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Neuroblastoma is the most common extracranial solid tumor diagnosed in children. This inaugural version of the NCCN Guidelines for Neuroblastoma provides recommendations for the diagnosis, risk classification, and treatment of neuroblastoma. The information in these guidelines was developed by the NCCN Neuroblastoma Panel, a multidisciplinary group of representatives with expertise in neuroblastoma, consisting of pediatric oncologists, radiologists, pathologists, surgeons, and radiation oncologists from NCCN Member Institutions. The evidence-based and consensus recommendations contained in the NCCN Guidelines are intended to guide clinicians in selecting the most appropriate treatments for their patients with this clinically heterogeneous disease.
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Oncologia , Neuroblastoma , Humanos , Neuroblastoma/terapia , Neuroblastoma/diagnóstico , Neuroblastoma/patologia , Oncologia/normas , Oncologia/métodos , Criança , Estadiamento de NeoplasiasRESUMO
BACKGROUND: We previously reported excellent three-year overall survival (OS) for patients with newly diagnosed intermediate-risk neuroblastoma treated with a biology- and response-based algorithm on the Children's Oncology Group study ANBL0531. We now present the long-term follow-up results. METHODS: All patients who met the age, stage, and tumor biology criteria for intermediate-risk neuroblastoma were eligible. Treatment was based on prognostic biomarkers and overall response. Event-free survival (EFS) and OS were estimated by the Kaplan-Meier method. RESULTS: The 10-year EFS and OS for the entire study cohort (n = 404) were 82.0% (95% confidence interval (CI), 77.2%-86.9%) and 94.7% (95% CI, 91.8%-97.5%), respectively. International Neuroblastoma Staging System stage 4 patients (n = 133) had inferior OS compared with non-stage 4 patients (n = 271; 10-year OS: 90.8% [95% CI, 84.5%-97.0%] vs 96.6% [95% CI, 93.9%-99.4%], p = .02). Infants with stage 4 tumors with ≥1 unfavorable biological feature (n = 47) had inferior EFS compared with those with favorable biology (n = 61; 10-year EFS: 66.8% [95% CI, 50.4%-83.3%] vs 86.9% [95% CI, 76.0%-97.8%], p = .02); OS did not differ (10-year OS: 84.4% [95% CI, 71.8%-97.0%] vs 95.0% [95% CI, 87.7%-100.0%], p = .08). Inferior EFS but not OS was observed among patients with tumors with (n = 26) versus without (n = 314) 11q loss of heterozygosity (10-year EFS: 68.4% [95% CI, 44.5%-92.2%] vs 83.9% [95% CI, 78.7%-89.2%], p = .03; 10-year OS: 88.0% [95% CI, 72.0%-100.0%] vs 95.7% [95% CI, 92.8%-98.6%], p = .09). CONCLUSIONS: The ANBL0531 trial treatment algorithm resulted in excellent long-term survival. More effective treatments are needed for subsets of patients with unfavorable biology tumors.
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Neuroblastoma , Humanos , Neuroblastoma/mortalidade , Neuroblastoma/terapia , Neuroblastoma/patologia , Masculino , Feminino , Seguimentos , Pré-Escolar , Lactente , Criança , Taxa de Sobrevida , Prognóstico , Adolescente , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Recém-Nascido , Estadiamento de NeoplasiasRESUMO
INTRODUCTION: Disparities in relapse and survival from high-risk neuroblastoma (HRNBL) persist among children from historically marginalized groups even in highly standardized clinical trial settings. Research in other cancers has identified differential treatment toxicity as one potential underlying mechanism. Whether racial and ethnic disparities in treatment-associated toxicity exist in HRNBL is poorly understood. METHODS: This is a retrospective study utilizing a previously assembled merged cohort of children with HRNBL on Children's Oncology Group (COG) post-consolidation immunotherapy trials ANBL0032 and ANBL0931 at Pediatric Health Information System (PHIS) centers from 2005 to 2014. Race and ethnicity were categorized to reflect historically marginalized populations as Hispanic, non-Hispanic Black (NHB), non-Hispanic other (NHO), and non-Hispanic White (NHW). Associations between race-ethnicity and intensive care unit (ICU)-level care utilization as a proxy for treatment-associated toxicity were examined with log binomial regression and summarized as risk ratio (RR) and corresponding 95% confidence interval (CI). RESULTS: The analytic cohort included 370 children. Overall, 88 (23.8%) patients required ICU-level care for a median of 3.0 days (interquartile range [IQR]: 1.0-6.5 days). Hispanic children had nearly three times the risk of ICU-level care (RR 3.1, 95% CI: 2.1-4.5; fully adjusted RR [aRR] 2.5, 95% CI: 1.6-3.7) compared to NHW children and the highest percentage of children requiring cardiovascular-driven ICU-level care. CONCLUSION: Children of Hispanic ethnicity with HRNBL receiving clinical trial-delivered therapy were more likely to experience ICU-level care compared to NHW children. These data suggest that further investigation of treatment-related toxicity as a modifiable mechanism underlying outcome disparities is warranted.
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Disparidades em Assistência à Saúde , Neuroblastoma , Humanos , Neuroblastoma/terapia , Masculino , Feminino , Estudos Retrospectivos , Criança , Pré-Escolar , Lactente , Aceitação pelo Paciente de Cuidados de Saúde/estatística & dados numéricos , Adolescente , Ensaios Clínicos como Assunto/estatística & dados numéricos , Seguimentos , Prognóstico , Hispânico ou Latino/estatística & dados numéricosRESUMO
Survival for patients with recurrent central nervous system (CNS) neuroblastoma remains poor. A single-institutional study demonstrated the potential of multimodality therapy, including compartmental intrathecal radioimmunotherapy (cRIT) with 131 I-3F8 or 131 I-8H9 to increase the survival of neuroblastoma patients with CNS relapse. However, not all patients are able to receive this therapy. We report three patients with CNS neuroblastoma who remain disease-free 3-9 years after receiving multimodality treatment without cRIT. Additional studies to identify patients most likely to benefit from cRIT are warranted.
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Neoplasias do Sistema Nervoso Central , Neuroblastoma , Humanos , Terapia Combinada , Radioimunoterapia , Neuroblastoma/terapia , Sistema Nervoso Central , Recidiva , Neoplasias do Sistema Nervoso Central/terapiaRESUMO
BACKGROUND: High-risk neuroblastoma patients with end-induction residual disease commonly receive post-induction therapy in an effort to increase survival by improving the response before autologous stem cell transplantation (ASCT). The authors conducted a multicenter, retrospective study to investigate the efficacy of this approach. METHODS: Patients diagnosed between 2008 and 2018 without progressive disease with a partial response or worse at end-induction were stratified according to the post-induction treatment: 1) no additional therapy before ASCT (cohort 1), 2) post-induction "bridge" therapy before ASCT (cohort 2), and 3) post-induction therapy without ASCT (cohort 3). χ2 tests were used to compare patient characteristics. Three-year event-free survival (EFS) and overall survival (OS) were estimated by the Kaplan-Meier method and survival curves were compared by log-rank test. RESULTS: The study cohort consisted of 201 patients: cohort 1 (n = 123), cohort 2 (n = 51), and cohort 3 (n = 27). Although the end-induction response was better for cohort 1 than cohorts 2 and 3, the outcomes for cohorts 1 and 2 were not significantly different (P = .77 for EFS and P = .85 for OS). Inferior outcomes were observed for cohort 3 (P < .001 for EFS and P = .06 for OS). Among patients with end-induction stable metastatic disease, 3-year EFS was significantly improved for cohort 2 versus cohort 1 (P = .04). Cohort 3 patients with a complete response at metastatic sites after post-induction therapy had significantly better 3-year EFS than those with residual metastatic disease (P = .01). CONCLUSIONS: Prospective studies to confirm the benefits of bridge treatment and the prognostic significance of metastatic response observed in this study are warranted.
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Transplante de Células-Tronco Hematopoéticas , Neuroblastoma , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Intervalo Livre de Doença , Humanos , Quimioterapia de Indução , Neoplasia Residual , Neuroblastoma/tratamento farmacológico , Neuroblastoma/patologia , Prognóstico , Estudos Prospectivos , Estudos Retrospectivos , Transplante Autólogo , Resultado do TratamentoRESUMO
BACKGROUND: At diagnosis, there are prognostic implications of low-level leukemic blasts (CNS 2) in the cerebrospinal fluid (CSF) of patients with acute lymphoblastic leukemia (ALL). However, the significance of post-induction CNS 2 results and the impact of equipment on CNS 2 prevalence have not been well studied. PROCEDURE: A single-institution retrospective cohort study was conducted to analyze the outcome of patients with ≥1 post-induction CNS 2. A subanalysis compared the proportion of CNS 2 CSF results using 2 different cytocentrifuges; the Shandon Cytospin used from 2005 to 2008 and the Wescor Cytopro used from 2010 to 2014. RESULTS: Over 4500 post-induction CSF samples were analyzed, of which 59 were CNS 2. In covariate-adjusted analyses, post-induction CNS 2 did not significantly increase relapse risk. The proportion of CNS 2 results increased 4.3-fold in noninfants and 6.3-fold in infants using the Wescor Cytopro. Cytocentrifuge machine did not affect CNS 3 prevalence. CONCLUSIONS: These findings support our current practice of not changing management based on a post-induction CNS 2 CSF and highlight how equipment changes can significantly influence testing results. More data are needed to analyze relapse by subpopulations, such as those with repeated CNS 2 findings.
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Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Líquido Cefalorraquidiano/química , Quimioterapia de Indução/métodos , Contagem de Leucócitos/instrumentação , Recidiva Local de Neoplasia/líquido cefalorraquidiano , Leucemia-Linfoma Linfoblástico de Células Precursoras/líquido cefalorraquidiano , Adolescente , Criança , Feminino , Seguimentos , Humanos , Lactente , Masculino , Recidiva Local de Neoplasia/tratamento farmacológico , Recidiva Local de Neoplasia/patologia , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamento farmacológico , Leucemia-Linfoma Linfoblástico de Células Precursoras/patologia , Prognóstico , Estudos Retrospectivos , Taxa de SobrevidaRESUMO
BACKGROUND: High-dose chemotherapy with autologous stem cell rescue (HDC-ASCR) has improved event-free survival for children with high-risk neuroblastoma. Common regimens include carboplatin/etoposide/melphalan (CEM), busulfan/melphalan (BuMel), and tandem HDC-ASCR [thiotepa/cyclophosphamide (TC) followed by CEM]. To complement clinical trial data and to evaluate the clinical burden associated with these regimens, resource ultilization (RU) was evaluated. An administrative database was used to evaluate RU in a previously developed high-risk neuroblastoma cohort. Single CEM and BuMel patients were followed for 60 days from the first day of the HDC-ASCR preparative regimen or until death, whichever came first. Tandem patients were followed from the first day of the first HDC-ASCR preparative regimen through day 60 from the first day of the second HDC-ASCR. Resources compared included inpatient days, ICU-level care, and medications administered. RESULTS: A cohort of 578 patients was evaluated; 422 patients underwent single HDC-ASCR with CEM, 67 received BuMel, 72 underwent TC/CEM, and 17 received only the first portion of tandem HDC-ASCR. The median number of inpatient days and days of exposure to antibiotics, opioids, and total parenteral nutrition were higher in the tandem group than in the CEM and BuMel groups. However, the rate of use of several ICU-level resources per 1000 hospital days was lower for the tandem group. CONCLUSIONS: These data suggest that while patients undergoing tandem HDC-ASCR were hospitalized longer, the severity of illness during hospitalization was not greater in tandem patients.
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Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Bases de Dados Factuais , Tempo de Internação , Neuroblastoma/terapia , Adolescente , Adulto , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Autoenxertos , Bussulfano/administração & dosagem , Bussulfano/efeitos adversos , Carboplatina/administração & dosagem , Carboplatina/efeitos adversos , Criança , Pré-Escolar , Etoposídeo/administração & dosagem , Etoposídeo/efeitos adversos , Feminino , Seguimentos , Humanos , Lactente , Recém-Nascido , Masculino , Melfalan/administração & dosagem , Melfalan/efeitos adversos , Transplante de Células-TroncoRESUMO
Behcet disease is a potentially life-threatening multisystemic vasculitis with thrombotic tendency. Mucocutaneous ulcers, arthritis, and uveitis are the most recognizable features, but may be absent at the time of medical evaluation. We report a case in which a 8-year old patient presented with spontaneous bilateral lower extremity deep venous thromboses, and screening for rheumatologic symptoms led to diagnosing Behcet. This case demonstrates that deep venous thromboses can be the initial event bringing a patient with Behcet to medical attention, highlighting the importance of screening for underlying rheumatologic diseases in pediatric patients who present with unprovoked thrombosis.
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Síndrome de Behçet/diagnóstico , Trombose Venosa/diagnóstico , Criança , Diagnóstico Diferencial , Humanos , Doenças Reumáticas/diagnósticoRESUMO
Atypical chronic myeloid leukemia, BCR-ABL1-negative, (aCML) is a rare myeloid neoplasm. Recent adult data suggest the leukemic cells in a subset of patients are dependent on JAK/STAT signaling and harbor CSF3R-activating mutations. We hypothesized that, similar to adult patients, the presence of CSF3R-activating mutations would be clinically relevant in pediatric myeloid neoplasms as patients would be sensitive to the JAK inhibitor, ruxolitinib. We report two cases of morphologically similar pediatric aCML, BCR-ABL1-negative based on WHO 2008 criteria. One patient had CSF3R-activating mutation (T618I) and demonstrated a robust response to ruxolitinib, which was used to bridge to a successful stem cell transplant. The other patient did not have a CSF3R-activating mutation and succumbed to refractory disease <6 months from diagnosis. This report documents CSF3R-T618I in pediatric aCML and demonstrates the efficacy of ruxolitinib in a pediatric malignancy. As the third documented case successfully treating aCML with ruxolitinib, this case highlights the importance of prompt CSF3R sequencing analysis for myeloproliferative and myelodysplastic/myeloproliferative neoplasms.
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Leucemia Mieloide Crônica Atípica BCR-ABL Negativa/tratamento farmacológico , Leucemia Mieloide Crônica Atípica BCR-ABL Negativa/genética , Pirazóis/uso terapêutico , Receptores de Fator Estimulador de Colônias/genética , Adolescente , Criança , Feminino , Humanos , Mutação , Nitrilas , PirimidinasRESUMO
BACKGROUND: High-dose chemotherapy with autologous stem cell rescue (ASCR) is a key component of high-risk neuroblastoma therapy. Resources required to support patients treated with ASCR conditioning regimens [carboplatin/etoposide/melphalan (CEM) and busulfan/melphalan (BuMel)] have not been directly compared. PROCEDURE: An administrative database was used to analyze resource utilization and outcomes in a cohort of high-risk neuroblastoma patients. Patients were followed for 60 days from start of conditioning or until death. Length of hospitalization, length of intensive care unit (ICU) level of care, incidence of sepsis and sinusoidal obstruction syndrome (SOS), and duration of use of specific supportive care resources were analyzed. RESULTS: Six of 171 CEM patients and zero of 59 BuMel patients died during the study period (P = 0.34). Duration of hospitalization was longer following BuMel (median 35 vs. 31 days; P = 0.01); however, there was no difference in duration of ICU-level care. Antibiotic use was longer following CEM (median 19 vs. 15 days; P = 0.01), as was antihypertensive use (median 5 vs. 1.6 days; P = 0.0024). Duration of opiate and nonnarcotic analgesic use was longer following CEM early in the study period. Resources consistent with a diagnosis of SOS were used in a higher proportion of BuMel patients. A higher proportion of BuMel treated patients required mechanical ventilation (17% vs. 6%; P = 0.03). CONCLUSIONS: We used administrative billing data to compare resources associated with ASCR conditioning regimens. CEM patients required more extended use of analgesics, antibiotics, and antihypertensives, while duration of hospitalization was longer, and SOS and the use of mechanical ventilation were more frequent following BuMel.
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Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Bases de Dados Factuais , Neuroblastoma/terapia , Transplante de Células-Tronco de Sangue Periférico , Células-Tronco , Condicionamento Pré-Transplante/métodos , Adolescente , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Autoenxertos , Bussulfano/administração & dosagem , Bussulfano/efeitos adversos , Carboplatina/administração & dosagem , Carboplatina/efeitos adversos , Criança , Pré-Escolar , Cuidados Críticos , Etoposídeo/administração & dosagem , Etoposídeo/efeitos adversos , Feminino , Seguimentos , Humanos , Incidência , Lactente , Tempo de Internação , Masculino , Melfalan/administração & dosagem , Melfalan/efeitos adversos , Sepse/induzido quimicamente , Sepse/tratamento farmacológico , Condicionamento Pré-Transplante/efeitos adversos , Estados UnidosRESUMO
International Classification of Diseases, 9th Revision (ICD-9) code(s) for neuroblastoma do not exist, preventing identification of these patients in administrative databases. To overcome this challenge, a three-step algorithm, using ICD-9 codes, exclusion criteria, and manual review of chemotherapy billing data, was utilized to assemble a high-risk neuroblastoma cohort (n = 952) from the Pediatric Health Information System (PHIS) Database and validated at a single institution [sensitivity 89.1%; positive predictive value (PPV) 96.1%]. This cohort provides a data source for future comparative effectiveness and clinical epidemiology studies in high-risk neuroblastoma patients.
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Bases de Dados Factuais , Sistemas de Informação em Saúde/estatística & dados numéricos , Neuroblastoma/epidemiologia , Adolescente , Adulto , Algoritmos , Antineoplásicos/economia , Institutos de Câncer/estatística & dados numéricos , Criança , Pré-Escolar , Estudos de Coortes , Uso de Medicamentos/economia , Feminino , Recursos em Saúde/estatística & dados numéricos , Hospitais Pediátricos/estatística & dados numéricos , Humanos , Lactente , Pacientes Internados/estatística & dados numéricos , Classificação Internacional de Doenças , Masculino , Neuroblastoma/diagnóstico , Neuroblastoma/tratamento farmacológico , Honorários por Prescrição de Medicamentos , Risco , Centros de Atenção Terciária/estatística & dados numéricos , Estados Unidos/epidemiologia , Adulto JovemRESUMO
PURPOSE: Although the International Neuroblastoma Risk Group Data Commons (INRGdc) has enabled seminal large cohort studies, the research is limited by the lack of real-world, electronic health record (EHR) treatment data. To address this limitation, we evaluated the feasibility of extracting treatment data directly from EHRs using the REDCap Clinical Data Interoperability Services (CDIS) module for future submission to the INRGdc. METHODS: Patients enrolled on the Children's Oncology Group neuroblastoma biology study ANBL00B1 (ClinicalTrials.gov identifier: NCT00904241) who received care at the University of Chicago (UChicago) or the Vanderbilt University Medical Center (VUMC) after the go-live dates for the Fast Healthcare Interoperability Resources (FHIR)-compliant EHRs were identified. Antineoplastic drug orders were extracted using the CDIS module. To validate the CDIS output, antineoplastic agents extracted through FHIR were compared with those queried through EHR relational databases (UChicago's Clinical Research Data Warehouse and VUMC's Epic Clarity database) and manual chart review. RESULTS: The analytic cohort consisted of 41 patients at UChicago and 32 VUMC patients. Antineoplastic drug orders were identified in the extracted EHR records of 39 (95.1%) UChicago patients and 26 (81.3%) VUMC patients. Manual chart review confirmed that patients with missing (n = 8) or discontinued (n = 1) orders in the CDIS output did not receive antineoplastic agents during the timeframe of the study. More than 99% of the antineoplastic drug orders in the EHR relational databases were identified in the corresponding CDIS output. CONCLUSION: Our results demonstrate the feasibility of extracting EHR treatment data with high fidelity using HL7-FHIR via REDCap CDIS for future submission to the INRGdc.
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Registros Eletrônicos de Saúde , Neuroblastoma , Humanos , Neuroblastoma/tratamento farmacológico , Neuroblastoma/terapia , Feminino , Masculino , Criança , Pré-Escolar , Interoperabilidade da Informação em Saúde , Lactente , Antineoplásicos/uso terapêutico , Bases de Dados FactuaisRESUMO
Recent insights have identified adrenergic (ADRN) and mesenchymal (MES) cell lineages as distinct biologic cell types and T-cell inflammation as a prognostic marker in neuroblastoma. We hypothesized that elucidating unique and overlapping aspects of these biologic features could serve as novel biomarkers for informing ongoing efforts to improve therapeutic approaches for children with high-risk neuroblastoma. We identified lineage-specific, single-stranded super-enhancers to define ADRN and MES specific genes. Publicly available RNA-seq of diagnostic tumor biopsies was used in Discovery and Validation cohorts. Each tumor was assigned a relative MES score and T-cell-inflamed (TCI) score. Survival was assessed using the Kaplan-Meier method, and differences were assessed by the log-rank test. Inflammation scores were correlated with MES scores and anticorrelated with MYCN-amplification in both cohorts. Among patients with high-risk, ADRN tumors, those with TCI tumors had superior overall survival to those with non-inflamed tumors. A similar, but non-significant, trend was observed in the Validation cohort. Conversely, there was no difference according to TCI status in the MES cohort in either the Discover or Validation Cohorts. High inflammation scores were correlated with improved survival in some patients with high-risk, ADRN but not MES neuroblastoma. Our findings bolster support for further developing T-cell based immunotherapy-based approaches for children with high-risk neuroblastoma of varying MES and ADRN expression.
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Purpose: T-cell inflammation (TCI) has been shown to be a prognostic marker in neuroblastoma, a tumor comprised of cells that can exist in two epigenetic states, adrenergic (ADRN) and mesenchymal (MES). We hypothesized that elucidating unique and overlapping aspects of these biologic features could serve as novel biomarkers. Patients and Methods: We detected lineage-specific, single-stranded super-enhancers defining ADRN and MES specific genes. Publicly available neuroblastoma RNA-seq data from GSE49711 (Cohort 1) and TARGET (Cohort 2) were assigned MES, ADRN, and TCI scores. Tumors were characterized as MES (top 33%) or ADRN (bottom 33%), and TCI (top 67% TCI score) or non-inflamed (bottom 33% TCI score). Overall survival (OS) was assessed using the Kaplan-Meier method, and differences were assessed by the log-rank test. Results: We identified 159 MES genes and 373 ADRN genes. TCI scores were correlated with MES scores (R=0.56, p<0.001 and R=0.38, p<0.001) and anticorrelated with MYCN -amplification (R=-0.29, p<0.001 and -0.18, p=0.03) in both cohorts. Among Cohort 1 patients with high-risk, ADRN tumors (n=59), those with TCI tumors (n=22) had superior OS to those with non-inflammed tumors (n=37) (p=0.01), though this comparison did not reach significance in Cohort 2. TCI status was not associated with survival in patients with high-risk MES tumors in either cohort. Conclusions: High inflammation scores were correlated with improved survival in some high-risk patients with, ADRN but not MES neuroblastoma. These findings have implications for approaches to treating high-risk neuroblastoma.
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BACKGROUND: Racial/ethnic survival disparities in neuroblastoma were first reported more than a decade ago. We sought to investigate if these disparities have persisted with current era therapy. METHODS: Two patient cohorts were identified in the International Neuroblastoma Risk Group Data Commons (INRGdc) (Cohort 1: diagnosed 2001-2009, n=4359; Cohort 2: diagnosed 2010-2019, n=4891). Chi-squared tests were used to assess the relationship between race/ethnicity and clinical and biologic features. Survival was estimated by the Kaplan-Meier method. Cox proportional hazards regression analyses were performed to investigate the association between racial/ethnic groups and prognostic markers. RESULTS: Significantly higher 5-year event-free survival (EFS) and overall survival (OS) were observed for Cohort 2 compared to Cohort 1 (P<0.001 and P<0.001, respectively). Compared to White patients, Black patients in both cohorts had a higher proportion of high-risk disease (Cohort 1: P<0.001; Cohort 2: P<0.001) and worse EFS (Cohort 1: P<0.001; Cohort 2 P<0.001) and OS (Cohort 1: P<0.001; Cohort 2: P<0.001). In Cohort 1, Native Americans also had a higher proportion of high-risk disease (P=0.03) and inferior EFS/OS. No significant survival disparities were observed for low- or intermediate-risk patients in either cohort or high-risk patients in Cohort 1. Hispanic patients with high-risk disease in Cohort 2 had significantly inferior OS (P=0.047). Significantly worse OS, but not EFS, (P=0.006 and P=0.02, respectively) was also observed among Black and Hispanic patients assigned to receive post-Consolidation dinutuximab on clinical trials (n=885). CONCLUSION: Racial/ethnic survival disparities have persisted over time and were observed among high-risk patients assigned to receive post-Consolidation dinutuximab.
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PURPOSE: Although chemoimmunotherapy is widely used for treatment of children with relapsed high-risk neuroblastoma (HRNB), little is known about timing, duration, and evolution of response after irinotecan/temozolomide/dinutuximab/granulocyte-macrophage colony-stimulating factor (I/T/DIN/GM-CSF) therapy. PATIENTS AND METHODS: Patients eligible for this retrospective study were age < 30 years at diagnosis of HRNB and received ≥ 1 cycle of I/T/DIN/GM-CSF for relapsed or progressive disease. Patients with primary refractory disease who progressed through induction were excluded. Responses were evaluated using the International Neuroblastoma Response Criteria. RESULTS: One hundred forty-six patients were included. Tumors were MYCN-amplified in 50 of 134 (37%). Seventy-one patients (49%) had an objective response to I/T/DIN/GM-CSF (objective response; 29% complete response, 14% partial response [PR], 5% minor response [MR], 21% stable disease [SD], and 30% progressive disease). Of patients with SD or better at first post-I/T/DIN/GM-CSF disease evaluation, 22% had an improved response per International Neuroblastoma Response Criteria on subsequent evaluation (13% of patients with initial SD, 33% with MR, and 41% with PR). Patients received a median of 4.5 (range, 1-31) cycles. The median progression-free survival (PFS) was 13.1 months, and the 1-year PFS and 2-year PFS were 50% and 28%, respectively. The median duration of response was 15.9 months; the median PFS off all anticancer therapy was 10.4 months after discontinuation of I/T/DIN/GM-CSF. CONCLUSION: Approximately half of patients receiving I/T/DIN/GM-CSF for relapsed HRNB had objective responses. Patients with initial SD were unlikely to have an objective response, but > 1 of 3 patients with MR/PR on first evaluation ultimately had complete response. I/T/DIN/GM-CSF was associated with extended PFS in responders both during and after discontinuation of treatment. This study establishes a new comparator for response and survival in patients with relapsed HRNB.
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Fator Estimulador de Colônias de Granulócitos e Macrófagos , Neuroblastoma , Criança , Humanos , Adulto , Intervalo Livre de Progressão , Fator Estimulador de Colônias de Granulócitos e Macrófagos/uso terapêutico , Irinotecano/uso terapêutico , Temozolomida/uso terapêutico , Estudos Retrospectivos , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Neuroblastoma/patologiaRESUMO
Neuroblastomas harbor ALK aberrations clinically resistant to crizotinib yet sensitive pre-clinically to the third-generation ALK inhibitor lorlatinib. We conducted a first-in-child study evaluating lorlatinib with and without chemotherapy in children and adults with relapsed or refractory ALK-driven neuroblastoma. The trial is ongoing, and we report here on three cohorts that have met pre-specified primary endpoints: lorlatinib as a single agent in children (12 months to <18 years); lorlatinib as a single agent in adults (≥18 years); and lorlatinib in combination with topotecan/cyclophosphamide in children (<18 years). Primary endpoints were safety, pharmacokinetics and recommended phase 2 dose (RP2D). Secondary endpoints were response rate and 123I-metaiodobenzylguanidine (MIBG) response. Lorlatinib was evaluated at 45-115 mg/m2/dose in children and 100-150 mg in adults. Common adverse events (AEs) were hypertriglyceridemia (90%), hypercholesterolemia (79%) and weight gain (87%). Neurobehavioral AEs occurred mainly in adults and resolved with dose hold/reduction. The RP2D of lorlatinib with and without chemotherapy in children was 115 mg/m2. The single-agent adult RP2D was 150 mg. The single-agent response rate (complete/partial/minor) for <18 years was 30%; for ≥18 years, 67%; and for chemotherapy combination in <18 years, 63%; and 13 of 27 (48%) responders achieved MIBG complete responses, supporting lorlatinib's rapid translation into active phase 3 trials for patients with newly diagnosed high-risk, ALK-driven neuroblastoma. ClinicalTrials.gov registration: NCT03107988 .
Assuntos
Carcinoma Pulmonar de Células não Pequenas , Neoplasias Pulmonares , Neuroblastoma , Adulto , Humanos , 3-Iodobenzilguanidina/uso terapêutico , Aminopiridinas/uso terapêutico , Quinase do Linfoma Anaplásico/genética , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Lactamas Macrocíclicas/efeitos adversos , Neoplasias Pulmonares/tratamento farmacológico , Recidiva Local de Neoplasia/tratamento farmacológico , Neuroblastoma/tratamento farmacológico , Neuroblastoma/genética , Inibidores de Proteínas Quinases/uso terapêutico , Criança , Lactente , Pré-Escolar , AdolescenteRESUMO
PURPOSE: Postconsolidation immunotherapy including dinutuximab, granulocyte-macrophage colony-stimulating factor, and interleukin-2 improved outcomes for patients with high-risk neuroblastoma enrolled on the randomized portion of Children's Oncology Group study ANBL0032. After random assignment ended, all patients were assigned to immunotherapy. Survival and toxicities were assessed. PATIENTS AND METHODS: Patients with a pre-autologous stem cell transplant (ASCT) response (excluding bone marrow) of partial response or better were eligible. Demographics, stage, tumor biology, pre-ASCT response, and adverse events were summarized using descriptive statistics. Event-free survival (EFS) and overall survival (OS) from time of enrollment (up to day +200 from last ASCT) were evaluated. RESULTS: From 2009 to 2015, 1,183 patients were treated. Five-year EFS and OS for the entire cohort were 61.1 ± 1.9% and 71.9 ± 1.7%, respectively. For patients ≥ 18 months old at diagnosis with International Neuroblastoma Staging System stage 4 disease (n = 662) 5-year EFS and OS were 57.0 ± 2.4% and 70.9 ± 2.2%, respectively. EFS was superior for patients with complete response/very good partial response pre-ASCT compared with those with PR (5-year EFS: 64.2 ± 2.2% v 55.4 ± 3.2%, P = .0133); however, OS was not significantly different. Allergic reactions, capillary leak, fever, and hypotension were more frequent during interleukin-2-containing cycles than granulocyte-macrophage colony-stimulating factor-containing cycles (P < .0001). EFS was superior in patients with higher peak dinutuximab levels during cycle 1 (P = .034) and those with a high affinity FCGR3A genotype (P = .0418). Human antichimeric antibody status did not correlate with survival. CONCLUSION: Analysis of a cohort assigned to immunotherapy after cessation of random assignment on ANBL0032 confirmed previously described survival and toxicity outcomes. EFS was highest among patients with end-induction complete response/very good partial response. Among patients with available data, higher dinutuximab levels and FCGR3A genotype were associated with superior EFS. These may be predictive biomarkers for dinutuximab therapy.
Assuntos
Fator Estimulador de Colônias de Granulócitos e Macrófagos , Interleucina-2 , Criança , Humanos , Lactente , Fator Estimulador de Colônias de Granulócitos e Macrófagos/efeitos adversos , Interleucina-2/efeitos adversos , Projetos de PesquisaRESUMO
BACKGROUND: Entrectinib is a TRKA/B/C, ROS1, ALK tyrosine kinase inhibitor approved for the treatment of adults and children aged ≥12 years with NTRK fusion-positive solid tumors and adults with ROS1 fusion-positive non-small-cell lung cancer. We report an analysis of the STARTRK-NG trial, investigating the recommended phase 2 dose (RP2D) and activity of entrectinib in pediatric patients with solid tumors including primary central nervous system tumors. METHODS: STARTRK-NG (NCT02650401) is a phase 1/2 trial. Phase 1, dose-escalation of oral, once-daily entrectinib, enrolled patients aged <22 years with solid tumors with/without target NTRK1/2/3, ROS1, or ALK fusions. Phase 2, basket trial at the RP2D, enrolled patients with intracranial or extracranial solid tumors harboring target fusions or neuroblastoma. Primary endpoints: phase 1, RP2D based on toxicity; phase 2, objective response rate (ORR) in patients harboring target fusions. Safety-evaluable patients: ≥1 dose of entrectinib; response-evaluable patients: measurable/evaluable baseline disease and ≥1 dose at RP2D. RESULTS: At data cutoff, 43 patients, median age of 7 years, were response-evaluable. In phase 1, 4 patients experienced dose-limiting toxicities. The most common treatment-related adverse event was weight gain (48.8%). Nine patients experienced bone fractures (20.9%). In patients with fusion-positive tumors, ORR was 57.7% (95% CI 36.9-76.7), median duration of response was not reached, and median (interquartile range) duration of treatment was 10.6 months (4.2-18.4). CONCLUSIONS: Entrectinib resulted in rapid and durable responses in pediatric patients with solid tumors harboring NTRK1/2/3 or ROS1 fusions.