RESUMO
Over 50% of patients with systemic LCH are not cured with front-line therapies, and data to guide salvage options are limited. We describe 58 patients with LCH who were treated with clofarabine. Clofarabine monotherapy was active against LCH in this cohort, including heavily pretreated patients with a systemic objective response rate of 92.6%, higher in children (93.8%) than adults (83.3%). BRAFV600E+ variant allele frequency in peripheral blood is correlated with clinical responses. Prospective multicentre trials are warranted to determine optimal dosing, long-term efficacy, late toxicities, relative cost and patient-reported outcomes of clofarabine compared to alternative LCH salvage therapy strategies.
Assuntos
Clofarabina , Histiocitose de Células de Langerhans , Humanos , Clofarabina/uso terapêutico , Clofarabina/administração & dosagem , Histiocitose de Células de Langerhans/tratamento farmacológico , Masculino , Feminino , Adulto , Adolescente , Criança , Pessoa de Meia-Idade , Pré-Escolar , Adulto Jovem , Idoso , Recidiva , Proteínas Proto-Oncogênicas B-raf/genética , Lactente , Resultado do Tratamento , Terapia de Salvação , Nucleotídeos de Adenina/uso terapêutico , Nucleotídeos de Adenina/administração & dosagem , Nucleotídeos de Adenina/efeitos adversos , Arabinonucleosídeos/uso terapêutico , Arabinonucleosídeos/administração & dosagem , Arabinonucleosídeos/efeitos adversosRESUMO
Mature B-cell lymphoma in children, adolescents and young adults comprises three major histological subtypes including in order of frequency Burkitt, germinal center diffuse large B-cell lymphoma and primary mediastinal B-cell lymphoma. The cure rate of the first two with aggressive short chemotherapy based on clinical grouping is â¼90% in resource rich countries. Recent data has shown that incorporation of immune therapy has enhanced event free survival in advanced patients. Future studies will address the possibility of reducing the burden of chemotherapy by substitution of immune based therapies.
Assuntos
Linfoma Difuso de Grandes Células B , Humanos , Criança , Adolescente , Adulto Jovem , Linfoma Difuso de Grandes Células B/diagnóstico , Linfoma Difuso de Grandes Células B/terapia , Linfócitos B , Centro GerminativoRESUMO
BACKGROUND: Ewing sarcoma breakpoint region 1 gene (EWSR1) rearrangements are largely associated with the Ewing sarcoma family of tumors. OBSERVATIONS: We report the first case of infantile, mixed phenotype acute leukemia, B/myeloid (bilineal and biphenotypic [B-lymphoid and B-lymphoid/myeloid]), with a t(2;22)(q35;q12). The EWSR1-fifth Ewing variant gene fusion and nonsense mutation in STAG2 were detected by next-generation sequencing and markedly high expression of fifth Ewing sarcoma variant mRNA detected by quantitative reverse transcription polymerase chain reaction. The patient was treated with a combined myeloid/lymphoid leukemia regimen followed by allogeneic stem cell transplant and was in complete remission at 3.8-year follow-up. CONCLUSIONS: Our case study underscores the importance of a comprehensive evaluation of acute leukemia and provides insights into the phenotype of EWSR1 rearranged neoplasms in the context of partner genes and cell type.
Assuntos
Proteínas de Ligação a DNA/genética , Leucemia Aguda Bifenotípica/genética , Leucemia Mieloide Aguda/genética , Proteínas de Fusão Oncogênica/genética , Proteína EWS de Ligação a RNA/genética , Fatores de Transcrição/genética , Proteínas de Ciclo Celular/genética , Códon sem Sentido , Feminino , Humanos , Lactente , Translocação GenéticaAssuntos
Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Neoplasias do Sistema Nervoso Central/tratamento farmacológico , Linfoma de Células B/tratamento farmacológico , Adolescente , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Linfoma de Burkitt/tratamento farmacológico , Criança , Feminino , Humanos , Imunoterapia/métodos , Injeções Espinhais , Estimativa de Kaplan-Meier , Masculino , Rituximab/administração & dosagem , Resultado do TratamentoRESUMO
Pediatric and adult patients with recurrent/refractory Burkitt lymphoma (BL) continue to have poor outcomes, emphasizing the need for newer therapeutic agents. Bruton's tyrosine kinase (BTK) is activated following B-cell receptor stimulation and in part regulates normal B-cell development. Ibrutinib, a selective and irreversible BTK inhibitor, has been efficacious in chronic lymphocytic leukemia (CLL), mantle cell lymphoma (MCL), Waldenström's macroglobulinemia, and marginal zone lymphoma. In this study, we investigated the efficacy of ibrutinib alone and in selective adjuvant combinations against BL in-vitro and in a human BL xenografted immune-deficient NOD.Cg-PrkdcscidIl2rgtm1Wjl/SzJ (NSG) mouse model. Our data demonstrated that phospho-BTK level was significantly reduced in BL cells treated with ibrutinib (p < 0.001). Moreover, we observed a significant decrease in cell proliferation as well as significant decrease in IC50 of ibrutinib in combination with dexamethasone, rituximab, obinutuzumab, carfilzomib, and doxorubicin (p < 0.001). In-vivo studies demonstrated ibrutinib treated mice had a significantly prolonged survival with median survival of mice following ibrutinib treatment (32 days) (24 days) (p < 0.02). In conclusion, our findings demonstrate the significant in-vitro and preclinical in-vivo effects of ibrutinib in BL. Based on our preclinical results in this investigation, there is an on-going clinical trial comparing overall survival in children and adolescents with relapsed/refractory BL treated with chemoimmunotherapy with or without ibrutinib (NCT02703272).
RESUMO
We determined the risk factors associated with poor survival in children and adolescents with de novo mature B cell non-Hodgkin lymphoma (B-NHL) who had refractory or relapsed disease during or after the French-American-British mature lymphoma B (FAB/LMB) 96 multi-agent chemotherapy. Among the 1 111 registered on study, 104 patients (9·4%) had refractory disease or disease relapse after first complete remission. Among these 104 patients, 28 (27%) patients had refractory disease and 76 (73%) had relapsed disease. The estimated 1- and 2-year overall survival (OS) (95% confidence interval) was 31·5% (23·3-41·0%) and 22·3% (15·3-31·4%), respectively. Prognostic analysis of OS using a Cox multivariate model showed that factors independently associated with OS included lactate dehydrogenase ≥2 upper normal limit [hazard ratio (HR) = 2·86 (1·57-5·2), P = 0·0006]; time to failure (>6 months) [HR = 0·59 (0·36-0·97), P = 0·038]; and failure in bone marrow [HR = 2·78 (1·65-4·68), P = 0·0001]. New therapeutic strategies are required to significantly reduce refractory disease and disease relapse in patients with newly diagnosed mature B-NHL and, more importantly, there is a critical need to develop novel retrieval approaches in patients with chemotherapy-resistant disease.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Linfoma de Células B/tratamento farmacológico , Adolescente , Doenças da Medula Óssea , Carmustina/uso terapêutico , Criança , Doxorrubicina/uso terapêutico , Feminino , Fluoruracila/uso terapêutico , Humanos , Isoenzimas/sangue , L-Lactato Desidrogenase/sangue , Linfoma de Células B/diagnóstico , Linfoma de Células B/epidemiologia , Linfoma de Células B/mortalidade , Masculino , Prognóstico , Modelos de Riscos Proporcionais , Fatores de Risco , Terapia de Salvação/métodos , Terapia de Salvação/mortalidade , Análise de Sobrevida , Fatores de TempoRESUMO
BACKGROUND: Central nervous system Langerhans cell histiocytosis (CNS-LCH) brain involvement may include mass lesions and/or a neurodegenerative disease (LCH-ND) of unknown etiology. The goal of this study was to define the mechanisms of pathogenesis that drive CNS-LCH. METHODS: Cerebrospinal fluid (CSF) biomarkers including CSF proteins and extracellular BRAFV600E DNA were analyzed in CSF from patients with CNS-LCH lesions compared with patients with brain tumors and other neurodegenerative conditions. Additionally, the presence of BRAFV600E was tested in peripheral mononuclear blood cells (PBMCs) as well as brain biopsies from LCH-ND patients, and the response to BRAF-V600E inhibitor was evaluated in 4 patients with progressive disease. RESULTS: Osteopontin was the only consistently elevated CSF protein in patients with CNS-LCH compared with patients with other brain pathologies. BRAFV600E DNA was detected in CSF of only 2/20 (10%) cases, both with LCH-ND and active lesions outside the CNS. However, BRAFV600E+ PBMCs were detected with significantly higher frequency at all stages of therapy in LCH patients who developed LCH-ND. Brain biopsies of patients with LCH-ND demonstrated diffuse perivascular infiltration by BRAFV600E+ cells with monocyte phenotype (CD14+ CD33+ CD163+ P2RY12- ) and associated osteopontin expression. Three of 4 patients with LCH-ND treated with BRAF-V600E inhibitor experienced significant clinical and radiologic improvement. CONCLUSION: In LCH-ND patients, BRAFV600E+ cells in PBMCs and infiltrating myeloid/monocytic cells in the brain is consistent with LCH-ND as an active demyelinating process arising from a mutated hematopoietic precursor from which LCH lesion CD207+ cells are also derived. Therapy directed against myeloid precursors with activated MAPK signaling may be effective for LCH-ND. Cancer 2018;124:2607-20. © 2018 American Cancer Society.
Assuntos
Neoplasias Encefálicas/diagnóstico , Histiocitose de Células de Langerhans/diagnóstico , Doenças Neurodegenerativas/diagnóstico , Osteopontina/líquido cefalorraquidiano , Proteínas Proto-Oncogênicas B-raf/genética , Adolescente , Adulto , Biomarcadores/sangue , Biomarcadores/líquido cefalorraquidiano , Biópsia , Encéfalo/patologia , Neoplasias Encefálicas/líquido cefalorraquidiano , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/patologia , Criança , Pré-Escolar , Diagnóstico Diferencial , Feminino , Células-Tronco Hematopoéticas/patologia , Histiocitose de Células de Langerhans/líquido cefalorraquidiano , Histiocitose de Células de Langerhans/genética , Histiocitose de Células de Langerhans/patologia , Humanos , Lactente , Recém-Nascido , Leucócitos Mononucleares/patologia , Sistema de Sinalização das MAP Quinases , Masculino , Doenças Neurodegenerativas/líquido cefalorraquidiano , Doenças Neurodegenerativas/genética , Doenças Neurodegenerativas/patologia , Proteínas Proto-Oncogênicas B-raf/antagonistas & inibidores , Estudos Retrospectivos , Adulto JovemRESUMO
Burkitt lymphoma (BL) is the most common histological subtype of non-Hodgkin lymphoma (NHL) in children and adolescents. Through the introduction of short intensive multi-agent chemoimmunotherapy, survival has improved significantly over the past 30 years. However, this successful approach is limited by significant chemotherapy-induced acute toxicity and risk of developing resistant disease, demonstrating the need to identify less toxic and targeted therapies. We analysed the comparative genomic signature and targetable signalling pathways in paediatric BL (PEBL) samples from the Children's Oncology Group study (ANHL01P1) by genomic profiling and selected genes were confirmed by quantitative real time polymerase chain reaction. These results were compared to PEBL samples from public databases and utilised the Gene Expression Omnibus (GEO) Series (GSE) 10172 and 4475 (n = 16), and 4732 (n = 15). Three hundred and seventy-six genes (approximately 25%) were similarly expressed among three PEBL sample groups. Several target genes in Toll-like receptor signalling, JAK-STAT signalling and MAPK signalling were significantly overexpressed in PEBL. In addition, several tyrosine kinases, including Bruton tyrosine kinase, protein tyrosine phosphatase and histone deacetylase inhibitor were highly expressed in PEBL. These pre-clinical results suggest that specific signal transduction pathways are overly expressed in PEBL and several pathways could serve as potential future therapeutic targets.
Assuntos
Linfoma de Burkitt/genética , Genômica/métodos , Transdução de Sinais/genética , Adolescente , Criança , Feminino , Expressão Gênica/genética , Perfilação da Expressão Gênica/métodos , Humanos , Lactente , Masculino , Proto-Oncogenes/genéticaRESUMO
Paediatric B-cell non-Hodgkin lymphoma (B-NHL) compromises a heterogeneous group of histological entities of which Burkitt lymphoma is the most common. In resource-rich countries, the expected cure rate is in excess of 85% with application of risk-adapted short intensive chemotherapy. In recent years, large paediatric cooperative group trials have sought to improve upon outcomes by decreasing the intensity of cytotoxic treatment as well as introducing targeted therapies, such as rituximab. These efforts have resulted in excellent outcomes, however there remains a group of high-risk patients for whom novel treatment approaches are needed. In this review, we will summarize the recent paediatric clinical trials in B-NHL as well as compare treatment approaches across the major cooperative groups. We will also highlight our current understanding of the molecular biology of paediatric B-NHL with a focus on how this may help guide future rational targeted therapy.
Assuntos
Linfoma de Células B/tratamento farmacológico , Terapia de Alvo Molecular/tendências , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Linfoma de Burkitt/tratamento farmacológico , Criança , Pré-Escolar , Ensaios Clínicos como Assunto , Feminino , Humanos , Lactente , Recém-Nascido , Linfoma Difuso de Grandes Células B/tratamento farmacológico , Masculino , Neoplasias do Mediastino/tratamento farmacológico , Pessoa de Meia-Idade , Terapia de Alvo Molecular/métodos , Adulto JovemRESUMO
Patient-specific primers from 10 children/adolescents with Burkitt leukaemia (BL) ± central nervous system disease who were treated with French-British-American/Lymphome Malins de Burkitt 96 C1 plus rituximab were developed from diagnostic blood/bone marrow. Minimal residual disease (MRD) was assessed by real-time polymerase chain reaction at the end of induction (EOI) and consolidation (EOC). Seventy per cent (7/10) and 71% (5/7) were MRD-positive at EOI and EOC, respectively, with no disease recurrences. MRD after induction and consolidation did not predict relapse and subsequent therapy appeared to eliminate MRD. Thus, assessing MRD at a later time point is warranted in future trials to determine its clinical significance.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Linfoma de Burkitt/sangue , Linfoma de Burkitt/tratamento farmacológico , Neoplasias do Sistema Nervoso Central/sangue , Neoplasias do Sistema Nervoso Central/tratamento farmacológico , Quimioterapia de Consolidação , Adolescente , Adulto , Criança , Pré-Escolar , Feminino , Humanos , Masculino , Neoplasia Residual , Projetos Piloto , Reação em Cadeia da Polimerase em Tempo RealRESUMO
Children and adolescents with Burkitt Lymphoma (BL) and combined central nervous system (CNS) and bone marrow involvement still have a poor prognosis with chemotherapy alone. We therefore investigated in children and adolescents with bone marrow (≥25% blasts) and/or CNS-positive Burkitt lymphoma the chemoimmunotherapy combination of rituximab (375 mg/m(2) ) and the standard chemotherapy arm of our previously reported French-American-British (FAB) Lymphome Malins de Burkitt (LMB) 96 trial. Central pathological and cytogenetic characterization was also performed. There were 40 evaluable patients with Burkitt histology (25 with leukaemia and 15 with CNS disease ± leukaemia). The chemoimmunotherapy regimen was well tolerated. The incidence of grade III/IV mucositis during induction cycles with combined chemotherapy and rituximab was 31% and 26%, respectively. The 3-year event-free survival (EFS)/overall survival (OS) was 90% (95% confidence interval [CI], 76-96%) in the entire cohort and 93% (95% CI, 61-99%) in patients with CNS disease. Based on the results of this trial, an international randomized study of FAB/LMB 96 chemotherapy ± rituximab for high-risk patients is currently under investigation.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Linfoma de Burkitt/tratamento farmacológico , Neoplasias do Sistema Nervoso Central/tratamento farmacológico , Linfoma de Células B/tratamento farmacológico , Adolescente , Anticorpos Monoclonais Murinos/administração & dosagem , Anticorpos Monoclonais Murinos/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Medula Óssea/patologia , Linfoma de Burkitt/genética , Criança , Quimioterapia de Consolidação , Ciclofosfamida/administração & dosagem , Ciclofosfamida/efeitos adversos , Citarabina/administração & dosagem , Citarabina/efeitos adversos , Intervalo Livre de Doença , Doxorrubicina/administração & dosagem , Doxorrubicina/efeitos adversos , Esquema de Medicação , Etoposídeo/administração & dosagem , Etoposídeo/efeitos adversos , Feminino , Genes myc , Humanos , Imunoterapia , Infusões Intravenosas , Estimativa de Kaplan-Meier , Linfoma de Células B/genética , Quimioterapia de Manutenção , Masculino , Metotrexato/administração & dosagem , Metotrexato/efeitos adversos , Prednisona/administração & dosagem , Prednisona/efeitos adversos , Indução de Remissão , Rituximab , Tiflite/induzido quimicamente , Vincristina/administração & dosagem , Vincristina/efeitos adversosRESUMO
Laboratory (LTLS) and clinical (CTLS) tumour lysis syndrome (TLS) are frequent complications in newly diagnosed children with advanced mature B cell non-Hodgkin lymphoma (B-NHL). Rasburicase, compared to allopurinol, results in more rapid reduction of uric acid in paediatric patients at risk for TLS. However, the safety and efficacy of rasburicase for the treatment or or prevention of TLS has not been prospectively evaluated. Children with newly diagnosed stage III-IV, bone marrow(+) and/or central nervous system(+) mature B-NHL received hydration and rasburicase prior to cytoreductive therapy. Rasburicase was safe and well-tolerated and there were no grade III-IV toxicities probably or directly related to rasburicase. Patients with an initial lactate dehydrogenase ≥2× upper limit of normal had a significantly elevated uric acid level (P = 0·005), increased incidence of TLS (P-0·005) and lower glomerular filtration rate (GFR; P < 0·001). Following rasburicase, there was only a 9% and 5% incidence of LTLS and CTLS, respectively. Furthermore, there was a significant improvement in estimated GFR from Day 0 to Day 7 following rasburicase (P = 0·0007) and only 1·3% of patients required new onset renal assisted support after rasburicase administration. A TLS strategy incorporating rasburicase prior to cytoreductive chemotherapy proved safe and effective in preventing new onset renal failure and was associated with a significant improvement in GFR.
Assuntos
Linfoma de Células B/complicações , Linfoma não Hodgkin/complicações , Síndrome de Lise Tumoral/prevenção & controle , Urato Oxidase/uso terapêutico , Injúria Renal Aguda/etiologia , Injúria Renal Aguda/prevenção & controle , Adolescente , Anticorpos Monoclonais Murinos/administração & dosagem , Anticorpos Monoclonais Murinos/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Criança , Pré-Escolar , Ciclofosfamida/administração & dosagem , Ciclofosfamida/efeitos adversos , Citarabina/administração & dosagem , Citarabina/efeitos adversos , Feminino , Humanos , Hidrocortisona/administração & dosagem , Hidrocortisona/efeitos adversos , Hiperuricemia/etiologia , Lactente , L-Lactato Desidrogenase/sangue , Linfoma de Células B/tratamento farmacológico , Linfoma de Células B/terapia , Linfoma não Hodgkin/tratamento farmacológico , Linfoma não Hodgkin/terapia , Masculino , Metotrexato/administração & dosagem , Metotrexato/efeitos adversos , Proteínas de Neoplasias/sangue , Projetos Piloto , Prednisona/administração & dosagem , Prednisona/efeitos adversos , Estudos Prospectivos , Rituximab , Síndrome de Lise Tumoral/sangue , Síndrome de Lise Tumoral/classificação , Urato Oxidase/efeitos adversos , Vincristina/administração & dosagem , Vincristina/efeitos adversos , Adulto JovemRESUMO
The ANHL01P1 trial was undertaken to determine pharmacokinetics and safety following the addition of rituximab to French-American-British/Lymphome Malins de Burkitt (FAB/LMB96) chemotherapy in 41 children and adolescents with Stage III/IV mature B-cell lymphoma/leukaemia. Patients received rituximab (375 mg/m(2) ) days -2 and 0 of two induction cycles and day 0 of two consolidation cycles. Highest peak levels were achieved following the second dose of each induction cycle [299 ± 19 and 384 ± 25 µg/ml (Group-B); 245 ± 31 and 321 ± 32 µg/ml (Group-C)] with sustained troughs and t½ of 26-29 d. Rituximab can be safely added to FAB chemotherapy with high early rituximab peak/trough levels and a long t½.
Assuntos
Anticorpos Monoclonais Murinos/sangue , Antineoplásicos/sangue , Linfoma de Células B/sangue , Adolescente , Adulto , Fatores Etários , Anticorpos Monoclonais Murinos/administração & dosagem , Antineoplásicos/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Ciclofosfamida/uso terapêutico , Doxorrubicina/uso terapêutico , Esquema de Medicação , Meia-Vida , Humanos , L-Lactato Desidrogenase/sangue , Linfoma de Células B/tratamento farmacológico , Linfoma de Células B/patologia , Metotrexato/uso terapêutico , Estadiamento de Neoplasias , Projetos Piloto , Prednisona/uso terapêutico , Rituximab , Vincristina/uso terapêutico , Adulto JovemRESUMO
Mediastinal large B-cell lymphoma (MLBL) represents 2% of mature B-cell non-Hodgkin lymphoma in patients ≤ 18 years of age. We analyzed data from childhood and adolescent patients with stage III MLBL (n = 42) and non-MLBL DLBCL (n = 69) treated with Group B therapy in the French-American-British/Lymphome Malins de Burkitt (FAB/LMB) 96 study. MLBL patients had a male/female 26/16; median age, 15.7 years (range, 12.5-19.7); and LDH < 2 versus ≥ 2 × the upper limit of normal, 23:19. Six MLBL patients (14%) had < a 20% response to initial COP (cyclophosphamide, vincristine, and prednisone) therapy. Central pathology revealed approximately 50% with classical features of primary MLBL. Five-year event-free survival for the stage III MLBL and non-MLBL DLBCL groups was 66% (95% confidence interval [CI], 49%-78%) and 85% (95% CI, 71%-92%), respectively (P < .001; 14%). The 5-year overall survival in the 42 MLBL patients was 73% (95% CI, 56%-84%). We conclude that MLBL in adolescent patients is associated with significantly inferior event-free survival compared with stage III non-MLBL DLBCL and can be of multiple histologies. Alternate treatment strategies should be investigated in the future taking into account both adult MLBL approaches and more recent biologic findings in adult MLBL.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Linfoma Difuso de Grandes Células B/tratamento farmacológico , Linfoma Difuso de Grandes Células B/patologia , Neoplasias do Mediastino/tratamento farmacológico , Neoplasias do Mediastino/patologia , Adolescente , Criança , Intervalo Livre de Doença , Feminino , Humanos , Estimativa de Kaplan-Meier , Linfoma Difuso de Grandes Células B/mortalidade , Masculino , Neoplasias do Mediastino/mortalidade , Estadiamento de Neoplasias , Resultado do TratamentoRESUMO
PURPOSE: Adolescents (age 15 to 21 years) compared with younger children with mature B-cell non-Hodgkin's lymphoma (NHL) have been historically considered to have an inferior prognosis. We therefore analyzed the impact of age and other diagnostic factors on the risk of treatment failure in children and adolescents treated on the French-American-British Mature B-Cell Lymphoma 96 (FAB LMB 96) trial. PATIENTS AND METHODS: Patients were divided by risk: group A (limited), group B (intermediate), and group C (advanced), as previously described. Prognostic factors analyzed for event-free survival (EFS) included age (< 15 v ≥ 15 years), stage (I/II v III/IV), primary site, lactate dehydrogenase (LDH), bone marrow/CNS (BM/CNS) involvement, and histology (diffuse large B-cell lymphoma v mediastinal B-cell lymphoma v Burkitt lymphoma or Burkitt-like lymphoma). RESULTS: The 3-year EFS for the whole cohort was 88% ± 1%. Age was not associated as a risk factor for increased treatment failure in either univariate analysis (P = .15) or multivariate analysis (P = .58). Increased LDH (≥ 2 × upper limit of normal [ULN] v < 2 × ULN), primary site, and BM-positive/CNS-positive disease were all independent risk factors associated with a significant increase in treatment failure rate (relative risk, 2.0; P < .001, P < .012, and P < .001, respectively). CONCLUSION: LDH level at diagnosis, mediastinal disease, and combined BM-positive/CNS-positive involvement are independent risk factors in children with mature B-cell NHL. Future studies should be developed to identify specific therapeutic strategies (immunotherapy) to overcome these risk factors and to identify the biologic basis associated with these prognostic factors in children with mature B-cell NHL.
Assuntos
L-Lactato Desidrogenase/metabolismo , Linfoma de Células B/tratamento farmacológico , Adolescente , Adulto , Fatores Etários , Intervalo Livre de Doença , Feminino , Humanos , Linfoma de Células B/enzimologia , Linfoma de Células B/patologia , Masculino , Estadiamento de Neoplasias , Fatores de Risco , Análise de Sobrevida , Taxa de Sobrevida , Falha de Tratamento , Resultado do Tratamento , Adulto JovemRESUMO
Children/adolescents with mature B-cell non-Hodgkin lymphoma (B-NHL) have an excellent prognosis but relapses still occur. While chromosomal aberrations and/or clonal immunoglobulin (Ig) gene rearrangements may indicate risk of failure, a more universal approach was developed to detect minimal disease (MD). Children/adolescents with intermediate-risk B-NHL were treated with French-British-American/Lymphome Malins de Burkitt 96 (FAB/LMB96) B4 modified chemotherapy and rituximab. Specimens from diagnosis, end of induction (EOI), and end of therapy (EOT) were assayed for MD. Initial specimens were screened for IGHV family usage with primer pools followed by individual primers to identify MD. Thirty-two diagnostic/staging specimens screened positive with primer pools and unique IGHV family primers were identified. Two patients relapsed; first relapse (4 months from diagnosis) was MD-positive at EOI, the second (36 months from diagnosis) was MD-positive at EOT. At EOI, recurrent rates were similar between the MRD-positive and MRD-negative patients (P = 0·40). At EOT, only 13/32 patients had MRD data available with one relapse in the MRD-positive group and no recurrences in the MRD-negative group (P = 0·077). The study demonstrated molecular-disseminated disease in which IgIGHV primer pools could be used to assess MD. This feasibility study supports future investigations to assess the validity and significance of MD screening in a larger cohort of patients with intermediate-risk mature B-NHL.
Assuntos
Linfoma de Células B/tratamento farmacológico , Adolescente , Anticorpos Monoclonais Murinos/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Criança , Métodos Epidemiológicos , Genes de Cadeia Pesada de Imunoglobulina , Genes Neoplásicos , Humanos , Linfoma de Células B/genética , Linfoma de Células B/patologia , Estadiamento de Neoplasias , Neoplasia Residual , Recidiva , Rituximab , Adulto JovemRESUMO
BACKGROUND: Using data from the Healthcare Cost and Utilization Project 2004 Nationwide Inpatient Sample, we estimated inpatient resource utilization among patients with hematologic malignancies, with and without concomitant acute renal failure. PATIENTS AND METHODS: We analyzed patients with hematologic malignancies (excluding Hodgkin disease), acute renal failure, and renal dialysis. Subgroup analyses were performed on specific types of hematologic malignancies, with and without acute renal failure and with and without renal dialysis. RESULTS: Among those with hematologic malignancies, acute renal failure, with and without concomitant renal dialysis, increases inpatient length of stay and costs. Mean length of stay and costs for all patients with acute renal failure and renal dialysis (n = 5148), acute renal failure without renal dialysis (n = 27,654), and no acute renal failure or renal dialysis (n = 350,601) were 17.6, 12.2, and 7.4 days, and $44,619, $25,638, and $13,947, respectively. CONCLUSION: Treatment of hematologic malignancies and concomitant acute renal failure and renal dialysis places an economic burden on the health care system. Reducing the incidence of acute renal failure and concomitant renal dialysis with supportive care in patients with hematologic malignancies can reduce inpatient resource use.
Assuntos
Injúria Renal Aguda/economia , Custos de Cuidados de Saúde , Neoplasias Hematológicas/economia , Tempo de Internação , Idoso , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Estudos RetrospectivosRESUMO
We report the 4th case of a primitive round cell sarcoma with the translocation (4;19)(q35;q13.1) as the primary cytogenetic abnormality. This undifferentiated sarcoma shows some features of Ewing sarcoma/primitive neuroectodermal tumor (ES/PNET), including a diffuse reactivity for FLI1, but it shows only focal and weak reactivity for CD99 and is negative for a rearrangement of EWS, the molecular signature of ES/PNET. Recognition of the histopathologic and cytogenetic features of this entity is necessary to avoid its misdiagnosis as ES/PNET, especially in small biopsy samples.
Assuntos
Cromossomos Humanos Par 19/genética , Cromossomos Humanos Par 4/genética , Sarcoma de Células Pequenas/genética , Neoplasias de Tecidos Moles/genética , Translocação Genética , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Criança , Aberrações Cromossômicas , Humanos , Imuno-Histoquímica , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/secundário , Masculino , Sarcoma de Células Pequenas/tratamento farmacológico , Sarcoma de Células Pequenas/secundário , Neoplasias de Tecidos Moles/tratamento farmacológico , Neoplasias de Tecidos Moles/patologiaRESUMO
Thrombocytopenia remains the major dose-limiting toxicity of myelosuppressive chemotherapy in children with solid tumours. Recombinant human interleukin-11 (rhIL-11) has been approved by the Food and Drug Administration as treatment for adults with solid tumours and lymphomas with severe chemotherapy-induced thrombocytopenia. We conducted a phase I/II trial of rhIL-11 following ifosfamide, carboplatin and etoposide (ICE) chemotherapy in children with solid tumours or lymphomas. Patients received ifosfamide 1800 mg/m(2)/d for 5 d, carboplatin 400 mg/m(2)/d for 2 d and etoposide 100 mg/m(2)/d for 5 d with rhIL-11 subcutaneous (s.c.) at 25-125 microg/kg/d on days 6-33. Forty-seven patients with median age 10.5 years (range, 0.7-26 years) were studied. Median days to absolute neutrophil count >/=0.5 x 10(9)/l, platelet count >/=50 x 10(9)/l and platelet transfusions were 23, 18, 18, 16.5 and 18.5, 21, 20, 18 and 3, 3, 4, and 2 d at doses 25, 50, 75 and 100 Schulteg/kg respectively. There was a dose-dependent increase in C(max) (7.6-25.5 ng/ml), AUC(0-rho) (57-209 ng.h/ml) and T(1/2) (4-8.2 h) respectively. There was a 4% incidence of anti-IL-11 antibody formation. Clinically important adverse events to rhIL-11 were papilloedema and periosteal bone formation. In summary, rhIL-11 was well tolerated at doses of =50 microg/kg (maximal tolerated dose) and associated with improved haematological recovery and reduced platelet transfusion requirements compared with historical controls receiving similar ICE chemotherapy without rhIL-11.