92], P = .0068). Inotuzumab, CAR reinfusion, and chemotherapy were used as postrelapse salvage therapy with greatest frequency, yet high variability in treatment sequencing and responses limits efficacy analysis across salvage approaches. CONCLUSION We describe poor survival across patients experiencing nonresponse to tisagenlecleucel. In the post-tisagenlecleucel relapse setting, patients can be salvaged; however, CD19– relapse is distinctly associated with decreased survival outcomes.

Immunodeficient mice reconstituted with immune systems from patients, or personalized immune (PI) mice, are powerful tools for understanding human disease. Compared with immunodeficient mice transplanted with human fetal thymus tissue and fetal liver–derived CD34+ cells administered i.v. (Hu/Hu mice), PI mice, which are transplanted with human fetal thymus and adult bone marrow (aBM) CD34+ cells, demonstrate reduced levels of human reconstitution. We characterized APC and APC progenitor repopulation in human immune system mice and detected significant reductions in blood, bone marrow (BM), and splenic APC populations in PI compared with Hu/Hu mice. APC progenitors and hematopoietic stem cells (HSCs) were less abundant in aBM CD34+ cells compared with fetal liver–derived CD34+ cell preparations, and this reduction in APC progenitors was reflected in the BM of PI compared with Hu/Hu mice 14–20 wk posttransplant. The number of HSCs increased in PI mice compared with the originally infused BM cells and maintained functional repopulation potential, because BM from some PI mice 28 wk posttransplant generated human myeloid and lymphoid cells in secondary recipients. Moreover, long-term PI mouse BM contained functional T cell progenitors, evidenced by thymopoiesis in thymic organ cultures. Injection of aBM cells directly into the BM cavity, transgenic expression of hematopoietic cytokines, and coinfusion of human BM-derived mesenchymal stem cells synergized to enhance long-term B cell and monocyte levels in PI mice. These improvements allow a sustained time frame of 18–22 wk where APCs and T cells are present and greater flexibility for modeling immune disease pathogenesis and immunotherapies in PI mice.

Chimeric antigen-receptor (CAR)-associated hemophagocytic lymphohistiocytosis (HLH)-like toxicities involving hyperferritinemia, multi-organ dysfunction, coagulopathy, and/or hemophagocytosis are described as occurring in a subset of patients with cytokine release syndrome (CRS). Case series report poor outcomes for those with B-acute lymphoblastic leukemia (B-ALL) who develop HLH-like toxicities, although larger outcomes analyses of children and young adults (CAYA) with B-ALL who develop these toxicities following commercial tisagenlecleucel are not described. Using a multi-institutional database of 185 CAYA with B-ALL, we conducted a retrospective cohort study including groups that developed HLH-like toxicities, high grade CRS without HLH-like toxicities, or no to low grade CRS without HLH-like toxicities. Primary objectives included characterizing the incidence, outcomes, and pre-infusion factors associated with HLH-like toxicities. Among 185 CAYA infused with tisagenlecleucel, 26 (14.1%) met criteria for HLH-like toxicities. One-year overall survival and relapse-free survival were 25.7% and 4.7% in those with HLH-like toxicities, compared with 80.1% and 57.6% in those without. In multivariable analysis for death, meeting criteria for HLH-like toxicities carried a hazard ratio of 4.61 (95% confidence interval: 2.41-8.83), controlling for disease burden, age, and sex. Patients who developed HLH-like toxicities had higher pre-tisagenlecleucel disease burden, ferritin, C-reactive protein levels, and lower platelet and absolute neutrophil counts than patients with high grade or no/low grade CRS without HLH-like toxicities. Overall, CAYA with B-ALL who developed HLH-like toxicities following tisagenlecleucel experienced high rates of relapse and non-relapse mortality, indicating the urgent need for further investigations into prevention and optimal management of patients who develop HLH-like toxicities following tisagenlecleucel.

A recent survey of pediatric hematology oncology (PHO) physicians identified that a majority believe fellows are struggling to find jobs that align with their goals. Career development for trainees has historically been home institution-specific, limiting fellows' exposures to career path possibilities. The "virtual-Symposium of Pediatric Hematology/Oncology of New York (v-SYMPHONY)" instituted a tristate Career Development Series for PHO trainees to better address their needs and increase awareness of the variety of PHO career opportunities.The v-SYMPHONY Career Development Series incorporated three sessions: (a) institutional perspective, (b) individual perspectives, and (c) nuts and bolts of job search. Pre- and post-series surveys were administered to participants to measure impact.Forty-one fellows registered for the series and completed a pre-survey. Over half (54%) were in their third or later year of fellowship. Careers with a clinical focus were the most commonly desired career path (59%). Most had received career development advice only from faculty within their institutions (90%). Post-surveys were completed by 11 PHO fellows. Overall, 100% of respondents reported benefiting from the career sessions and recommended the series should be repeated annually. Over 90% learned new information to prepare for the job search.The v-SYMPHONY Career Development Series for PHO fellows across multiple institutions was established and was extremely well received by its participants. PHO fellows agreed that these sessions were beneficial in helping prepare them for the job search process. An annual regional Career Development Series is feasible and is strongly suggested to support PHO fellows.

Risk factors associated with the progression of acute kidney injury to chronic kidney disease in pediatric allogeneic hematopoietic cell transplantation (AlloHCT) recipients are not well described. We retrospectively investigated the risk factors for the progression to CKD in 275 AlloHCT recipients. AKI and CKD grading was defined according to the Kidney Disease Improving Global Outcomes classification. PRI90 was defined as persistent renal insufficiency (estimated GFR

Remarkable complete response rates have been shown with tisagenlecleucel, a chimeric antigen receptor (CAR) T-cell therapy targeting CD19, in patients up to age 26 years with refractory/relapsed B-cell acute lymphoblastic leukemia; it is US Food and Drug Administration approved forthis indication. Currently, patients receive a single dose of tisagenlecleucel across a wide doserange of 0.2 to 5.0× 106 and 0.1 to 2.5× 108 CAR T cells per kg for patients ≤50 and >50 kg, respectively. The effect of cell dose on survival and remission is not yet well established. Our primary goal was to determine if CAR T-cell dose affects overall survival (OS), event-free survival (EFS), or relapse-free-survival (RFS) in tisagenlecleucel recipients. Retrospective data were collected from Pediatric Real World CAR Consortium member institutions and included 185 patients infused with commercial tisagenlecleucel. The median dose of viable transduced CAR T cells was 1.7× 106 CAR T cells per kg. To assess the impact of cell dose, we divided responders into dose quartiles: 0.134 to 1.300× 106 (n= 48 [27%]), 1.301 to 1.700× 106 (n= 46 [26%]), 1.701 to 2.400×106 (n= 43 [24%]), and 2.401 to 5.100× 106 (n= 43 [24%]). OS, EFS, and RFS were improved in patients who received higher doses of tisagenlecleucel (P= .031, .0079, and .0045, respectively). Higher doses of tisagenlecleucel were not associated with increased toxicity. Because the current tisagenlecleucel package insert dose range remains broad, this work has implications in regard totargeting higher cell doses, within the approved dose range, to optimize patients' potential for long-standing remission.

Chimeric antigen receptor (CAR) T cells provide a therapeutic option in hematologic malignancies. However, treatment failure after initial response approaches 50%. In allogeneic hematopoietic cell transplantation, optimal fludarabine exposure improves immune reconstitution, resulting in lower nonrelapse mortality and increased survival. We hypothesized that optimal fludarabine exposure in lymphodepleting chemotherapy before CAR T-cell therapy would improve outcomes. In a retrospective analysis of patients with relapsed/refractory B-cell acute lymphoblastic leukemia undergoing CAR T-cell (tisagenlecleucel) infusion after cyclophosphamide/fludarabine lymphodepleting chemotherapy, we estimated fludarabine exposure as area under the curve (AUC; mg × h/L) using a validated population pharmacokinetic (PK) model. Fludarabine exposure was related to overall survival (OS), cumulative incidence of relapse (CIR), and a composite end point (loss of B-cell aplasia [BCA] or relapse). Eligible patients (n = 152) had a median age of 12.5 years (range

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

Steroid-refractory acute graft-versus-host disease (SR-aGVHD) following hematopoietic cell transplantation (HSCT) is associated with poor clinical outcomes. Currently, there are no safe and effective therapies approved for use in the pediatric population under the age of 12 years. Accordingly, there is an urgent need for new treatments that are safe, well tolerated, and effective in managing this debilitating and potentially fatal complication of HSCT. In early phase clinical trials, mesenchymal stromal cells (MSCs) have demonstrated efficacy in the treatment of acute GVHD (aGVHD) in pediatric patients. We now report the results of a phase 3, prospective, single-arm, multicenter study (NCT02336230) in 54 children with primary SR-aGVHD who were naive to other immunosuppressant therapies for aGVHD treated with MSC product (remestemcel-L) dosed at 2 × 106 cells/kg twice weekly for 4 weeks. Remestemcel-L therapy significantly improved day 28 overall response rate (OR) compared with the prespecified control OR value of 45% (70.4% versus 45%, P = .0003). The statistically significant OR (70.4%) was sustained through day 100, including an increase in complete response from 29.6% at day 28 to 44.4% at day 100. Overall survival was 74.1% at day 100 and 68.5% at day 180. Overall response in all participants at day 28 was highly predictive of improved survival through 180 days, and survival was significantly greater in day 28 responders compared with nonresponders through day 100 (86.8% versus 47.1% for responders and nonresponders, respectively, P = .0001) and through day 180 (78.9% versus 43.8%, P = .003). Remestemcel-L was well tolerated with no identified infusion-related toxicities or other safety concerns. This study provides robust, prospective evidence of the safety, tolerability, and efficacy of remestemcel-L as first-line therapy after initial steroid failure in pediatric SR-aGVHD.

Clinical outcomes in children with steroid-refractory acute graft-versus-host disease (SR-aGVHD) are generally poor, with a high mortality rate and limited therapeutic options. Here we report our updated investigational experience with mesenchymal stromal cell (MSC) therapy with remestemcel-L in a multicenter expanded access protocol (ClinicalTrials.gov identifier NCT00759018) in 241 children with aGVHD who failed to respond to steroids with or without other secondary and tertiary immunosuppressive therapies. A total of 241 children with grade B-D SR-aGVHD were enrolled at 50 sites in 8 countries and received 8 biweekly i.v. infusions of human MSCs, 2 × 106 per kg for 4 weeks, with an option for an additional 4 weekly infusions after day +28 for subjects who achieved either a partial response (PR) or mixed response. The mean age of the subjects was 9.6 years; 39% were female, and 60% were white. Most of the subjects had grade C (30%) or grade D (50%) disease, and in most cases, the subjects had failed to respond to other immunosuppressive agents after failing steroids. The primary endpoint was overall response (OR; the sum of complete response [CR] and PR) at day +28. Across all subjects, a 28-day OR was observed in 157 patients (65.1%), with 34 (14.1%) achieving CR and 123 (51.3%) achieving PR. Stratified by aGVHD grade at baseline, the OR rate at day +28 was 72.9% for patients with aGVHD grade B, 67.1% for those with aGVHD grade C, and 60.8% for those with aGVHD grade D. Survival through day +100, a secondary endpoint of the study, was 66.9% (n = 160 of 239). Importantly, survival through day +100 was significantly greater in subjects who achieved a day +28 OR compared with nonresponders (82.1% versus 38.6%; P < .001, log-rank test). Remestemcel-L safety was generally well tolerated, with no infusional toxicity and no identified safety concerns. In summary, this update to the remestemcel-L expanded access program confirms the reported clinical and survival benefits of remestemcel-L therapy in children with aGVHD who have exhausted all conventional therapeutic options.

Key Points CD19 CAR therapy for R/R EM disease, particularly CNS, offers a beneficial option with similar toxicity and survival to BM disease.There was no increased cytokine release syndrome or neurotoxicity in patients with R/R EM disease, including active CNS disease at infusion., Visual Abstract, Chimeric antigen receptor (CAR) T cells have transformed the therapeutic options for relapsed/refractory (R/R) B-cell acute lymphoblastic leukemia. Data for CAR therapy in extramedullary (EM) involvement are limited. Retrospective data were abstracted from the Pediatric Real World CAR Consortium (PRWCC) of 184 infused patients from 15 US institutions. Response (complete response) rate, overall survival (OS), relapse-free survival (RFS), and duration of B-cell aplasia (BCA) in patients referred for tisagenlecleucel with EM disease (both central nervous system (CNS)3 and non-CNS EM) were compared with bone marrow (BM) only. Patients with CNS disease were further stratified for comparison. Outcomes are reported on 55 patients with EM disease before CAR therapy (CNS3, n = 40; non-CNS EM, n = 15). The median age at infusion in the CNS cohort was 10 years (range

Infants with B-cell acute lymphoblastic leukemia (B-ALL) have poor outcomes because of chemotherapy resistance leading to high relapse rates. Tisagenlecleucel, a CD19-directed chimeric antigen receptor T-cell (CART) therapy, is US Food and Drug Administration approved for relapsed or refractory B-ALL in patients ≤25 years; however, the safety and efficacy of this therapy in young patients is largely unknown because children M1 marrow) were refractory to this therapy (n = 5). Overall, tisagenlecleucel was tolerable in this population, with only 3 patients experiencing ≥grade 3 cytokine release syndrome. No neurotoxicity was reported. This is the largest report of tisagenlecleucel use in infant B-ALL and shows that this therapy is safe and can be effective in this population. Incorporating this novel immunotherapy into the treatment of infant B-ALL offers a promising therapy for a highly aggressive leukemia.

Introduction Chimeric antigen receptor (CAR) T cell therapy has been extremely efficacious in pediatric patients with multiply relapsed and/or refractory B-cell acute lymphoblastic leukemia (B-ALL) with overall remission rates of 81% by three months post-infusion (Maude et al., N Engl J Med, 2018), and achieved FDA approval for this indication. In order for the product to meet the standards of this approval for commercial release, both the leukapheresis and manufactured products must meet a variety of specific requirements, some of which are more stringent than those in these pivotal clinical trials. The Managed Access Program (MAP) provides access to tisagenlecleucel for patients with B-ALL or diffuse large B-cell lymphoma that is out of specification (OOS) for whom repeat leukapheresis is not feasible. Patients may also receive OOS tisagenlecleucel by applying for a single-patient Investigational New Drug (IND). Previous reports have shown no difference in efficacy or toxicity between patients receiving tisagenlecleucel that meets commercial release specifications and those receiving OOS tisagenlecleucel (Grupp, et al., Blood Abstr 614, 2019; Jaglowski, et al., Blood Abstr 627, 2019). This study seeks to evaluate outcomes in pediatric and young adult patients who received tisagenlecleucel via the MAP or a single-patient IND in our Pediatric Real World CAR Consortium (PRWCC). Methods Retrospective data were abstracted from the PRWCC database of patients with relapsed/refractory B-ALL from fifteen different US institutions who received tisagenlecleucel as an FDA-approved therapy outside the context of a clinical trial. Patients whose cellular product was obtained through the MAP (NCT03601442) or with single patient IND approval due having either a cryopreserved leukapheresis product and/or manufactured tisagenlecleucel that did not meet specifications for commercial release were categorized as MAP/IND and those whose product met all release criteria were categorized as standard of care (SOC). Results Among 185 total infused patients in our database, 24 (13%) received tisagenlecleucel either via the MAP (n=14) or a single patient IND (n=10). Baseline patient and disease characteristics were not significantly different for MAP/IND patients versus the SOC cohorts (Table 1). Median duration of follow-up post-CAR T cell infusion for these infused patients was 342.5 days (range 107-780) versus 318 days (range 6-863) for the SOC cohort (p=0.43). Reasons for products being OOS included cell viability 9 months prior (n=1), and determination of residual beads >50 beads/3x106cells (n=1). Overall survival at 6- and 12-months was 96% versus 83% and 85% versus 70% for the MAP/IND versus SOC, respectively. Event-free survival at 6- and 12-months was 65% versus 63% and 55% versus 51%, respectively. Probability of continued remission at 6- and 12-months among patients who achieved a complete remission (CR) at day 28 was 79% versus 75% and 66% versus 63% for the MAP/IND versus SOC, respectively (Figure 1). Comparing toxicities between patients in the MAP/IND versus SOC cohorts, cytokine release syndrome (CRS, any grade) occurred in 46% versus 61%, CRS (>grade 3) in 17% versus 19%, immune effector cell-associated neurotoxicity syndrome (ICANS) in 8% versus 22%, and infectious complications in 54% vs. 37%, respectively (p=ns for all). Conclusions In our retrospective cohort evaluating the use of tisagenlecleucel to treat pediatric and young adult patients with relapsed/refractory B-ALL in the real-world setting, neither the efficacy nor safety of tisagenlecleucel seem to be compromised by use of products OOS for commercial release. Larger studies are needed to further delineate specific cut-offs outside of which either efficacy and/or safety may truly be impacted. Disclosures Phillips: Novartis: Membership on an entity's Board of Directors or advisory committees. Stefanski:Novartis: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Margossian:Novartis: Membership on an entity's Board of Directors or advisory committees; Jazz Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees. Verneris:Novartis: Membership on an entity's Board of Directors or advisory committees; Fate Therapeutics: Consultancy, Current equity holder in publicly-traded company; Bmogen: Consultancy, Current equity holder in publicly-traded company; Uptodate: Consultancy. Myers:Novartis: Consultancy, Honoraria, Other: ELIANA trial Steering Committee, Speakers Bureau. Brown:Janssen: Membership on an entity's Board of Directors or advisory committees; Servier: Membership on an entity's Board of Directors or advisory committees; Jazz: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees. Qayed:Mesoblast: Consultancy; Novartis: Consultancy. Hermiston:Novartis: Membership on an entity's Board of Directors or advisory committees; Sobi: Membership on an entity's Board of Directors or advisory committees. Satwani:Mesoblast: Consultancy; Takeda: Consultancy. Curran:Novartis: Consultancy, Research Funding; Celgene: Research Funding; Mesoblast: Consultancy. Mackall:Apricity Health: Consultancy, Current equity holder in private company; Lyell Immunopharma: Consultancy, Current equity holder in private company; BMS: Consultancy; Nektar Therapeutics: Consultancy; Allogene: Current equity holder in publicly-traded company; NeoImmune Tech: Consultancy. Laetsch:Novartis: Consultancy, Research Funding; Bayer: Research Funding; Pfizer: Research Funding; Cellectis: Consultancy.

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

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.

OBJECTIVESDuring the coronavirus disease 2019 pandemic, professional organizations recommended preferential transfer of pediatric patients from general hospitals to children’s hospitals. Patients previously receiving all care at other facilities would be new to children’s hospitals. As a proxy for care consolidation, we sought to describe changes in new patient encounters at children’s hospitals and test associations between local severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) incidences and new patient encounters.METHODSThis retrospective cohort study included patients aged 6 months to 18 years admitted to children’s hospitals from March 15, 2019, to June 30, 2019 (control) and 2020 (pandemic period). Primary outcome was odds ratio of being a new versus established patient by study period. Generalized linear models estimated odds of being a new patient with adjustment for diagnosis. Analyses were also stratified by local SARS-CoV-2 transmission.RESULTSThere were 205 283 encounters (45.3% new patients). New patients were more common in the pandemic period than in the control (46.4 vs 44.7%, OR 1.07, 95% confidence interval [CI]: 1.05 to 1.09). After adjusting for diagnosis, pandemic new patients were no more common than control new patients (adjusted odds ratio 1.00, 95% CI: 0.98 to 1.02). Compared with hospitals experiencing low local SARS-CoV-2 transmission, admission encounters at both medium and high transmission hospitals were more likely to be new (adjusted odds ratio 1.08, 95% CI: 1.03 to 1.14 and 1.09, 95% CI: 1.03 to 1.15, respectively).CONCLUSIONSDuring the early coronavirus disease 2019 pandemic, proportional increases in new patients to children’s hospitals appeared to be due to changes in diagnoses but were also associated with local SARS-CoV-2 transmission. Pediatric care consolidation may have occurred; how this may have impacted outcomes for hospitalized children is unclear.

COVID‐19 has upended medical practice and education, but has also catalyzed enhancements in the field. Early on, a local group of researchers united to investigate the impact of the pandemic on pediatric hematology oncology (PHO). From this group, a regional educational series was established, “virtual‐Symposium of Pediatric Hematology/Oncology of New York” (v‐SYMPHONY). The implementation of these endeavors while PHO fellowship applications are declining has highlighted our perceptions that education, mentoring, and career expectations are not keeping up with the needs of current trainees. We describe our regional experience joining together to further education and research, and reflect on the current landscape of PHO training and workforce.

In humans receiving intestinal transplantation (ITx), long-term multilineage blood chimerism often develops. Donor T cell macrochimerism (≥4%) frequently occurs without graft-versus-host disease (GVHD) and is associated with reduced rejection. Here we demonstrate that patients with macrochimerism had high graft-versus-host (GvH) to host-versus-graft (HvG) T cell clonal ratios in their allografts. These GvH clones entered the circulation, where their peak levels were associated with declines in HvG clones early after transplant, suggesting that GvH reactions may contribute to chimerism and control HvG responses without causing GVHD. Consistently, donor-derived T cells, including GvH clones, and CD34(+) hematopoietic stem and progenitor cells (HSPCs) were simultaneously detected in the recipients’ BM more than 100 days after transplant. Individual GvH clones appeared in ileal mucosa or PBMCs before detection in recipient BM, consistent with an intestinal mucosal origin, where donor GvH-reactive T cells expanded early upon entry of recipient APCs into the graft. These results, combined with cytotoxic single-cell transcriptional profiles of donor T cells in recipient BM, suggest that tissue-resident GvH-reactive donor T cells migrated into the recipient circulation and BM, where they destroyed recipient hematopoietic cells through cytolytic effector functions and promoted engraftment of graft-derived HSPCs that maintain chimerism. These mechanisms suggest an approach to achieving intestinal allograft tolerance.

Mesenchymal stromal cells (MSC) are multipotent precursor cells that can be derived from a variety of tissue sources, with a working definition based on immunophenotyping and cell differentiation capacity. Despite historical roots in the field of tissue engineering, they have generated great interest as cell therapies for their immune regulatory function, which has led to numerous clinical trials for a range of inflammatory and autoimmune conditions. Importantly, due to the lack of traditional MHC expression and their expression of other immune regulatory proteins, they can be used from third party donors without generating a dangerous alloreactivity. After 20 years of clinical trials, they have earned themselves an excellent safety record but are currently only approved for use in Canada, New Zealand, Japan, South Korea and Europe due to a lack of consistent efficacy data. In the United States, the indication that has seen the most progress is steroid refractory acute graft-versus-host disease (SR-aGVHD). Issues with early clinical trials can be attributed to both challenges with defining optimal patient populations and trial design as well as limitations related to commercial manufacturing. Earlier this year, the encouraging data for a repeat Phase III trial in pediatric patients with SR-aGVHD was published. This review provides information on the proposed mechanism of action of MSCs, clinical utilization of MSCs with focus on SR-aGVHD and potential modalities that can improve the efficacy of MSCs.

10016 Background: Population-level data show significantly inferior outcomes for Hispanic children, adolescents, and young adults (CAYA) diagnosed with B-cell acute lymphoblastic leukemia (B-ALL) relative to non-Hispanic whites (NHW). Here, we compare outcomes between Hispanic and NHW CAYA patients with relapsed and/or refractory (RR) B-ALL receiving tisagenlecleucel, a CD19-specific chimeric antigen receptor (CAR) T cell therapy. Methods: We used data from the Pediatric Real World CAR Consortium retrospective cohort of 200 patients who underwent cell shipment for standard-of-care tisagenlecleucel between August 2017 and March 2020 (N=15 US institutions). Race/ethnicity was identified by medical record review. Patients reported as belonging to more than one racial/ethnic group were classified as multiracial and excluded from analysis. Baseline factors, outcomes, and safety post-infusion were characterized for Hispanic vs. NHW infused patients. Outcomes included complete response (CR) rate, overall survival (OS), duration of response (DOR), and duration of B-cell aplasia (DBA). A multivariate Cox model for OS was constructed, including all baseline factors. Results: Among 185 infused patients, 90 (48.6%) were NHW and 70 (37.8%) were Hispanic. Among 15 non-infused patients, 3 (20.0%) were NHW and 5 (33.3%) were Hispanic. Hispanic patients were significantly older at diagnosis (mean: 10.7 vs. 8.3 years, p=0.02) and had significantly shorter time from diagnosis to infusion (mean: 34.4 vs. 46.4 months, p=0.04). Hispanic and NHW patients did not significantly differ across sex, leukemia type, number of prior lines of therapy, receipt of prior CD19-directed therapy, level of disease burden pre-infusion, and number of relapses pre-infusion. Hispanic and NHW patients did not significantly differ across 1-month CR, 6-month OS, 1-year OS, 18-month OS, 6-month DOR, 1-year DOR, 6-month DBA, and 1-year DBA (Table). On multivariate analysis including the above covariates, OS did not significantly differ for Hispanic patients (HR=1.04, p=0.92). Hispanic and NHW patients did not significantly differ across grade ≥ 3 cytokine release syndrome, grade ≥ 3 neurotoxicity, grade 4 neutropenia, tumor lysis syndrome, or number of infections post-infusion. Conclusions: Outcomes were similar between Hispanic and NHW CAYA RR B-ALL patients receiving tisagenlecleucel in the real-world setting. Increasing access to CAR therapy among Hispanic CAYA B-ALL patients could help mitigate population-level disparities in outcomes observed after receipt of conventional therapies. [Table: see text]

BACKGROUND HCT leaves patients in a relative state of immune deficiency both during their initial transplant admission and for several years following discharge. NTM are generally harmless colonizers of the outside environment, but for immunocompromised patients, they can cause significant disease due to a paucity of T-cell defense. While routine prophylaxis against NTM is recommended for patients with low CD4 counts in certain clinical settings (eg, AIDS), this is not yet established for HCT patients despite their higher risk. METHODS Here we build upon our prior work to determine risk factors for NTM in pediatric HCT patients by comparing NTM patient characteristics to matched HCT controls. RESULTS We followed 272 patients across a 13-year time period, with 11 cases of NTM. Patients with NTM had a significantly lower CD4 count at Day 365 than matched HCT controls (105.5 ± 97.0 cells/µl vs. 856.2 ± 446.1 cells/µl, respectively; p = .001). No other potential risk factors (eg, CMV, GvHD, disease type) were found to be statistically significant, including use of T-cell depleting agents. This is consistent with an average diagnosis of NTM at Day +323 (ie, outside immediate post-transplant period). All-cause mortality was similar between NTM and control HCT groups, with an NTM attributable mortality of

Purpose Pediatric oncology patients undergoing active chemotherapy are suspected to be at a high risk for severe disease secondary to severe acute respiratory syndrome coronavirus‐2 (SARS‐CoV‐2) infection; however, data to support this are lacking. We aim to describe the characteristics of coronavirus disease 2019 (COVID‐19) in this population and also its impact on pediatric cancer care in the New York region during the peak of the pandemic. Patients and Methods This multicenter, retrospective study included 13 institutions. Clinical and laboratory information on 98 patients ≤21 years of age receiving active anticancer therapy, who tested positive for SARS‐CoV‐2 by nasopharyngeal swab polymerase chain reaction (PCR), was collected. Results Of the 578 pediatric oncology patients tested for COVID‐19, 98 were positive, of whom 73 were symptomatic. Most experienced mild disease, 28 required inpatient management, 25 needed oxygen support, and seven required mechanical ventilation. There is a slightly higher risk of severe disease in males and obese patients, though not statistically significant. Persistent lymphopenia was noted in severe cases. Delays in cancer therapy occurred in 67% of SARS‐CoV‐2‐positive patients. Of four deaths, none were solely attributable to COVID‐19. The impact of the pandemic on pediatric oncology care was significant, with 54% of institutions reporting delays in chemotherapy, 46% delays in surgery, and 30% delays in transplant. Conclusion In this large multi‐institutional cohort, we observed that mortality and morbidity from COVID‐19 amongst pediatric oncology patients were low overall, but higher than reported in general pediatrics. Certain subgroups might be at higher risk of severe disease. Delays in cancer care due to SARS‐CoV‐2 remain a concern.

Chronic granulomatous disease (CGD) is a primary immune deficiency due to defects in phagocyte respiratory burst leading to severe and life-threatening infections. Patients with CGD also suffer from disorders of inflammation and immune dysregulation including colitis and granulomatous lung disease, among others. Additionally, patients with CGD may be at increased risk of systemic inflammatory disorders such as hemophagocytic lymphohistiocytosis (HLH). The presentation of HLH often overlaps with symptoms of systemic inflammatory response syndrome (SIRS) or sepsis and therefore can be difficult to identify, especially in patients with a primary immune deficiency in which incidence of infection is increased. Thorough evaluation and empiric treatment for bacterial and fungal infections is necessary as HLH in CGD is almost always secondary to infection. Simultaneous treatment of infection with anti-microbials and inflammation with immunosuppression may be needed to blunt the hyperinflammatory response in secondary HLH. Herein, we present a series of X-linked CGD patients who developed HLH secondary to or with concurrent disseminated CGD-related infection. In two patients, CGD was a known diagnosis prior to development of HLH and in the other two CGD was diagnosed as part of the evaluation for HLH. Concurrent infection and HLH were fatal in three; one case was successfully treated, ultimately receiving hematopoietic stem cell transplantation. The current literature on presentation, diagnosis, and treatment of HLH in CGD is reviewed.

Risk factors associated with the progression of acute kidney injury to chronic kidney disease in pediatric allogeneic hematopoietic cell transplantation (AlloHCT) recipients are not well described. We retrospectively investigated the risk factors for the progression to CKD in 275 AlloHCT recipients. AKI and CKD grading was defined according to the Kidney Disease Improving Global Outcomes classification. PRI90 was defined as persistent renal insufficiency (estimated GFR 90 ml/min/1.73 m

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 Survival disparities by race/ethnicity and socioeconomic status (SES) are observed in a wide range of pediatric treatment settings including oncology and solid organ transplantation. To date, few studies have examined the effects of race and SES on outcomes in pediatric allogeneic hematopoietic cell transplantation (HCT). We explored whether survival differed by race/ethnicity or SES in children receiving HCT for nonmalignant conditions at a single institution serving a diverse patient population. Procedures The Kaplan-Meier method was used to estimate overall survival (OS) with the log-rank test for between-group comparisons. Cox proportional hazards models were used to identify risk factors for OS, adjusting for treatment- and disease-related factors. Results Of 133 subjects, 0 to 21 years, 19% were non-Hispanic (NH) white, 34% were NH black, 40% were Hispanic, and 7% were Asian. Sixty-seven percent of the subjects had public insurance; 49% lived in neighborhoods with poverty rate ≥20%. Primary diagnoses included hemoglobinopathies (56%), bone marrow failure (22%), and other conditions (22%). Median follow-up was 5.8 years (range 0.1-14.5). Analysis revealed no difference in OS by race, insurance type, or neighborhood SES. Conclusions Findings from this single-institution study suggest that in pediatric patients undergoing HCT for nonmalignant conditions, treatment at a tertiary care center with a multidisciplinary approach may mitigate drivers of disparities observed in other settings. Additional studies are now needed to further elucidate the complex interrelationships among race, SES, and clinical outcomes for children undergoing HCT.