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French "real life" experience of clofarabine in children with refractory or relapsed acute lymphoblastic leukaemia.

ABSTRACT: BACKGROUND:Clofarabine alone or in combination with cyclophosphamide and etoposide has shown a good efficacy and a tolerable toxicity profile in previous studies of children with relapsed or refractory leukaemia. This report describes a retrospective study of 38 French patients who received clofarabine as a monotherapy or in combination for relapsed or refractory acute lymphoblastic leukaemia (ALL) outside of clinical trials after marketing authorization. METHODS:We retrospectively analysed data for 38 patients, up to 21 years old, attending 17 French centres. Thirty patients received clofarabine alone or in combination for a bone marrow relapse of acute lymphoblastic leukaemia (ALL) or refractory disease and eight patients for a high level of minimal residual disease (MRD). Survival and response durations were estimated by the Kaplan-Meier method. RESULTS:For the 30 patients who received clofarabine for a bone marrow relapse of ALL (number of relapse, 1-3; median, 1), the overall remission rate (ORR) was 37%: eight complete remission (CR) and three complete remission without platelet recovery (CRp). Ten of the 11 responding patients subsequently underwent haematopoietic stem cell transplantation (HSCT).Only four of the eight patients who received clofarabine while in remission for a high level of MRD, showed a moderate improvement of MRD. Seven of these eight patients received HSCT and six of them were alive at the end of the study. One other patient was alive without receiving HSCT.However, clofarabine treatment was associated with a high risk of infection and hepatotoxicity. Febrile neutropenia grade ? 3 was reported in 79% of patients and documented infections grade ? 3 occurred in nine patients (24%). Hepatotoxicity grade 3 was reported in nine patients (24%). We observed four deaths related to treatment. CONCLUSION:In our experience, the efficacy of clofarabine is poorer than previously reported. Its toxicity is high and can be life threatening. Prospective studies on clofarabine used during earlier phases of the disease may help to define how best this new drug can be exploited for childhood and adolescent ALL.

SUBMITTER: Trioche P

PROVIDER: S-EPMC3599405 | biostudies-literature | 2012 Dec

REPOSITORIES: biostudies-literature

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French "real life" experience of clofarabine in children with refractory or relapsed acute lymphoblastic leukaemia.

Trioche Pascale P Nelken Brigitte B Michel Gérard G Pellier Isabelle I Petit Arnaud A Bertrand Yves Y Rohrlich Pierre P Schmitt Claudine C Sirvent Nicolas N Boutard Patrick P Margueritte Geneviève G Pautard Brigitte B Ducassou Stéphane S Plantaz Dominique D Robert Alain A Thomas Caroline C Desseaux Kristell K Chevret Sylvie S Baruchel André A

Experimental hematology & oncology 20121210 1

<h4>Background</h4>Clofarabine alone or in combination with cyclophosphamide and etoposide has shown a good efficacy and a tolerable toxicity profile in previous studies of children with relapsed or refractory leukaemia. This report describes a retrospective study of 38 French patients who received clofarabine as a monotherapy or in combination for relapsed or refractory acute lymphoblastic leukaemia (ALL) outside of clinical trials after marketing authorization.<h4>Methods</h4>We retrospectivel ...[more]

PMID: 23227903

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Project description:Relapsed acute lymphoblastic leukaemia (ALL) is a leading cause of death due to disease in young people, but the biological determinants of treatment failure remain poorly understood. Recent genome-wide profiling of structural DNA alterations in ALL have identified multiple submicroscopic somatic mutations targeting key cellular pathways, and have demonstrated substantial evolution in genetic alterations from diagnosis to relapse. However, DNA sequence mutations in ALL have not been analysed in detail. To identify novel mutations in relapsed ALL, we resequenced 300 genes in matched diagnosis and relapse samples from 23 patients with ALL. This identified 52 somatic non-synonymous mutations in 32 genes, many of which were novel, including the transcriptional coactivators CREBBP and NCOR1, the transcription factors ERG, SPI1, TCF4 and TCF7L2, components of the Ras signalling pathway, histone genes, genes involved in histone modification (CREBBP and CTCF), and genes previously shown to be targets of recurring DNA copy number alteration in ALL. Analysis of an extended cohort of 71 diagnosis-relapse cases and 270 acute leukaemia cases that did not relapse found that 18.3% of relapse cases had sequence or deletion mutations of CREBBP, which encodes the transcriptional coactivator and histone acetyltransferase CREB-binding protein (CREBBP, also known as CBP). The mutations were either present at diagnosis or acquired at relapse, and resulted in truncated alleles or deleterious substitutions in conserved residues of the histone acetyltransferase domain. Functionally, the mutations impaired histone acetylation and transcriptional regulation of CREBBP targets, including glucocorticoid responsive genes. Several mutations acquired at relapse were detected in subclones at diagnosis, suggesting that the mutations may confer resistance to therapy. These results extend the landscape of genetic alterations in leukaemia, and identify mutations targeting transcriptional and epigenetic regulation as a mechanism of resistance in ALL.

Project description:BackgroundThe 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.MethodsELIANA, 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 × 106 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.FindingsBetween 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.InterpretationThese 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.FundingNovartis.

Dataset Information

French "real life" experience of clofarabine in children with refractory or relapsed acute lymphoblastic leukaemia.

Publications

French "real life" experience of clofarabine in children with refractory or relapsed acute lymphoblastic leukaemia.

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