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BACKGROUND: Minimal disease quantification may predict event-free survival (EFS) and overall survival (OS). METHODS: We evaluated mRNA expression of five neuroblastoma-associated genes (NB5 assay) in bone marrows (BM) of patients with newly diagnosed high-risk neuroblastoma who received consistent immunotherapy. mRNA expression of CHGA, DCX, DDC, PHOX2B, and TH genes in BM of 479 patients enrolled on the immunotherapy arm of Children's Oncology Group trials ANBL0032 and ANBL0931 was evaluated using real-time polymerase chain reaction (PCR)-based TaqMan low-density array. Results from end-consolidation and end-therapy were analyzed for association with five-year EFS/OS and patient and tumor characteristics. Tests of statistical significance were two-sided. RESULTS: NB5 assay detected neuroblastoma-related mRNA in 222 of 286 (77.6%) of BMs obtained at end-consolidation and 188 of 304 (61.8%) at end-therapy. Any mRNA level detected in end-therapy BM correlated with significantly worse EFS (57% [49.6%-63.7%] vs 73.0% [63.5%-80.4%]; P = 0.005), but not OS. Analysis limited to patients in complete response at end-therapy still found a significant difference in EFS with detectable versus not detectable NB5 assay results (58.9% [49.5%-67.1%] vs 76.6% [66.1%-84.2%]; P = 0.01). End-consolidation results did not correlate with EFS or OS. Multivariable analysis determined end-therapy NB5 assay BM results (P = 0.02), age at diagnosis (P = 0.002), and preconsolidation response (P = 0.02) were significantly associated with EFS independent of other clinical and biological parameters evaluated, including end-therapy response. CONCLUSIONS: If further validated in additional patient cohorts, the NB5 assay's ability to independently predict EFS from end-therapy could improve patient stratification for novel maintenance therapy trials after current end-therapy to improve outcome.
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Medula Óssea , Neuroblastoma , Biomarcadores Tumorais/análise , Medula Óssea/patologia , Criança , Humanos , Lactente , Neuroblastoma/genética , Neuroblastoma/metabolismo , Neuroblastoma/terapia , Prognóstico , RNA MensageiroRESUMO
BACKGROUND: Preclinical and preliminary clinical data indicate that ch14.18, a monoclonal antibody against the tumor-associated disialoganglioside GD2, has activity against neuroblastoma and that such activity is enhanced when ch14.18 is combined with granulocyte-macrophage colony-stimulating factor (GM-CSF) or interleukin-2. We conducted a study to determine whether adding ch14.18, GM-CSF, and interleukin-2 to standard isotretinoin therapy after intensive multimodal therapy would improve outcomes in high-risk neuroblastoma. METHODS: Patients with high-risk neuroblastoma who had a response to induction therapy and stem-cell transplantation were randomly assigned, in a 1:1 ratio, to receive standard therapy (six cycles of isotretinoin) or immunotherapy (six cycles of isotretinoin and five concomitant cycles of ch14.18 in combination with alternating GM-CSF and interleukin-2). Event-free survival and overall survival were compared between the immunotherapy group and the standard-therapy group, on an intention-to-treat basis. RESULTS: A total of 226 eligible patients were randomly assigned to a treatment group. In the immunotherapy group, a total of 52% of patients had pain of grade 3, 4, or 5, and 23% and 25% of patients had capillary leak syndrome and hypersensitivity reactions, respectively. With 61% of the number of expected events observed, the study met the criteria for early stopping owing to efficacy. The median duration of follow-up was 2.1 years. Immunotherapy was superior to standard therapy with regard to rates of event-free survival (66±5% vs. 46±5% at 2 years, P=0.01) and overall survival (86±4% vs. 75±5% at 2 years, P=0.02 without adjustment for interim analyses). CONCLUSIONS: Immunotherapy with ch14.18, GM-CSF, and interleukin-2 was associated with a significantly improved outcome as compared with standard therapy in patients with high-risk neuroblastoma. (Funded by the National Institutes of Health and the Food and Drug Administration; ClinicalTrials.gov number, NCT00026312.)
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Anticorpos Monoclonais/uso terapêutico , Gangliosídeos/imunologia , Imunoterapia , Neuroblastoma/terapia , Anticorpos Monoclonais/efeitos adversos , Antineoplásicos/uso terapêutico , Criança , Pré-Escolar , Terapia Combinada , Quimioterapia Combinada , Fator Estimulador de Colônias de Granulócitos e Macrófagos/uso terapêutico , Humanos , Imunoterapia/efeitos adversos , Lactente , Análise de Intenção de Tratamento , Interleucina-2/uso terapêutico , Isotretinoína/uso terapêutico , Neuroblastoma/tratamento farmacológico , Neuroblastoma/mortalidade , Transplante de Células-Tronco , Análise de SobrevidaRESUMO
The relevancy of the urinary tract as a source of infection during febrile neutropenia is not known. The authors sought to determine the frequency of urinary tract infections (UTIs) in pediatric cancer patients with febrile neutropenia. Urine was collected from a mid-stream void before the administration of antibiotics. Demographic, clinical, and laboratory data were collected. The frequency of UTI and usefulness of urinalysis and localizing signs in predicting UTI in pediatric cancer patients with fever and neutropenia were determined. Forty-five patients had 58 febrile neutropenic episodes eligible for study participation. No patient presented with localizing signs. The urinalysis was negative in 53 episodes and positive in 5 episodes. Four patients had 5 UTIs. The frequency of UTI was 8.6% (5 of 58 febrile neutropenia episodes). Four patients had bacteremia, none of whom had a UTI. The sensitivity, specificity, and negative predictive value of urinalysis was 40%, 94%, and 94%, respectively, and for localizing signs was undefined, 100%, and 91%, respectively. UTI is as common as bacteremia in the current pediatric cancer patients with fever and neutropenia. Urinalysis and urine culture should be obtained routinely as part of the diagnostic evaluation of patients with fever and neutropenia.
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Febre/epidemiologia , Neoplasias/epidemiologia , Neutropenia/epidemiologia , Infecções Urinárias/epidemiologia , Adolescente , Adulto , Bacteriemia/complicações , Bacteriemia/epidemiologia , Bacteriemia/urina , Criança , Pré-Escolar , Feminino , Febre/complicações , Febre/urina , Humanos , Masculino , Neoplasias/complicações , Neoplasias/urina , Neutropenia/complicações , Neutropenia/urina , Infecções Urinárias/complicações , Infecções Urinárias/urinaRESUMO
PURPOSE: Previously our randomized phase III trial demonstrated that immunotherapy including dinutuximab, a chimeric anti-GD2 mAb, GM-CSF, and IL2 improved survival for children with high-risk neuroblastoma that had responded to induction and consolidation therapy. These results served as the basis for FDA approval of dinutuximab. We now present long-term follow-up results and evaluation of predictive biomarkers. PATIENTS AND METHODS: Patients recieved six cycles of isotretinoin with or without five cycles of immunotherapy which consists of dinutuximab with GM-CSF alternating with IL2. Accrual was discontinued early due to meeting the protocol-defined stopping rule for efficacy, as assessed by 2-year event-free survival (EFS). Plasma levels of dinutuximab, soluble IL2 receptor (sIL2R), and human anti-chimeric antibody (HACA) were assessed by ELISA. Fcγ receptor 2A and 3A genotypes were determined by PCR and direct sequencing. RESULTS: For 226 eligible randomized patients, 5-year EFS was 56.6 ± 4.7% for patients randomized to immunotherapy (n = 114) versus 46.1 ± 5.1% for those randomized to isotretinoin only (n = 112; P = 0.042). Five-year overall survival (OS) was 73.2 ± 4.2% versus 56.6 ± 5.1% for immunotherapy and isotretinoin only patients, respectively (P = 0.045). Thirteen of 122 patients receiving dinutuximab developed HACA. Plasma levels of dinutuximab, HACA, and sIL2R did not correlate with EFS/OS, or clinically significant toxicity. Fcγ receptor 2A and 3A genotypes did not correlate with EFS/OS. CONCLUSIONS: Immunotherapy with dinutuximab improved outcome for patients with high-risk neuroblastoma. Early stoppage for efficacy resulted in a smaller sample size than originally planned, yet clinically significant long-term differences in survival were observed.
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Anticorpos Monoclonais/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Interleucina-2/administração & dosagem , Neuroblastoma/tratamento farmacológico , Adolescente , Anticorpos Monoclonais/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Criança , Pré-Escolar , Seguimentos , Humanos , Lactente , Interleucina-2/efeitos adversos , Isotretinoína/administração & dosagem , Isotretinoína/efeitos adversos , Masculino , Neuroblastoma/mortalidade , Intervalo Livre de Progressão , Proteínas Recombinantes/administração & dosagem , Proteínas Recombinantes/efeitos adversosRESUMO
Acute leukemias in children with CR3, refractory relapse, or induction failure (IF) have a poor prognosis. Clofarabine has single agent activity in relapsed leukemia and synergy with cytarabine. We sought to determine the safety and overall survival in a Phase I/II trial of conditioning with clofarabine (doses 40 - 52 mg/m2), cytarabine 1000 mg/m2, and 1200 cGy TBI followed by alloSCT in children, adolescents, and young adults with poor-risk leukemia. Thirty-seven patients; Age 12 years (1-22 years); ALL/AML: 34:3 (18 IF, 10 CR3, 13 refractory relapse); 15 related, 22 unrelated donors. Probabilities of neutrophil, platelet engraftment, acute GvHD, and chronic GvHD were 94%, 84%, 49%, and 30%, respectively. Probability of day 100 TRM was 8.1%. 2-year EFS (event free survival) and OS (overall survival) were 38.6% (CI95: 23-54%), and 41.3% (CI95: 25-57%). Multivariate analysis demonstrated overt disease at time of transplant (relative risk (RR) 3.65, CI95: 1.35-9.89, P = 0.011) and umbilical cord blood source (RR 2.17, CI95: 1.33-4.15, P = 0.019) to be predictors of worse EFS/OS. This novel myeloablative conditioning regimen followed by alloSCT is safe and well tolerated in CAYA with very poor-risk ALL or AML. Further investigation in CAYA with better risk ALL and AML undergoing alloSCT is warranted.
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Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Transplante de Células-Tronco Hematopoéticas/métodos , Leucemia/terapia , Agonistas Mieloablativos/uso terapêutico , Condicionamento Pré-Transplante/métodos , Irradiação Corporal Total/métodos , Doença Aguda , Adolescente , Criança , Pré-Escolar , Clofarabina/uso terapêutico , Citarabina/uso terapêutico , Feminino , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Transplante de Células-Tronco Hematopoéticas/mortalidade , Humanos , Lactente , Leucemia/complicações , Leucemia/mortalidade , Leucemia Mieloide Aguda/terapia , Masculino , Agonistas Mieloablativos/efeitos adversos , Leucemia-Linfoma Linfoblástico de Células Precursoras/terapia , Condicionamento Pré-Transplante/efeitos adversos , Condicionamento Pré-Transplante/mortalidade , Transplante Homólogo , Resultado do Tratamento , Adulto JovemRESUMO
[This corrects the article DOI: 10.3389/fimmu.2018.01355.].
RESUMO
Purpose: A phase 3 randomized study (COG ANBL0032) demonstrated significantly improved outcome by adding immunotherapy with ch14.18 antibody to isotretinoin as post-consolidation therapy for high-risk neuroblastoma (NB). This study, ANBL0931, was designed to collect FDA-required safety/toxicity data to support FDA registration of ch14.18. Experimental design: Newly diagnosed high-risk NB patients who achieved at least a partial response to induction therapy and received myeloablative consolidation with stem cell rescue were enrolled to receive six courses of isotretinoin with five concomitant cycles of ch14.18 combined with GM-CSF or IL2. Ch14.18 infusion time was 10-20 h per dose. Blood was collected for cytokine analysis and its association with toxicities and outcome. Results: Of 105 patients enrolled, five patients developed protocol-defined unacceptable toxicities. The most common grade ≥ 3 non-hematologic toxicities of immunotherapy for cycles 1-5, respectively, were neuropathic pain (41, 28, 22, 31, 24%), hypotension (10, 17, 4, 14, 8%), allergic reactions (ARs) (3, 10, 5, 7, 2%), capillary leak syndrome (1, 4, 0, 2, 0%), and fever (21, 59, 6, 32, 5%). The 3-year event-free survival and overall survival were 67.6 ± 4.8% and 79.1 ± 4.2%, respectively. AR during course 1 was associated with elevated serum levels of IL-1Ra and IFNγ, while severe hypotension during this course was associated with low IL5 and nitrate. Higher pretreatment CXCL9 level was associated with poorer event-free survival (EFS). Conclusion: This study has confirmed the significant, but manageable treatment-related toxicities of this immunotherapy and identified possible cytokine biomarkers associated with select toxicities and outcome. EFS and OS appear similar to that previously reported on ANBL0032.
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Purpose: In 2010, a Children's Oncology Group (COG) phase III randomized trial for patients with high-risk neuroblastoma (ANBL0032) demonstrated improved event-free survival (EFS) and overall survival (OS) following treatment with an immunotherapy regimen of dinutuximab, GM-CSF, IL2, and isotretinoin compared with treatment with isotretinoin alone. Dinutuximab, a chimeric anti-GD2 monoclonal antibody, acts in part via natural killer (NK) cells. Killer immunoglobulin-like receptors (KIR) on NK cells and their interactions with KIR-ligands can influence NK cell function. We investigated whether KIR/KIR-ligand genotypes were associated with EFS or OS in this trial.Experimental Design: We genotyped patients from COG study ANBL0032 and evaluated the effect of KIR/KIR-ligand genotypes on clinical outcomes. Cox regression models and log-rank tests were used to evaluate associations of EFS and OS with KIR/KIR-ligand genotypes.Results: In this trial, patients with the "all KIR-ligands present" genotype as well as patients with inhibitory KIR2DL2 with its ligand (HLA-C1) together with inhibitory KIR3DL1 with its ligand (HLA-Bw4) were associated with improved outcome if they received immunotherapy. In contrast, for patients with the complementary KIR/KIR-ligand genotypes, clinical outcome was not significantly different for patients who received immunotherapy versus those receiving isotretinoin alone.Conclusions: These data show that administration of immunotherapy is associated with improved outcome for neuroblastoma patients with certain KIR/KIR-ligand genotypes, although this was not seen for patients with other KIR/KIR-ligand genotypes. Further investigation of KIR/KIR-ligand genotypes may clarify their role in cancer immunotherapy and may enable KIR/KIR-ligand genotyping to be used prospectively for identifying patients likely to benefit from certain cancer immunotherapy regimens. Clin Cancer Res; 24(1); 189-96. ©2017 AACRSee related commentary by Cheung and Hsu, p. 3.
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Genótipo , Neuroblastoma/genética , Neuroblastoma/mortalidade , Receptores KIR/genética , Anticorpos Monoclonais/farmacologia , Anticorpos Monoclonais/uso terapêutico , Antineoplásicos Imunológicos/farmacologia , Antineoplásicos Imunológicos/uso terapêutico , Linhagem Celular Tumoral , Ensaios Clínicos Fase III como Assunto , Feminino , Humanos , Imunoterapia , Ligantes , Masculino , Neuroblastoma/imunologia , Neuroblastoma/terapia , Receptores KIR2DL1/genética , Receptores KIR2DL1/metabolismo , Receptores KIR3DL1/genética , Receptores KIR3DL1/metabolismoRESUMO
Accurate detection of central nervous system (CNS) involvement in children with newly diagnosed acute lymphoblastic leukemia (ALL) could have profound prognostic and therapeutic implications. We examined various cerebrospinal fluid (CSF) preservation methods to yield adequate DNA stability for polymerase chain reaction (PCR) analysis and developed a quantitative real-time PCR assay to detect occult CNS leukemia. Sixty CSF specimens were maintained in several storage conditions for varying amounts of time, and we found that preserving CSF in 1:1 serum-free RPMI tissue culture medium offers the best stability of DNA for PCR analysis. Sixty CSF samples (30 at diagnosis and 30 at the end of induction therapy) from 30 children with ALL were tested for CNS leukemic involvement by real-time PCR using patient-specific antigen receptor gene rearrangement primers. Six of thirty patient diagnosis samples were PCR-positive at levels ranging from 0.5 to 66% leukemic blasts in the CSF. Four of these patients had no clinical or cytomorphological evidence of CNS leukemia involvement at that time. All 30 CSF samples drawn at the end of induction therapy were PCR-negative. The data indicate that real-time PCR analysis of CSF is an excellent tool to assess occult CNS leukemia involvement in patients with ALL and can possibly be used to refine CNS status classification.
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Neoplasias do Sistema Nervoso Central/diagnóstico , DNA de Neoplasias/líquido cefalorraquidiano , Reação em Cadeia da Polimerase/métodos , Leucemia-Linfoma Linfoblástico de Células Precursoras/diagnóstico , Neoplasias do Sistema Nervoso Central/genética , Neoplasias do Sistema Nervoso Central/secundário , Criança , Humanos , Leucemia-Linfoma Linfoblástico de Células Precursoras/patologia , Preservação Biológica/métodos , PrognósticoRESUMO
Acquired mutations in exon 2 of the GATA1 gene are detected in most Down syndrome (DS) patients with transient leukemia (TL) and acute megakaryoblastic leukemia (AMKL). We sought to determine if GATA1 mutations can be utilized as markers for minimal residual disease (MRD). GATA1 mutations were screened by SSCP analysis and sequenced. Using GATA1 mutation-specific primers, follow-up bone marrow samples from four patients were assayed by quantitative PCR. We show that molecular monitoring of GATA1 mutations is possible in Down syndrome patients with TL and AMKL, and GATA1 could be a stable marker for MRD monitoring.
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Síndrome de Down/genética , Fator de Transcrição GATA1/genética , Leucemia Megacarioblástica Aguda/diagnóstico , Leucemia Megacarioblástica Aguda/genética , Leucemia/diagnóstico , Leucemia/genética , Pré-Escolar , Cromossomos Humanos Par 21/genética , Clonagem Molecular , Síndrome de Down/complicações , Éxons , Feminino , Humanos , Lactente , Recém-Nascido , Leucemia/complicações , Leucemia Megacarioblástica Aguda/complicações , Masculino , Mutação , Neoplasia Residual , Reação em Cadeia da Polimerase/métodos , Indução de RemissãoRESUMO
We describe a case of relapsed pediatric pre-B acute lymphoblastic leukemia (ALL) with a simultaneous presentation of an intracerebral lymphoid mass. Cytogenetic, immunophenotypic and molecular analysis (immunoglobulin heavy chain and T-cell receptor gene rearrangements) revealed that the brain neoplasm was distinct from the relapsed leukemia. We discuss the etiology of this extremely rare event, and raise issues about the clonality of lymphoid neoplasms and the behavior of hematopoietic cells within the central nervous system (CNS).
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Neoplasias do Sistema Nervoso Central/complicações , Neoplasias do Sistema Nervoso Central/diagnóstico , Leucemia-Linfoma Linfoblástico de Células Precursoras/complicações , Leucemia-Linfoma Linfoblástico de Células Precursoras/diagnóstico , Sequência de Bases , Neoplasias do Sistema Nervoso Central/genética , Criança , Citogenética , Feminino , Humanos , Cadeias Pesadas de Imunoglobulinas/genética , Imunofenotipagem , Dados de Sequência Molecular , Reação em Cadeia da Polimerase , Leucemia-Linfoma Linfoblástico de Células Precursoras/genética , Recidiva , Fatores de TempoRESUMO
OBJECTIVE: The aim of this study was to evaluate our experience with laparoscopic surgery in children with sickle cell disease. METHODS: A retrospective chart review was performed to analyze the indication for surgery, perioperative management, surgical technique, complications, duration of hospitalization, and outcome. One pediatric surgeon performed all procedures. RESULTS: Thirteen children underwent laparoscopic surgery for the following indications: symptomatic cholelithiasis/cholecystitis in 9; recurrent splenic sequestration in 3; and hypersplenism/symptomatic cholelithiasis in 1. The 7 boys and 6 girls had a median age of 7.8 years. Patients undergoing splenectomy only were younger than those undergoing cholecystectomy (median age, 3.6 years versus 11.5 years, respectively). Four children underwent endoscopic retrograde cholangiopancreatography (ERCP) and sphincterotomy because of common bile duct dilatation and stones. Twelve patients received packed red blood cell transfusions prior to surgery. The median operative time was 150 minutes, and the median hospitalization was 3 days. Four patients suffered postoperative complications (2 with acute chest syndrome, 1 with recurrent abdominal pain, and 1 with priapism). The patient with abdominal pain was found to have a retained stone in the common bile duct, which was retrieved via endoscopic retrograde cholangiopancreatography and sphincterotomy. All complications resolved with medical management. CONCLUSIONS: Laparoscopic surgery is safe in children with sickle cell disease. Meticulous attention to perioperative management, transfusion guidelines, and pulmonary care may decrease the incidence of acute chest syndrome.
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Anemia Falciforme , Colecistectomia Laparoscópica , Laparoscopia , Cuidados Pré-Operatórios , Esplenectomia , Anemia Falciforme/complicações , Transfusão de Sangue , Criança , Colelitíase/complicações , Colelitíase/cirurgia , Feminino , Humanos , Masculino , Complicações Pós-Operatórias , Estudos Retrospectivos , Esplenomegalia/complicações , Esplenomegalia/cirurgiaAssuntos
Transtornos da Coagulação Sanguínea/diagnóstico , Testes de Coagulação Sanguínea , Cuidados Pré-Operatórios , Adolescente , Adulto , Criança , Pré-Escolar , Feminino , Humanos , Lactente , Recém-Nascido , Masculino , Programas de Rastreamento , Valor Preditivo dos Testes , Estudos RetrospectivosRESUMO
Early assessment of cancer response to the treatment is of great importance in clinical oncology. Most antitumor drugs, among them DNA topoisomerase (topo) inhibitors, target nuclear DNA. The aim of the present study was to explore feasibility of the assessment of DNA damage response (DDR) as potential biomarker, eventually related to the clinical response, during treatment of human leukemias. We have measured DDR as reported by activation of ATM through its phosphorylation on Ser 1981 (ATM-S1981(P)) concurrent with histone H2AX phosphorylation on Ser139 (gammaH2AX) in leukemic blast cells from the blood of twenty patients, 16 children/adolescents and 4 adults, diagnosed with acute leukemias and treated with topo2 inhibitors doxorubicin, daunomycin, mitoxantrone or idarubicin. Phosphorylation of H2AX and ATM was detected using phospho-specific Abs and measured in individual cells by flow cytometry. The increase in the level of ATM-S1981(P) and gammaH2AX, varying in extent between the patients, was observed in blasts from the blood collected one hour after completion of the drug infusion with respect to the pre-treatment level. A modest degree of correlation was observed between the induction of ATM activation and H2AX phosphorylation in blasts of individual patients. The number of the studied patients (20) and the number of the clinically non-responding ones (2) was too low to draw a conclusion whether the assessment of DDR can be clinically prognostic. The present findings, however, demonstrate the feasibility of assessment of DDR during the treatment of leukemias with drugs targeting DNA.
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Proteínas de Ciclo Celular/sangue , Dano ao DNA , Proteínas de Ligação a DNA/sangue , Histonas/sangue , Leucemia Mieloide Aguda/tratamento farmacológico , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamento farmacológico , Proteínas Serina-Treonina Quinases/sangue , Proteínas Supressoras de Tumor/sangue , Adolescente , Adulto , Idoso , Proteínas Mutadas de Ataxia Telangiectasia , Biomarcadores , Proteínas de Ciclo Celular/metabolismo , Criança , DNA Topoisomerases/metabolismo , Proteínas de Ligação a DNA/metabolismo , Daunorrubicina/uso terapêutico , Inibidores Enzimáticos/uso terapêutico , Histonas/metabolismo , Humanos , Idarubicina/uso terapêutico , Mitoxantrona/uso terapêutico , Fosforilação , Proteínas Serina-Treonina Quinases/metabolismo , Inibidores da Topoisomerase , Proteínas Supressoras de Tumor/metabolismoRESUMO
PURPOSE: Recurrence of high-risk neuroblastoma is common despite multimodality therapy. ch14.18, a chimeric human/murine anti-G(D2) antibody, lyses neuroblastoma cells. This study determined the maximum tolerable dose (MTD) and toxicity of ch14.18 given in combination with interleukin-2 (IL-2) after high-dose chemotherapy (HDC)/stem-cell rescue (SCR). Biologic correlates including ch14.18 levels, soluble IL-2 receptor levels, and human antichimeric antibody (HACA) activity were evaluated. PATIENTS AND METHODS: Patients were given ch14.18 for 4 days at 28-day intervals. Patients received IL-2 during the second and fourth courses of ch14.18 and granulocyte-macrophage colony-stimulating factor (GM-CSF) during the first, third, and fifth courses. The MTD was determined based on toxicities occurring with the second course. After the determination of the MTD, additional patients were treated to confirm the MTD and to clarify appropriate supportive care. RESULTS: Twenty-five patients were enrolled. The MTD of ch14.18 was determined to be 25 mg/m(2)/d for 4 days given concurrently with 4.5 x 10(6) U/m(2)/d of IL-2 for 4 days. IL-2 was also given at a dose of 3 x 10(6) U/m(2)/d for 4 days starting 1 week before ch14.18. Two patients experienced dose-limiting toxicity due to ch14.18 and IL-2. Common toxicities included pain, fever, nausea, emesis, diarrhea, urticaria, mild elevation of hepatic transaminases, capillary leak syndrome, and hypotension. No death attributable to toxicity of therapy occurred. No additional toxicity was seen when cis-retinoic acid (cis-RA) was given between courses of ch14.18. No patient treated at the MTD developed HACA. CONCLUSION: ch14.18 in combination with IL-2 was tolerable in the early post-HDC/SCR period. cis-RA can be administered safely between courses of ch14.18 and cytokines.
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Anticorpos Monoclonais/uso terapêutico , Transplante de Medula Óssea , Fator Estimulador de Colônias de Granulócitos e Macrófagos/uso terapêutico , Transplante de Células-Tronco Hematopoéticas , Interleucina-2/uso terapêutico , Neuroblastoma/terapia , Adolescente , Anticorpos Monoclonais/efeitos adversos , Criança , Pré-Escolar , Feminino , Fator Estimulador de Colônias de Granulócitos e Macrófagos/efeitos adversos , Humanos , Lactente , Recém-Nascido , Interleucina-2/efeitos adversos , MasculinoRESUMO
Limited information is available regarding the use of amifostine in pediatric hematopoietic stem cell transplant (HSCT) patients. Melphalan, carboplatin, etoposide +/- cyclophosphamide is a commonly used preparatory regimen in pediatric solid tumor HSCT. Therefore, we decided to determine the feasibility of the addition of amifostine (750 mg/m b.i.d. x 4 d) to melphalan (200 mg/m), carboplatin (1200 mg/m), and etoposide (800 mg/m) (level 1) and escalating doses of cyclophosphamide (3000 mg/m and 3800 mg/m, levels 2 and 3, respectively) followed by autologous HSCT. Thirty-two patients with a variety of pediatric solid tumors were studied. Seventeen patients were accrued at level 1, 9 at level 2, and 6 at level 3. Major toxicities during the administration of the preparatory regimen were hypocalcemia, emesis, and hypotension. Hypocalcemia required aggressive calcium supplementation during the conditioning phase. No dose limiting toxicities were encountered at level 3. Amifostine at 750 mg/m b.i.d. for 4 days can be administered with a double alkylator regimen consisting of melphalan (200 mg/m), cyclophosphamide (up to 3800 mg/m), carboplatin (1200 mg/m), and etoposide (800 mg/m) with manageable toxicities.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Transplante de Células-Tronco Hematopoéticas , Neoplasias/terapia , Adolescente , Adulto , Amifostina/administração & dosagem , Amifostina/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Transplante de Medula Óssea , Neoplasias Ósseas/diagnóstico , Neoplasias Ósseas/terapia , Carboplatina/administração & dosagem , Neoplasias do Sistema Nervoso Central/diagnóstico , Neoplasias do Sistema Nervoso Central/terapia , Criança , Pré-Escolar , Terapia Combinada , Ciclofosfamida/administração & dosagem , Relação Dose-Resposta a Droga , Esquema de Medicação , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos , Etoposídeo/administração & dosagem , Estudos de Viabilidade , Doença de Hodgkin/diagnóstico , Doença de Hodgkin/terapia , Humanos , Hipocalcemia/induzido quimicamente , Hipocalcemia/patologia , Neoplasias Renais/diagnóstico , Neoplasias Renais/terapia , Melfalan/administração & dosagem , Neoplasias/diagnóstico , Neuroblastoma/diagnóstico , Neuroblastoma/terapia , Projetos Piloto , Recidiva , Fatores de Risco , Sarcoma/diagnóstico , Sarcoma/terapia , Transplante Autólogo , Transplante Homólogo , Resultado do Tratamento , Tumor de Wilms/diagnóstico , Tumor de Wilms/terapiaRESUMO
BACKGROUND: Central venous lines are placed in children with acute lymphoblastic leukemia at diagnosis, despite significant cytopenias, to facilitate the administration of chemotherapy and blood sampling. The present study aimed to determine the safety of central line placement in these patients. METHODS: We reviewed the charts of 115 consecutive patients treated during a 10-year period. Data abstracted comprised age, gender, presenting and preoperative blood counts, type of central line, blood products transfused preoperatively, duration of neutropenia (absolute neutrophil count [ANC], <500/microl), treatment, and central line-associated complications. RESULTS: There were 66 male and 49 female patients with a median age of 4 years. Seventy-one patients were classified as standard-risk and 44 as high-risk. Respective median blood counts at diagnosis and prior to surgery were white cell count (microl), 4,200 and 5,550; hemoglobin (g/dl), 7.7 and 9.4; platelet count (microl), 63,000 and 72,000; and ANC (microl), 3,950 and 4,900. The median duration of neutropenia was 15 days in the standard-risk group and 18 days in the high-risk group. Thirty-eight patients were not transfused preoperatively. There were no episodes of bacteremia. Seven patients (7%) with life-ports experienced a complication: in four blood could not be aspirated, two ports needed realignment, and one a wound infection developed without dehiscence. Four patients (27%) with external lines had a complication: one each with line occlusion, accidental removal by patient, line rupture, and line leakage at insertion site. The complication rate between ports and external lines was different (P = 0.045). CONCLUSIONS: Central line placement prior to anti-leukemia treatment is safe. Most complications are mechanical and not due to leukemia, chemotherapy, or cytopenias.
Assuntos
Cateterismo Venoso Central/efeitos adversos , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamento farmacológico , Adolescente , Criança , Pré-Escolar , Feminino , Humanos , Lactente , Masculino , Leucemia-Linfoma Linfoblástico de Células Precursoras/diagnóstico , Estudos RetrospectivosRESUMO
PURPOSE: To determine if granulocyte colony-stimulating factor (G-CSF) with empirical antibiotics accelerates febrile neutropenia resolution compared with antibiotics without it. PATIENTS AND METHODS: Eligible children were treated without prophylactic G-CSF and presented with fever (temperature >38.3 degrees C) and neutropenia afterward. Patients with acute myelogenous leukemia and myelodysplastic syndrome were excluded. Assignments were randomized between G-CSF (5 microg/kg/day) or none beginning within 24 hr of antibiotics. Subcutaneous administration was recommended, but intravenous G-CSF was allowed. Patients remained on study until absolute neutrophil count (ANC) >500/microl and > or =48 hr without fever. RESULTS: One of 67 patients enrolled was ineligible, 59 had acute lymphoblastic leukemia (ALL). Thirty-four were assigned to antibiotics, 32 to G-CSF plus antibiotics. Adding G-CSF significantly reduced neutropenia and febrile neutropenia recovery times. Median days to febrile neutropenia resolution was nine earlier with G-CSF (4 vs. 13 days) (P < 0.0001). However, there was no difference in the resolution of fever between arms. Hospitalization median was shorter by 1 day with G-CSF (4 vs. 5 days) (P = 0.04). There was no difference in the duration of IV and oral antibiotic treatment, addition of antifungal therapy, and shock incidence. A trend for decreased incidence of late fever with G-CSF was noted (6.3 vs. 23.5%) (P = 0.08). CONCLUSIONS: Adding G-CSF to empiric antibiotic coverage accelerates chemotherapy-induced febrile neutropenia resolution by 9 days in pediatric patients, mainly with ALL, which results in a small but significant difference in the median length of hospitalization.
Assuntos
Antibacterianos/uso terapêutico , Febre/tratamento farmacológico , Fator Estimulador de Colônias de Granulócitos/uso terapêutico , Neutropenia/tratamento farmacológico , Adolescente , Adulto , Antineoplásicos/efeitos adversos , Criança , Pré-Escolar , Quimioterapia Combinada , Feminino , Febre/induzido quimicamente , Humanos , Lactente , Tempo de Internação , Masculino , Neoplasias/complicações , Neoplasias/tratamento farmacológico , Neutropenia/induzido quimicamente , Estatísticas não Paramétricas , Fatores de TempoRESUMO
The authors describe two consecutive pediatric patients with relapsed Hodgkin lymphoma after autologous hematopoietic stem cell transplantation who had objective responses with a novel combination of gemcitabine and vinorelbine. This novel and promising combination needs to be studied in a larger number of relapsed Hodgkin disease patients.