Exagamglogene Autotemcel for Severe Sickle Cell Disease.

BACKGROUND: Exagamglogene autotemcel (exa-cel) is a nonviral cell therapy designed to reactivate fetal hemoglobin synthesis by means of ex vivo clustered regularly interspaced short palindromic repeats (CRISPR)-Cas9 gene editing of autologous CD34+ hematopoietic stem and progenitor cells (HSPCs) at the erythroid-specific enhancer region of BCL11A. METHODS: We conducted a phase 3, single-group, open-label study of exa-cel in patients 12 to 35 years of age with sickle cell disease who had had at least two severe vaso-occlusive crises in each of the 2 years before screening. CD34+ HSPCs were edited with the use of CRISPR-Cas9. Before the exa-cel infusion, patients underwent myeloablative conditioning with pharmacokinetically dose-adjusted busulfan. The primary end point was freedom from severe vaso-occlusive crises for at least 12 consecutive months. A key secondary end point was freedom from inpatient hospitalization for severe vaso-occlusive crises for at least 12 consecutive months. The safety of exa-cel was also assessed. RESULTS: A total of 44 patients received exa-cel, and the median follow-up was 19.3 months (range, 0.8 to 48.1). Neutrophils and platelets engrafted in each patient. Of the 30 patients who had sufficient follow-up to be evaluated, 29 (97%; 95% confidence interval [CI], 83 to 100) were free from vaso-occlusive crises for at least 12 consecutive months, and all 30 (100%; 95% CI, 88 to 100) were free from hospitalizations for vaso-occlusive crises for at least 12 consecutive months (P<0.001 for both comparisons against the null hypothesis of a 50% response). The safety profile of exa-cel was generally consistent with that of myeloablative busulfan conditioning and autologous HSPC transplantation. No cancers occurred. CONCLUSIONS: Treatment with exa-cel eliminated vaso-occlusive crises in 97% of patients with sickle cell disease for a period of 12 months or more. (CLIMB SCD-121; ClinicalTrials.gov number, NCT03745287.).

Identification of unstable regulatory and autoreactive effector T cells that are expanded in patients with FOXP3 mutations.

Studies of the monogenic autoimmune disease immunodysregulation polyendocrinopathy enteropathy X-linked syndrome (IPEX) have elucidated the essential function of the transcription factor FOXP3 and thymic-derived regulatory T cells (Tregs) in controlling peripheral tolerance. However, the presence and the source of autoreactive T cells in IPEX remain undetermined. Here, we investigated how FOXP3 deficiency affects the T cell receptor (TCR) repertoire and Treg stability in vivo and compared T cell abnormalities in patients with IPEX with those in patients with autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy syndrome (APECED). To study Tregs independently of their phenotype and to analyze T cell autoreactivity, we combined Treg-specific demethylation region analyses, single-cell multiomic profiling, and bulk TCR sequencing. We found that patients with IPEX, unlike patients with APECED, have expanded autoreactive T cells originating from both autoreactive effector T cells (Teffs) and Tregs. In addition, a fraction of the expanded Tregs from patients with IPEX lost their phenotypic and functional markers, including CD25 and FOXP3. Functional experiments with CRISPR-Cas9-mediated FOXP3 knockout Tregs and Tregs from patients with IPEX indicated that the patients' Tregs gain a TH2-skewed Teff-like function, which is consistent with immune dysregulation observed in these patients. Analyses of FOXP3 mutation-carrier mothers and a patient with IPEX after hematopoietic stem cell transplantation indicated that Tregs expressing nonmutated FOXP3 prevent the accumulation of autoreactive Teffs and unstable Tregs. These findings could be directly used for diagnostic and prognostic purposes and for monitoring the effects of immunomodulatory treatments.

Clofarabine for Lymphodepletion Before CAR-T-Cell Infusion: A Brief Case Report.

Given the shortage of fludarabine, alternative preparative lymphodepleting regimens for CAR-T-cell therapy need to be identified. We present a case of relapsed/refractory B-cell acute lymphoblastic leukemia requiring multiple lines of salvage therapy with persistent extensive disease, who underwent lymphodepletion with clofarabine and cyclophosphamide before tisagenlecleucel CD19+ CAR-T-cell infusion with eventual remission. We offer evidence of clofarabine's activity against B-cell acute lymphoblastic leukemia in combination with tisagenlecleucel therapy. In this patient, clofarabine did not decrease CAR-T-cell effectiveness, supported by presence of cytokine release syndrome and ultimate minimal residual disease negativity both on flow cytometry and next-generation sequencing.

A diagnostic classifier for pediatric chronic graft-versus-host disease: results of the ABLE/PBMTC 1202 study.

The National Institutes of Health Consensus criteria for chronic graft-versus-host disease (cGVHD) diagnosis can be challenging to apply in children, making pediatric cGVHD diagnosis difficult. We aimed to identify diagnostic pediatric cGVHD biomarkers that would complement the current clinical criteria and help differentiate cGVHD from non-cGVHD. The Applied Biomarkers of Late Effects of Childhood Cancer (ABLE) study, open at 27 transplant centers, prospectively evaluated 302 pediatric patients after hematopoietic cell transplant (234 evaluable). Forty-four patients developed cGVHD. Mixed and fixed effect regression analyses were performed on diagnostic cGVHD onset blood samples for cellular and plasma biomarkers, with individual markers declared relevant if they met 3 criteria: an effect ratio ≥1.3 or ≤0.75; an area under the curve (AUC) of ≥0.60; and a P value <5.814 × 10-4 (Bonferroni correction) (mixed effect) or <.05 (fixed effect). To address the complexity of cGVHD diagnosis in children, we built a machine learning-based classifier that combined multiple cellular and plasma biomarkers with clinical factors. Decreases in regulatory natural killer cells, naïve CD4 T helper cells, and naïve regulatory T cells, and elevated levels of CXCL9, CXCL10, CXCL11, ST2, ICAM-1, and soluble CD13 (sCD13) characterize the onset of cGVHD. Evaluation of the time dependence revealed that sCD13, ST2, and ICAM-1 levels varied with the timing of cGVHD onset. The cGVHD diagnostic classifier achieved an AUC of 0.89, with a positive predictive value of 82% and a negative predictive value of 80% for diagnosing cGVHD. Our polyomic approach to building a diagnostic classifier could help improve the diagnosis of cGVHD in children but requires validation in future prospective studies. This trial was registered at www.clinicaltrials.gov as #NCT02067832.

Long-Term Organ Function After HCT for SCD: A Report From the Sickle Cell Transplant Advocacy and Research Alliance.

Hematopoietic cell transplantation (HCT) is an established cure for sickle cell disease (SCD) supported by long-term survival, but long-term organ function data are lacking. We sought to describe organ function and assess predictors for dysfunction in a retrospective cohort (n = 247) through the Sickle cell Transplant Advocacy and Research alliance. Patients with <1-year follow-up or graft rejection/second HCT were excluded. Organ function data were collected from last follow-up. Primary measures were organ function, comparing pre- and post-HCT. Bivariable and multivariable analyses were performed for predictors of dysfunction. Median age at HCT was 9.4 years; the majority had HbSS (88.2%) and severe clinical phenotype (65.4%). Most received matched related (76.9%) bone marrow (83.3%) with myeloablative conditioning (MAC; 57.1%). Acute and chronic graft-versus-host disease (GVHD) developed in 24.0% and 24.8%. Thirteen patients (5.3%) died ≥1 year after HCT, primarily from GVHD or infection. More post-HCT patients had low ejection or shortening fractions than pre-HCT (0.6% â†’ 6.0%, P = .007 and 0% â†’ 4.6%, P = .003). The proportion with lung disease remained stable. Eight patients (3.2%) had overt stroke; most had normal (28.3%) or stable (50.3%) brain magnetic resonance imaging. On multivariable analysis, cardiac dysfunction was associated with MAC (odds ratio [OR] = 2.71; 95% confidence interval [CI], 1.09-6.77; P = .033) and severe acute GVHD (OR = 2.41; 95% CI, 1.04-5.62; P = .041). Neurologic events were associated with central nervous system indication (OR = 2.88; 95% CI, 2.00-4.12; P < .001). Overall organ dysfunction was associated with age ≥16 years (OR = 2.26; 95% CI, 1.35-3.78; P = .002) and clinically severe disease (OR = 1.64; 95% CI, 1.02-2.63; P = .043). In conclusion, our results support consideration of HCT at younger age and use of less intense conditioning.

Outcomes following posttransplant virus-specific T-cell therapy in patients with sickle cell disease.

Hematopoietic stem cell transplantation (HSCT) is being increasingly used as a curative approach for sickle cell disease (SCD). With the risk of graft-versus-host disease (GVHD), especially in the human leukocyte antigen-mismatched donors, intense immunosuppression is required leading to an increased risk of viral infection. Post-HSCT, adoptive transfer of virus-specific T-cell (VST) therapies have not been well-studied in patients with SCD. Here, we report the outcomes of patients with SCD at a single-center who received VSTs after transplant to prevent or treat viral infections. Thirteen patients who received HSCT from human leukocyte antigen-matched (n = 9) or -mismatched (n = 4) donors for SCD were treated with a total of 15 VST products for the treatment or prophylaxis of multiple viruses (cytomegalovirus, Epstein-Barr virus, adenovirus, BK virus, human herpes virus 6 +/- human parainfluenza virus 3). Of the patients evaluated, 46.2% (n = 6)) received VSTs as treatment for viral infection. Eighty percent of patients with active viremia (n = 4/5) achieved remission of at least 1 target virus. Seven additional patients (53.8%) received VSTs prophylactically and 6 of 7 (85.7%) remained virus-free after infusion. No immediate infusion-related toxicities occurred, and severe de novo acute GVHD occurred in only 2 (15.4%) patients. Given the good safety profile, high-rate of clinical responses and sustained remissions when administered with standard antiviral treatments, the routine use of VSTs after HSCT as prophylaxis or treatment may improve the overall safety of transplant for patients with SCD.

Assessment of donor cell engraftment after hematopoietic stem cell transplantation for sickle cell disease: A review of current and future methods.

Hematopoietic stem cell transplantation (HSCT) is the only established curative treatment for sickle cell disease (SCD), a debilitating red blood cell (RBC) disorder with significant prevalence worldwide. Accurate assessment of RBC engraftment following HSCT is essential to evaluate the status of the graft and can enable early intervention to treat or prevent graft rejection. Currently, chimerism measurement is performed on whole blood samples, which mainly reflect white blood cell (WBC) chimerism. This approach has limitations in assessing engraftment in patients with SCD because RBCs engraft non-linearly with WBCs. Direct measures of RBC chimerism exist but are not routinely used. In this review, we critically examine the current methodologies for assessing donor engraftment; highlight the limitations of these different methods, and present emerging and novel technologies with the potential to improve clinical monitoring of RBC engraftment post-HSCT for SCD. Promising alternative methodologies include RBC-specific flow cytometry, RBC-specific RNA analysis, and quantification of plasma cell-free DNA derived specifically from nucleated RBCs.

Metabolomic identification of α-ketoglutaric acid elevation in pediatric chronic graft-versus-host disease.

Chronic graft-versus-host disease (cGVHD) is the most common cause for non-relapse mortality postallogeneic hematopoietic stem cell transplant (HSCT). However, there are no well-defined biomarkers for cGVHD or late acute GVHD (aGVHD). This study is a longitudinal evaluation of metabolomic patterns of cGVHD and late aGVHD in pediatric HSCT recipients. A quantitative analysis of plasma metabolites was performed on 222 evaluable pediatric subjects from the ABLE/PBMTC1202 study. We performed a risk-assignment analysis at day + 100 (D100) on subjects who later developed either cGVHD or late aGVHD after day 114 to non-cGVHD controls. A second analysis at diagnosis used fixed and mixed multiple regression to compare cGVHD at onset to time-matched non-cGVHD controls. A metabolomic biomarker was considered biologically relevant only if it met all 3 selection criteria: (1) P ≤ .05; (2) effect ratio of ≥1.3 or ≤0.75; and (3) receiver operator characteristic AUC ≥0.60. We found a consistent elevation in plasma α-ketoglutaric acid before (D100) and at the onset of cGVHD, not impacted by cGVHD severity, pubertal status, or previous aGVHD. In addition, late aGVHD had a unique metabolomic pattern at D100 compared with cGVHD. Additional metabolomic correlation patterns were seen with the clinical presentation of pulmonary, de novo, and progressive cGVHD. α-ketoglutaric acid emerged as the single most significant metabolite associated with cGVHD, both in the D100 risk-assignment and later diagnostic onset analysis. These distinctive metabolic patterns may lead to improved subclassification of cGVHD. Future validation of these exploratory results is needed. This trial was registered at www.clinicaltrials.gov as #NCT02067832.

Granulocyte Colony-Stimulating Factor Is Safe and Well Tolerated following Allogeneic Transplantation in Patients with Sickle Cell Disease.

Granulocyte colony-stimulating factor (G-CSF) used after hematopoietic stem cell transplantation (HSCT) can enhance neutrophil recovery in patients rendered neutropenic by the preparative regimen. G-CSF is contraindicated in patients with sickle cell disease (SCD), because life-threatening complications can ensue in the presence of sickle vasculopathy. The safety profile of G-CSF after HSCT for SCD has not been described, however. We report clinical outcomes in the first 100 days post-HSCT in 62 patients supported with G-CSF until neutrophil recovery on a clinical trial of reduced- intensity conditioning HSCT for SCD. The patients received G-CSF for a median of 9 days (range, 5 to 33 days) post-transplantation from the best available stem cell source. Preparation for transplantation included a target hemoglobin S level of ≤45%. Neutrophil engraftment (absolute neutrophil count >0.5 × 103/mL) was achieved at a median of 13 days (range, 10 to 34 days), and platelet engraftment (>50 × 103/mL) was achieved at a median of 19 days (range, 12 to 71 days). The median duration of inpatient hospitalization following stem cell infusion (day 0) was 21.5 days (range, 11 to 33 days). No patient developed SCD-related complications following G-CSF use. The most common organ toxicities encountered between G-CSF initiation (on day +7) and day +100 were anorexia (n = 14), hypertension (n = 11), and electrolyte imbalance requiring correction (n = 9). Central nervous system-related events were noted in 5 patients, all of whom had preexisting cerebral vasculopathy/moyamoya disease, attributed to reversible posterior leukoencephalopathy syndrome in the presence of calcineurin inhibitor therapy and hypertension. We conclude that G-CSF does not adversely impact SCD HSCT recipients and can be safely used post-transplantation to enhance neutrophil recovery.

Length of Stay and Health Care Utilization Among Pediatric Autologous Hematopoietic Cell Transplantation Recipients.

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% age <12 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, age >12 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 age >12 years (estimate, -$6,776; 95% CI, -$71,787 to -$11,402; P = .007) or <2 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, whereas >5 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. Age <12 years and Hispanic ethnicity were risk factors for increased LOS, whereas age <2 years and >12 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.

Low CD4 count may be a risk factor for non-tuberculous mycobacteria infection in pediatric hematopoietic cell transplant recipients.

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 <10%. CONCLUSION: Since reduced CD4 counts are associated with NTM, and cost and morbidity are high, azithromycin prophylaxis for CD4 count <200 cells/µl in high-risk patients should be considered.

Limitations of Applying the Hematopoietic Cell Transplantation Comorbidity Index in Pediatric Patients Receiving Allogeneic Hematopoietic Cell Transplantation.

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.

Infections in Infants with SCID: Isolation, Infection Screening, and Prophylaxis in PIDTC Centers.

PURPOSE: The Primary Immune Deficiency Treatment Consortium (PIDTC) enrolled children with severe combined immunodeficiency (SCID) in a prospective natural history study of hematopoietic stem cell transplant (HSCT) outcomes over the last decade. Despite newborn screening (NBS) for SCID, infections occurred prior to HSCT. This study's objectives were to define the types and timing of infection prior to HSCT in patients diagnosed via NBS or by family history (FH) and to understand the breadth of strategies employed at PIDTC centers for infection prevention. METHODS: We analyzed retrospective data on infections and pre-transplant management in patients with SCID diagnosed by NBS and/or FH and treated with HSCT between 2010 and 2014. PIDTC centers were surveyed in 2018 to understand their practices and protocols for pre-HSCT management. RESULTS: Infections were more common in patients diagnosed via NBS (55%) versus those diagnosed via FH (19%) (p = 0.012). Outpatient versus inpatient management did not impact infections (47% vs 35%, respectively; p = 0.423). There was no consensus among PIDTC survey respondents as to the best setting (inpatient vs outpatient) for pre-HSCT management. While isolation practices varied, immunoglobulin replacement and antimicrobial prophylaxis were more uniformly implemented. CONCLUSION: Infants with SCID diagnosed due to FH had lower rates of infection and proceeded to HSCT more quickly than did those diagnosed via NBS. Pre-HSCT management practices were highly variable between centers, although uses of prophylaxis and immunoglobulin support were more consistent. This study demonstrates a critical need for development of evidence-based guidelines for the pre-HSCT management of infants with SCID following an abnormal NBS. TRIAL REGISTRATION: NCT01186913.

Financial impact of post-transplant complications among children undergoing allogeneic hematopoietic cell transplantation.

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 < 0.001), lung injury ($108,529, SE = 28,196, p < 0.001), liver injury ($90,805, SE = 28,660, p = 0.002), and grade II-IV aGVHD ($137,866, SE = 28,472, p < 0.001) as associated with significantly increased cost. Our study highlights the significant impact complications have on the overall cost of alloHCT. The identification that complications associated with high morbidity (aGVHD, pulmonary disease) are also associated with the highest financial burden emphasizes the need for future research in these areas to expand management options and improve outcomes for our patients.

Hematopoietic Cell Transplantation in Patients With Primary Immune Regulatory Disorders (PIRD): A Primary Immune Deficiency Treatment Consortium (PIDTC) Survey.

Primary Immune Regulatory Disorders (PIRD) are an expanding group of diseases caused by gene defects in several different immune pathways, such as regulatory T cell function. Patients with PIRD develop clinical manifestations associated with diminished and exaggerated immune responses. Management of these patients is complicated; oftentimes immunosuppressive therapies are insufficient, and patients may require hematopoietic cell transplant (HCT) for treatment. Analysis of HCT data in PIRD patients have previously focused on a single gene defect. This study surveyed transplanted patients with a phenotypic clinical picture consistent with PIRD treated in 33 Primary Immune Deficiency Treatment Consortium centers and European centers. Our data showed that PIRD patients often had immunodeficient and autoimmune features affecting multiple organ systems. Transplantation resulted in resolution of disease manifestations in more than half of the patients with an overall 5-years survival of 67%. This study, the first to encompass disorders across the PIRD spectrum, highlights the need for further research in PIRD management.

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

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

Immune profile differences between chronic GVHD and late acute GVHD: results of the ABLE/PBMTC 1202 studies.

Human graft-versus-host disease (GVHD) biology beyond 3 months after hematopoietic stem cell transplantation (HSCT) is complex. The Applied Biomarker in Late Effects of Childhood Cancer study (ABLE/PBMTC1202, NCT02067832) evaluated the immune profiles in chronic GVHD (cGVHD) and late acute GVHD (L-aGVHD). Peripheral blood immune cell and plasma markers were analyzed at day 100 post-HSCT and correlated with GVHD diagnosed according to the National Institutes of Health consensus criteria (NIH-CC) for cGVHD. Of 302 children enrolled, 241 were evaluable as L-aGVHD, cGVHD, active L-aGVHD or cGVHD, and no cGVHD/L-aGVHD. Significant marker differences, adjusted for major clinical factors, were defined as meeting all 3 criteria: receiver-operating characteristic area under the curve ≥0.60, P ≤ .05, and effect ratio ≥1.3 or ≤0.75. Patients with only distinctive features but determined as cGVHD by the adjudication committee (non-NIH-CC) had immune profiles similar to NIH-CC. Both cGVHD and L-aGVHD had decreased transitional B cells and increased cytolytic natural killer (NK) cells. cGVHD had additional abnormalities, with increased activated T cells, naive helper T (Th) and cytotoxic T cells, loss of CD56bright regulatory NK cells, and increased ST2 and soluble CD13. Active L-aGVHD before day 114 had additional abnormalities in naive Th, naive regulatory T (Treg) cell populations, and cytokines, and active cGVHD had an increase in PD-1- and a decrease in PD-1+ memory Treg cells. Unsupervised analysis appeared to show a progression of immune abnormalities from no cGVHD/L-aGVHD to L-aGVHD, with the most complex pattern in cGVHD. Comprehensive immune profiling will allow us to better understand how to minimize L-aGVHD and cGVHD. Further confirmation in adult and pediatric cohorts is needed.

Healthcare utilization and financial impact of acute-graft-versus host disease among children undergoing allogeneic hematopoietic cell transplantation.

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 < 0.001. Patients with SR-aGVHD had increased hospitalization compared with the patients with steroid responsive aGVHD (152.8 ± 66.6days vs. 111.3 ± 59.3 days, p = 0.004), with associated increased alloHCT cost of ~$200,000. On multivariable analysis of risk factor for alloHCT cost, aGVHD, was associated with significantly higher cost ($141,094 [SE = 31247], p < 0.001). In summary, aGVHD and SR-aGVHD is associated with prolonged hospitalization and higher cost and inferior survival among children. Better aGVHD prevention strategies are desperately needed. Despite significant advances, lack of effective salvage regimens for SR-aGVHD remains a major concern.