362 results on '"Mechinaud, F."'
Search Results
152. Re-evaluating and recalibrating predictors of bacterial infection in children with cancer and febrile neutropenia.
- Author
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Haeusler GM, Phillips R, Slavin MA, Babl FE, De Abreu Lourenco R, Mechinaud F, and Thursky KA
- Abstract
Background: Numerous paediatric febrile neutropenia (FN) clinical decision rules (CDRs) have been derived. Validation studies show reduced performance in external settings. We evaluated the association between variables common across published FN CDRs and bacterial infection and recalibrated existing CDRs using these data., Methods: Prospective data from the Australian-PICNICC study which enrolled 858 FN episodes in children with cancer were used. Variables shown to be significant predictors of infection or adverse outcome in >1 CDR were analysed using multivariable logistic regression. Recalibration included re-evaluation of beta-coefficients (logistic model) or recursive-partition analysis (tree-based models)., Findings: Twenty-five unique variables were identified across 17 FN CDRs. Fourteen were included in >1 CDR and 10 were analysed in our dataset. On univariate analysis, location, temperature, hypotension, rigors, severely unwell and decreasing platelets, white cell count, neutrophil count and monocyte count were significantly associated with bacterial infection. On multivariable analysis, decreasing platelets, increasing temperature and the appearance of being clinically unwell remained significantly associated. Five rules were recalibrated. Across all rules, recalibration increased the AUC-ROC and low-risk yield as compared to non-recalibrated data. For the SPOG-adverse event CDR, recalibration also increased sensitivity and specificity and external validation showed reproducibility., Interpretation: Degree of marrow suppression (low platelets), features of inflammation (temperature) and clinical judgement (severely unwell) have been consistently shown to predict infection in children with FN. Recalibration of existing CDRs is a novel way to improve diagnostic performance of CDRs and maintain relevance over time., Funding: National Health and Medical Research Council Grant (APP1104527)., Competing Interests: Dr Haeusler reports grants from the Victorian Cancer Agency and the Murdoch Children's Research Institute during the conduct of the study. Dr Babl reports grants from The Royal Children's Hospital Foundation and the NHMRC during the conduct of the study. Dr De Abreu Lourenco reports grants from the NHMRC during the conduct of this study. Dr Thusky, Dr Slavin, Dr Mechinaud and Dr Phillips have nothing to disclose., (© 2020 Published by Elsevier Ltd.)
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- 2020
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153. Physical activity for children undergoing acute cancer treatment: A qualitative study of parental perspectives.
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Grimshaw SL, Taylor NF, Mechinaud F, Conyers R, and Shields N
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- Adolescent, Child, Child, Preschool, Female, Follow-Up Studies, Humans, Male, Neoplasms psychology, Neoplasms therapy, Prognosis, Qualitative Research, Exercise psychology, Neoplasms rehabilitation, Parents psychology, Sedentary Behavior
- Abstract
Background: Little is known about how to facilitate participation in physical activity among children receiving acute cancer treatment., Objective: To understand the parental perspectives on physical activity for children during acute cancer treatment and explore strategies to overcome physical inactivity., Methods: A qualitative study was completed. Data were collected via semistructured interviews with parents of children (aged 4-18 years) who were in their first nine months of cancer treatment. Data were analyzed thematically., Results: Twenty parents were interviewed. A childhood cancer diagnosis and subsequent treatment were described as setting in motion a spiral of physical inactivity. Parents identified movement restrictions as a result of commencing treatment and the hospital environment as factors initiating this decline. Parents described the subsequent impact of movement restrictions on their child over time including loss of independence, isolation, and low motivation. These three consequences further contributed to an inability and unwillingness to be physically active. Parents responded in a variety of ways to their child's inactivity, and many were motivated to overcome the barriers to physical activity yet exhibited a reduced capacity to do so. Suggested intervention strategies highlighted the need for comprehensive support from the organization providing treatment., Conclusions: Reasons for reduced physical activity in children receiving acute treatment for cancer are complex and multifactorial. Inactivity cannot be addressed by children and parents alone but requires support from the oncology team through changes to the environment, services, and policies to promote physical activity. These findings may be used to inform targeted, effective, and feasible physical activity interventions., (© 2020 Wiley Periodicals, Inc.)
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- 2020
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154. Genome-Wide Association Meta-Analysis of Single-Nucleotide Polymorphisms and Symptomatic Venous Thromboembolism during Therapy for Acute Lymphoblastic Leukemia and Lymphoma in Caucasian Children.
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Mateos MK, Tulstrup M, Quinn MC, Tuckuviene R, Marshall GM, Gupta R, Mayoh C, Wolthers BO, Barbaro PM, Ruud E, Sutton R, Huttunen P, Revesz T, Trakymiene SS, Barbaric D, Tedgård U, Giles JE, Alvaro F, Jonsson OG, Mechinaud F, Saks K, Catchpoole D, Kotecha RS, Dalla-Pozza L, Chenevix-Trench G, Trahair TN, MacGregor S, and Schmiegelow K
- Abstract
Symptomatic venous thromboembolism (VTE) occurs in five percent of children treated for acute lymphoblastic leukemia (ALL), but whether a genetic predisposition exists across different ALL treatment regimens has not been well studied., Methods: We undertook a genome-wide association study (GWAS) meta-analysis for VTE in consecutively treated children in the Nordic/Baltic acute lymphoblastic leukemia 2008 (ALL2008) cohort and the Australian Evaluation of Risk of ALL Treatment-Related Side-Effects (ERASE) cohort. A total of 92 cases and 1481 controls of European ancestry were included., Results: No SNPs reached genome-wide significance ( p < 5 × 10
-8 ) in either cohort. Among the top 34 single-nucleotide polymorphisms (SNPs) ( p < 1 × 10-6 ), two loci had concordant effects in both cohorts: ALOX15B (rs1804772) (MAF: 1%; p = 3.95 × 10-7 ) that influences arachidonic acid metabolism and thus platelet aggregation, and KALRN (rs570684) (MAF: 1%; p = 4.34 × 10-7 ) that has been previously associated with risk of ischemic stroke, atherosclerosis, and early-onset coronary artery disease., Conclusion: This represents the largest GWAS meta-analysis conducted to date associating SNPs to VTE in children and adolescents treated on childhood ALL protocols. Validation of these findings is needed and may then lead to patient stratification for VTE preventive interventions. As VTE hemostasis involves multiple pathways, a more powerful GWAS is needed to detect combination of variants associated with VTE.- Published
- 2020
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155. Results from an international phase 2 study of the anti-CD22 immunotoxin moxetumomab pasudotox in relapsed or refractory childhood B-lineage acute lymphoblastic leukemia.
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Shah NN, Bhojwani D, August K, Baruchel A, Bertrand Y, Boklan J, Dalla-Pozza L, Dennis R, Hijiya N, Locatelli F, Martin PL, Mechinaud F, Moppett J, Rheingold SR, Schmitt C, Trippett TM, Liang M, Balic K, Li X, Vainshtein I, Yao NS, Pastan I, and Wayne AS
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- Adolescent, Bacterial Toxins adverse effects, Child, Child, Preschool, Exotoxins adverse effects, Female, Humans, Infant, Male, Recurrence, Bacterial Toxins administration & dosage, Bacterial Toxins pharmacokinetics, Biomarkers, Tumor blood, Exotoxins administration & dosage, Exotoxins pharmacokinetics, Precursor B-Cell Lymphoblastic Leukemia-Lymphoma blood, Precursor B-Cell Lymphoblastic Leukemia-Lymphoma drug therapy
- Abstract
Background: In a multicenter phase 1 study of children with relapsed/refractory acute lymphoblastic leukemia (ALL), moxetumomab pasudotox, an anti-CD22 immunotoxin, demonstrated a manageable safety profile and preliminary evidence of clinical activity. A phase 2 study further evaluated efficacy., Procedure: This international, multicenter, phase 2 study enrolled children with relapsed/refractory B-cell precursor ALL who received moxetumomab pasudotox 40 µg/kg intravenously every other day, for six doses per 21-day cycle. The primary objective was to evaluate the complete response (CR) rate. Secondary objectives included safety, pharmacokinetics, and immunogenicity evaluations., Results: Thirty-two patients (median age, 10 years) were enrolled at 16 sites; 30 received study drug and were evaluable for safety; 28 were evaluable for response. The objective response rate was 28.6%, with three patients (10.7%) achieving morphologic CR, and five patients (17.9%) achieving partial response. Disease progression occurred in 11 patients (39.3%). Ten patients (33.3%) experienced at least one treatment-related serious adverse event, including capillary leak syndrome (CLS; n = 6), hemolytic uremic syndrome (HUS; n = 4), and treatment-related death (n = 1) from pulmonary edema. No differences were observed in inflammatory markers in patients who did or did not develop CLS or HUS., Conclusions: Despite a signal for clinical activity, this phase 2 study was terminated at interim analysis for a CR rate that did not reach the stage 1 target. Preclinical data suggest enhanced efficacy of moxetumomab pasudotox via continuous infusion or in combination regimens; thus, further studies designed to optimize the efficacy and safety of moxetumomab pasudotox in pediatric ALL may be warranted., (© 2020 Wiley Periodicals, Inc.)
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- 2020
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156. Immunogenicity of the inactivated influenza vaccine in children who have undergone allogeneic haematopoietic stem cell transplant.
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Ryan AL, Wadia UD, Jacoby P, Cheung LC, Kerr F, Fraser C, Tapp H, Mechinaud F, Carolan LA, Laurie KL, Barr IG, Blyth CC, Gottardo NG, Richmond PC, and Kotecha RS
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- Antibodies, Viral, Australia, Child, Humans, Influenza A Virus, H3N2 Subtype, Prospective Studies, Vaccines, Inactivated, Hematopoietic Stem Cell Transplantation, Influenza A Virus, H1N1 Subtype, Influenza Vaccines, Influenza, Human prevention & control
- Abstract
Influenza vaccination is recommended for children following allogeneic haematopoietic stem cell transplant (HSCT), however there is limited evidence regarding its benefit. A prospective multicentre study was conducted to evaluate the immunogenicity of the inactivated influenza vaccine in children who have undergone HSCT compared with healthy age-matched controls. Participants were vaccinated between 2013 and 2016 according to Australian guidelines. Influenza-specific hemagglutinin inhibition antibody titres were performed prior to each vaccination and 4 weeks following the final vaccination. A nasopharyngeal aspirate for influenza was performed on participants that developed influenza-like illness. There were 86 children recruited; 43 who had undergone HSCT and 43 controls. For the HSCT group, seroprotection and seroconversion rates were 81.4% and 60.5% for H3N2, 41.9% and 32.6% for H1N1, and 44.2% and 39.5% for B strain respectively. There was a significant geometric mean fold increase to the H3N2 (GMFI 5.80, 95% CI 3.68-9.14, p < 0.001) and B (GMFI 3.44, 95% CI 2.36-5.00, p = 0.048) strains. Serological response was superior in age-matched controls to all vaccine strains. There were no serious adverse events following vaccination. For children who underwent HSCT, incidence of laboratory-proven influenza infection was 2.3%. Overall, this study provides evidence to support annual inactivated influenza vaccine administration to children following HSCT.
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- 2020
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157. Risk stratification in children with cancer and febrile neutropenia: A national, prospective, multicentre validation of nine clinical decision rules.
- Author
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Haeusler GM, Thursky KA, Slavin MA, Babl FE, De Abreu Lourenco R, Allaway Z, Mechinaud F, and Phillips R
- Abstract
Background: Reduced intensity treatment of low-risk febrile neutropenia (FN) in children with cancer is safe and improves quality of life. Identifying children with low-risk FN using a validated risk stratification strategy is recommended. This study prospectively validated nine FN clinical decision rules (CDRs) designed to predict infection or adverse outcome., Methods: Data were collected on consecutive FN episodes in this multicentre, prospective validation study. The reproducibility and discriminatory ability of each CDR in the validation cohort was compared to the derivation dataset and details of missed outcomes were reported., Findings: There were 858 FN episodes in 462 patients from eight hospitals included. Bacteraemia occurred in 111 (12·9%) and a non-bacteraemia microbiological documented infection in 185 (21·6%). Eight CDRs exhibited reproducibility and sensitivity ranged from 64% to 96%. Rules that had >85% sensitivity in predicting outcomes classified few patients (<20%) as low risk. For three CDRs predicting a composite outcome of any bacterial or viral infection, the sensitivity and discriminatory ability improved for prediction of bacterial infection alone. Across all CDRs designed to be implemented at FN presentation, the sensitivity improved at day 2 assessment., Interpretation: While reproducibility was observed in eight out of the nine CDRs, no rule perfectly differentiated between children with FN at high or low risk of infection. This is in keeping with other validation studies and highlights the need for additional safeguards against missed infections or adverse outcomes before implementation can be considered., Competing Interests: GMH reports grants from the Victorian Cancer Agency during the conduct of the study. FEB reports grants from The Royal Children's Hospital Foundation during the conduct of the study. RDAL reports grants from the NHMRC during the conduct of this study. KAT, MS, ZA and FM and RP have nothing to disclose., (© 2019 Published by Elsevier Ltd.)
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- 2020
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158. Patient-reported quality of life after tisagenlecleucel infusion in children and young adults with relapsed or refractory B-cell acute lymphoblastic leukaemia: a global, single-arm, phase 2 trial.
- Author
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Laetsch TW, Myers GD, Baruchel A, Dietz AC, Pulsipher MA, Bittencourt H, Buechner J, De Moerloose B, Davis KL, Nemecek E, Driscoll T, Mechinaud F, Boissel N, Rives S, Bader P, Peters C, Sabnis HS, Grupp SA, Yanik GA, Hiramatsu H, Stefanski HE, Rasouliyan L, Yi L, Shah S, Zhang J, and Harris AC
- Subjects
- Adolescent, Adult, Cell- and Tissue-Based Therapy methods, Child, Female, Follow-Up Studies, Humans, Immunotherapy methods, Infusions, Intravenous, Male, Neoplasm Recurrence, Local pathology, Precursor B-Cell Lymphoblastic Leukemia-Lymphoma pathology, Prognosis, Survival Rate, Young Adult, Drug Resistance, Neoplasm, Neoplasm Recurrence, Local therapy, Patient Reported Outcome Measures, Precursor B-Cell Lymphoblastic Leukemia-Lymphoma therapy, Quality of Life, Receptors, Antigen, T-Cell administration & dosage, Salvage Therapy
- Abstract
Background: The ELIANA trial showed that 61 (81%) of 75 paediatric and young adult patients with relapsed or refractory B-cell acute lymphoblastic leukaemia achieved overall remission after treatment with tisagenlecleucel, a chimeric antigen receptor targeted against the CD19 antigen. We aimed to evaluate patient-reported quality of life in these patients before and after tisagenlecleucel infusion., Methods: ELIANA, a global, single-arm, open-label, phase 2 trial, was done in 25 hospitals across Australia, Austria, Belgium, Canada, France, Germany, Italy, Japan, Norway, Spain, and the USA. Patients with B-cell acute lymphoblastic leukaemia aged at least 3 years at the time of screening and 21 years or younger at the time of initial diagnosis who were in second or greater bone marrow relapse, chemorefractory, relapsed after allogeneic stem-cell transplantation, or were otherwise ineligible for allogeneic stem-cell transplantation were enrolled. Patients received a single intravenous administration of a target dose of 0·2-5 × 10
6 transduced viable T cells per kg for patients weighing 50 kg or less or 0·1-2·5 × 108 transduced viable T cells for patients weighing more than 50 kg. The primary outcome, reported previously, was the proportion of patients who achieved remission. A prespecified secondary endpoint, reported here, was patient-reported quality of life measured with the Pediatric Quality of Life Inventory (PedsQL) and European Quality of Life-5 Dimensions questionnaire (EQ-5D). Patients completed the questionnaires at baseline, day 28, and months 3, 6, 9, and 12 after treatment. The data collected were summarised using descriptive statistics and post-hoc mixed models for repeated measures. Change from baseline response profiles were illustrated with cumulative distribution function plots. The proportion of patients achieving the minimal clinically important difference and normative mean value were reported. Analysis was per protocol. This study is registered with ClinicalTrials.gov, NCT02435849., Findings: Between April 8, 2015, and April 25, 2017, 107 patients were screened, 92 were enrolled, and 75 received tisagenlecleucel. 58 patients aged 8-23 years were included in the analysis of quality of life. At baseline, 50 (86%) patients had completed the PedsQL questionnaire and 48 (83%) had completed the EQ-5D VAS. Improvements in patient-reported quality-of-life scores were observed for all measures at month 3 after tisagenlecleucel infusion (mean change from baseline to month 3 was 13·3 [95% CI 8·9-17·6] for the PedsQL total score and 16·8 [9·4-24·3] for the EQ-5D visual analogue scale). 30 (81%) of 37 patients achieved the minimal clinically important difference at month 3 for the PedsQL total score and 24 (67%) of 36 patients achieved this for the EQ-5D visual analogue scale., Interpretation: These findings, along with the activity and safety results of ELIANA, suggest a favourable benefit-risk profile of tisagenlecleucel in the treatment of paediatric and young adult patients with relapsed or refractory B-cell acute lymphoblastic leukaemia., Funding: Novartis., (Copyright © 2019 Elsevier Ltd. All rights reserved.)- Published
- 2019
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159. Targeted therapy and disease monitoring in CNTRL-FGFR1-driven leukaemia.
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Brown LM, Bartolo RC, Davidson NM, Schmidt B, Brooks I, Challis J, Petrovic V, Khuong-Quang DA, Mechinaud F, Khaw SL, Majewski IJ, Oshlack A, and Ekert PG
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- Antineoplastic Combined Chemotherapy Protocols therapeutic use, Child, Humans, Infant, Male, Oncogene Fusion, Oncogene Proteins, Fusion genetics, Polymerase Chain Reaction methods, Protein Kinase Inhibitors therapeutic use, Cell Cycle Proteins genetics, Leukemia genetics, Leukemia therapy, Molecular Targeted Therapy methods, Receptor, Fibroblast Growth Factor, Type 1 genetics
- Abstract
We report two patients with leukaemia driven by the rare CNTRL-FGFR1 fusion oncogene. This fusion arises from a t(8;9)(p12;q33) translocation, and is a rare driver of biphenotypic leukaemia in children. We used RNA sequencing to report novel features of expressed CNTRL-FGFR1, including CNTRL-FGFR1 fusion alternative splicing. From this knowledge, we designed and tested a Droplet Digital PCR assay that detects CNTRL-FGFR1 expression to approximately one cell in 100 000 using fusion breakpoint-specific primers and probes. We also utilised cell-line models to show that effective tyrosine kinase inhibitors, which may be included in treatment regimens for this disease, are only those that block FGFR1 phosphorylation., (© 2019 Wiley Periodicals, Inc.)
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- 2019
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160. TCR α + β + /CD19 + cell-depleted hematopoietic stem cell transplantation for pediatric patients.
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Mitchell R, Cole T, Shaw PJ, Mechinaud F, O'Brien T, and Fraser C
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- Adolescent, Antigens, CD19 metabolism, Australia, Child, Child, Preschool, Fanconi Anemia therapy, Female, Graft vs Host Disease, Humans, Immunologic Deficiency Syndromes therapy, Infant, Leukemia therapy, Male, Neutrophils cytology, Pediatrics, Recurrence, Retrospective Studies, Treatment Outcome, Cell Separation, Hematopoietic Stem Cell Transplantation methods, Receptors, Antigen, T-Cell, alpha-beta metabolism, Transplantation Conditioning
- Abstract
TCR α
+ β+ /CD19+ cell depletion is an emerging technique for ex vivo graft manipulation in HSCT. We report 20 pediatric patients who underwent TCR α+ β+ /CD19+ cell-depleted HSCT in four Australian centers. Conditioning regimen was dependent on HSCT indication, which included immunodeficiency (n = 14), Fanconi anemia (n = 3), and acute leukemia (n = 3). Donor sources were haploidentical parent (n = 17), haploidentical sibling (n = 2), or matched unrelated donor (n = 1). Mean cell dose was 8.2 × 108 /kg TNC, 12.1 × 106 /kg CD34+ cells, and 0.4 × 105 /kg TCR α+ β+ cells. All patients achieved primary neutrophil and platelet engraftment, with average time to neutrophil engraftment 11 days (range 8-22) and platelet engraftment 24 days (range 12-69). TRM at 1 year was 15%. Rate of grade II-IV aGVHD at 1 year was 20% with no grade III-IV aGVHD seen. CMV reactivation occurred in 81% of CMV-positive recipients, with one patient developing CMV disease. Average time to CD4 recovery (>400 × 106 /L) was 258 days. Overall survival for the cohort at 5 years was 80%. This report highlights the initial experience of TCR α+ β+ /CD19+ cell-depleted HSCT in Australian centers, with high rates of engraftment, low rates of aGVHD, and acceptable TRM., (© 2019 Wiley Periodicals, Inc.)- Published
- 2019
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161. Hematopoietic stem cell transplantation for children with acute myeloid leukemia in second remission: A report from the Australasian Bone Marrow Transplant Recipient Registry and the Australian and New Zealand Children's Haematology Oncology Group.
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Selim A, Alvaro F, Cole CH, Fraser CJ, Mechinaud F, O'Brien TA, Shaw PJ, Tapp H, Teague L, Nivison-Smith I, and Moore AS
- Subjects
- Adolescent, Australia, Child, Child, Preschool, Female, Follow-Up Studies, Humans, Infant, Infant, Newborn, Leukemia, Myeloid, Acute pathology, Male, Neoplasm Recurrence, Local pathology, Neoplasm, Residual pathology, Prognosis, Registries, Remission Induction, Retrospective Studies, Survival Rate, Hematopoietic Stem Cell Transplantation mortality, Leukemia, Myeloid, Acute therapy, Neoplasm Recurrence, Local therapy, Neoplasm, Residual therapy
- Abstract
Background: Approximately one-third of children with acute myeloid leukemia (AML) relapse, requiring re-treatment and allogeneic hematopoietic stem cell transplantation (HSCT). Although achieving second complete remission (CR2) prior to HSCT is desirable, once CR2 is attained, it is unclear if there is any benefit from further chemotherapy prior to HSCT. Moreover, although pre-HSCT minimal residual disease (MRD) has prognostic value in acute lymphoblastic leukemia, the benefit of MRD reduction after achieving CR prior to HSCT is less clear for AML., Procedure: To address these questions, we analyzed data from pediatric transplant centers in Australia and New Zealand concerning relapsed childhood AML cases occurring between 1998 and 2013. Given the retrospective nature of our analysis and assay data available, we analyzed patients on the basis of measurable residual disease (MeRD) by any methodology, rather than MRD in the conventional sense., Results: We observed improved overall survival (OS) in children receiving two chemotherapy cycles, compared to one cycle or three or more cycles pre-HSCT. Improved OS with two cycles remained significant for patients without MeRD after cycle 1., Conclusions: These data suggest that a second chemotherapy cycle pre-HSCT may improve survival by lowering disease burden. Prospective trials assessing strategies to reduce pre-HSCT MRD in relapsed childhood AML are warranted., (© 2019 Wiley Periodicals, Inc.)
- Published
- 2019
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162. Use of TCR α + β + /CD19 + -Depleted Haploidentical Hematopoietic Stem Cell Transplant Is a Viable Option in Patients With Primary Immune Deficiency Without Matched Sibling Donor.
- Author
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Brettig T, Smart J, Choo S, Mechinaud F, Mitchell R, Raj TS, and Cole T
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- Adolescent, Antigens, CD19, B-Lymphocytes immunology, Child, Child, Preschool, Female, Humans, Infant, Male, Primary Immunodeficiency Diseases immunology, Siblings, T-Lymphocytes immunology, Tissue Donors, Hematopoietic Stem Cell Transplantation, Primary Immunodeficiency Diseases therapy, Receptors, Antigen, T-Cell, alpha-beta immunology
- Abstract
Allogeneic hematopoietic stem cell transplantation (HSCT) is curative for many patients with primary immune deficiency (PID). Haploidentical donors have historically been associated with higher rates of graft-versus-host disease (GvHD) and graft failure. Use of T cell receptor (TCR) α
+ β+ /CD19+ -depleted grafts has resulted in improved haploidentical HSCT outcomes. We sought to evaluate outcomes of TCR α+ β+ /CD19+ -depleted haploidentical HSCT in pediatric patients with PID at a single center in Australia. Specifically, we evaluated immune reconstitution, looking at time to T cell and B cell reconstitution, and B cell function post-HSCT. Eleven patients with a mean age of 7.92 years (range 0.33-17.17 years) were included. The median time to B cell recovery was 93 days (range 41-205 days), and the median time to cessation of immunoglobulin replacement was 281.5 days (range 41-205 days). All patients who had ceased immunoglobulin replacement had an adequate response to pneumococcal conjugate (Prevenar 13) vaccine. The median time to CD4+ recovery was 132 days (range 30-296 days), and naive T cells were present in all surviving patients by 4 months post-HSCT. Eight of 11 patients are surviving, with six patients having whole blood chimerism greater than 95%, one patient with whole blood chimerism of 82.8%, and another with 76.0%. All of these patients clinically had no evidence of underlying immunodeficiency. Likelihood of overall survival at 2 years post-HSCT was 81.8%. Cumulative incidence of acute GvHD was 27.3%. Cumulative incidence of CMV viremia was 63.6%. All patients previously exposed to CMV had reactivation post-HSCT, but were controlled with pre-emptive CMV treatment. Assuming most children with PID have a haploidentical donor available, use of this technique is likely to result in good outcomes for patients who do not have a suitable matched sibling or matched unrelated donor.- Published
- 2019
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163. ALK-positive histiocytosis: an expanded clinicopathologic spectrum and frequent presence of KIF5B-ALK fusion.
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Chang KTE, Tay AZE, Kuick CH, Chen H, Algar E, Taubenheim N, Campbell J, Mechinaud F, Campbell M, Super L, Chantranuwat C, Yuen ST, Chan JKC, and Chow CW
- Subjects
- Adolescent, Adult, Child, Preschool, Crizotinib therapeutic use, Female, Genetic Predisposition to Disease, Histiocytes pathology, Histiocytosis drug therapy, Histiocytosis enzymology, Histiocytosis pathology, Hong Kong, Humans, Infant, Infant, Newborn, Male, Phenotype, Protein Kinase Inhibitors therapeutic use, Singapore, Treatment Outcome, Victoria, Cell Proliferation drug effects, Gene Fusion, Histiocytes enzymology, Histiocytosis genetics, Oncogene Proteins, Fusion genetics
- Abstract
In 2008, we presented three cases of ALK-positive histiocytosis as a novel systemic histiocytic proliferation of early infancy with hepatosplenomegaly and dramatic hematological disturbances. This series of 10 cases (including the original three cases) describes an expanded clinicopathological spectrum and the molecular findings of this histiocytic proliferation. Six patients had disseminated disease: five presented in early infancy with eventual disease resolution, and the sixth presented at 2 years of age and died of intestinal, bone marrow, and brain involvement. The other four patients had localized disease involving nasal skin, foot, breast, and intracranial cavernous sinus - the first three had no recurrence after surgical resection, while the cavernous sinus lesion showed complete resolution with crizotinib therapy. The lesional histiocytes were very large, with irregularly folded nuclei, fine chromatin, and abundant eosinophilic cytoplasm, sometimes with emperipolesis. There could be an increase in foamy histiocytes and Touton giant cells with time, resembling juvenile xanthogranuloma. Immunostaining showed that the histiocytes were positive for ALK, histiocytic markers (CD68, CD163) and variably S100, while being negative for CD1a, CD207, and BRAF-V600E. Next-generation sequencing-based anchored multiplex PCR (Archer® FusionPlex®) performed in six cases identified KIF5B-ALK gene fusion in five and COL1A2-ALK fusion in one. There was no correlation of gene fusion type with disease localization or dissemination. The clinicopathological spectrum of ALK-positive histiocytosis is broader than originally described, and this entity is characterized by frequent presence of KIF5B-ALK gene fusion. We recommend that every unusual histiocytic proliferative disorder, especially disseminated lesions, be tested for ALK expression because of the potential efficacy of ALK inhibitor therapy in unresectable or disseminated disease.
- Published
- 2019
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164. Assessment of physical function in children with cancer: A systematic review.
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Grimshaw SL, Taylor NF, Mechinaud F, and Shields N
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- Adolescent, Child, Child, Preschool, Female, Humans, Infant, Infant, Newborn, Male, Exercise, Neoplasms physiopathology
- Abstract
Background: Appropriate selection of robust assessment tools is essential to monitor physical function in children with cancer during and after treatment. This systematic review aims to identify and critically appraise the measurement properties of physical function measures currently used for children with cancer., Procedure: Two systematic searches of seven electronic databases [Cumulative Index to Nursing and Allied Health Literature (CINHAL), Medline, PubMed, PsychINFO, Sportsdiscus, EMBASE, and Allied and Complementary Medicine Database (AMED)] were completed to identify physical function measures used in children with cancer and to evaluate their measurement properties. Methodological quality and the adequacy of measurement properties specific to populations of children with cancer were critically appraised using the COSMIN framework to ascertain which measures have evidence to support their use in children with cancer., Results: One hundred and one physical function measures were identified across 154 studies. Measurement property data were available for 12 measures. The measurement properties of only two outcome measures were assessed in more than one study. Despite some positive measurement property data, there was no assessment tool that had consistent and adequate evidence overall to recommend its use in childhood cancer populations. Poor methodological quality of the included studies was the main limiting factor., Conclusions: There is very limited population specific evidence to guide the selection of physical function measures in children with cancer. Further research into the reliability, validity and responsiveness of physical function measures in children with cancer is needed to provide a basis for more effective clinical assessment and management., (© 2018 Wiley Periodicals, Inc.)
- Published
- 2018
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165. Treatment and secondary prophylaxis with ethanol lock therapy for central line-associated bloodstream infection in paediatric cancer: a randomised, double-blind, controlled trial.
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Wolf J, Connell TG, Allison KJ, Tang L, Richardson J, Branum K, Borello E, Rubnitz JE, Gaur AH, Hakim H, Su Y, Federico SM, Mechinaud F, Hayden RT, Monagle P, Worth LJ, Curtis N, and Flynn PM
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- Adolescent, Australia, Bacteremia etiology, Bacteremia prevention & control, Catheterization, Central Venous adverse effects, Catheters, Indwelling adverse effects, Child, Child, Preschool, Double-Blind Method, Female, Humans, Infant, Male, Secondary Prevention, Treatment Outcome, United States, Young Adult, Anti-Infective Agents, Local administration & dosage, Catheter-Related Infections prevention & control, Ethanol administration & dosage, Neoplasms therapy
- Abstract
Background: Central line-associated bloodstream infections (CLABSIs) affect about 25% of children with cancer, and treatment failure is common. Adjunctive ethanol lock therapy might prevent treatment failure but high-quality evidence is scarce. We evaluated ethanol lock therapy as treatment and secondary prophylaxis for CLABSI in children with cancer or haematological disorders., Methods: This randomised, double-blind, placebo-controlled superiority trial, with two interim futility and efficacy analyses (done when the first 46 and 92 evaluable participants completed study requirements), was done at two paediatric hospitals in the USA and Australia. Patients aged 6 months to 24 years, inclusive, with cancer or a haematological disorder and new CLABSI were eligible. Participants were randomly assigned (1:1) to receive either ethanol lock therapy (70% ethanol) or placebo (heparinised saline) for 2-4 h per lumen daily for 5 days (treatment phase), then for up to 3 non-consecutive days per week for 24 weeks (prophylaxis phase). The primary composite outcome was treatment failure, consisting of attributable catheter removal or death, new or persistent (>72 h) infection, or additional lock therapy during the treatment phase, and recurrent CLABSI during the prophylaxis phase. This trial is registered with ClinicalTrials.gov, number NCT01472965., Findings: 94 evaluable participants were enrolled between Dec 14, 2011, and Sept 12, 2016, of whom 48 received ethanol lock therapy and 46 received placebo. The study met futility criteria at the second interim analysis. Treatment failure was similar with ethanol lock therapy (21 [44%] of 48) and placebo (20 [43%] of 46; relative risk [RR] 1·0, 95% CI 0·6-1·6; p=0·98). Some adverse events, including infusion reactions and catheter occlusion, were more frequent in the ethanol lock therapy group than in the placebo group. Catheter occlusion requiring thrombolytic therapy was more common with ethanol lock therapy (28 [58%] of 48) than with placebo (15 [33%] of 46; RR 1·8, 95% CI 1·1-2·9; p=0·012). Discontinuation of lock therapy because of adverse effects or patient request occurred in a similar proportion of participants in the ethanol lock therapy (nine [19%] of 48) and placebo groups (ten [22%] of 46; p=0·72)., Interpretation: Ethanol lock therapy did not prevent CLABSI treatment failure and it increased catheter occlusion. Routine ethanol lock therapy for treatment or secondary prophylaxis is not recommended in this population., Funding: American Lebanese Syrian Associated Charities to St Jude Children's Research Hospital and an Australian Government Research Training Scholarship., (Copyright © 2018 Elsevier Ltd. All rights reserved.)
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- 2018
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166. Management of fever and neutropenia in children with cancer: A survey of Australian and New Zealand practice.
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Haeusler GM, Slavin MA, Bryant PA, Babl FE, Mechinaud F, and Thursky KA
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- Adolescent, Ambulatory Care methods, Ambulatory Care standards, Anti-Bacterial Agents therapeutic use, Australia, Child, Child, Preschool, Combined Modality Therapy, Drug Therapy, Combination, Female, Fever etiology, Health Care Surveys, Humans, Male, Medical Audit, Neutropenia etiology, New Zealand, Pediatrics standards, Pediatrics statistics & numerical data, Practice Guidelines as Topic, Practice Patterns, Physicians' standards, Quality Assurance, Health Care, Quality Improvement, Risk Assessment, Fever therapy, Guideline Adherence statistics & numerical data, Neoplasms complications, Neutropenia therapy, Practice Patterns, Physicians' statistics & numerical data
- Abstract
Aim: Variation in the management of fever and neutropenia (FN) in children is well described. The aim of this study was to explore the current management of FN across Australia and New Zealand and highlight areas for improvement., Methods: A practice survey was administered to paediatric health-care providers via four clinical and research networks. Using three clinical case vignettes, we explored risk stratification, empiric antibiotics, initial investigations, intravenous-oral switch, ambulatory management and antibiotic duration in children with cancer and FN., Results: A response was received from 104 participants from 16 different hospitals. FN guideline compliance was rated as moderate or poor by 24% of respondents, and seven different fever definitions were described. There was little variation in the selected empiric monotherapy and dual-therapy regimens, and almost all respondents recommended first-dose antibiotics within 1 h. However, 27 different empiric antibiotic combinations were selected for beta-lactam allergy. An incorrect risk status was assigned to the low-risk case by 27% of respondents and to the high-risk case by 41%. Compared to current practice, significantly more respondents would manage the low-risk case in the ambulatory setting provided adequate resources were in place (43 vs. 85%, P < 0.0001). There was variation in the use of empiric glycopeptides as well as use of aminoglycosides beyond 48 h., Conclusion: Although the antibiotics selected for empiric management of FN are appropriate and consistent, variation and inaccuracies exist in risk stratification, the selection of monotherapy over dual therapy, empiric antibiotics chosen for beta-lactam allergy, use of glycopeptides and duration of aminoglycosides., (© 2018 Paediatrics and Child Health Division (The Royal Australasian College of Physicians).)
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- 2018
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167. Single centre results of targeted busulphan, fludarabine and serotherapy conditioning in haematopoietic stem cell transplantation for haemophagocytic lymphohistiocytosis.
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Richards S, Choo S, Mechinaud F, and Cole T
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- Busulfan administration & dosage, Combined Modality Therapy, Female, Humans, Lymphohistiocytosis, Hemophagocytic drug therapy, Lymphohistiocytosis, Hemophagocytic pathology, Male, Vidarabine administration & dosage, Vidarabine analogs & derivatives, Antineoplastic Combined Chemotherapy Protocols therapeutic use, Hematopoietic Stem Cell Transplantation methods, Immunization, Passive methods, Lymphohistiocytosis, Hemophagocytic therapy, Transplantation Conditioning methods
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- 2018
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168. The clinical utility of fluorodeoxyglucose-positron emission tomography for investigation of fever in immunocompromised children.
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Wang SS, Mechinaud F, Thursky K, Cain T, Lau E, and Haeusler GM
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- Adolescent, Anti-Infective Agents therapeutic use, Antineoplastic Agents adverse effects, Antineoplastic Agents therapeutic use, Child, Child, Preschool, Female, Hematopoietic Stem Cell Transplantation, Humans, Immunosuppressive Agents adverse effects, Immunosuppressive Agents therapeutic use, Infant, Infections diagnostic imaging, Infections drug therapy, Infections immunology, Male, Neoplasms complications, Neoplasms drug therapy, Neoplasms immunology, Retrospective Studies, Fever of Unknown Origin etiology, Fluorodeoxyglucose F18, Immunocompromised Host, Infections complications, Positron Emission Tomography Computed Tomography methods, Radiopharmaceuticals
- Abstract
Aim: Fever in immunocompromised children presents significant challenges. We aimed to determine the clinical impact of fluorodeoxyglucose-positron emission tomography (FDG-PET) in combination with computed tomography (CT) in children with malignancy or following haematopoietic stem cell transplantation with prolonged or recurrent fever., Methods: Immunocompromised children who underwent FDG-PET/CT for investigation of prolonged or recurrent fever were identified from hospital databases. The clinical impact of the FDG-PET/CT was considered 'high' if it contributed to any of the following: diagnosis of a new site infection/inflammation, change to antimicrobials or chemotherapy, or additional investigations or specialist consult contributing to final diagnosis., Results: Fourteen patients underwent an FDG-PET/CT for prolonged or recurrent fever. Median age was 11 years and 46% had diagnosis of acute lymphoblastic leukaemia. The median absolute neutrophil count on the day of FDG-PET/CT was 0.47 cells/μL. The clinical impact of FDG-PET/CT was 'high' in 11 (79%) patients, contributing to rationalisation of antimicrobials in three, and cessation of antimicrobials in five. Compared to conventional imaging, FDG PET/CT identified seven additional sites of clinically significant infection/inflammation in seven patients. Of the 10 patients who had a cause of fever identified, FDG-PET/CT contributed to the final diagnosis in six (60%)., Conclusion: This study has identified potential utility for FDG-PET/CT in immunocompromised children with prolonged or recurrent fever. Further prospective studies are needed to compare FDG-PET/CT versus conventional imaging, to identify the optimal timing of FDG-PET/CT and to study the role of subsequent scans to monitor response to therapy., (© 2017 Paediatrics and Child Health Division (The Royal Australasian College of Physicians).)
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- 2018
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169. External Validation of Six Pediatric Fever and Neutropenia Clinical Decision Rules.
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Haeusler GM, Thursky KA, Slavin MA, Mechinaud F, Babl FE, Bryant P, De Abreu Lourenco R, and Phillips R
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- Adolescent, Child, Child, Preschool, Humans, Infant, Infant, Newborn, Reproducibility of Results, Sensitivity and Specificity, Bacteremia diagnosis, Decision Support Techniques, Drug-Related Side Effects and Adverse Reactions diagnosis, Fever of Unknown Origin diagnosis, Neoplasms complications, Neutropenia complications
- Abstract
Background: Fever and neutropenia (FN) clinical decision rules (CDRs) are recommended to help distinguish children with cancer at high and low risk of severe infection. The aim of this study was to validate existing pediatric FN CDRs designed to stratify children with cancer at high or low risk of serious infection or medical complication., Methods: Pediatric CDRs suitable for validation were identified from a literature search. Relevant data were extracted from an existing data set of 650 retrospective FN episodes in children with cancer. The sensitivity and specificity of each of the CDR were compared with the derivation studies to assess reproducibility., Results: Six CDRs were identified for validation: 2 were designed to predict bacteremia and 4 to predict adverse events. Five CDRs exhibited reproducibility in our cohort. A rule predicting bacteremia had the highest sensitivity (100%; 95% confidence interval (CI): 93%-100%) although poor specificity (17%), with only 15% identified as low risk. For adverse events, the highest sensitivity achieved was 84% (95% CI: 75%-90%), with specificity of 29% and 27% identified as low risk. A rule intended for application after a 24-hour period of inpatient observation yielded a sensitivity of 80% (95% CI: 73-86) and specificity of 46%, with 44% identified as low risk., Conclusions: Five CDRs were reproducible, although not all can be recommended for implementation because of either inadequate sensitivity or failure to identify a clinically meaningful number of low-risk patients. The 24-hour rule arguably exhibits the best balance between sensitivity and specificity in our population.
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- 2018
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170. Tisagenlecleucel in Children and Young Adults with B-Cell Lymphoblastic Leukemia.
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Maude SL, Laetsch TW, Buechner J, Rives S, Boyer M, Bittencourt H, Bader P, Verneris MR, Stefanski HE, Myers GD, Qayed M, De Moerloose B, Hiramatsu H, Schlis K, Davis KL, Martin PL, Nemecek ER, Yanik GA, Peters C, Baruchel A, Boissel N, Mechinaud F, Balduzzi A, Krueger J, June CH, Levine BL, Wood P, Taran T, Leung M, Mueller KT, Zhang Y, Sen K, Lebwohl D, Pulsipher MA, and Grupp SA
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- Adolescent, Antibodies, Monoclonal, Humanized administration & dosage, Antigens, CD19, Child, Child, Preschool, Female, Humans, Infusions, Intravenous, Male, Precursor Cell Lymphoblastic Leukemia-Lymphoma mortality, Remission Induction, Survival Analysis, Young Adult, Antineoplastic Combined Chemotherapy Protocols therapeutic use, Precursor Cell Lymphoblastic Leukemia-Lymphoma drug therapy, Receptors, Antigen, T-Cell antagonists & inhibitors, Receptors, Antigen, T-Cell therapeutic use
- Abstract
Background: In a single-center phase 1-2a study, the anti-CD19 chimeric antigen receptor (CAR) T-cell therapy tisagenlecleucel produced high rates of complete remission and was associated with serious but mainly reversible toxic effects in children and young adults with relapsed or refractory B-cell acute lymphoblastic leukemia (ALL)., Methods: We conducted a phase 2, single-cohort, 25-center, global study of tisagenlecleucel in pediatric and young adult patients with CD19+ relapsed or refractory B-cell ALL. The primary end point was the overall remission rate (the rate of complete remission or complete remission with incomplete hematologic recovery) within 3 months., Results: For this planned analysis, 75 patients received an infusion of tisagenlecleucel and could be evaluated for efficacy. The overall remission rate within 3 months was 81%, with all patients who had a response to treatment found to be negative for minimal residual disease, as assessed by means of flow cytometry. The rates of event-free survival and overall survival were 73% (95% confidence interval [CI], 60 to 82) and 90% (95% CI, 81 to 95), respectively, at 6 months and 50% (95% CI, 35 to 64) and 76% (95% CI, 63 to 86) at 12 months. The median duration of remission was not reached. Persistence of tisagenlecleucel in the blood was observed for as long as 20 months. Grade 3 or 4 adverse events that were suspected to be related to tisagenlecleucel occurred in 73% of patients. The cytokine release syndrome occurred in 77% of patients, 48% of whom received tocilizumab. Neurologic events occurred in 40% of patients and were managed with supportive care, and no cerebral edema was reported., Conclusions: In this global study of CAR T-cell therapy, a single infusion of tisagenlecleucel provided durable remission with long-term persistence in pediatric and young adult patients with relapsed or refractory B-cell ALL, with transient high-grade toxic effects. (Funded by Novartis Pharmaceuticals; ClinicalTrials.gov number, NCT02435849 .).
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- 2018
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171. Phase I study of oral sonidegib (LDE225) in pediatric brain and solid tumors and a phase II study in children and adults with relapsed medulloblastoma.
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Kieran MW, Chisholm J, Casanova M, Brandes AA, Aerts I, Bouffet E, Bailey S, Leary S, MacDonald TJ, Mechinaud F, Cohen KJ, Riccardi R, Mason W, Hargrave D, Kalambakas S, Deshpande P, Tai F, Hurh E, and Geoerger B
- Subjects
- Administration, Oral, Adolescent, Adult, Aged, Biphenyl Compounds pharmacokinetics, Biphenyl Compounds pharmacology, Brain Neoplasms pathology, Cerebellar Neoplasms pathology, Child, Child, Preschool, Female, Follow-Up Studies, Humans, Male, Medulloblastoma pathology, Middle Aged, Neoplasm Recurrence, Local pathology, Neoplasms pathology, Prognosis, Pyridines pharmacokinetics, Pyridines pharmacology, Tissue Distribution, Young Adult, Biphenyl Compounds administration & dosage, Brain Neoplasms drug therapy, Cerebellar Neoplasms drug therapy, Medulloblastoma drug therapy, Neoplasm Recurrence, Local drug therapy, Neoplasms drug therapy, Pyridines administration & dosage
- Abstract
Background: Sonidegib (LDE225) is a potent, selective hedgehog (Hh) inhibitor of Smoothened. This study explored the safety and pharmacokinetics of sonidegib in children with relapsed/recurrent tumors followed by a phase II trial in pediatric and adult patients with relapsed medulloblastoma (MB) to assess tumor response., Methods: Pediatric patients aged ≥1 to <18 years were included according to a Bayesian design starting at 372 mg/m2 of continuous once daily oral sonidegib. Tumor samples were analyzed for Hh pathway activation using a validated 5-gene Hh signature assay. In phase II, pediatric patients were treated at the recommended phase II dose (RP2D) while adults received 800 mg daily., Results: Sixteen adult (16 MB) and 60 pediatric (39 MB, 21 other) patients with an age range of 2-17 years were enrolled. The RP2D of sonidegib in pediatric patients was established at 680 mg/m2 once daily. The phase II study was closed prematurely. The 5-gene Hh signature assay showed that the 4 complete responders (2 pediatric and 2 adult) and 1 partial responder (adult) all had Hh-activated tumors, while 5 patients with activated Hh had either stable disease (n = 3) or progressive disease (n = 2). No patient with an Hh-negative signature (n = 50) responded. The safety profile for pediatric patients was generally consistent with the one established for adult patients; however, growth plate changes were observed in prepubertal pediatric patients., Conclusions: Sonidegib was well tolerated and the RP2D in pediatric patients was 680 mg/m2 once daily. Five of the 10 MB patients with activated Hh pathway demonstrated complete or partial responses., (© The Author(s) 2017. Published by Oxford University Press on behalf of the Society for Neuro-Oncology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com)
- Published
- 2017
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172. Sources of error in measurement of minimal residual disease in childhood acute lymphoblastic leukemia.
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Latham S, Hughes E, Budgen B, Mechinaud F, Crock C, Ekert H, Campbell P, and Morley A
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- Adolescent, Child, Child, Preschool, Female, Humans, Infant, Male, Neoplasm, Residual, Precursor Cell Lymphoblastic Leukemia-Lymphoma pathology
- Abstract
Introduction: The level of minimal residual disease (MRD) in marrow predicts outcome and guides treatment in childhood acute lymphoblastic leukemia (ALL) but accurate prediction depends on accurate measurement., Methods: Forty-one children with ALL were studied at the end of induction. Two samples were obtained from each iliac spine and each sample was assayed twice. Assay, sample and side-to-side variation were quantified by analysis of variance and presumptively incorrect decisions related to high-risk disease were determined using the result from each MRD assay, the mean MRD in the patient as the measure of the true value, and each of 3 different MRD cut-off levels which have been used for making decisions on treatment., Results: Variation between assays, samples and sides each differed significantly from zero and the overall standard deviation for a single MRD estimation was 0.60 logs. Multifocal residual disease seemed to be at least partly responsible for the variation between samples. Decision errors occurred at a frequency of 13-14% when the mean patient MRD was between 10-2 and 10-5. Decision errors were observed only for an MRD result within 1 log of the cut-off value used for assessing high risk. Depending on the cut-off used, 31-40% of MRD results were within 1 log of the cut-off value and 21-16% of such results would have resulted in a decision error., Conclusion: When the result obtained for the level of MRD is within 1 log of the cut-off value used for making decisions, variation in the assay and/or sampling may result in a misleading assessment of the true level of marrow MRD. This may lead to an incorrect decision on treatment.
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- 2017
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173. Chemotherapy-related cardiotoxicity: are Australian practitioners missing the point?
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Conyers R, Costello B, La Gerche A, Tripaydonis A, Burns C, Ludlow L, Lange P, Ekert P, Mechinaud F, Cheung M, Martin M, and Elliot D
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- Adolescent, Anthracyclines adverse effects, Australia epidemiology, Cardiotoxicity diagnostic imaging, Cardiotoxicity epidemiology, Cardiovascular Diseases epidemiology, Child, Child, Preschool, Cohort Studies, Female, Humans, Infant, Male, Medical Audit standards, Medical Audit trends, Retrospective Studies, Young Adult, Antineoplastic Agents adverse effects, Cardiotoxins adverse effects, Cardiovascular Diseases chemically induced, Cardiovascular Diseases diagnostic imaging, Physicians standards
- Abstract
Background: It has long been established that cardiotoxicity occurs as a result of exposure to certain chemotherapeutics, particularly anthracyclines. Historically, clinicians equate cardiotoxicity with a poor prognosis, in a small percentage of patients and deem long-term surveillance as optional. Emerging evidence suggests that anthracycline cardiotoxicity (ACT) is a life-long risk with an incidence approaching 20%., Aims: To elucidate the incidence of anthracycline cardiotoxicity within a current paediatric oncology survivor cohort., Methods: Participants were identified through the Haematology-Oncology database at the Royal Children's Hospital, Melbourne. Patients were identified from a retrospective audit of outpatient attendances between January 2008 and December 2015. Patients with a cancer diagnosis exposed to anthracyclines were eligible for the study. Patient demographics and echocardiogram findings were recorded with patients subcategorised according to degree of ACT. More significant ACT defined as fractional shortening (FS) <24% and less significant if FS 24-28% or a decline in baseline ejection fraction of >10%., Results: Two hundred and eighty-six of a total 481 identified patients were eligible for study inclusion. Twenty patients displayed significant ACT with FS <24%. Ten patients had a FS 24-28% and 25 patients with a decline in ejection fraction from baseline of >10%. Overall, 6.6% demonstrated significant cardiac complications, whilst 19.6 % demonstrated some degree of ACT and decline in myocardial function. When stratified for cumulative anthracycline dose, the incidence of severe cardiac dysfunction was 5.1% (<250 mg/m
2 ) and 25% (>250 mg/m2 ) CONCLUSION: This study demonstrates, in keeping with modern literature, the higher incidence of anthracycline associated cardiac toxicity and a need for better surveillance and follow up., (© 2017 Royal Australasian College of Physicians.)- Published
- 2017
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174. Predicting Infectious ComplicatioNs in Children with Cancer: an external validation study.
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Haeusler GM, Thursky KA, Mechinaud F, Babl FE, De Abreu Lourenco R, Slavin MA, and Phillips R
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- Adolescent, Australia, Child, Child, Preschool, Decision Support Techniques, Female, Fever complications, Fever microbiology, Humans, Infections complications, Infections microbiology, Length of Stay, Male, Neoplasms complications, Neoplasms microbiology, Neoplasms pathology, Neutropenia complications, Neutropenia microbiology, Risk Factors, Fever epidemiology, Infections epidemiology, Neoplasms epidemiology, Neutropenia epidemiology
- Abstract
Background: The aim of this study was to validate the 'Predicting Infectious ComplicatioNs in Children with Cancer' (PICNICC) clinical decision rule (CDR) that predicts microbiologically documented infection (MDI) in children with cancer and fever and neutropenia (FN). We also investigated costs associated with current FN management strategies in Australia., Methods: Demographic, episode, outcome and cost data were retrospectively collected on 650 episodes of FN. We assessed the discrimination, calibration, sensitivity and specificity of the PICNICC CDR in our cohort compared with the derivation data set., Results: Using the original variable coefficients, the CDR performed poorly. After recalibration the PICNICC CDR had an area under the receiver operating characteristic (AUC-ROC) curve of 0.638 (95% CI 0.590-0.685) and calibration slope of 0.24. The sensitivity, specificity, positive predictive value and negative predictive value of the PICNICC CDR at presentation was 78.4%, 39.8%, 28.6% and 85.7%, respectively. For bacteraemia, the sensitivity improved to 85.2% and AUC-ROC to 0.71. Application at day 2, taking into consideration the proportion of MDI known (43%), further improved the sensitivity to 87.7%. Length of stay is the main contributor to cost of FN treatment, with an average cost per day of AUD 2183 in the low-risk group., Conclusions: For prediction of any MDI, the PICNICC rule did not perform as well at presentation in our cohort as compared with the derivation study. However, for bacteraemia, the predictive ability was similar to that of the derivation study, highlighting the importance of recalibration using local data. Performance also improved after an overnight period of observation. Implementation of a low-risk pathway, using the PICNICC CDR after a short period of inpatient observation, is likely to be safe and has the potential to reduce health-care expenditure.
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- 2017
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175. Use of ubiquitous, highly heterozygous copy number variants and digital droplet polymerase chain reaction to monitor chimerism after allogeneic haematopoietic stem cell transplantation.
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Whitlam JB, Ling L, Swain M, Harrington T, Mirochnik O, Brooks I, Cronin S, Challis J, Petrovic V, Bruno DL, Mechinaud F, Conyers R, and Slater H
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- Allografts, Female, Humans, In Situ Hybridization, Fluorescence methods, Male, Sensitivity and Specificity, DNA Copy Number Variations, Hematopoietic Stem Cell Transplantation, Polymerase Chain Reaction methods, Transplantation Chimera genetics
- Abstract
Chimerism analysis has an important role in the management of allogeneic hematopoietic stem cell transplantation. It informs response to disease relapse, graft rejection, and graft-versus-host disease. We have developed a method for chimerism analysis using ubiquitous copy number variation (CNV), which has the benefit of a "negative background" against which multiple independent informative markers are quantified using digital droplet polymerase chain reaction. A panel of up to 38 CNV markers with homozygous deletion frequencies of approximately 0.4-0.6 were used. Sensitivity, precision, reproducibility, and informativity were assessed. CNV chimerism results were compared against established fluorescence in situ hybridization, single nucleotide polymorphism, and short tandem repeat-based methods with excellent correlation. Using 30 ng of input DNA per well, the limit of detection was 0.05% chimerism and the limit of quantification was 0.5% chimerism. High informativity was seen with a median of four informative markers detectable per individual in 39 recipients and 43 donor genomes studied. The strength of this approach was exemplified in a multiple donor case involving four genomes (three related). The precision, sensitivity, and informativity of this approach recommend it for use in clinical practice., (Copyright © 2017 ISEH - International Society for Experimental Hematology. Published by Elsevier Inc. All rights reserved.)
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- 2017
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176. Relapsed or Refractory Lymphoblastic Lymphoma in Children: Results and Analysis of 23 Patients in the EORTC 58951 and the LMT96 Protocols.
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Michaux K, Bergeron C, Gandemer V, Mechinaud F, Uyttebroeck A, and Bertrand Y
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- Adolescent, Allografts, Child, Child, Preschool, Disease-Free Survival, Female, Hematopoietic Stem Cell Transplantation, Humans, Infant, Male, Precursor B-Cell Lymphoblastic Leukemia-Lymphoma diagnosis, Precursor T-Cell Lymphoblastic Leukemia-Lymphoma diagnosis, Prospective Studies, Survival Rate, Precursor B-Cell Lymphoblastic Leukemia-Lymphoma mortality, Precursor B-Cell Lymphoblastic Leukemia-Lymphoma therapy, Precursor T-Cell Lymphoblastic Leukemia-Lymphoma mortality, Precursor T-Cell Lymphoblastic Leukemia-Lymphoma therapy
- Abstract
Background: The treatment of children with T-cell lymphoblastic lymphoma (T-LBL) and precursor B-cell lymphoblastic lymphoma (pB-LBL) has improved during the last decades. However, patients with relapsed or refractory lymphomas still have a poor prognosis., Methods: We report the characteristics and evolution of T-LBL and pB-LBL relapses in two multicenter prospective studies (LMT 96, European Organization for Research and Treatment of Cancer 58951)., Results: From 1997 to 2008, 194 patients were included in these studies (157 T-LBL; 37 pB-LBL); among them, 23 patients underwent relapse or progression (18 T-LBL and 5 pB-LBL). The median age was 7.7 years (range 1.4-16.3). The survival rate at 8 years was 8.7% (21 deaths). The median time from diagnosis to relapse was 9 months [1-69] and 11 months [1-45] for T-LBL and pB-LBL, respectively. Twenty-two patients received a second-line treatment but remission was achieved in only seven patients. In 10 patients, intensification with hematopoietic stem cell transplantation (HSCT) was performed and four of them had a second relapse. Two patients still alive had T-LBL, experienced relapses 15 and 69 months after diagnosis, and received HSCT. Relapse during the intensive phase and second-line treatment without HSCT were identified as risk factors for bad prognosis (P = 0.01)., Conclusions: The results of second-line treatment, including intensive chemotherapy and HSCT, show that salvage treatment is still disappointing in controlling refractory forms. Early identification of patients at high risk of relapse is mandatory, allowing earlier intensification. Valid prognostic parameters, such as biological markers, are needed. International cooperation is warranted to collect more data on these rare diagnoses., (© 2016 Wiley Periodicals, Inc.)
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- 2016
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177. Improvement of overall survival after allogeneic hematopoietic stem cell transplantation for children and adolescents: a three-decade experience of a single institution.
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Brissot E, Rialland F, Cahu X, Strullu M, Corradini N, Thomas C, Blin N, Rialland X, Thebaud E, Chevallier P, Moreau P, Milpied N, Harousseau JL, Mechinaud F, and Mohty M
- Subjects
- Adolescent, Adult, Allografts, Child, Child, Preschool, Disease-Free Survival, Follow-Up Studies, Humans, Infant, Retrospective Studies, Survival Rate, Hematologic Neoplasms mortality, Hematologic Neoplasms therapy, Hematopoietic Stem Cell Transplantation
- Abstract
Allogeneic stem cell transplantation (allo-SCT) has become an essential component of the treatment for a variety of diseases in pediatric patients. During the past decades, advances in the transplant technology, availability of hematopoietic stem cells and supportive care not only have resulted in improved outcomes, but also have expanded the transplant options. However, these features have been studied mainly in adult populations. This investigation analyzed changes in patient profile, transplantation, graft characteristics and outcome among 250 children and adolescent patients who received allo-SCT in a single center between 1983 and 2010. In the 2000-2010, compared with the 1983-1999 period, a significantly higher 5-year overall survival (64% versus 52%, P=0.03) was observed together with a significant decrease of non-relapse mortality (27% versus 9%, P=0.0002). The progression-free survival was comparable between the two periods (49% versus 57%; P=0.17). The 5-year cumulative incidence of relapse was 24% between 1983 and 1999, and 34% between 2000 and 2010 (P=0.08). Major advances in supportive care practice have been made over the past decade, resulting in a significant survival benefit for the pediatric population undergoing allo-SCT. However, post-transplant relapse remains the leading cause of failure of this therapeutic approach, and preventing relapse represents a major challenge today.
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- 2016
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178. Different outcome of T cell acute lymphoblastic leukemia with translocation t(11;14) treated in two consecutive children leukemia group EORTC trials.
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Simon P, Suciu S, Clappier E, Cave H, Sirvent N, Plat G, Thyss A, Mechinaud F, Costa VM, Ferster A, Lutz P, Mazingue F, Plantaz D, Plouvier E, Bertrand Y, Benoit Y, Dastugue N, and Rohrlich PS
- Subjects
- Adolescent, Child, Child, Preschool, Cohort Studies, Female, Humans, Male, Precursor T-Cell Lymphoblastic Leukemia-Lymphoma mortality, Prospective Studies, Retrospective Studies, Survival Rate trends, Treatment Outcome, Chromosomes, Human, Pair 11 genetics, Chromosomes, Human, Pair 14 genetics, Precursor T-Cell Lymphoblastic Leukemia-Lymphoma diagnosis, Precursor T-Cell Lymphoblastic Leukemia-Lymphoma genetics, Translocation, Genetic genetics
- Abstract
Acute lymphoblastic leukemia of T cell lineage (T-ALL) is an aggressive malignant disease which accounts for 15 % of childhood ALL. T(11;14) is the more frequent chromosomal abnormality in childhood T-ALL, but its prognostic value remained controversial. Our aim was to analyze the outcome of childhood T-ALL with t(11;14) to know if the presence of this translocation is associated with a poor prognosis. We conducted a retrospective study from a series of 20 patients with t(11;14), treated in two consecutive trials from the European Organization for Research and Treatment of Cancer Children Leukemia Group over a 19-year period from 1989 to 2008. There were no significant differences between the 2 consecutive groups of patients with t(11;14) regarding the clinical and biological features at diagnosis. Among 19 patients who reached complete remission, 9 patients relapsed. We noticed 7 deaths all relapse- or failure-related. In the 58881 study, a presence of t(11;14) was associated with a poor outcome with an event-free survival at 5 years at 22.2 % versus 65.1 % for the non-t(11;14) T-ALL (p = 0.0004). In the more recent protocol, the outcome of T-ALL with t(11;14) reached that of non-t(11;14) T-ALL with an event-free survival at 5 years at 65.5 versus 74.9 % (p = 0.93). The presence of t(11;14) appeared as a poor prognostic feature in the 58881 trial whereas this abnormality no longer affected the outcome in the 58951 study. This difference is probably explained by the more intensive chemotherapy in the latest trial.
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- 2016
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179. Novel mutations in TNFRSF7/CD27: Clinical, immunologic, and genetic characterization of human CD27 deficiency.
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Alkhairy OK, Perez-Becker R, Driessen GJ, Abolhassani H, van Montfrans J, Borte S, Choo S, Wang N, Tesselaar K, Fang M, Bienemann K, Boztug K, Daneva A, Mechinaud F, Wiesel T, Becker C, Dückers G, Siepermann K, van Zelm MC, Rezaei N, van der Burg M, Aghamohammadi A, Seidel MG, Niehues T, and Hammarström L
- Subjects
- Adolescent, Child, Preschool, Epstein-Barr Virus Infections diagnosis, Epstein-Barr Virus Infections immunology, Epstein-Barr Virus Infections pathology, Exome, Female, Flow Cytometry, Heterozygote, Hodgkin Disease diagnosis, Hodgkin Disease immunology, Hodgkin Disease pathology, Homozygote, Humans, Immunophenotyping, Infant, Lymphohistiocytosis, Hemophagocytic diagnosis, Lymphohistiocytosis, Hemophagocytic immunology, Lymphohistiocytosis, Hemophagocytic pathology, Lymphoproliferative Disorders diagnosis, Lymphoproliferative Disorders immunology, Lymphoproliferative Disorders pathology, Male, Tumor Necrosis Factor Receptor Superfamily, Member 7 deficiency, Tumor Necrosis Factor Receptor Superfamily, Member 7 immunology, Uveitis diagnosis, Uveitis immunology, Uveitis pathology, Young Adult, Epstein-Barr Virus Infections genetics, Hodgkin Disease genetics, Lymphohistiocytosis, Hemophagocytic genetics, Lymphoproliferative Disorders genetics, Mutation, Tumor Necrosis Factor Receptor Superfamily, Member 7 genetics, Uveitis genetics
- Abstract
Background: The clinical and immunologic features of CD27 deficiency remain obscure because only a few patients have been identified to date., Objective: We sought to identify novel mutations in TNFRSF7/CD27 and to provide an overview of clinical, immunologic, and laboratory phenotypes in patients with CD27 deficiency., Methods: Review of the medical records and molecular, genetic, and flow cytometric analyses of the patients and family members were performed. Treatment outcomes of previously described patients were followed up., Results: In addition to the previously reported homozygous mutations c.G24A/p.W8X (n = 2) and c.G158A/p.C53Y (n = 8), 4 novel mutations were identified: homozygous missense c.G287A/p.C96Y (n = 4), homozygous missense c.C232T/p.R78W (n = 1), heterozygous nonsense c.C30A/p.C10X (n = 1), and compound heterozygous c.C319T/p.R107C-c.G24A/p.W8X (n = 1). EBV-associated lymphoproliferative disease/hemophagocytic lymphohistiocytosis, Hodgkin lymphoma, uveitis, and recurrent infections were the predominant clinical features. Expression of cell-surface and soluble CD27 was significantly reduced in patients and heterozygous family members. Immunoglobulin substitution therapy was administered in 5 of the newly diagnosed cases., Conclusion: CD27 deficiency is potentially fatal and should be excluded in all cases of severe EBV infections to minimize diagnostic delay. Flow cytometric immunophenotyping offers a reliable initial test for CD27 deficiency. Determining the precise role of CD27 in immunity against EBV might provide a framework for new therapeutic concepts., (Copyright © 2015 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.)
- Published
- 2015
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180. Paediatric leukaemia DNA methylation profiling using MBD enrichment and SOLiD sequencing on archival bone marrow smears.
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Wong NC, Meredith GD, Marnellos G, Dudas M, Parkinson-Bates M, Halemba MS, Chatterton Z, Maksimovic J, Ashley DM, Mechinaud F, Craig JM, and Saffery R
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- Bone Marrow, Cell Line, Tumor, Child, Databases, Genetic, Humans, Sequence Analysis, DNA methods, DNA Methylation, Leukemia genetics
- Abstract
Background: Acute Lymphoblastic Leukaemia (ALL) is the most common cancer in children. Over the past four decades, research has advanced the treatment of this cancer from a less than 60% chance of survival to over 85% today. The causal molecular mechanisms remain unclear. Here, we performed sequencing-based genomic DNA methylation profiling of eight paediatric ALL patients using archived bone marrow smear microscope slides., Findings: SOLiD™ sequencing data was collected from Methyl-Binding Domain (MBD) enriched fractions of genomic DNA. The primary tumour and remission bone marrow sample was analysed from eight patients. Four patients relapsed and the relapsed tumour was analysed. Input and MBD-enriched DNA from each sample was sequenced, aligned to the hg19 reference genome and analysed for enrichment peaks using MACS (Model-based Analysis for ChIP-Seq) and HOMER (Hypergeometric Optimization of Motif EnRichment). In total, 3.67 gigabases (Gb) were sequenced, 2.74 Gb were aligned to the reference genome (average 74.66% alignment efficiency). This dataset enables the interrogation of differential DNA methylation associated with paediatric ALL. Preliminary results reveal concordant regions of enrichment indicative of a DNA methylation signature., Conclusion: Our dataset represents one of the first SOLiD™MBD-Seq studies performed on paediatric ALL and is the first to utilise archival bone marrow smears. Differential DNA methylation between cancer and equivalent disease-free tissue can be identified and correlated with existing and published genomic studies. Given the rarity of paediatric haematopoietic malignancies, relative to adult counterparts, our demonstration of the utility of archived bone marrow smear samples to high-throughput methylation sequencing approaches offers tremendous potential to explore the role of DNA methylation in the aetiology of cancer.
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- 2015
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181. Impact of early molecular response in children with chronic myeloid leukemia treated in the French Glivec phase 4 study.
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Millot F, Guilhot J, Baruchel A, Petit A, Bertrand Y, Mazingue F, Lutz P, Vérité C, Berthou C, Galambrun C, Sirvent N, Yakouben K, Schmitt C, Gandemer V, Reguerre Y, Couillault G, Mechinaud F, and Cayuela JM
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- Adolescent, Benzamides therapeutic use, Child, Child, Preschool, Cytogenetic Analysis, Disease-Free Survival, France, Fusion Proteins, bcr-abl genetics, Humans, Imatinib Mesylate, Infant, Piperazines therapeutic use, Pyrimidines therapeutic use, Leukemia, Myelogenous, Chronic, BCR-ABL Positive drug therapy, Leukemia, Myelogenous, Chronic, BCR-ABL Positive genetics
- Abstract
Studies in adults have shown that an early molecular response to imatinib predicts clinical outcome in chronic myeloid leukemia (CML). We investigated the impact of the BCR-ABL1 transcript level measured 3 months after starting imatinib in a cohort of 40 children with CML. Children with a BCR-ABL1/ABL ratio higher than 10% at 3 months after the start of imatinib had a larger spleen size and a higher white blood cell count compared with those with BCR-ABL1/ABL ≤10%. Children with BCR-ABL1/ABL ≤10% 3 months after starting imatinib had higher rates of complete cytogenetic response and major molecular response at 12 months compared with those with BCR-ABL1/ABL >10%. With a median follow-up of 71 months (range, 22-96 months), BCR-ABL1/ABL ≤10% correlated with better progression-free survival. Thus, early molecular response at 3 months predicts outcome in children treated with imatinib for CML. This trial was registered at www.clinicaltrials.gov as #NCT00845221., (© 2014 by The American Society of Hematology.)
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- 2014
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182. Continuous reduced nonrelapse mortality after allogeneic hematopoietic stem cell transplantation: a single-institution's three decade experience.
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Malard F, Chevallier P, Guillaume T, Delaunay J, Rialland F, Harousseau JL, Moreau P, Mechinaud F, Milpied N, and Mohty M
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- Adolescent, Adult, Aged, Female, Hematopoietic Stem Cell Transplantation mortality, Humans, Male, Middle Aged, Retrospective Studies, Survival Analysis, Transplantation Conditioning mortality, Transplantation, Homologous mortality, Young Adult, Hematopoietic Stem Cell Transplantation adverse effects, Transplantation Conditioning adverse effects, Transplantation, Homologous adverse effects
- Abstract
This study analyzed changes in patients, transplantation, graft characteristics, and outcome among 827 patients who received their first allo-SCT in a single center between 1983 and 2010. In the 2001 to 2010 decade, compared with the 1983 to 1990 and 1991 to 2000 decades, patients were significantly older and presented with higher risk diseases, reduced intensity conditioning and alternative donors were used more often, and stem cell sources changed from bone marrow to peripheral blood stem cells and cord blood. In the 2001 to 2010 decade, we observed a significant decrease in nonrelapse mortality (NRM) (P = .0007 and P < .0001, respectively) and an increase in relapse incidence (P = .04 and P = .009, respectively), but overall survival (OS) was increased (P = .11 and P = .009, respectively), and there was a trend towards an increased progression-free survival (P = .30 and P = .09, respectively), as compared with the 1983 to 1990 and 1991 to 2000 decades. Chronic graft-versus-host disease (GVHD) was significantly increased, whereas grades III to IV acute GVHD remained stable. These data suggest that, despite the fact that older and higher risk patients with more comorbidities underwent transplantation in the last 10 years, NRM decreased while the incidence of relapse increased and the OS improved., (Copyright © 2014 American Society for Blood and Marrow Transplantation. Published by Elsevier Inc. All rights reserved.)
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- 2014
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183. Validation of DNA methylation biomarkers for diagnosis of acute lymphoblastic leukemia.
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Chatterton Z, Burke D, Emslie KR, Craig JM, Ng J, Ashley DM, Mechinaud F, Saffery R, and Wong NC
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- Adolescent, Case-Control Studies, Child, Child, Preschool, False Negative Reactions, False Positive Reactions, Female, Forkhead Transcription Factors genetics, Gene Dosage, Genetic Markers, Homeodomain Proteins genetics, Humans, Infant, Limit of Detection, Male, Neoplasm, Residual diagnosis, Neoplasm, Residual genetics, Precursor Cell Lymphoblastic Leukemia-Lymphoma drug therapy, Precursor Cell Lymphoblastic Leukemia-Lymphoma genetics, Promoter Regions, Genetic, Reference Standards, Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization, DNA Methylation, Precursor Cell Lymphoblastic Leukemia-Lymphoma diagnosis
- Abstract
Background: DNA methylation biomarkers capable of diagnosis and subtyping have been found for many cancers. Fifteen such markers have previously been identified for pediatric acute lymphoblastic leukemia (ALL). Validation of these markers is necessary to assess their clinical utility for molecular diagnostics. Substantial efficiencies could be achieved with these DNA methylation markers for disease tracking with potential to replace patient-specific genetic testing., Methods: We evaluated DNA methylation of promoter regions of TLX3 (T-cell leukemia homeobox) and FOXE3 (forkhead box E3) in bone marrow biopsies from 197 patients classified as leukemic (n = 95) or clear of the disease (n = 102) by MALDI-TOF. Using a single nucleotide extension assay (methylSABER), we tested 10 bone marrow biopsies collected throughout the course of patient chemotherapy. Using reference materials, diagnostic thresholds and limits of detection were characterized for both methods., Results: Reliable detection of DNA methylation of TLX3 and FOXE3 segregated ALL from those clear of disease with minimal false-negative and false-positive results. The limit of detection with MALDI-TOF was 1000-5000 copies of methylated allele. For methylSABER, the limit of detection was 10 copies of methylated TLX3, which enabled monitoring of minimal residual disease in ALL patients., Conclusions: Mass spectrometry procedures can be used to regionally multiplex and detect rare DNA methylation events, establish DNA methylation loci as clinically applicable biomarkers for disease diagnosis, and track pediatric ALL., (© 2014 The American Association for Clinical Chemistry.)
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- 2014
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184. Hypermethylation and down-regulation of DLEU2 in paediatric acute myeloid leukaemia independent of embedded tumour suppressor miR-15a/16-1.
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Morenos L, Chatterton Z, Ng JL, Halemba MS, Parkinson-Bates M, Mechinaud F, Elwood N, Saffery R, and Wong NC
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- Adolescent, Antineoplastic Agents therapeutic use, Cell Line, Tumor, Child, Child, Preschool, Chromosome Aberrations, Chromosomes, Human, Pair 11, Chromosomes, Human, Pair 8, DNA Methylation, Epigenesis, Genetic, Female, Genetic Loci, Humans, Infant, Leukemia, Myeloid, Acute drug therapy, Leukemia, Myeloid, Acute genetics, Leukemia, Myeloid, Acute pathology, Male, MicroRNAs genetics, RNA, Long Noncoding, Remission Induction, Signal Transduction, Transferases, Tumor Suppressor Proteins genetics, Gene Expression Regulation, Leukemic, Leukemia, Myeloid, Acute metabolism, MicroRNAs metabolism, Protein Processing, Post-Translational, Tumor Suppressor Proteins metabolism
- Abstract
Background: Acute Myeloid Leukaemia (AML) is a highly heterogeneous disease. Studies in adult AML have identified epigenetic changes, specifically DNA methylation, associated with leukaemia subtype, age of onset and patient survival which highlights this heterogeneity. However, only limited DNA methylation studies have elucidated any associations in paediatric AML., Methods: We interrogated DNA methylation on a cohort of paediatric AML FAB subtype M5 patients using the Illumina HumanMethylation450 (HM450) BeadChip, identifying a number of target genes with p <0.01 and Δβ >0.4 between leukaemic and matched remission (n = 20 primary leukaemic, n = 13 matched remission). Amongst those genes identified, we interrogate DLEU2 methylation using locus-specific SEQUENOM MassARRAY® EpiTYPER® and an increased validation cohort (n = 28 primary leukaemic, n = 14 matched remission, n = 17 additional non-leukaemic and cell lines). Following methylation analysis, expression studies were undertaken utilising the same patient samples for singleplex TaqMan gene and miRNA assays and relative expression comparisons., Results: We identified differential DNA methylation at the DLEU2 locus, encompassing the tumour suppressor microRNA miR-15a/16-1 cluster. A number of HM450 probes spanning the DLEU2/Alt1 Transcriptional Start Site showed increased levels of methylation in leukaemia (average over all probes >60%) compared to disease-free haematopoietic cells and patient remission samples (<24%) (p < 0.001). Interestingly, DLEU2 mRNA down-regulation in leukaemic patients (p < 0.05) was independent of the embedded mature miR-15a/16-1 expression. To assess prognostic significance of DLEU2 DNA methylation, we stratified paediatric AML patients by their methylation status. A subset of patients recorded methylation values for DLEU2 akin to non-leukaemic specimens, specifically patients with sole trisomy 8 and/or chromosome 11 abnormalities. These patients also showed similar miR-15a/16-1 expression to non-leukaemic samples, and potential improved disease prognosis., Conclusions: The DLEU2 locus and embedded miRNA cluster miR-15a/16-1 is commonly deleted in adult cancers and shown to induce leukaemogenesis, however in paediatric AML we found the region to be transcriptionally repressed. In combination, our data highlights the utility of interrogating DNA methylation and microRNA in combination with underlying genetic status to provide novel insights into AML biology.
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- 2014
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185. T-cell therapy using a bank of EBV-specific cytotoxic T cells: lessons from a phase I/II feasibility and safety study.
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Gallot G, Vollant S, Saïagh S, Clémenceau B, Vivien R, Cerato E, Bignon JD, Ferrand C, Jaccard A, Vigouroux S, Choquet S, Dalle JH, Frachon I, Bruno B, Mothy M, Mechinaud F, Leblond V, Milpied N, and Vié H
- Subjects
- Adolescent, Adult, Aged, Cell Line, Child, Epstein-Barr Virus Infections immunology, Epstein-Barr Virus Infections virology, Feasibility Studies, Female, Humans, Lymphoma immunology, Lymphoma virology, Male, Middle Aged, Viral Load, Young Adult, Epstein-Barr Virus Infections therapy, Herpesvirus 4, Human immunology, Immunotherapy, Adoptive, Lymphoma therapy, T-Lymphocytes, Cytotoxic immunology
- Abstract
We report herein the results we obtained and the limitations we experienced during the production and use of a bank of Epstein-Barr virus (EBV)-transformed human cytotoxic T lymphocytes (EBV-CTLs). To assess the feasibility and toxicity of this strategy, we selected and stored, in liquid nitrogen, 4 billion EBV-CTLs from each of the 13 selected donors. Subsequently, in a multicenter phase I/II study, 11 patients with EBV-associated lymphoma resistant to conventional treatments received 1-3 doses of 5 million EBV-CTLs/kg with 1-3 and 0-4 compatibilities for human leukocyte antigen (HLA)-I and HLA-II, respectively. Except for one event of fever after injection, no immediate or delayed toxicity, no graft versus host disease, and no graft rejection attributable to CTL infusion were observed. Three patients presented complete remission and 1 partial remission after treatment. Considering the clinical options currently available, and the constrains associated with CTL preparation and implementation, we conclude that CTL banks should consist of a reasonably small number of cell lines with documented specificities. This objective could be more easily achieved if the few homozygous donors for the most frequent HLA alleles of the targeted population could be made available for such a project.
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- 2014
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186. Epigenetic deregulation in pediatric acute lymphoblastic leukemia.
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Chatterton Z, Morenos L, Mechinaud F, Ashley DM, Craig JM, Sexton-Oates A, Halemba MS, Parkinson-Bates M, Ng J, Morrison D, Carroll WL, Saffery R, and Wong NC
- Subjects
- Case-Control Studies, Child, CpG Islands, DNA Methylation, Female, Humans, Male, Precursor B-Cell Lymphoblastic Leukemia-Lymphoma metabolism, Precursor B-Cell Lymphoblastic Leukemia-Lymphoma pathology, Epigenesis, Genetic, Precursor B-Cell Lymphoblastic Leukemia-Lymphoma genetics
- Abstract
Similar to most cancers, genome-wide DNA methylation profiles are commonly altered in pediatric acute lymphoblastic leukemia (ALL); however, recent observations highlight that a large portion of malignancy-associated DNA methylation alterations are not accompanied by related gene expression changes. By analyzing and integrating the methylome and transcriptome profiles of pediatric B-cell ALL cases and primary tissue controls, we report 325 genes hypermethylated and downregulated and 45 genes hypomethylated and upregulated in pediatric B-cell ALL, irrespective of subtype. Repressed cation channel subunits and cAMP signaling activators and transducers are overrepresented, potentially indicating a reduced cellular potential to receive and propagate apoptotic signals. Furthermore, we report specific DNA methylation alterations with concurrent gene expression changes within individual ALL subtypes. The ETV6-RUNX1 translocation was associated with downregulation of ASNS and upregulation of the EPO-receptor, while Hyperdiploid patients (> 50 chr) displayed upregulation of B-cell lymphoma (BCL) members and repression of PTPRG and FHIT. In combination, these data indicate genetically distinct B-cell ALL subtypes contain cooperative epimutations and genome-wide epigenetic deregulation is common across all B-cell ALL subtypes.
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- 2014
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187. Progressive emergence of an oseltamivir-resistant A(H3N2) virus over two courses of oseltamivir treatment in an immunocompromised paediatric patient.
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Hurt AC, Leang SK, Tiedemann K, Butler J, Mechinaud F, Kelso A, Downie P, and Barr IG
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- Antiviral Agents pharmacology, Child, Preschool, Humans, Immunocompromised Host, Influenza A Virus, H3N2 Subtype genetics, Male, Mutation, Missense, Oseltamivir pharmacology, Selection, Genetic, Antiviral Agents therapeutic use, Drug Resistance, Viral, Influenza A Virus, H3N2 Subtype drug effects, Influenza A Virus, H3N2 Subtype isolation & purification, Influenza, Human drug therapy, Influenza, Human virology, Oseltamivir therapeutic use
- Abstract
A minor viral population of oseltamivir-resistant A(H3N2) viruses (E119V neuraminidase mutation) was selected and maintained in a continually infected immunocompromised child following initial oseltamivir treatment. A subsequent course of oseltamivir given 7 weeks later rapidly selected for the E119V variant resulting in a near-pure population of the resistant virus. The study highlights the challenges of oseltamivir treatment of immunocompromised patients that are continually shedding virus and demonstrates the ability of the E119V oseltamivir-resistant virus to be maintained for prolonged periods even in the absence of drug-selective pressure., (© 2013 John Wiley & Sons Ltd.)
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- 2013
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188. Dasatinib in children and adolescents with relapsed or refractory leukemia: results of the CA180-018 phase I dose-escalation study of the Innovative Therapies for Children with Cancer Consortium.
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Zwaan CM, Rizzari C, Mechinaud F, Lancaster DL, Lehrnbecher T, van der Velden VH, Beverloo BB, den Boer ML, Pieters R, Reinhardt D, Dworzak M, Rosenberg J, Manos G, Agrawal S, Strauss L, Baruchel A, and Kearns PR
- Subjects
- Adolescent, Antineoplastic Agents pharmacokinetics, Benzamides administration & dosage, Benzamides adverse effects, Child, Child, Preschool, Dasatinib, Diarrhea chemically induced, Dose-Response Relationship, Drug, Drug Administration Schedule, Female, Headache chemically induced, Humans, Imatinib Mesylate, Infant, Kaplan-Meier Estimate, Leukemia, Myelogenous, Chronic, BCR-ABL Positive metabolism, Leukemia, Myelogenous, Chronic, BCR-ABL Positive pathology, Leukemia, Myeloid, Acute metabolism, Leukemia, Myeloid, Acute pathology, Male, Nausea chemically induced, Piperazines administration & dosage, Piperazines adverse effects, Precursor Cell Lymphoblastic Leukemia-Lymphoma metabolism, Precursor Cell Lymphoblastic Leukemia-Lymphoma pathology, Protein Kinase Inhibitors administration & dosage, Protein Kinase Inhibitors adverse effects, Protein-Tyrosine Kinases antagonists & inhibitors, Pyrimidines pharmacokinetics, Sample Size, Therapies, Investigational, Thiazoles pharmacokinetics, Treatment Outcome, Vomiting chemically induced, Young Adult, Antineoplastic Agents administration & dosage, Antineoplastic Agents adverse effects, Leukemia, Myelogenous, Chronic, BCR-ABL Positive drug therapy, Leukemia, Myeloid, Acute drug therapy, Precursor Cell Lymphoblastic Leukemia-Lymphoma drug therapy, Pyrimidines administration & dosage, Pyrimidines adverse effects, Thiazoles administration & dosage, Thiazoles adverse effects
- Abstract
Purpose: Dasatinib is a potent BCR-ABL inhibitor with proven efficacy in adults with newly diagnosed chronic myeloid leukemia (CML) in chronic phase (CP) and in imatinib-resistant/intolerant disease. This phase I study of the Innovative Therapies for Children with Cancer Consortium assessed dasatinib safety and efficacy in pediatric patients., Patients and Methods: Escalating once-daily dasatinib doses (60 to 120 mg/m(2)) were administered to children (n = 58) with (i) imatinib-pretreated CML or Philadelphia chromosome (Ph)-positive acute lymhoblastic leukemia (ALL) and (ii) treatment-refractory Ph-negative ALL or acute myeloid leukemia (AML)., Results: Dasatinib safety and efficacy profiles compared favorably with those in adults. The most common drug-related nonhematologic adverse events were nausea (31%, all grades; 2%, grade 3 to 4), headache (22%, 3%), diarrhea (21%, 0%), and vomiting (17%, 2%). Of 17 patients with CML-CP, 14 (82%) achieved complete cytogenetic response (CCyR) and eight (47%) achieved major molecular response. After ≥ 24 months of follow-up, median complete hematologic response (CHR) and major cytogenetic response (MCyR) durations were not reached. Of 17 patients with advanced-phase CML or Ph-positive ALL, six (35%) achieved confirmed CHR and 11 (65%) achieved CCyR. Median MCyR duration was 4.6 months (95% CI, 2.1 to 17.4 months). No patient with Ph-negative ALL or AML responded. Dasatinib pediatric pharmacokinetic parameters were comparable with those in adult studies, showing rapid absorption (time to reach maximum concentration, 0.5 to 6.0 hours) and elimination (mean half-life, 3.0 to 4.4 hours)., Conclusion: Dasatinib 60 mg/m(2) and 80 mg/m(2) once-daily dosing were selected for phase II studies in children with Ph-positive leukemias.
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- 2013
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189. Antibiotic-resistant Gram-negative bacteremia in pediatric oncology patients--risk factors and outcomes.
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Haeusler GM, Mechinaud F, Daley AJ, Starr M, Shann F, Connell TG, Bryant PA, Donath S, and Curtis N
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- Adolescent, Anti-Bacterial Agents pharmacology, Anti-Bacterial Agents therapeutic use, Bacteremia drug therapy, Bacteremia microbiology, Bacteremia mortality, Child, Child, Preschool, Female, Gram-Negative Bacteria isolation & purification, Gram-Negative Bacterial Infections drug therapy, Gram-Negative Bacterial Infections microbiology, Gram-Negative Bacterial Infections mortality, Humans, Immunocompromised Host, Infant, Infant, Newborn, Male, Prevalence, Risk Factors, Survival Analysis, Treatment Outcome, Young Adult, Bacteremia epidemiology, Drug Resistance, Bacterial, Gram-Negative Bacteria drug effects, Gram-Negative Bacterial Infections epidemiology, Neoplasms complications
- Abstract
Background: Infection with antibiotic-resistant (AR) Gram-negative (GN) bacteria is associated with increased morbidity and mortality. The aim of this study was to determine risk factors and outcomes associated with GN bacteremia with acquired resistance to antibiotics used in the empiric treatment of febrile neutropenia in pediatric oncology patients at our institution., Methods: All episodes of GN bacteremia in oncology patients at the Royal Children's Hospital Melbourne, from 2003 to 2010 were retrospectively reviewed. Information regarding age, diagnosis, phase of treatment, inpatient status, previous AR GN infection, treatment with inotropes or ventilatory support, admission to intensive care unit, and hospital and intensive care unit length of stay were obtained from electronic records., Results: A total of 280 episodes of GN bacteremia in 210 patients were identified. Of these, 42 episodes in 35 patients were caused by an AR GN organism. Factors independently associated with AR GN bacteremia were high-intensity chemotherapy (odds ratio 3.7, 95% confidence interval: 1.2-11.4), hospital-acquired bacteremia (odds ratio 4.3, 95% confidence interval: 2.0-9.6) and isolation of AR GN bacteria from any site within the preceding 12 months (odds ratio 9.9, 95% confidence interval: 3.8-25.5). Episodes of AR GN bacteremia were associated with longer median hospital length of stay (23.5 days versus 14.0 days; P = 0.0007), longer median intensive care unit length of stay (3.8 days versus 1.6 days; P = 0.02) and a higher rate of invasive ventilation (15% versus 5.2%; P = 0.03). No significant difference in infection-related or all-cause mortality between the 2 groups was identified., Conclusions: In pediatric oncology patients, AR GN bacteremia is associated with an increased rate of adverse outcomes and is more likely in patients who have received high-intensity chemotherapy, have been in hospital beyond 48 hours and who have had previous AR GN infection or colonization.
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- 2013
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190. Evaluation of microRNA expression in patient bone marrow aspirate slides.
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Morenos L, Saffery R, Mechinaud F, Ashley D, Elwood N, Craig JM, and Wong NC
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- Humans, Leukemia genetics, MicroRNAs metabolism, Real-Time Polymerase Chain Reaction, Tissue Preservation methods, Transcriptome, Bone Marrow metabolism, Leukemia diagnosis, MicroRNAs isolation & purification
- Abstract
Like formalin fixed paraffin embedded (FFPE) tissues, archived bone marrow aspirate slides are an abundant and untapped resource of biospecimens that could enable retrospective molecular studies of disease. Historically, RNA obtained from slides is limited in utility because of their low quality and highly fragmented nature. MicroRNAs are small (≈ 22 nt) non-coding RNA that regulate gene expression, and are speculated to preserve well in FFPE tissue. Here we investigate the use of archived bone marrow aspirate slides for miRNA expression analysis in paediatric leukaemia. After determining the optimal method of miRNA extraction, we used TaqMan qRT-PCR to identify reference miRNA for normalisation of other miRNA species. We found hsa-miR-16 and hsa-miR-26b to be the most stably expressed between lymphoblastoid cell lines, primary bone marrow aspirates and archived samples. We found the average fold change in expression of hsa-miR-26b and two miRNA reportedly dysregulated in leukaemia (hsa-miR-128a, hsa-miR-223) was <0.5 between matching archived slide and bone marrow aspirates. Differential expression of hsa-miR-128a and hsa-miR-223 was observed between leukaemic and non-leukaemic bone marrow from archived slides or flash frozen bone marrow. The demonstration that archived bone marrow aspirate slides can be utilized for miRNA expression studies offers tremendous potential for future investigations into the role miRNA play in the development and long term outcome of hematologic, as well as non-hematologic, diseases.
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- 2012
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191. Second neoplasm in children treated in EORTC 58881 trial for acute lymphoblastic malignancies: low incidence of CNS tumours.
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Renard M, Suciu S, Bertrand Y, Uyttebroeck A, Ferster A, van der Werff Ten Bosch J, Mazingue F, Plouvier E, Robert A, Boutard P, Millot F, Munzer M, Mechinaud F, Lescoeur B, Baila L, Vandecruys E, Benoit Y, and Philippet P
- Subjects
- Adolescent, Antineoplastic Combined Chemotherapy Protocols administration & dosage, Antineoplastic Combined Chemotherapy Protocols adverse effects, Asparaginase administration & dosage, Asparaginase adverse effects, Central Nervous System Neoplasms therapy, Child, Child, Preschool, Clinical Trials as Topic, Daunorubicin administration & dosage, Daunorubicin adverse effects, Disease-Free Survival, Female, Follow-Up Studies, Humans, Incidence, Infant, Male, Neoplasms, Second Primary therapy, Precursor Cell Lymphoblastic Leukemia-Lymphoma therapy, Prednisone administration & dosage, Prednisone adverse effects, Remission Induction, Retrospective Studies, Survival Rate, Vincristine administration & dosage, Vincristine adverse effects, Central Nervous System Neoplasms mortality, Neoplasms, Second Primary mortality, Precursor Cell Lymphoblastic Leukemia-Lymphoma mortality
- Abstract
Background: Intensive chemotherapy has markedly improved the survival of children with acute lymphoblastic leukaemia (ALL) or lymphoblastic lymphoma (LL). Evaluation of late effects and analysis of factors contributing to their occurrence has become of major importance. Second neoplasm (SN) belongs to the most severe late events., Procedure: We report the incidence of SN which occurred in patients recruited in EORTC trial 58881 for children with ALL or LL. The front-line treatment regimen was adapted from the BFM protocol, but did not include cranial radiotherapy, even in patients with initial involvement of the central nervous system. A total of 2,216 patients were recruited, of whom 2,136 achieved complete remission (CR)., Results: At a median follow-up of 7.5 years, 22 (1%) patients developed a SN: 20 during or after completion of front-line therapy and 2 in second CR, after relapse treatment including haematopoietic stem cell transplantation (HSCT). Ten patients developed acute myeloblastic leukaemia. Only one SN, a glioblastoma, was a brain tumour. Other SN were: two Hodgkin lymphomas, one non-Hodgkin lymphoma, two thyroid cancers, one osteosarcoma, two soft tissue sarcomas, one Ewing sarcoma, one cutaneous histiocytosis and one peritoneal carcinomatosis. The cumulative incidences of SN at 5, 8 and 13 years after registration were 0.8% (SE 0.2%), 1.0% (SE 0.2%) and 3.0% (SE 1.9%), respectively., Conclusion: The overall incidence rate of SN is comparable to that reported previously. In spite of short follow-up time, the low incidence of brain tumours might be related to the omission of cranial radiotherapy., (Copyright © 2011 Wiley-Liss, Inc.)
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- 2011
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192. Road traffic and childhood leukemia: the ESCALE study (SFCE).
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Amigou A, Sermage-Faure C, Orsi L, Leverger G, Baruchel A, Bertrand Y, Nelken B, Robert A, Michel G, Margueritte G, Perel Y, Mechinaud F, Bordigoni P, Hémon D, and Clavel J
- Subjects
- Air Pollutants toxicity, Child, Child, Preschool, Humans, Infant, Inhalation Exposure statistics & numerical data, Nitrogen Dioxide analysis, Nitrogen Dioxide toxicity, Risk Assessment, Vehicle Emissions toxicity, Air Pollutants analysis, Air Pollution statistics & numerical data, Automobiles statistics & numerical data, Leukemia epidemiology, Registries statistics & numerical data, Vehicle Emissions analysis
- Abstract
Background: Traffic is a source of environmental exposures, including benzene, which may be related to childhood leukemia., Objectives: A national registry-based case-control study [ESCALE (Etude Sur les Cancers et les Leucémies de l'Enfant, Study on Environmental and Genetic Risk Factors of Childhood Cancers and Leukemia)] carried out in France was used to assess the effect of exposure to road traffic exhaust fumes on the risk of childhood leukemia., Methods: Over the study period, 2003-2004, 763 cases and 1,681 controls < 15 years old were included, and the controls were frequency matched with the cases on age and sex. The ESCALE data were collected by a standardized telephone interview of the mothers. Various indicators of exposure to traffic and pollution were determined using the geocoded addresses at the time of diagnosis for the cases and of interview for the controls. Indicators of the distance from, and density of, main roads and traffic nitrogen dioxide (NO(2)) concentrations derived from traffic emission data were used. Odds ratios (ORs) were estimated using unconditional regression models adjusted for potential confounders., Results: Acute leukemia (AL) was significantly associated with estimates of traffic NO(2) concentration at the place of residence > 27.7 µg/m(3) compared with NO(2) concentration < 21.9 µg/m(3) [OR=1.2; confidence interval (CI), 1.0-1.5] and with the presence of a heavy-traffic road within 500 m compared with the absence of a heavy-traffic road in the same area (OR=2.0; 95% CI, 1.0-3.6). There was a significant association between AL and a high density of heavy-traffic roads within 500 m compared with the reference category with no heavy-traffic road within 500 m (OR=2.2; 95% CI, 1.1-4.2), with a significant positive linear trend of the association of AL with the total length of heavy-traffic road within 500 m., Conclusion: This study supports the hypothesis that living close to heavy-traffic roads may increase the risk of childhood leukemia.
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- 2011
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193. l-asparaginase loaded red blood cells in refractory or relapsing acute lymphoblastic leukaemia in children and adults: results of the GRASPALL 2005-01 randomized trial.
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Domenech C, Thomas X, Chabaud S, Baruchel A, Gueyffier F, Mazingue F, Auvrignon A, Corm S, Dombret H, Chevallier P, Galambrun C, Huguet F, Legrand F, Mechinaud F, Vey N, Philip I, Liens D, Godfrin Y, Rigal D, and Bertrand Y
- Subjects
- Adolescent, Adult, Antineoplastic Agents adverse effects, Antineoplastic Agents blood, Antineoplastic Agents therapeutic use, Asparaginase adverse effects, Asparaginase blood, Asparaginase therapeutic use, Bioreactors, Child, Child, Preschool, Dose-Response Relationship, Drug, Drug Administration Schedule, Drug Delivery Systems, Humans, Infant, Male, Middle Aged, Precursor Cell Lymphoblastic Leukemia-Lymphoma blood, Young Adult, Antineoplastic Agents administration & dosage, Asparaginase administration & dosage, Drug Carriers, Erythrocytes enzymology, Precursor Cell Lymphoblastic Leukemia-Lymphoma drug therapy
- Abstract
l-asparaginase encapsulated within erythrocytes (GRASPA(®) ) should allow serum asparagine depletion over a longer period than the native form of the enzyme, using lower doses and allowing better tolerance. The GRASPALL 2005-01 study, a multicentre randomized controlled trial, investigated three doses of GRASPA(®) for the duration of asparagine depletion in a phase I/II study in adults and children with acute lymphoblastic leukaemia (ALL) in first relapse. Between February 2006 and April 2008, 18 patients received GRASPA(®) (50 iu/kg: n = 6,100 iu/kg: n = 6, 150 iu/kg: n = 6) after randomization, and six patients were assigned to the Escherichia coli native l-asparaginase (E. colil-ASNase) control group. GRASPA(®) was effective at depleting l-asparagine. One single injection of 150 iu/kg of GRASPA(®) provided similar results to 8 × 10,000 iu/m(2) intravenous injections of E. colil-ASNase. The safety profile of GRASPA(®) showed a reduction in the number and severity of allergic reactions and a trend towards less coagulation disorders. Other expected adverse events were comparable to those observed with E. colil-ASNase and there was also no difference between the three doses of GRASPA(®) ., (© 2011 Blackwell Publishing Ltd.)
- Published
- 2011
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194. Childhood Langerhans cell histiocytosis associated with T cell acute lymphoblastic leukemia.
- Author
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Aubert-Wastiaux H, Barbarot S, Mechinaud F, Bossard C, and Stalder JF
- Subjects
- Adjuvants, Immunologic administration & dosage, Adjuvants, Immunologic therapeutic use, Administration, Topical, Aminoquinolines administration & dosage, Aminoquinolines therapeutic use, Child, Preschool, Comorbidity, Fatal Outcome, Histiocytosis, Langerhans-Cell metabolism, Humans, Imiquimod, Immunohistochemistry, Male, Histiocytosis, Langerhans-Cell epidemiology, Precursor T-Cell Lymphoblastic Leukemia-Lymphoma epidemiology
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- 2011
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195. Germline mutations of the CBL gene define a new genetic syndrome with predisposition to juvenile myelomonocytic leukaemia.
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Pérez B, Mechinaud F, Galambrun C, Ben Romdhane N, Isidor B, Philip N, Derain-Court J, Cassinat B, Lachenaud J, Kaltenbach S, Salmon A, Désirée C, Pereira S, Menot ML, Royer N, Fenneteau O, Baruchel A, Chomienne C, Verloes A, and Cavé H
- Subjects
- Child, Child, Preschool, Developmental Disabilities complications, Developmental Disabilities genetics, Female, Genetic Predisposition to Disease, Humans, Leukemia, Myelomonocytic, Juvenile complications, Male, Syndrome, Germ-Line Mutation, Growth Disorders complications, Growth Disorders genetics, Leukemia, Myelomonocytic, Juvenile genetics, Microcephaly complications, Microcephaly genetics, Proto-Oncogene Proteins c-cbl genetics
- Abstract
Background: CBL missense mutations have recently been associated with juvenile myelomonocytic leukaemia (JMML), an aggressive myeloproliferative and myelodysplastic neoplasm of early childhood characterised by excessive macrophage/monocyte proliferation. CBL, an E3 ubiquitin ligase and a multi-adaptor protein, controls proliferative signalling networks by downregulating the growth factor receptor signalling cascades in various cell types., Methods and Results: CBL mutations were screened in 65 patients with JMML. A homozygous mutation of CBL was found in leukaemic cells of 4/65 (6%) patients. In all cases, copy neutral loss of heterozygosity of the 11q23 chromosomal region, encompassing the CBL locus, was demonstrated. Three of these four patients displayed additional features suggestive of an underlying developmental condition. A heterozygous germline CBL p.Y371H substitution was found in each of them and was inherited from the father in one patient. The germline mutation represents the first hit, with somatic loss of heterozygosity being the second hit positively selected in JMML cells. The three patients display a variable combination of dysmorphic features, hyperpigmented skin lesions and microcephaly that enable a 'CBL syndrome' to be tentatively delineated. Learning difficulties and postnatal growth retardation may be part of the phenotype., Conclusion: A report of germline mutations of CBL in three patients with JMML is presented here, confirming the existence of an unreported inheritable condition associated with a predisposition to JMML.
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- 2010
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196. Acute childhood leukaemia and residence next to petrol stations and automotive repair garages: the ESCALE study (SFCE).
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Brosselin P, Rudant J, Orsi L, Leverger G, Baruchel A, Bertrand Y, Nelken B, Robert A, Michel G, Margueritte G, Perel Y, Mechinaud F, Bordigoni P, Hémon D, and Clavel J
- Subjects
- Acute Disease, Adolescent, Age Distribution, Air Pollutants adverse effects, Benzene adverse effects, Carcinogens, Environmental adverse effects, Case-Control Studies, Child, Child, Preschool, Educational Status, Environmental Exposure analysis, Environmental Monitoring methods, Epidemiological Monitoring, Female, France epidemiology, Humans, Infant, Infant, Newborn, Leukemia etiology, Male, Residence Characteristics, Sex Distribution, Social Class, Environmental Exposure adverse effects, Gasoline adverse effects, Leukemia epidemiology
- Abstract
Background: The association between acute childhood leukaemia and residing next to petrol stations and automotive repair garages was analysed in a national registry-based case-control study carried out in France in 2003-2004., Methods: Population controls were frequency matched with cases on age and gender. Data were collected by standardised telephone interview with the mothers. The latter were asked to report the proximity of their homes to petrol stations, automotive repair garages and other businesses from the conception of the index child to the diagnosis (for cases) or interview (for controls). Odds ratios were estimated using unconditional regression models adjusted for age, gender, number of children under 15 years of age in the household, degree of urbanisation and type of housing., Results: 765 cases of acute leukaemia and 1681 controls were included. Acute leukaemia was significantly associated with residence next to petrol stations or automotive repair garages (OR 1.6, 95% CI 1.2 to 2.2) and next to a petrol station (OR 1.9, 95% CI 1.2 to 3.0). The OR showed no tendency to increase with duration of exposure. The results were not modified by adjustment for potential confounding factors including urban/rural status and type of housing., Conclusions: The results support the findings of our previous study and suggest that living next to a petrol station may be associated with acute childhood leukaemia. The results also suggest that the role of low-level exposure to benzene in acute childhood leukaemia deserves further evaluation.
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- 2009
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197. Persistence of CD33 expression at relapse in CD33(+) acute myeloid leukaemia patients after receiving Gemtuzumab in the course of the disease.
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Chevallier P, Robillard N, Ayari S, Guillaume T, Delaunay J, Mechinaud F, Avet-Loiseau H, Mohty M, Harousseau JL, and Garand R
- Subjects
- Adolescent, Adult, Aged, Antibodies, Monoclonal, Humanized, Child, Preschool, Drug Therapy, Combination, Female, Follow-Up Studies, Gemtuzumab, Humans, Leukemia, Myeloid, Acute drug therapy, Male, Middle Aged, Retrospective Studies, Sialic Acid Binding Ig-like Lectin 3, Young Adult, Aminoglycosides therapeutic use, Antibodies, Monoclonal therapeutic use, Antigens, CD blood, Antigens, Differentiation, Myelomonocytic blood, Antineoplastic Agents therapeutic use, Leukemia, Myeloid, Acute immunology
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- 2008
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198. SFCE (Société Française de Lutte contre les Cancers et Leucémies de l'Enfant et de l'Adolescent) recommendations for the management of tumor lysis syndrome (TLS) with rasburicase: an observational survey.
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Bertrand Y, Mechinaud F, Brethon B, Mialou V, Auvrignon A, Nelken B, Notz-Carrère A, Plantaz D, Patte C, Urbieta M, Baruchel A, and Leverger G
- Subjects
- Adolescent, Child, Child, Preschool, Data Collection, Dose-Response Relationship, Drug, Female, Humans, Infant, Male, Recombinant Proteins therapeutic use, Risk Assessment, Tumor Lysis Syndrome epidemiology, Tumor Lysis Syndrome prevention & control, Gout Suppressants therapeutic use, Hematologic Neoplasms complications, Tumor Lysis Syndrome drug therapy, Urate Oxidase therapeutic use
- Abstract
Rasburicase (Fasturtec), a recombinant urate oxidase, is highly effective in preventing and treating hyperuricemia in children with hematologic malignancies. We conducted a prospective, multicenter observational study in 174 patients at 8 pediatric hemato-oncology centers to establish whether the SFCE (Société Française de Lutte contre les Cancers et Leucémies de l'Enfant et de l'Adolescent) recommendations for the use of rasburicase in the management of pediatric patients at risk of tumor lysis syndrome (TLS) are valid in routine clinical practice. Patients were classified as being at high or low risk of TLS according to the Children's Oncology Group criteria and were treated in accordance with the SFCE recommendations. The primary end point was the number of patients requiring a higher dose of rasburicase or a longer duration of treatment than advised in the SFCE recommendations. Of the 135 patients at high risk of TLS, 27 patients received a higher dose and 35 patients received a longer duration of treatment. Some patients received treatment with rasburicase for less than the recommended duration (median 4 d for high-risk patients). One patient required hemodialysis. Only minor adjustments to the SFCE recommendations were required to ensure the optimal use of rasburicase in pediatric patients at risk of TLS.
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- 2008
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199. Treatment of childhood T-cell lymphoblastic lymphoma according to the strategy for acute lymphoblastic leukaemia, without radiotherapy: long term results of the EORTC CLG 58881 trial.
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Uyttebroeck A, Suciu S, Laureys G, Robert A, Pacquement H, Ferster A, Marguerite G, Mazingue F, Renard M, Lutz P, Rialland X, Mechinaud F, Cavé H, Baila L, and Bertrand Y
- Subjects
- Adolescent, Child, Child, Preschool, Disease-Free Survival, Female, Humans, Infant, Male, Precursor T-Cell Lymphoblastic Leukemia-Lymphoma mortality, Recurrence, Treatment Outcome, Antineoplastic Combined Chemotherapy Protocols therapeutic use, Precursor T-Cell Lymphoblastic Leukemia-Lymphoma drug therapy
- Abstract
From June 1989 through to November 1998, 121 children with newly diagnosed T-cell lymphoblastic lymphoma (T-LBL) were included in the EORTC 58881 trial conducted by the Children's Leukaemia Group. The therapy regimen was based on a Berlin-Frankfurt-Munster protocol, for a total duration of 24 months. Cranial irradiation, prophylactic cranial and local, was omitted, even for patients with central nervous involvement at diagnosis. In total, 119 patients were evaluable. The median follow-up was 6.7 years. The overall event-free survival (EFS) rate at 6 years was 77.5% (standard error (SE)=4%). Median time of relapse was 1 year after complete remission (range 0.2-5.9 years). Only two (1.8%) patients had an isolated central nervous system relapse. For patients with complete response (n=16) to the 7-day prephase, the EFS rate at 6 years was 100% versus 14% (P<0.001) for patients with no response (n=7). Overall survival rate at 6 years was 86% (SE=3%). An intensive acute lymphoblastic leukaemia type chemotherapy regimen without irradiation leads to a high cure and survival rate in childhood T-LBL without an increased CNS recurrence. This suggests that prophylactic cranial irradiation can safely be omitted. Response to the prephase appeared to be a strong prognostic factor for EFS.
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- 2008
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200. Prospective validation of a novel IV busulfan fixed dosing for paediatric patients to improve therapeutic AUC targeting without drug monitoring.
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Vassal G, Michel G, Espérou H, Gentet JC, Valteau-Couanet D, Doz F, Mechinaud F, Galambrun C, Neven B, Zouabi H, Nguyen L, and Puozzo C
- Subjects
- Adolescent, Age Factors, Antineoplastic Agents, Alkylating administration & dosage, Area Under Curve, Body Weight, Busulfan administration & dosage, Child, Child, Preschool, Cyclophosphamide therapeutic use, Dose-Response Relationship, Drug, Drug Monitoring, Female, Humans, Infant, Infusions, Intravenous, Male, Melphalan therapeutic use, Models, Biological, Prospective Studies, Stem Cell Transplantation, Antineoplastic Agents, Alkylating pharmacokinetics, Busulfan pharmacokinetics, Hematologic Diseases drug therapy, Neoplasms drug therapy
- Abstract
Introduction: Oral busulfan clearance is age-dependent and children experience a wide variability in plasma exposure. BSA- or age-based dosing is used with therapeutic drug monitoring (TDM) to reduce this variability., Purpose: A new intravenous (IV) dosing of busulfan (Bu) based on body weight, designed to improve AUC targeting without TDM and dose-adjustment, was prospectively evaluated., Method: Bu was administered as a 2 h IV infusion every 6 h over 4 days (16 administrations). Five dose levels were defined on body weight as follows: 1.0 mg/kg for <9 kg; 1.2 mg/kg for 9 to <16 kg; 1.1 mg/kg for 16-23 kg; 0.95 mg/kg for >23-34 kg; 0.80 mg/kg for >34 kg. Bu treatment was followed by Cyclophosphamide or Melphalan prior to allogeneic or autologous transplantation in 55 children aged 0.3-17.2 years (median 5.6 years)., Results: No difference in AUC values was observed between weight strata (mean +/- SD 1248 +/- 205 micromol.min), whereas a significant difference in Bu clearance was demonstrated. This new dosing enabled to achieve a mean exposure comparable to that in adults. At dose 1, 91% of patients achieved the targeted AUC range (900-1500 micromol.min) while no patients were underexposed. At doses 9 and 13, over 75% of patients remained within that target whilst most of the others were slightly above. Successful engraftment was achieved in all patients. In conclusion, from infants to adults this new dosing enabled, without TDM and dose adjustment, to successfully target a therapeutic AUC window.
- Published
- 2008
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