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High-dose methotrexate (HD-MTX) is used in the treatment of children with central nervous system (CNS) tumors; however, toxicity information is limited. We characterized toxicities following 102 administrations of HD-MTX (4.6-13.5 g/m2) infused over 4 or 24 h in 38 children with a CNS tumor before 6 years of age (2010-2020). Delayed clearance of methotrexate occurred following 24% of infusions. Common Terminology Criteria for Adverse Events v5 grade 2-3 mucositis was observed in 47% of individuals, Grade 4 neutropenia in 76%, and grade 3-4 thrombocytopenia in 58%. No neurotoxicity was observed. HD-MTX can be safely used with supportive care and monitoring.
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Antimetabólitos Antineoplásicos , Neoplasias do Sistema Nervoso Central , Metotrexato , Humanos , Metotrexato/efeitos adversos , Metotrexato/administração & dosagem , Feminino , Neoplasias do Sistema Nervoso Central/tratamento farmacológico , Masculino , Pré-Escolar , Antimetabólitos Antineoplásicos/efeitos adversos , Antimetabólitos Antineoplásicos/administração & dosagem , Lactente , Criança , Seguimentos , Estudos Retrospectivos , Prognóstico , Mucosite/induzido quimicamente , Neutropenia/induzido quimicamenteRESUMO
PURPOSE: To update the ASCO-Oncology Nursing Society (ONS) standards for antineoplastic therapy administration safety in adult and pediatric oncology and highlight current standards for antineoplastic therapy for adult and pediatric populations with various routes of administration and location. METHODS: ASCO and ONS convened a multidisciplinary Expert Panel with representation of multiple organizations to conduct literature reviews and add to the standards as needed. The evidence base was combined with the opinion of the ASCO-ONS Expert Panel to develop antineoplastic safety standards and guidance. Public comments were solicited and considered in preparation of the final manuscript. RESULTS: The standards presented here include clarification and expansion of existing standards to include home administration and other changes in processes of ordering, preparing, and administering antineoplastic therapy; the advent of immune effector cellular therapy; the importance of social determinants of health; fertility preservation; and pregnancy avoidance. In addition, the standards have added a fourth verification. STANDARDS: Standards are provided for which health care organizations and those involved in all aspects of patient care can safely deliver antineoplastic therapy, increase the quality of care, and reduce medical errors.Additional information is available at www.asco.org/standards and www.ons.org/onf.
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BACKGROUND: Pediatric allogeneic hematopoietic cell transplant (allo-HCT) recipients are at risk for morbidity and mortality from human adenovirus (HAdV). HAdV can be detected in an asymptomatic state, referred to as infection or with signs or symptoms of illness, referred to as disease. Standardized case definitions are needed to distinguish infection from disease and allow for consistent reporting in both observational cohort studies and therapeutic clinical trials. METHODS: A working group of experts in virology, transplant infectious disease, and HCT was assembled to develop HAdV infection and disease definitions with the degree of certainty (i.e., possible, probable, and proven). Definitions were further refined through an iterative process and independently applied by two central review committees (CRCs) to 20 pediatric allo-HCT recipients with at least one HAdV-positive PCR. RESULTS: Initial HAdV infection and disease definitions were developed and updated through an iterative process after reviewing clinical and virological details for 81 subjects with at least one positive HAdV PCR detected in a clinical specimen. Independent application of final definitions to 20 HAdV positive allo-HCT recipients by two CRCs yielded similar number of HAdV infection or disease events but with variation of degree of certainty for some events. CONCLUSIONS: Application of definitions by a CRC for a study of HAdV infection and disease is feasible and can provide consistency in the assignment of outcomes. Definitions need further refinement to improve reproducibility and to provide guidance on determining clinical improvement or worsening after initial diagnosis of HAdV infection or disease.
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Infecções por Adenovirus Humanos , Adenovírus Humanos , Transplante de Células-Tronco Hematopoéticas , Criança , Humanos , Infecções por Adenovirus Humanos/diagnóstico , Reprodutibilidade dos Testes , Transplante Homólogo , Estudos de CoortesRESUMO
Background: Datasets on rare diseases, like pediatric acute myeloid leukemia (AML) and acute lymphoblastic leukemia (ALL), have small sample sizes that hinder machine learning (ML). The objective was to develop an interpretable ML framework to elucidate actionable insights from small tabular rare disease datasets. Methods: The comprehensive framework employed optimized data imputation and sampling, supervised and unsupervised learning, and literature-based discovery (LBD). The framework was deployed to assess treatment-related infection in pediatric AML and ALL. Results: An interpretable decision tree classified the risk of infection as either "high risk" or "low risk" in pediatric ALL (n = 580) and AML (n = 132) with accuracy of â¼79%. Interpretable regression models predicted the discrete number of developed infections with a mean absolute error (MAE) of 2.26 for bacterial infections and an MAE of 1.29 for viral infections. Features that best explained the development of infection were the chemotherapy regimen, cancer cells in the central nervous system at initial diagnosis, chemotherapy course, leukemia type, Down syndrome, race, and National Cancer Institute risk classification. Finally, SemNet 2.0, an open-source LBD software that links relationships from 33+ million PubMed articles, identified additional features for the prediction of infection, like glucose, iron, neutropenia-reducing growth factors, and systemic lupus erythematosus (SLE). Conclusions: The developed ML framework enabled state-of-the-art, interpretable predictions using rare disease tabular datasets. ML model performance baselines were successfully produced to predict infection in pediatric AML and ALL.
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Case identification in administrative databases is challenging as diagnosis codes alone are not adequate for case ascertainment. We utilized machine learning (ML) to efficiently identify pediatric patients with newly diagnosed acute lymphoblastic leukemia. We tested nine ML models and validated the best model internally and externally. The optimal model had 97% positive predictive value (PPV) and 99% sensitivity in internal validation; 94% PPV and 82% sensitivity in external validation. Our ML model identified a large cohort of 21,044 patients, demonstrating an efficient approach for cohort assembly and enhancing the usability of administrative data.
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Algoritmos , Leucemia-Linfoma Linfoblástico de Células Precursoras , Criança , Humanos , Valor Preditivo dos Testes , Leucemia-Linfoma Linfoblástico de Células Precursoras/diagnóstico , Aprendizado de Máquina , Bases de Dados FactuaisRESUMO
BACKGROUND: 11ß-hydroxysteroid dehydrogenase type 1 (11ß-HSD1) regulates intracellular cortisol and its inhibition by the small molecule inhibitor, Xanamem™, may provide a disease-modifying strategy for Alzheimer's disease (AD). Animal models suggest a range of 30-60% enzyme inhibition may suffice to provide neuroprotection. OBJECTIVE: To determine the regional brain occupancy of 11ß-HSD1 by Xanamem™ in cognitively normal participants (CN) and mild cognitive impairment (MCI)/mild AD patients to investigate potential dosing ranges for future efficacy studies. METHODS: Seventeen MCI/AD and 23 CN were included. Regional brain time-activity curves (TAC), standardized uptake values (SUV40-60) and volume of distribution (VT) from Logan plot with image derived input function from 11C-TARACT positron emission tomography (PET) were used to assess the degree of 11ß-HSD1 occupancy by increasing doses of Xanamem™ (5âmg, 10âmg, 20âmg or 30âmg daily for 7 days). RESULTS: All measures showed high 11ß-HSD1 occupancy with Xanamem to similar degree in CN and MCI/AD. The dose-response relationship was relatively flat above 5âmg. Respective median (interquartile range [Q1-Q3]) 11ß-HSD1 occupancy in the MCI/AD and CN groups after treatment with 10âmg Xanamem were 80% [79-81%] and 75% [71-76%] in the neocortex, 69% [64-70%] and 61% [52-63%] in the medial temporal lobe, 80% [79-80%] and 73% [68-73%] in the basal ganglia, and 71% [67-75%] and 66% [62-68%] in the cerebellum. CONCLUSIONS: TAC, SUV40-60, and VT measures indicate Xanamem achieves high target occupancy levels with near saturation at 10âmg daily. These data support exploration of doses of≤10âmg daily in future clinical studies.
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11-beta-Hidroxiesteroide Desidrogenase Tipo 1 , Doença de Alzheimer , Tiofenos , Tropanos , Animais , Humanos , 11-beta-Hidroxiesteroide Desidrogenase Tipo 1/metabolismo , Doença de Alzheimer/diagnóstico por imagem , Doença de Alzheimer/tratamento farmacológico , Tomografia por Emissão de Pósitrons , Encéfalo/metabolismoRESUMO
PURPOSE: The optimal management of fever without severe neutropenia (absolute neutrophil count [ANC] ≥500/µL) in pediatric patients with cancer is undefined. The previously proposed Esbenshade Vanderbilt (EsVan) models accurately predict bacterial bloodstream infections (BSIs) in this population and provide risk stratification to aid management, but have lacked prospective external validation. MATERIALS AND METHODS: Episodes of fever with a central venous catheter and ANC ≥500/µL occurring in pediatric patients with cancer were prospectively collected from 18 academic medical centers. Variables included in the EsVan models and 7-day clinical outcomes were collected. Five versions of the EsVan models were applied to the data with calculation of C-statistics for both overall BSI rate and high-risk organism BSI (gram-negative and Staphylococcus aureus BSI), as well as model calibration. RESULTS: In 2,565 evaluable episodes, the BSI rate was 4.7% (N = 120). Complications for the whole cohort were rare, with 1.1% (N = 27) needing intensive care unit (ICU) care by 7 days, and the all-cause mortality rate was 0.2% (N = 5), with only one potential infection-related death. C-statistics ranged from 0.775 to 0.789 for predicting overall BSI, with improved accuracy in predicting high-risk organism BSI (C-statistic 0.800-0.819). Initial empiric antibiotics were withheld in 14.9% of episodes, with no deaths or ICU admissions attributable to not receiving empiric antibiotics. CONCLUSION: The EsVan models, especially EsVan2b, perform very well prospectively across multiple academic medical centers and accurately stratify risk of BSI in episodes of non-neutropenic fever in pediatric patients with cancer. Implementation of routine screening with risk-stratified management for non-neutropenic fever in pediatric patients with cancer could safely reduce unnecessary antibiotic use.
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Bacteriemia , Infecções Bacterianas , Infecções , Neoplasias , Sepse , Humanos , Criança , Estudos Prospectivos , Bacteriemia/diagnóstico , Bacteriemia/epidemiologia , Bacteriemia/microbiologia , Febre/diagnóstico , Febre/etiologia , Neoplasias/complicações , Sepse/diagnóstico , Antibacterianos/uso terapêuticoRESUMO
This single-center, retrospective study evaluated age as a risk factor for relapsed/refractory disease and/or death in 153 children with B-cell acute lymphoblastic leukemia. The study sample included children near the 10-year age cutoff for high-risk disease (6.0-13.9 years at diagnosis) and without other high-risk features (high white cell count, unfavorable cytogenetics). Children 10.0-13.9 years treated per high-risk protocols did not have inferior outcomes compared with children aged 6.0-9.9 years initiating treatment per standard-risk protocols. The study indicates that, in the era of cytogenetics, an age threshold of 10 years might not be an independent prognostic marker. Multicenter analyses are needed.
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Leucemia-Linfoma Linfoblástico de Células Precursoras B , Leucemia-Linfoma Linfoblástico de Células Precursoras , Criança , Humanos , Estudos Retrospectivos , Leucemia-Linfoma Linfoblástico de Células Precursoras/diagnóstico , Leucemia-Linfoma Linfoblástico de Células Precursoras/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras/terapia , Leucemia-Linfoma Linfoblástico de Células Precursoras B/diagnóstico , Leucemia-Linfoma Linfoblástico de Células Precursoras B/terapia , Fatores de Risco , Prognóstico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêuticoRESUMO
Adolescents and young adults (AYAs; ages 15-39 years) with acute lymphoblastic leukemia (ALL) have worse outcomes than pediatric patients with ALL. Multiple factors contribute to this differential survival. AYAs are more likely to have higher-risk leukemia biology than children with ALL. AYA patients have more choices for treatment facility and treatment protocol, as well as barriers to clinical trial enrollment, both of which can affect survival. AYAs must also navigate psychosocial factors inherent to their unique developmental stage. Furthermore, AYAs typically sustain more treatment-related toxicities than pediatric patients. Treatment on pediatric or pediatric-inspired ALL protocols at pediatric cancer centers has been associated with improved outcomes for AYAs with ALL, but there is still variation in the treatment that AYAs with ALL receive. Clinical trials focused on AYAs with ALL and individualized decision-making regarding choice of treatment facility and treatment protocol are needed to optimize the survival and long-term outcomes of this patient population.
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Leucemia Mieloide Aguda , Leucemia-Linfoma Linfoblástico de Células Precursoras , Humanos , Criança , Adolescente , Adulto Jovem , Leucemia Mieloide Aguda/tratamento farmacológico , Leucemia-Linfoma Linfoblástico de Células Precursoras/terapiaRESUMO
The optimization of outcomes for pediatric cancer patients relies on the successful advancement of supportive care to ease the treatment burden and mitigate the long-term impacts of cancer therapy. Advancing pediatric supportive care requires research prioritization as well as the development and implementation of innovations. Like the prevailing theme throughout pediatric oncology, there is a clear need for personalized or precision approaches that are consistent, evidence-based, and guided by clinical practice guidelines. By incorporating technology and datasets, we can address questions which may not be feasible to explore in clinical trials. Now is the time to listen to patients' voices by using patient-reported outcomes (PROs) to ensure that their contributions and experiences inform clinical care plans. Furthermore, while the extrapolation of knowledge and approaches from adult populations may suffice in the absence of pediatric-specific evidence, there is a critical need to specifically understand and implement elements of general and developmental pediatrics like growth, nutrition, development, and physical activity into care. Increased research funding for pediatric supportive care is critical to address resource availability, equity, and disparities across the globe. Our patients deserve to enjoy healthy, productive lives with optimized and enriched supportive care that spans the spectrum from diagnosis to survivorship.
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Children with acute leukemia are at increased risk of kidney injury. Using electronic health record data from three centers between 2010 and 2018, this study retrospectively described acute kidney injury (AKI) and chronic kidney disease (CKD) prevalence in children with acute lymphoblastic or myeloid leukemia (ALL, AML) using Common Terminology Criteria for Adverse Events (CTCAE) and Kidney Disease Improving Global Outcomes (KDIGO) definitions. AKI during therapy was 25% (ALL) and 32% (AML) using CTCAE, versus 84% (ALL) and 74% (AML) using KDIGO. CKD prevalence was low and Grade 1/Stage 2. Further investigation is needed to optimally define kidney injury in acute leukemia.
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Injúria Renal Aguda , Leucemia Mieloide Aguda , Insuficiência Renal Crônica , Criança , Humanos , Estudos Retrospectivos , Mortalidade Hospitalar , Rim , Injúria Renal Aguda/induzido quimicamente , Injúria Renal Aguda/epidemiologia , Insuficiência Renal Crônica/epidemiologia , Leucemia Mieloide Aguda/terapia , Leucemia Mieloide Aguda/complicações , Eletrônica , Fatores de RiscoRESUMO
Hematologic malignancy is a risk factor for severe coronavirus disease 2019 (COVID-19) in adults; however, data specific to children with leukemia are limited. High-quality infectious adverse event data from the ongoing Children's Oncology Group (COG) standard-risk B acute lymphoblastic leukemia/lymphoma (ALL/LLy) trial, AALL1731, were analyzed to provide a disease-specific estimate of SARS-CoV-2 infection outcomes in pediatric ALL. Of 253 patients with reported infections, the majority (77.1%) were asymptomatic or mildly symptomatic (CTCAE grade 1/2) and there was a single COVID-19-related death. These data suggest SARS-CoV-2 infection does not confer substantial morbidity among young patients with B-lymphoblastic leukemia/lymphoma (B-ALL/LLy).
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The objective of the Cancer Control and Supportive Care (CCL) Committee in the Children's Oncology Group (COG) is to reduce the overall morbidity and mortality of therapy-related toxicities in children, adolescents, and young adults with cancer. We have targeted five major domains that cause clinically important toxicity: (i) infections and inflammation; (ii) malnutrition and metabolic dysfunction; (iii) chemotherapy-induced nausea and vomiting; (iv) neuro- and oto-toxicty; and (v) patient-reported outcomes and health-related quality of life. Subcommittees for each domain prioritize randomized controlled trials and biology aims to determine which strategies best mitigate the toxicities. The findings of these trials are impactful, informing clinical practice guidelines (CPGs) and directly leading to changes in the standard of care for oncology practice. With the development of new therapies, there will be new toxicities, and the COG CCL Committee is dedicated to developing interventions to minimize acute and delayed toxicities, lessen morbidity and mortality, and improve quality of life in pediatric and young adult patients with cancer.
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Neoplasias , Qualidade de Vida , Adolescente , Adulto Jovem , Criança , Humanos , Neoplasias/tratamento farmacológico , Oncologia , Atenção à Saúde , VômitoRESUMO
The MTXPK.org webtool was launched in December 2019 and was developed to facilitate model-informed supportive care and optimal use of glucarpidase following the administration of high-dose methotrexate (HDMTX). One limitation identified during the original development of the MTXPK.org tool was the perceived generalizability because the modeled population comprised solely of Nordic pediatric patients receiving 24-h infusions for the treatment of acute lymphoblastic leukemia. The goal of our study is to describe the pharmacokinetics of HDMTX from a diverse patient population (e.g., races, ethnicity, indications for methotrexate, and variable infusion durations) and identify meaningful factors that account for methotrexate variability and improve the model's performance. To do this, retrospectively analyzed pharmacokinetic and toxicity data from pediatric and adolescent young adult patients who were receiving HDMTX (>0.5 g/m2 ) for the treatment of a cancer diagnosis from three pediatric medical centers. We performed population pharmacokinetic modeling referencing the original MTXPK.org NONMEM model (includes body surface area and serum creatinine as covariates) on 1668 patients, 7506 administrations of HDMTX, and 30,250 concentrations. Our results support the parameterizations of short infusion duration (<8 h) and the presence of Down syndrome on methotrexate clearance, the parameterization of severe hypoalbuminemia (<2.5 g/dL) on the intercompartmental clearance (Q2 and Q3), and the parameterization of pleural effusion on the volume of distribution (V1 and V2). These novel parameterizations will increase the generalizability of the MTXPK.org model once they are added to the webtool.
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Metotrexato , Leucemia-Linfoma Linfoblástico de Células Precursoras , Adolescente , Adulto Jovem , Criança , Humanos , Antimetabólitos Antineoplásicos/farmacocinética , Estudos Retrospectivos , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamento farmacológicoRESUMO
BACKGROUND: Despite improvements in survival for children with T-cell acute lymphoblastic leukemia and lymphoma (T-ALL/LLy), morbidity remains high. However, data are lacking regarding comprehensive descriptions of clinically relevant adverse events (AEs) experienced during early intensive chemotherapy. PROCEDURE: This single-institution retrospective study evaluated children aged 1-21 years with T-ALL/T-LLy diagnosed from 2010 to 2020. Physician chart abstraction identified and graded 20 clinically relevant AEs. AE rates were analyzed by T-ALL or LLy, minimal residual disease status, induction steroid, and use of antimicrobial prophylaxis. Statistical comparisons used the Kruskal-Wallis test (continuous variables) and Chi-square or Fisher's exact test (categorical variables). RESULTS: The cohort included 120 patients (T-ALL: 88; T-LLy: 32). Most patients experienced AEs during induction (85 out of 120; 70.8%) and consolidation (89 out of 111; 80.2%). Nonsepsis infection was common in induction (26 out of 120; 21.7%) and consolidation (35 out of 111; 31.5%). Patients treated with dexamethasone during induction had significantly higher rates of nonsepsis infection and/or sepsis during consolidation than those who received prednisone (p < .01). CONCLUSIONS: Clinically significant AEs are extremely common during induction and consolidation therapy for patients with T-ALL/LLy. Infectious AEs are particularly prevalent. These results can inform conversations with patients and families and aid in the development of toxicity-related aims in the next generation of, prospective clinical trials in T-ALL/LLy.
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Linfoma , Leucemia-Linfoma Linfoblástico de Células T Precursoras , Criança , Humanos , Leucemia-Linfoma Linfoblástico de Células T Precursoras/tratamento farmacológico , Leucemia-Linfoma Linfoblástico de Células T Precursoras/diagnóstico , Estudos Retrospectivos , Estudos Prospectivos , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Linfoma/tratamento farmacológico , Linfócitos TRESUMO
BACKGROUND: Administrative datasets are useful for identifying rare disease cohorts such as pediatric acute myeloid leukemia (AML). Previously, cohorts were assembled using labor-intensive, manual reviews of patients' longitudinal chemotherapy data. METHODS: We utilized a two-step machine learning (ML) method to (i) identify pediatric patients with newly diagnosed AML, and (ii) among the identified AML patients, their chemotherapy courses, in an administrative/billing database. Using 2558 patients previously manually reviewed, multiple ML algorithms were derived from 75% of the study sample, and the selected model was tested in the remaining hold-out sample. The selected model was also applied to assemble a new pediatric AML cohort and further assessed in an external validation, using a standalone cohort established by manual chart abstraction. RESULTS: For patient identification, the selected Support Vector Machine model yielded a sensitivity of 0.97 and a positive predictive value (PPV) of 0.97 in the hold-out test sample. For course-specific chemotherapy regimen and start date identification, the selected Random Forest model yielded overall PPV greater than or equal to 0.88 and sensitivity greater than or equal to 0.86 across all courses in the test sample. When applied to new cohort assembly, ML identified 3016 AML patients with 10,588 treatment courses. In the external validation subset, PPV was greater than or equal to 0.75 and sensitivity was greater than or equal to 0.82 for patient identification, and PPV was greater than or equal to 0.93 and sensitivity was greater than or equal to 0.94 for regimen identifications. CONCLUSION: A carefully designed ML model can accurately identify pediatric AML patients and their chemotherapy courses from administrative databases. This approach may be generalizable to other diseases and databases.
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Leucemia Mieloide Aguda , Humanos , Criança , Leucemia Mieloide Aguda/tratamento farmacológico , Valor Preditivo dos Testes , Bases de Dados Factuais , Algoritmos , Aprendizado de MáquinaRESUMO
BACKGROUND: There is little longitudinal information about the type and frequency of harm resulting from medication errors among outpatient children with cancer. We aimed to characterize rates and types of medication errors and harm to outpatient children with leukemia and lymphoma over 7 months of treatment. METHODS: We recruited children taking medications at home for leukemia or lymphoma from three pediatric cancer centers. Errors were identified by chart review, in-home medication review, observation of administration, and interviews. Physician reviewers confirmed error (Fleiss' κ = 0.95), harm (Fleiss' κ = 0.82), and suggested interventions. Generalized linear mixed models with random effects were used to account for clustering by site. RESULTS: Among 131 children taking 1669 medications with 367 home visits, 408 errors were identified, including 242 with potential for harm and 39 with harm (1.0 harm per 1000 patient-days [95% CI, 0.1-9.8]). Ten percent of children were injured by errors and 42% had errors with potential for harm. Twenty-six percent of caregivers reported that miscommunication led to missed doses or overdoses at home. Children on >13 medications had significantly more serious medication errors than those on fewer medications (77% vs 61%; p = .05). Physician reviewers judged that improved communication among caregivers and between caregivers and clinicians may have prevented the most harm (66%). CONCLUSIONS: In this longitudinal study, 10% children with leukemia or lymphoma experienced adverse drug events because of outpatient medication errors. Improvements addressing communication with and among caregivers should be codeveloped with families and based on human-factors engineering. PLAIN LANGUAGE SUMMARY: In this longitudinal study, medication errors in the clinic, pharmacy, or at home among children with leukemia or lymphoma over a 7-month period were common, and 10% suffered harm because of errors. Children on >13 medications had significantly more serious medication errors than those on fewer medications (77% vs 61%; p = .05). Physician reviewers judged that improved communication among caregivers and between caregivers and clinicians may have prevented the most harm (66%). Improvements addressing communication with and among caregivers should be codeveloped with families and based on human-factors engineering.
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Leucemia , Linfoma , Neoplasias , Criança , Humanos , Pacientes Ambulatoriais , Estudos Longitudinais , Erros de Medicação/prevenção & controle , Preparações Farmacêuticas , Linfoma/tratamento farmacológico , Leucemia/tratamento farmacológico , Neoplasias/tratamento farmacológicoRESUMO
BACKGROUND: Pediatric Epstein-Barr virus-negative monomorphic post solid organ transplant lymphoproliferative disorder [EBV(-)M-PTLD] comprises approximately 10% of M-PTLD. No large multi-institutional pediatric-specific reports on treatment and outcome are available. METHODS: A multi-institutional retrospective review of solid organ recipients diagnosed with EBV(-)M-PTLD aged ≤21 years between 2001 and 2020 in 12 centers in the United States and United Kingdom was performed, including demographics, staging, treatment, and outcomes data. RESULTS: Thirty-six patients were identified with EBV(-)M-PTLD. Twenty-three (63.9%) were male. Median age (range) at transplantation, diagnosis of EBV(-)M-PTLD, and interval from transplant to PTLD were 2.2 years (0.1-17), 14 years (3.0-20), and 8.5 years (0.6-18.3), respectively. Kidney (n = 17 [47.2%]) and heart (n = 13 [36.1%]) were the most commonly transplanted organs. Most were Murphy stage III (n = 25 [69.4%]). Lactate dehydrogenase was elevated in 22/34 (64.7%) and ≥2 times upper limit of normal in 11/34 (32.4%). Pathological diagnoses included diffuse large B-cell lymphoma (n = 31 [86.1%]) and B-non-Hodgkin lymphoma (B-NHL) not otherwise specified (NOS) (n = 5 [13.9%]). Of nine different regimens used, the most common were: pediatric mature B-NHL-specific regimen (n = 13 [36.1%]) and low-dose cyclophosphamide, prednisone, and rituximab (n = 9 [25%]). Median follow-up from diagnosis was 3.0 years (0.3-11.0 years). Three-year event-free survival (EFS) and overall survival (OS) were 64.8% and 79.9%, respectively. Of the seven deaths, six were from progressive disease. CONCLUSIONS: EFS and OS were comparable to pediatric EBV(+) PTLD, but inferior to mature B-NHL in immunocompetent pediatric patients. The wide range of therapeutic regimens used directs our work toward developing an active multi-institutional registry to design prospective studies. PLAIN LANGUAGE SUMMARY: Pediatric Epstein-Barr virus-negative monomorphic post solid organ transplant lymphoproliferative disorders (EBV(-)M-PTLD) have comparable outcomes to EBV(+) PTLD, but are inferior to diffuse large B-cell lymphoma in immunocompetent pediatric patients. The variety of treatment regimens used highlights the need to develop a pediatric PTLD registry to prospectively evaluate outcomes. The impact of treatment regimen on relapse risk could not be assessed because of small numbers. In the intensive pediatric B-non-Hodgkin lymphoma chemoimmunotherapy group, 11 of 13 patients remain alive in complete remission after 0.6 to 11 years.
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Infecções por Vírus Epstein-Barr , Linfoma Difuso de Grandes Células B , Linfoma não Hodgkin , Transtornos Linfoproliferativos , Transtornos Mieloproliferativos , Transplante de Órgãos , Criança , Humanos , Masculino , Feminino , Infecções por Vírus Epstein-Barr/complicações , Infecções por Vírus Epstein-Barr/epidemiologia , Herpesvirus Humano 4 , Estudos Prospectivos , Transtornos Linfoproliferativos/diagnóstico , Transtornos Linfoproliferativos/etiologia , Linfoma não Hodgkin/complicações , Linfoma Difuso de Grandes Células B/patologia , Transtornos Mieloproliferativos/complicações , Estudos Retrospectivos , Transplante de Órgãos/efeitos adversosRESUMO
Burkitt lymphoma arising in paediatric post-solid-organ transplantation-Burkitt lymphoma (PSOT-BL) is a clinically aggressive malignancy and a rare form of post-transplant lymphoproliferative disorder (PTLD). We evaluated 35 patients diagnosed with PSOT-BL at 14 paediatric medical centres in the United States. Median age at organ transplantation was 2.0 years (range: 0.1-14) and age at PSOT-BL diagnosis was 8.0 years (range: 1-17). All but one patient had late onset of PSOT-BL (≥2 years post-transplant), with a median interval from transplant to PSOT-BL diagnosis of 4.0 years (range: 0.4-12). Heart (n = 18 [51.4%]) and liver (n = 13 [37.1%]) were the most frequently transplanted organs. No patients had loss of graft or treatment-related mortality. A variety of treatment regimens were used, led by intensive Burkitt lymphoma-specific French-American-British/Lymphomes Malins B (FAB/LMB), n = 13 (37.1%), and a low-intensity regimen consisting of cyclophosphamide, prednisone and rituximab (CPR) n = 12 (34.3%). Median follow-up was 6.7 years (range: 0.5-17). Three-year event-free and overall survival were 66.2% and 88.0%, respectively. Outcomes of PSOT-BL patients receiving BL-specific intensive regimens are comparable to reported BL outcomes in immunocompetent children. Multi-institutional collaboration is feasible and provides the basis of prospective data collection to determine the optimal treatment regimen for PSOT-BL.
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Linfoma de Burkitt , Transtornos Linfoproliferativos , Transplante de Órgãos , Humanos , Criança , Lactente , Pré-Escolar , Adolescente , Linfoma de Burkitt/terapia , Linfoma de Burkitt/tratamento farmacológico , Transplante de Órgãos/efeitos adversos , Ciclofosfamida/uso terapêutico , Rituximab/uso terapêutico , Prednisona/uso terapêutico , Transtornos Linfoproliferativos/etiologia , Resultado do Tratamento , Estudos Retrospectivos , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversosRESUMO
In this commentary, we highlight the central role that data standards play in facilitating data-driven efforts to advance research in pediatric oncology. We discuss the current state of data standards for pediatric oncology and propose five steps to achieve an improved future state with benefits for clinicians, researchers, and patients.