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Immune effector cell (IEC) therapy represents a transformative advancement in oncology, leveraging the immune system to combat various malignancies. This article outlines a comprehensive framework for establishing and maintaining quality standards in IEC therapy amidst rapid scientific and clinical advancements. We emphasize the integration of structured process measures, robust quality assurance, and meticulous outcome evaluation to ensure treatment efficacy and safety. Key components include multidisciplinary expertise, stringent accreditation protocols, and advanced data management systems, which facilitate standardized reporting and continual innovation. The collaborative effort among stakeholders-ranging from patients and healthcare providers to regulatory bodies-is crucial in delivering high-quality IEC therapies. This framework aims to enhance patient outcomes and cement the role of IEC therapy as a cornerstone of modern oncology, promoting continuous improvement and adherence to high standards across the therapeutic spectrum.
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Bloodstream infections (BSI) are one of the leading causes of morbidity and mortality in children and young adults receiving chemotherapy for malignancy or undergoing hematopoietic stem cell transplantation (HSCT). Antibiotic prophylaxis is commonly used to decrease the risk of BSI; however, antibiotics carry an inherent risk of complications. The aim of this manuscript is to review levofloxacin prophylaxis in pediatric oncology patients and HSCT recipients. We reviewed published literature on levofloxacin prophylaxis to prevent BSI in pediatric oncology patients and HSCT recipients. Nine manuscripts were identified. The use of levofloxacin is indicated in neutropenic children and young adults receiving intensive chemotherapy for leukemia or undergoing HSCT. These results support the efficacy of levofloxacin in pediatric patients with leukemia receiving intensive chemotherapy and should be considered in pediatric patients undergoing HSCT prior to engraftment.
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The implications of previous central nervous system (CNS) involvement in children with acute myeloid leukemia (AML) undergoing hematopoietic cell transplantation (HCT) remain inadequately understood. Patients with CNS disease require more upfront CNS-directed intrathecal therapy, but little is known about whether transplant conditioning regimens should be intensified or if previous CNS involvement impacts post-HCT outcomes. While total body irradiation (TBI) remains standard for pediatric acute lymphoblastic leukemia myeloablative conditioning, it has been largely replaced with chemotherapy-only myeloablation in pediatric AML, primarily due to toxicity and late effects associated with TBI. In the setting of previous CNS involvement, it has been suggested that TBI-based myeloablation may have advantages due to superior CNS tissue penetration and thus decreased rates of AML relapse post-HCT. We analyzed a publicly available dataset derived from the Center for International Blood and Marrow Transplantation Research (CIBMTR) registry to characterize the impact of TBI in HCT preparative regimens in pediatric AML patients with a history of CNS involvement. The study dataset was obtained from the CIBMTR data repository. The study cohort included patients aged ≤21 years who underwent initial allogeneic HCT with myeloablative conditioning for de novo AML in the first or second complete remission (CR) between 2008 and 2016, who provided consent for research. Patients with mismatched related donor transplants and noncalcineurin inhibitor graft-versus-host disease (GVHD) prophylaxis were excluded. The dataset was further modified by excluding patients with missing disease site data or those with non-CNS extramedullary disease. Patients were categorized as CNS-positive or -negative AML (AML-CNS(+) and AML-CNS(-), respectively) based on the disease status at diagnosis. The Cox regression model and Fine-Grey methods were employed to delineate the effects of TBI and CNS disease on key HCT outcomes. The study cohort comprised 550 pediatric AML patients, of which 25% (n = 136) were AML-CNS(+). CNS involvement was more prevalent in patients aged 0 to 3 years, patients who were in the second CR, and those with a mismatched unrelated donor or umbilical cord blood. AML-CNS(+) patients demonstrated a lower relapse rate (hazard ratio: 0.50, 95% confidence interval: 0.33 to 0.76) compared to AML-CNS(-) patients, with comparable disease-free survival (DFS) and overall survival (OS) (P = .10 and 0.20, respectively) in the two cohorts. The entire TBI-treated cohort showed an association with increased risks of grade 2 to 4 acute GVHD, bloodstream infections, and endocrine dysfunction. TBI use within the AML-CNS(+) cohort was associated with a lower relapse rate but increased risks of nonrelapse mortality and a trend of higher grade 3 to 4 acute GVHD. In this population-based analysis of pediatric patients with de novo AML undergoing HCT, TBI-based conditioning regimens did not confer an advantage in DFS or OS compared to non-TBI regimens, irrespective of CNS disease status. However, TBI use was associated with increased risks of short- and long-term comorbidities. These findings underscore the need for careful consideration of TBI in pediatric AML.
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Trasplante de Células Madre Hematopoyéticas , Leucemia Mieloide Aguda , Acondicionamiento Pretrasplante , Irradiación Corporal Total , Humanos , Trasplante de Células Madre Hematopoyéticas/efectos adversos , Niño , Leucemia Mieloide Aguda/terapia , Irradiación Corporal Total/efectos adversos , Preescolar , Adolescente , Femenino , Masculino , Acondicionamiento Pretrasplante/métodos , Lactante , Neoplasias del Sistema Nervioso Central/terapia , Neoplasias del Sistema Nervioso Central/radioterapia , Resultado del Tratamiento , Enfermedad Injerto contra Huésped/etiologíaRESUMEN
Disrupted sleep is commonly reported during hematopoietic stem cell transplant. In this study, we use actigraphy to measure sleep parameters, and qualitative measures of quality of life, depression, and sleep in pediatric and young adult transplant recipients to describe their time course through transplant. Eight patients had evaluable actigraphy data, and 10 patients completed the surveys. The median age of the 6 male and 7 female participants was 13.94 years old. Sleep duration and efficiency measured by actigraphy were suboptimal prior to transplant, then declined to a nadir between Day +7 to +14. Self-reported sleep quality, depression, and quality of life were worst at Day +14 to +30 but improved by Day +100. Findings support efforts to improve sleep, which may improve recovery, mental health and quality of life.
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Actigrafía , Depresión , Trasplante de Células Madre Hematopoyéticas , Calidad de Vida , Sueño , Humanos , Calidad de Vida/psicología , Masculino , Femenino , Trasplante de Células Madre Hematopoyéticas/psicología , Adolescente , Niño , Depresión/psicología , Sueño/fisiología , Adulto Joven , Calidad del Sueño , Trastornos del Sueño-Vigilia/psicología , Trastornos del Sueño-Vigilia/epidemiología , Encuestas y Cuestionarios , AdultoRESUMEN
To understand transplant center recommendations on return-to-school timing and related support for hematopoietic cell transplant (HCT) survivors, we conducted a two-phase, cross-sectional, web-based survey: In Phase I, medical directors of pediatric HCT centers from the National Marrow Donor Program/ Be The Match Registry were asked regarding the availability of a return to school standardized operating procedure (SOP). In Phase II, HCT physician members of the Pediatric Transplantation and Cellular Therapy Consortium were approached to study inter-physician practice variability regarding return to school post-HCT, factors affecting their decision-making, and support provided by HCT centers for return to school. Out of 46 respondents in Phase I (55% response rate), 28 (61%) reported having a SOP. Wide variations in recommendations were noted in 12 received SOPs. In Phase II, 122 physicians (60 centers) responded (30.6% response rate). The majority (60%) recommended autologous HCT recipients return to school within 6 months post-HCT but 65% recommended allogeneic HCT recipients return to school after 6 months or once off immunosuppression. Our findings indicate a lack of consensus within and across HCT centers regarding recommended return to school timing and underscore need for a guideline to standardize this process to ensure patient safety and re-integration into school.
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Trasplante de Células Madre Hematopoyéticas , Humanos , Estados Unidos , Estudios Transversales , Femenino , Masculino , Niño , Encuestas y Cuestionarios , Instituciones Académicas , AdolescenteRESUMEN
BACKGROUND: Pediatric hematopoietic stem cell transplantation (HCT) is an intensive medical procedure that places substantial financial and logistical burdens on families and is associated with significant health risks, such as graft-versus-host disease (GVHD), and infections. The influence of the social determinants of health (SDoH) on outcomes following pediatric HCT is understudied. This study aimed to examine whether SDoH predicts outcomes following pediatric HCT. PROCEDURE: Data were collected from 84 children who received HCT (Mage = 5.8 years, SD = 3.7) and their primary caregiver. Detailed demographic information was collected from caregivers at baseline, and child health information was extracted from the electronic medical records. Multivariate logistic regression was used to examine the association between SDoH and health outcomes within a 24-month period following pediatric HCT. RESULTS: After controlling for malignancy as reason for transplant and donor type, lower family income predicted the incidence of chronic GVHD. Neighborhood deprivation, total family income, public health insurance, caregiver relationship status, caregiver educational attainment, and perceived family financial difficulties did not predict acute GVHD or the number of infections. CONCLUSIONS: Total family income is a simple family indicator of SDoH that predicts chronic GVHD after pediatric allogeneic HCT. These findings provide further support for the importance of screening of child and family SDoH risks to ensure that fundamental needs can be met to mitigate potential health disparities for up to 2 years following pediatric HCT.
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Enfermedad Injerto contra Huésped , Trasplante de Células Madre Hematopoyéticas , Humanos , Niño , Preescolar , Determinantes Sociales de la Salud , Trasplante de Células Madre Hematopoyéticas/efectos adversos , Trasplante de Células Madre Hematopoyéticas/métodos , Enfermedad Injerto contra Huésped/epidemiología , Enfermedad Injerto contra Huésped/etiología , Enfermedad Injerto contra Huésped/patología , Evaluación de Resultado en la Atención de SaludRESUMEN
There is a need for proficient nursing practice in specialized critical care settings, such as a pediatric Bone Marrow Transplant (BMT) Unit. The staffing crisis continues to be problematic for areas around the country. Nursing tenure has been positively correlated with improving patient outcomes and confidence in giving care, so efforts must be made to retain pediatric BMT nurses. The purpose of this study was to investigate factors of resilience and how it pertains to the retention of pediatric BMT nurses through (1) Understanding current BMT nursing turnover and trend why nurses are leaving; (2) Measure resilience throughout BMT nursing cohort, covering all tenure of nurses; and (3) Interview senior nurses within the cohort to identify themes relating to retention and resilience using grounded theory methodology. This research was carried out in the Bone Marrow Transplant (BMT) Unit at Cincinnati Children's Hospital Medical Center (CCHMC). The study spanned from 2014 to 2019, during which researchers gathered extensive data to evaluate the turnover risk among BMT nurses. A detailed follow-up was conducted in 2019 to further assess this risk. To measure resilience levels, a group of 115 nurses in the unit completed the Connor Davidson Resilience Scale (CD-RISC). Additionally, in-depth interviews were conducted with 9 senior nurses in the cohort, continuing until theoretical saturation was reached, ensuring a comprehensive understanding of the factors influencing nurse turnover in the unit. Researchers looked retrospectively at nursing turnover from 2014 to 2019. Investigators determined the risk of new nurses leaving was between 22 and 24 months (HR 0.025). Further, follow-up was conducted for data points between 2019-present time, which showed a drastic change in the hazard rate curvature. However, the risk remained relatively the same at 22 to 24 months (HR 0.03). There was no statistical significance found between CD-RISC results and age (P = .465), gender (P = .725), working experience (P = .15), or education (P = .14). Through a constant comparative process, several themes were identified as positive, negative, and ambiguous contributions to the retention of nurses. The risk of nurses leaving after 2 years decreases significantly; therefore, we determined that a nurse with a commitment to pediatric BMT occurs with 2 years' experience. Although our initial hypothesis was that senior nurses had greater resilience than less tenured nurses, there was no statistical significance as the effect of resilience is small. However, we identified several additional factors pertinent to the pediatric BMT field which may be associated with nursing retention.
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Enfermeras Pediátricas , Pruebas Psicológicas , Resiliencia Psicológica , Humanos , Niño , Estudios Retrospectivos , FenotipoRESUMEN
Post-transplant cyclophosphamide (PTCy) is increasingly used to reduce graft-versus-host disease after hematopoietic cell transplantation (HCT); however, it might be associated with more infections. All patients who were ≥2 years old, receiving haploidentical or matched sibling donor (Sib) HCT for acute leukemias or myelodysplastic syndrome, and either calcineurin inhibitor (CNI)- or PTCy-based GVHD prophylaxis [Haploidentical HCT with PTCy (HaploCy), 757; Sibling with PTCy (SibCy), 403; Sibling with CNI-based (SibCNI), 1605] were included. Most bacterial infections occurred within the first 100 days; 953 patients (34.5%) had at least 1 infection and 352 patients (13%) had ≥2 infections. Patients receiving PTCy had a greater incidence of bacterial infections by day 180 [HaploCy 46%; SibCy 48%; SibCNI 35%; p < 0.001]. Compared with the SibCNI without infection cohort, 1.99-fold, 3.33-fold, 2.78-fold, and 2.53-fold increased TRM was seen for the HaploCy cohort without infection and HaploCy, SibCy, and SibCNI cohorts with infection, respectively. Bacterial infections increased mortality [HaploCy (HR1.84, 99% CI: 1.45-2.33, p < 0.0001), SibCy cohort (HR,1.68, 99% CI: 1.30-2.19, p < 0.0001), and SibCNI cohort (HR,1.76, 99% CI: 1.43-2.16, p < 0.0001). PTCy was associated with increased bacterial infections regardless of donor, and bacterial infections were associated with increased mortality irrespective of GVHD prophylaxis. Patients receiving PTCy should be monitored carefully for bacterial infections following PTCy.
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Infecciones Bacterianas , Enfermedad Injerto contra Huésped , Trasplante de Células Madre Hematopoyéticas , Humanos , Preescolar , Ciclofosfamida/uso terapéutico , Trasplante de Células Madre Hematopoyéticas/efectos adversos , Enfermedad Injerto contra Huésped/etiología , Donantes de Tejidos , Inhibidores de la Calcineurina/uso terapéutico , Infecciones Bacterianas/etiología , Estudios RetrospectivosRESUMEN
The standard treatment for Langerhans cell histiocytosis (LCH) is chemotherapy, although the failure rates are high. Since MAP-kinase activating mutations are found in most cases, BRAF- and MEK-inhibitors have been used successfully to treat patients with refractory or relapsed disease. However, data on long-term responses in children are limited and there are no data on the use of these inhibitors as first-line therapy. We treated 34 patients (26 with LCH, 2 with juvenile xanthogranuloma, 2 with Rosai-Dorfman disease, and 4 with presumed single site-central nervous system histiocytosis) with dabrafenib and/or trametinib, either as first line or after relapse or failure of chemotherapy. Sixteen patients, aged 1.3-21 years, had disease that was recurrent or refractory to chemotherapy, nine of whom had multisystem LCH with risk-organ involvement. With a median treatment duration of 4.3 years, 15 (94%) patients have sustained favorable responses. Eighteen patients, aged 0.2-45 years, received an inhibitor as first-line treatment. All of these have had sustained favorable responses, with a median treatment duration of 2.5 years. Three patients with presumed isolated central nervous system/pituitary stalk histiocytosis had stabilization or improvement of their disease. Overall, inhibitors were well tolerated. Five patients with single-system LCH discontinued therapy and remain off therapy without recurrence. In contrast, all four patients with multisystem disease who discontinued therapy had to restart treatment. Our data suggest that children suffering from histiocytoses can be treated safely and effectively with dabrafenib or trametinib. Additional studies are, however, needed to determine the long-term safety and optimal duration of therapy.
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Histiocitosis de Células de Langerhans , Piridonas , Pirimidinonas , Niño , Humanos , Histiocitosis de Células de Langerhans/tratamiento farmacológico , Imidazoles/uso terapéutico , Oximas/efectos adversos , Mutación , Proteínas Proto-Oncogénicas B-raf/genéticaRESUMEN
Fungal infection (FI) after allogeneic hematopoietic cell transplantation (HCT) is associated with increased morbidity and mortality. Neutropenia, HLA mismatch, graft-versus-host disease (GVHD), and viral infections are risk factors for FI. The objectives of this Center for International Blood and Marrow Transplant Research registry study were to compare the incidence and density of FI occurring within 180 days after HCT in matched sibling (Sib) transplants with either calcineurin inhibitor (CNI)-based or post-transplantation cyclophosphamide (PTCy)-based GVHD prophylaxis and related haploidentical transplants receiving PTCy, and to examine the impact of FI by day 180 on transplantation outcomes. METHODS: Patients who underwent their first HCT between 2012 and 2017 for acute myeloid leukemia, acute lymphoblastic leukemia, and myelodysplastic syndrome and received a related haploidentical transplant with PTCy (HaploCy; n = 757) or a Sib transplant with PTCy (SibCy; n = 403) or CNI (SibCNI; n = 1605) were analyzed. The incidence of FI by day 180 post-HCT was calculated as cumulative incidence with death as the competing risk. The associations of FI with overall survival, transplant-related mortality, chronic GVHD, and relapse at 2 years post-HCT were examined in Cox proportional hazards regression models. Factors significantly associated with the outcome variable at a 1% level were kept in the final model. RESULTS: By day 180 post-HCT, 56 (7%) HaploCy, 24 (6%), SibCy, and 59 (4%) SibCNI recipients developed ≥1 FI (P < .001). The cumulative incidence of yeast FI was 5.2% (99% confidence interval [CI], 3.3% to 7.3%) for HaploCy, 2.2% (99% CI, .7% to 4.5%) for SibCy, and 1.9% (99% CI, 1.1% to 2.9%) for SibCNI (P = .001), and that of mold FI was 2.9% (99% CI, 1.5% to 4.7%), 3.7% (99% CI, 91.7% to 6.6%), and 1.7% (99% CI, 1.0% to 2.6%), respectively (P = .040). FI was associated with an increased risk of death, with an adjusted hazard ratio (HR) of 4.06 (99% CI, 2.2 to 7.6) for HaploCy, 4.7 (99% CI, 2.0 to 11.0) for SibCy, and 3.4 (99% CI, 1.8 to 6.4) for SibCNI compared with SibCNI without FI (P < .0001 for all). Similar associations were noted for transplantation-related mortality. FI did not impact rates of relapse or chronic GVHD. CONCLUSIONS: Rates of FI by day 180 ranged between 1.9% and 5.2% for yeast FI and from 1.7% to 3.7% for mold FI across the 3 cohorts. The use of PTCy was associated with higher rates of yeast FI only in HaploHCT and with mold FI in both HaploHCT and SibHCT. The presence of FI by day 180 was associated with increased risk for overall mortality and transplant-related mortality at 2 years regardless of donor type or PTCy use. Although rates of FI were low with PTCy, FI is associated with an increased risk of death, underscoring the need for improved management strategies.
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Enfermedad Injerto contra Huésped , Trasplante de Células Madre Hematopoyéticas , Micosis , Humanos , Incidencia , Saccharomyces cerevisiae , Ciclofosfamida/uso terapéutico , Trasplante de Células Madre Hematopoyéticas/efectos adversos , Enfermedad Injerto contra Huésped/epidemiología , Enfermedad Injerto contra Huésped/prevención & control , Enfermedad Injerto contra Huésped/tratamiento farmacológico , Inhibidores de la Calcineurina/uso terapéutico , Micosis/epidemiología , Micosis/prevención & control , Micosis/tratamiento farmacológico , RecurrenciaRESUMEN
ABSTRACT: High-risk, complement mediated, untreated transplant-associated thrombotic microangiopathy (hrTMA) has dismal outcomes due to multi-organ dysfunction syndrome (MODS). The complement C5 blocker eculizumab shows promising results in hrTMA, but has not been prospectively studied in hematopoietic stem cell transplant (HCT) recipients. We performed the first multi-institutional prospective study in children and young adults to evaluate eculizumab as an early targeted intervention for hrTMA/MODS. We hypothesized that eculizumab would more than double survival in HCT recipients with hrTMA, compared to our prior study of prospectively screened, untreated hrTMAs serving as historical controls. HrTMA features (elevated terminal complement (sC5b-9) and proteinuria measured by random urine protein/creatinine ratio (≥1mg/mg)) were required for inclusion. The primary endpoint was survival at 6 six-months from hrTMA diagnosis. Secondary endpoints were cumulative incidence of MODS 6 months after hrTMA diagnosis and 1-year posttransplant survival. Eculizumab dosing included intensive loading, induction, and maintenance phases for up to 24 weeks of therapy. All 21 evaluated study subjects had MODS. Primary and secondary study endpoints were met by demonstrating survival of 71% (P < .0001) 6 months after hrTMA diagnosis and 62% 1 year after transplant. Of fifteen survivors, 11 (73%) fully recovered organ function and are well. Our study demonstrates significant improvement in survival and recovery of organ function in hrTMA using an intensified eculizumab dosing and real time biomarker monitoring. This study serves as a benchmark for planning future studies that should focus on preventative measures or targeted therapy to be initiated prior to organ injury. This trial was registered at www.clinicaltrials.gov as #NCT03518203.
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Trasplante de Células Madre Hematopoyéticas , Microangiopatías Trombóticas , Niño , Humanos , Adulto Joven , Anticuerpos Monoclonales Humanizados/uso terapéutico , Proteínas del Sistema Complemento , Trasplante de Células Madre Hematopoyéticas/efectos adversos , Trasplante de Células Madre Hematopoyéticas/métodos , Estudios Prospectivos , Trasplante de Células Madre/efectos adversos , Microangiopatías Trombóticas/tratamiento farmacológico , Microangiopatías Trombóticas/etiología , Microangiopatías Trombóticas/diagnósticoRESUMEN
ABSTRACT: The health care use (HCU) burden of transplant-associated thrombotic microangiopathy (TA-TMA) and its treatments are unknown. The objective of this study was to investigate inpatient costs associated with meeting criteria for TA-TMA in the first year after hematopoietic cell transplant (HCT). This institutional review board-approved retrospective multicenter study included serial children who underwent HCT from 1 January 2015 to 1 July 2019. A standardized unit cost (adjusted for geographic location, differences in cost of living, and inflation) for inpatient hospitalization was extracted from the Pediatric Health Information System data and linked to clinical data. Both total cost and cost per day from 15 days before stem cell infusion to 1-year after HCT were calculated. Among allogeneic (allo) transplant recipients, after adjusting for severe grade 3/4 acute graft-versus-host disease (GVHD), infections, and HLA mismatch, costs were not different in TA-TMA (n = 137) vs no TA-TMA (n = 238). Severe GVHD was significantly associated with increased costs. Among allo high-risk (HR) TMA-TMA, unadjusted costs were significantly higher in the eculizumab-treated cohort (n = 19) than in the supportive care group (n = 36). However, after adjusting for gastrointestinal bleeding that occurred disproportionately in the eculizumab (n = 6) vs supportive care (n = 0) cohort, eculizumab treatment was not associated with increased total costs. More studies are needed to determine the etiology of increased HCU costs in those with HR-TA-TMA and predict those more likely to benefit from eculizumab, reducing HCU and improving outcomes.
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Enfermedad Injerto contra Huésped , Trasplante de Células Madre Hematopoyéticas , Niño , Humanos , Anticuerpos Monoclonales Humanizados/uso terapéutico , Enfermedad Injerto contra Huésped/tratamiento farmacológico , Enfermedad Injerto contra Huésped/etiología , Trasplante de Células Madre Hematopoyéticas/efectos adversos , Aceptación de la Atención de Salud , Estudios RetrospectivosRESUMEN
Diffuse alveolar hemorrhage (DAH) is a life-threatening complication of hematopoietic cellular therapy (HCT). This study aimed to evaluate the effect of DAH treatments on outcomes using data from consecutive HCT patients clinically diagnosed with DAH from 3 institutions between January 2018-August 2022. Endpoints included sustained complete response (sCR) defined as bleeding cessation without recurrent bleeding, and non-relapse mortality (NRM). Forty children developed DAH at a median of 56.5 days post-HCT (range 1-760). Thirty-five (88%) had at least one concurrent endothelial disorder, including transplant-associated thrombotic microangiopathy (n=30), sinusoidal obstructive syndrome (n=19), or acute graft versus host disease (n=10). Fifty percent had a concurrent pulmonary infection at the time of DAH. Common treatments included steroids (n=17, 25% sCR), inhaled tranexamic acid (INH TXA,n=26, 48% sCR), and inhaled recombinant activated factor VII (INH fVIIa, n=10, 73% sCR). NRM was 56% 100 days after first pulmonary bleed and 70% at 1 year. Steroid treatment was associated with increased risk of NRM (HR 2.25 95% CI 1.07-4.71, p=0.03), while treatment with INH TXA (HR 0.43, 95% CI 0.19- 0.96, p=0.04) and INH fVIIa (HR 0.22, 95% CI 0.07-0.62, p=0.005) were associated with decreased risk of NRM. Prospective studies are warranted to validate these findings.
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Higher body mass index (BMI) is characterized as a chronic inflammatory state with endothelial dysfunction. Endothelial injury after allogeneic hematopoietic stem cell transplantation (allo-HSCT) puts patients at risk for such complications as transplantation-associated thrombotic microangiopathy (TA-TMA) and acute graft-versus-host-disease (aGVHD). To evaluate the impact of increased BMI on endothelial injury after allo-HSCT in pediatric and young adult patients, we conducted a retrospective cohort study evaluating 476 consecutive allo-HSCT children and young adult recipients age 0 to 20 years. Our analysis was subdivided based on distinct age categories (<2 years and 2 to 20 years). BMI was considered as a variable but was also expressed in standard deviations from the mean adjusted for age and sex (z-score), based on established criteria from the World Health Organization (age <2 years) and the Centers for Disease Control and Prevention (age 2 to 20 years) to account for differences associated with age. Primary endpoints included the incidences of TA-TMA and aGVHD. Increased BMI z-score was associated with TA-TMA after allo-HSCT in patients age <2 years (median, 18.1; IQR, 17 to 20; P = .006) and in patients age 2 to 20 years (median, 18.7; IQR, 16 to 21.9; P = .02). Higher BMI z-score correlated with TA-TMA risk in both age groups, with a BMI z-score of .9 in the younger cohort and .7 (IQR, -.4 to 1.6; P = .04) in the older cohort. Increased BMI z-score was associated with an increased risk of TA-TMA in a multivariate analysis of the entire cohort (odds ratio [OR], 1.2; 95% confidence interval [CI], 1.05 to 1.37; P = .008). Multivariate analysis also demonstrated that patients with BMI in the 85th percentile or greater had an increased risk of developing TA-TMA compared to those with a lower BMI percentile (OR, 2.66; 95% CI, 1.62 to 4.32; P < .001). Baseline and day +7 ST2 levels were elevated in subjects with TA-TMA compared to those without TA-TMA in both age groups. Baseline sC5b-9 concentration was not correlated with BMI z-score, but sC5b-9 concentration was increased markedly by 7 days post-allo-HSCT in patients age <2 years who later developed TA-TMA compared to those who never developed TA-TMA (P = .001). The median BMI z-score was higher for patients with aGVHD compared to patients without aGVHD (.7 [range, -3.9 to 3.9] versus .2 [range, -7.8 to 5.4]; P = .03). We show that high BMI is associated with augmented risk of endothelial injury after HSCT, specifically TA-TMA. These data identify a high-risk population likely to benefit from early interventions to prevent endothelial injury and prompt treatment of established endothelial injury.
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Enfermedad Injerto contra Huésped , Trasplante de Células Madre Hematopoyéticas , Microangiopatías Trombóticas , Estados Unidos , Adulto Joven , Humanos , Niño , Recién Nacido , Lactante , Preescolar , Adolescente , Adulto , Estudios Retrospectivos , Índice de Masa Corporal , Microangiopatías Trombóticas/complicaciones , Factores de Riesgo , Trasplante de Células Madre Hematopoyéticas/efectos adversosRESUMEN
Mucopolysaccharidosis type I (MPS I) is a rare genetic disorder characterized by the deficiency of the alpha-L-iduronidase enzyme necessary for the degradation of glycosaminoglycans (GAG) in the lysosome. Hurler syndrome is the most severe form of MPS I, manifesting as multiorgan dysfunction, cognitive delay, and death, usually within ten years if left untreated. Hematopoietic stem cell transplantation (HSCT) is the optimal treatment option, providing a permanent solution to enzyme deficiency and halting cognitive decline; however, the HSCT complications transplantation-associated thrombotic microangiopathy (TA-TMA) and graft-versus-host disease (GVHD) are known risk factors for bloodstream infection (BSI). BSI is a serious complication of HSCT, contributing to poor outcomes and transplantation-related morbidity. There are little data evaluating BSI after HSCT in the Hurler syndrome population. We performed a retrospective analysis of patients with Hurler syndrome who underwent HSCT at our center between 2013 and 2020 to determine the incidence of BSI within the first year post-transplantation. Patient BSI data were collected through the first year post-HSCT. Variables including patient demographics and transplantation-related characteristics were collected, including information on BSI and mortality. Twenty-five patients with a total of 28 HSCTs were included in the analysis; the majority (n = 17; 68%) were male, with a median age of 1.1 years (interquartile range, .35 to 1.44 years) at the time of transplantation. The most common graft source was cord blood (n = 15; 54%), followed by bone marrow (n = 13; 46%), with the majority from matched unrelated donors (n = 14; 52%) and mismatched unrelated donors (n = 13; 44%). Sixteen BSIs were diagnosed in 12 patients (48%). Most infections (n = 7; 43.8%) were diagnosed in the first 20 days post-transplantation, with fewer infections observed at later time points. Seven of the 9 Hurler patients diagnosed with TA-TMA (78%) also had a BSI. The incidence rate of BSIs in Hurler patients (n = 12; 48%) was higher than the rates reported in the general pediatric HSCT population at 1-year post-transplantation (15% to 35%). Given the high rate of both TA-TMA and a BSI in Hurler patients, we suspect a possible correlation between the 2. Additionally, due to the time it takes for GAG levels to normalize post-HSCT in Hurler patients, it is reasonable to suspect that the high BSI rates in these patients are linked to their Hurler diagnosis. These findings bring awareness to possible disease-related factors contributing to high BSI rates in the Hurler population post-HSCT.
Asunto(s)
Enfermedades Transmisibles , Trasplante de Células Madre Hematopoyéticas , Mucopolisacaridosis I , Sepsis , Humanos , Masculino , Niño , Femenino , Mucopolisacaridosis I/complicaciones , Mucopolisacaridosis I/epidemiología , Mucopolisacaridosis I/terapia , Incidencia , Estudios Retrospectivos , Enfermedades Transmisibles/etiología , Sepsis/etiología , Trasplante de Células Madre Hematopoyéticas/efectos adversos , Trasplante de Células Madre Hematopoyéticas/métodosRESUMEN
The field of hematopoietic cell transplantation and cell therapy (HCT/CT) is advancing rapidly to bring an ever-expanding collection of potentially curative therapies to patients with malignant and non-malignant diseases. The impact of these therapies depends on our ability to implement them as new evidence becomes available to advance the quality of care. There is often a long delay between evidence development and adoption of therapies based on that evidence into clinical practice. In this review, we describe the potential factors based on an implementation framework that could act as facilitators or barriers to adoption of therapies in the context of HCT/CT. We highlight two examples, the first to showcase the efforts to improve the efficiency of adoption of new findings and accelerate improvement in care of HCT/CT patients and the second to discuss the challenges in real world implementation of chimeric antigen receptor T cell therapy. We conclude by reviewing strategies to improve translation of evidence and ways to measure their success.
Asunto(s)
Trasplante de Células Madre Hematopoyéticas , Humanos , Trasplante de Células Madre Hematopoyéticas/efectos adversos , Inmunoterapia Adoptiva/efectos adversosRESUMEN
CD19-directed chimeric antigen receptor T lymphocytes (CAR-T) have led to durable remissions in children with refractory and/or multiply relapsed B-lymphoblastic leukemia. For those who relapse or lose B-cell aplasia post CAR-T, the role of CAR-T reinfusion is unclear. We report two cases of durable remission with tisagenlecleucel reinfusion despite failure to achieve or maintain B-cell aplasia, and compare these cases to six additional children who received multiple tisagenlecleucel infusions at our institution. Our experience suggests that reinfusion is safe and may be a definitive therapy for a small subset of patients. Reinfusion can also reintroduce remission and/or B-cell aplasia, allowing for subsequent therapies.
Asunto(s)
Leucemia-Linfoma Linfoblástico de Células Precursoras , Receptores Quiméricos de Antígenos , Niño , Humanos , Receptores de Antígenos de Linfocitos T/uso terapéutico , Leucemia-Linfoma Linfoblástico de Células Precursoras/terapia , Inducción de Remisión , Antígenos CD19 , Proteínas Adaptadoras Transductoras de Señales , Inmunoterapia AdoptivaRESUMEN
Bridging therapy (BT) given during the period between T-cell collection and initiation of lymphodepleting chemotherapy is indicated for most children with B-cell acute lymphoblastic leukemia (B-ALL) undergoing treatment with tisagenlecleucel (tisa-cel), a CD19-directed chimeric antigen receptor T-cell (CAR-T) therapy. Both conventional chemotherapy agents and B-cell directed antibody-based therapies such as antibody-drug conjugates and bispecific T-cell engagers have been used as systemic forms of BT. The purpose of this retrospective study was to evaluate if there are detectable differences in clinical outcomes based on the type of BT given (conventional chemotherapy or inotuzumab). A retrospective analysis was performed on all patients treated with tisa-cel at Cincinnati Children's Hospital Medical Center for B-ALL with bone marrow disease (with or without extramedullary disease). Patients who did not receive systemic BT were excluded. Only 1 patient received blinatumomab as BT and was therefore not included in this analysis to focus the analysis on the use of inotuzumab. Pre-infusion characteristics and post-infusion outcomes were collected. Fisher's exact test was used for categorical variables, and t-test or Mann-Whitney test was used for continuous parametric and non-parametric variables respectively. Mantel-Cox was used for survival analyses. Thirty-two patients received BT before CD19 CAR-T for medullary leukemia; 24 received conventional chemotherapy, and 8 received inotuzumab ozogamicin (InO). Cohorts were evenly matched regarding CAR-T indication, recipient age, and median CAR-T cell dose. There were no significant differences between the groups for attaining a minimal residual disease (MRD)-negative complete response after CAR-T, the percentage of patients who maintained prolonged B-cell aplasia, or the median duration of B-cell aplasia. Thirty-seven percent of patients in the conventional chemotherapy group and 43% in the antibody-based therapy group relapsed, with a median time to relapse in both groups of 5 months. No differences in event-free survival, the cumulative incidence of relapse, or overall survival were seen between the two groups. Initial response to tisa-cel, relapse rate, and survival were similar between patients who received BT with conventional chemotherapy or InO therapy. Because low disease burden at the time of infusion is a positive prognostic factor, choice of bridging regimen should focus on therapy that is anticipated to effectively lower disease burden and minimize treatment-related toxicity. Given the limitations associated with the single center retrospective analysis, a larger, multicenter study is needed to further explore these findings.