Publications by authors named "Nathalie Grardel"

37 Publications

Oncogenetic landscape and clinical impact of IDH1 and IDH2 mutations in T-ALL.

J Hematol Oncol 2021 05 3;14(1):74. Epub 2021 May 3.

Laboratory of Onco-Hematology, Assistance Publique-Hôpitaux de Paris (AP-HP), Hôpital Necker Enfants-Malades, Université de Paris, 149 rue de Sèvres, 75015, Paris, France.

IDH1 and IDH2 mutations (IDH1/2) are recognized as recurrent genetic alterations in acute myeloid leukemia (AML) and associated with both clinical impact and therapeutic opportunity due to the recent development of specific IDH1/2 inhibitors. In T-cell acute lymphoblastic leukemia (T-ALL), their incidence and prognostic implications remain poorly reported. Our targeted next-generation sequencing approach allowed comprehensive assessment of genotype across the entire IDH1 and IDH2 locus in 1085 consecutive unselected and newly diagnosed patients with T-ALL and identified 4% of, virtually exclusive (47 of 49 patients), IDH1/2. Mutational patterns of IDH1/2 in T-ALL present some specific features compared to AML. Whereas IDH2 mutation was frequent in T-ALL (25 of 51 mutations), the IDH2 AML hotspot was absent. IDH2 mutations were associated with older age, an immature phenotype, more frequent RAS gain-of-function mutations and epigenetic regulator loss-of-function alterations (DNMT3A and TET2). IDH2 mutations, contrary to IDH1 mutations, appeared to be an independent prognostic factor in multivariate analysis with the NOTCH1/FBXW7/RAS/PTEN classifier. IDH2 were significantly associated with a high cumulative incidence of relapse and very dismal outcome, suggesting that IDH2-mutated T-ALL cases should be identified at diagnosis in order to benefit from therapeutic intensification and/or specific IDH2 inhibitors.
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http://dx.doi.org/10.1186/s13045-021-01068-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8091755PMC
May 2021

Epidemiology, clinical picture and long-term outcomes of FIP1L1-PDGFRA-positive myeloid neoplasm with eosinophilia: Data from 151 patients.

Am J Hematol 2020 11 19;95(11):1314-1323. Epub 2020 Sep 19.

Department of Hematology, INSERM U 1052, CRCL, Centre Léon Bérard, Lyon, France.

FIP1L1-PDGFRA-positive myeloid neoplasm with eosinophilia (F/P+ MN-eo) is a rare disease: robust epidemiological data are lacking and reported issues are scarce, of low sample-size and limited follow-up. Imatinib mesylate (IM) is highly efficient but no predictive factor of relapse after discontinuation has yet been identified. One hundred and fifty-one patients with F/P+ MN-eo (143 males; mean age at diagnosis 49 years; mean annual incidence: 0.18 case per million population) were included in this retrospective nationwide study involving all French laboratories who perform the search of F/P fusion gene (study period: 2003-2019). The main organs involved included the spleen (44%), skin (32%), lungs (30%), heart (19%) and central nervous system (9%). Serum vitamin B12 and tryptase levels were elevated in 74/79 (94%) and 45/57 (79%) patients, respectively, and none of the 31 patients initially treated with corticosteroids achieved complete hematologic remission. All 148 (98%) IM-treated patients achieved complete hematologic and molecular (when tested, n = 84) responses. Forty-six patients eventually discontinued IM, among whom 20 (57%) relapsed. In multivariate analysis, time to IM initiation (continuous HR: 1,01 [0.99-1,03]; P = .05) and duration of IM treatment (continuous HR: 0,97 [0,95-0,99]; P = .004) were independent factors of relapse after discontinuation of IM. After a mean follow-up of 80 (56) months, the 1, 5- and 10-year overall survival rates in IM-treated patients were 99%, 95% and 84% respectively. In F/P+ MN-eo, prompt initiation of IM and longer treatment durations may prevent relapses after discontinuation of IM.
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http://dx.doi.org/10.1002/ajh.25945DOI Listing
November 2020

An 80-Year-Old Woman With a Solitary Pulmonary Nodule.

Chest 2020 03;157(3):e85-e89

Pathology Department, Centre de Biologie Pathologie, University of Lille, CHU Lille, Lille, France.

Case Presentation: An 80-year-old-woman was referred for evaluation of chest pain that appeared after providing care at home for her sick husband, which included helping him to get up and move about. The pain was initially triggered by lifting heavy objects but then became constant, without exacerbating or relieving factors. The pain was located in the left hemithorax and was not associated with shortness of breath or cough. Because the patient did not feel any better after a month, her general practitioner ordered a radiograph, which revealed a suspicious pulmonary nodule in the left upper lobe. She was a lifelong nonsmoker and denied any drug abuse. She had not been professionally exposed to lung carcinogens. She had a medical history of type 2 diabetes, ischemic cardiomyopathy, and renal artery stenosis. Her father died of lung cancer. She resided in Lille, France, and did not report any recent travel.
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http://dx.doi.org/10.1016/j.chest.2019.10.056DOI Listing
March 2020

Clinical and biological features of PTPN2-deleted adult and pediatric T-cell acute lymphoblastic leukemia.

Blood Adv 2019 07;3(13):1981-1988

Université Paris Descartes Sorbonne Cité, Institut Necker-Enfants Malades, Institut National de Recherche Médicale U1151, Laboratory of Onco-Hematology, Assistance Publique-Hôpitaux de Paris, Hôpital Necker Enfants-Malades, Paris, France.

Protein tyrosine phosphatase nonreceptor type 2 (PTPN2) is a phosphatase known to be a tumor suppressor gene in T-cell acute lymphoblastic leukemia (T-ALL). Because the full clinicobiologic characteristics of PTPN2 loss remain poorly reported, we aimed to provide a comprehensive analysis of PTPN2 deletions within a cohort of 430 patients, including 216 adults and 214 children treated according to the GRAALL03/05 (#NCT00222027 and #NCT00327678) and the FRALLE2000 protocols, respectively. We used multiplex ligation-dependent probe amplification to identify an 8% incidence of PTPN2 deletion, which was comparable in adult (9%) and pediatric (6%) populations. PTPN2 deletions were significantly associated with an αβ lineage and TLX1 deregulation. Analysis of the mutational genotype of adult T-ALL revealed a positive correlation between PTPN2 deletions and gain-of-function alterations in the IL7R/JAK-STAT signaling pathway as well as PHF6 and WT1 mutations. Of note, PTPN2 and PTEN (phosphatase and tensin homolog) deletions were mutually exclusive. Regarding treatment response, PTPN2-deleted T-ALLs were associated with a higher glucocorticoid response and a trend for improved survival in children, but not in adults, with a 5-year cumulative incidence of relapse of 8% for PTPN2-deleted pediatric cases vs 26% ( = .177).
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http://dx.doi.org/10.1182/bloodadvances.2018028993DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6616254PMC
July 2019

Oncogenetic mutations combined with MRD improve outcome prediction in pediatric T-cell acute lymphoblastic leukemia.

Blood 2018 01 19;131(3):289-300. Epub 2017 Oct 19.

Université Paris Descartes Sorbonne Cité, Institut Necker-Enfants Malades, INSERM U1151, Paris, France.

Risk stratification in childhood T-cell acute lymphoblastic leukemia (T-ALL) is mainly based on minimal residual disease (MRD) quantification. Whether oncogenetic mutation profiles can improve the discrimination of MRD-defined risk categories was unknown. Two hundred and twenty FRALLE2000T-treated patients were tested retrospectively for and alterations. Patients with () mutations and () germ line (GL) were classified as oncogenetic low risk (gLoR; n = 111), whereas those with GL and GL mutations or and mutations were classified as high risk (gHiR; n = 109). Day 35 MRD status was available for 191 patients. Five-year cumulative incidence of relapse (CIR) and disease-free survival were 36% and 60% for gHiR patients and 11% and 89% for gLoR patients, respectively. Importantly, among the 60% of patients with MRD <10, 5-year CIR was 29% for gHiR patients and 4% for gLoR patients. Based on multivariable Cox models and stepwise selection, the 3 most discriminating variables were the oncogenetic classifier, MRD, and white blood cell (WBC) count. Patients harboring a WBC count ≥200 × 10/L, gHiR classifier, and MRD ≥10 demonstrated a 5-year CIR of 46%, whereas the 58 patients (30%) with a WBC count <200 × 10/L, gLoR classifier, and MRD <10 had a very low risk of relapse, with a 5-year CIR of only 2%. In childhood T-ALL, the mutation profile is an independent predictor of relapse. When combined with MRD and a WBC count ≥200 × 10/L, it identifies a significant subgroup of patients with a low risk of relapse.
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http://dx.doi.org/10.1182/blood-2017-04-778829DOI Listing
January 2018

Detection of a new heterozygous germline ETV6 mutation in a case with hyperdiploid acute lymphoblastic leukemia.

Eur J Haematol 2018 Jan 9;100(1):104-107. Epub 2017 Nov 9.

Laboratory of Hematology, CHU Lille, Lille, France.

ETV6 is a target of recurrent aberrations in sporadic and familial acute lymphoblastic leukemia (ALL). Here, we report on a new pedigree with a germline ETV6 mutation in which the index patient and his father developed high hyperdiploid (HeH) ALL and polycythemia vera at age 13 and 51, respectively. The index patient achieved durable complete remission without transplantation but had persistent moderate thrombocytopenia without bleeding tendency. To determine the prevalence of ETV6 alterations in HeH-ALL, we screened 81 unrelated subjects with HeH-ALL by single nucleotide polymorphism array and high-throughput sequencing for the ETV6 gene. Overall, ETV6 microdeletions and mutations were identified in 9% of cases, all of which were somatic and considered as secondary events. Apart from the index patient, no germline ETV6 aberration was identified. Finally, we reviewed the literature for ETV6 germline aberrations and predispositions to ALL.
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http://dx.doi.org/10.1111/ejh.12981DOI Listing
January 2018

Impact of cytogenetic abnormalities in adults with Ph-negative B-cell precursor acute lymphoblastic leukemia.

Blood 2017 10 8;130(16):1832-1844. Epub 2017 Aug 8.

Department of Hematology, University Hospital Saint-Louis, AP-HP, University Paris Diderot, Paris, France.

Multiple cytogenetic subgroups have been described in adult Philadelphia chromosome (Ph)-negative B-cell precursor (BCP) acute lymphoblastic leukemia (ALL), often comprising small numbers of patients. In this study, we aimed to reassess the prognostic value of cytogenetic abnormalities in a large series of 617 adult patients with Ph-negative BCP-ALL (median age, 38 years), treated in the intensified Group for Research on Adult Acute Lymphoblastic Leukemia (GRAALL)-2003/2005 trials. Combined data from karyotype, DNA index, fluorescence in situ hybridization, and polymerase chain reaction screening for relevant abnormalities were centrally reviewed and were informative in 542 cases (88%), allowing classification in 10 exclusive primary cytogenetic subgroups and in secondary subgroups, including complex and monosomal karyotypes. Prognostic analyses focused on cumulative incidence of failure (including primary refractoriness and relapse), event-free survival, and overall survival. Only 2 subgroups, namely t(4;11)/ and 14q32/ translocations, displayed a significantly worse outcome in this context, still observed after adjustment for age and after censoring patients who received allogeneic stem cell transplantation (SCT) in first remission at SCT time. A worse outcome was also observed in patients with low hypodiploidy/near triploidy, but this was likely related to their higher age and worse tolerance to therapy. The other cytogenetic abnormalities, including complex and monosomal karyotypes, had no prognostic value in these intensive protocols designed for adult patients up to the age of 60 years.
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http://dx.doi.org/10.1182/blood-2017-05-783852DOI Listing
October 2017

Coexistence of age-related EBV-associated follicular hyperplasia and large B-cell EBV+ lymphoma of the elderly. Two distinct features of the same T-cell dysfunction related to senescence?

Pathol Res Pract 2017 Mar 23;213(3):277-280. Epub 2016 Dec 23.

Univ. Lille, Institute of Pathology, Centre de Biologie Pathologie, CHU Lille, F-59000 Lille, France.

Age-related EBV-associated lymphoproliferative disorders form a new clinicopathological group. Until recently, this group was associated with diffuse large B-cell lymphoma (DLBCL), characterised by an aggressive clinical presentation and a poor prognosis. Recent findings in Western Caucasian patients, however, suggest that this entity covers a wide spectrum of diseases, ranging from reactive follicular hyperplasia (HR) to DLBCL. We report the case of an 85-year-old Caucasian man showing lymphadenopathy and numerous hypodense lesions of the liver. Examination of a lymph node revealed follicular hyperplasia with EBV expression confined to germinal centres. The patient was treated with Rituximab and subsequently, the lesions of the liver were explored. They showed extensive necrosis and a polymorphic large B-cell population with strong EBV expression. This is the first report to describe age-related EBV-associated follicular hyperplasia at one site coexisting with DLBCL at another. This case warrants undertaking further investigations each time a diagnosis of age-related EBV-HR is associated with extranodal lesions.
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http://dx.doi.org/10.1016/j.prp.2016.12.012DOI Listing
March 2017

High-throughput sequencing in acute lymphoblastic leukemia: Follow-up of minimal residual disease and emergence of new clones.

Leuk Res 2017 02 21;53:1-7. Epub 2016 Nov 21.

Univ. Lille, CHU Lille, Department of Hematology, F-59000 Lille, France. Electronic address:

Minimal residual disease (MRD) is known to be an independent prognostic factor in patients with acute lymphoblastic leukemia (ALL). High-throughput sequencing (HTS) is currently used in routine practice for the diagnosis and follow-up of patients with hematological neoplasms. In this retrospective study, we examined the role of immunoglobulin/T-cell receptor-based MRD in patients with ALL by HTS analysis of immunoglobulin H and/or T-cell receptor gamma chain loci in bone marrow samples from 11 patients with ALL, at diagnosis and during follow-up. We assessed the clinical feasibility of using combined HTS and bioinformatics analysis with interactive visualization using Vidjil software. We discuss the advantages and drawbacks of HTS for monitoring MRD. HTS gives a more complete insight of the leukemic population than conventional real-time quantitative PCR (qPCR), and allows identification of new emerging clones at each time point of the monitoring. Thus, HTS monitoring of Ig/TR based MRD is expected to improve the management of patients with ALL.
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http://dx.doi.org/10.1016/j.leukres.2016.11.009DOI Listing
February 2017

Acquisition of genomic events leading to lymphoblastic transformation in a rare case of myeloproliferative neoplasm with BCR-JAK2 fusion transcript.

Eur J Haematol 2016 Oct 26;97(4):399-402. Epub 2016 Mar 26.

INSERM UMR-S 1172, Cancer Research Institute, Lille, France.

We report a case of myeloproliferative neoplasm (MPN) with an atypical t(9;22;15)(p24;q11;q21) translocation, leading to a BCR-JAK2 fusion, associated with a trisomy of chromosome 8 in clonal evolution at karyotype. Patient's evolution was marked by an aggressive clinical course with rapid progression to blast phase within the first year after diagnosis. Examination of matched chronic phase and blast crisis samples by SNP-array karyotyping identified secondary acquired cryptic genetic events at the time of lymphoblastic transformation, including biallelic IKZF1 alteration and EBF1 and CDKN2A/B codeletions. This case is the first report describing acquisition of secondary genetic events leading to acute lymphoblastic progression in a rare MPN with BCR-JAK2 fusion.
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http://dx.doi.org/10.1111/ejh.12752DOI Listing
October 2016

Multi-loci diagnosis of acute lymphoblastic leukaemia with high-throughput sequencing and bioinformatics analysis.

Br J Haematol 2016 05 21;173(3):413-20. Epub 2016 Feb 21.

CRIStAL, UMR 9189, CNRS, Université de Lille, Lille, France.

High-throughput sequencing (HTS) is considered a technical revolution that has improved our knowledge of lymphoid and autoimmune diseases, changing our approach to leukaemia both at diagnosis and during follow-up. As part of an immunoglobulin/T cell receptor-based minimal residual disease (MRD) assessment of acute lymphoblastic leukaemia patients, we assessed the performance and feasibility of the replacement of the first steps of the approach based on DNA isolation and Sanger sequencing, using a HTS protocol combined with bioinformatics analysis and visualization using the Vidjil software. We prospectively analysed the diagnostic and relapse samples of 34 paediatric patients, thus identifying 125 leukaemic clones with recombinations on multiple loci (TRG, TRD, IGH and IGK), including Dd2/Dd3 and Intron/KDE rearrangements. Sequencing failures were halved (14% vs. 34%, P = 0.0007), enabling more patients to be monitored. Furthermore, more markers per patient could be monitored, reducing the probability of false negative MRD results. The whole analysis, from sample receipt to clinical validation, was shorter than our current diagnostic protocol, with equal resources. V(D)J recombination was successfully assigned by the software, even for unusual recombinations. This study emphasizes the progress that HTS with adapted bioinformatics tools can bring to the diagnosis of leukaemia patients.
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http://dx.doi.org/10.1111/bjh.13981DOI Listing
May 2016

Diagnosis of intrachromosomal amplification of chromosome 21 (iAMP21) by molecular cytogenetics in pediatric acute lymphoblastic leukemia.

Clin Case Rep 2015 Oct 26;3(10):814-6. Epub 2015 Aug 26.

Medical Cytogenetics Institute, Jeanne de Flandre Hospital Lille, France ; INSERM UMR-S 1172, Cancer Research Institute Lille, France.

Intrachromosomal amplification of chromosome 21 (iAMP21) defines a distinct cytogenetic subgroup of B-cell precursor acute lymphoblastic leukemia (BCP-ALL) with poor prognosis that should be investigated in routine practice. Single-nucleotide polymorphism (SNP)-array provides a useful method to detect such cases showing a highly characteristic profile.
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http://dx.doi.org/10.1002/ccr3.357DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4614646PMC
October 2015

Paroxysmal nocturnal hemoglobinuria (PNH) and T cell large granular lymphocyte (LGL) leukemia--an unusual association: another cause of cytopenia in PNH.

Ann Hematol 2015 Oct 9;94(10):1759-60. Epub 2015 Jul 9.

Laboratoire d'Hématologie, Centre de Biologie Pathologie, CHRU Lille, 2 Boulevard du Pr Jules Leclercq, 59037, Lille Cedex 1, France,

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http://dx.doi.org/10.1007/s00277-015-2439-3DOI Listing
October 2015

CD200/BTLA deletions in pediatric precursor B-cell acute lymphoblastic leukemia treated according to the EORTC-CLG 58951 protocol.

Haematologica 2015 Oct 2;100(10):1311-9. Epub 2015 Jul 2.

Department of Pediatric Hematology-Oncology and Stem Cell Transplantation, Ghent University Hospital, Belgium

DNA copy number analysis has been instrumental for the identification of genetic alterations in B-cell precursor acute lymphoblastic leukemia. Notably, some of these genetic defects have been associated with poor treatment outcome and might be relevant for future risk stratification. In this study, we characterized recurrent deletions of CD200 and BTLA genes, mediated by recombination-activating genes, and used breakpoint-specific polymerase chain reaction assay to screen a cohort of 1154 cases of B-cell precursor acute lymphoblastic leukemia uniformly treated according to the EORTC-CLG 58951 protocol. CD200/BTLA deletions were identified in 56 of the patients (4.8%) and were associated with an inferior 8-year event free survival in this treatment protocol [70.2% ± 1.2% for patients with deletions versus 83.5% ± 6.4% for non-deleted cases (hazard ratio 2.02; 95% confidence interval 1.23-3.32; P=0.005)]. Genetically, CD200/BTLA deletions were strongly associated with ETV6-RUNX1-positive leukemias (P<0.0001), but were also identified in patients who did not have any genetic abnormality that is currently used for risk stratification. Within the latter population of patients, the presence of CD200/BTLA deletions was associated with inferior event-free survival and overall survival. Moreover, the multivariate Cox model indicated that these deletions had independent prognostic impact on event-free survival when adjusting for conventional risk criteria. All together, these findings further underscore the rationale for copy number profiling as an important tool for risk stratification in human B-cell precursor acute lymphoblastic leukemia. This trial was registered at www.ClinicalTrials.gov as #NCT00003728.
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http://dx.doi.org/10.3324/haematol.2015.126953DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4591763PMC
October 2015

CD3-CD4+ lymphoid variant of hypereosinophilic syndrome: nodal and extranodal histopathological and immunophenotypic features of a peripheral indolent clonal T-cell lymphoproliferative disorder.

Haematologica 2015 Aug 14;100(8):1086-95. Epub 2015 Feb 14.

Institute of Hematology and Inserm Unit U837, Lille University Hospital, Université Lille Nord de France, Lille.

The CD3(-)CD4(+) lymphoid variant of hypereosinophilic syndrome is characterized by hypereosinophilia and clonal circulating CD3(-)CD4(+) T cells. Peripheral T-cell lymphoma has been described during this disease course, and we observed in our cohort of 23 patients 2 cases of angio-immunoblastic T-cell lymphoma. We focus here on histopathological (n=12 patients) and immunophenotypic (n=15) characteristics of CD3(-)CD4(+) lymphoid variant of hypereosinophilic syndrome. Atypical CD4(+) T cells lymphoid infiltrates were found in 10 of 12 CD3(-)CD4(+) L-HES patients, in lymph nodes (n=4 of 4 patients), in skin (n=9 of 9) and other extra-nodal tissues (gut, lacrymal gland, synovium). Lymph nodes displayed infiltrates limited to the interfollicular areas or even an effacement of nodal architecture, associated with proliferation of arborizing high endothelial venules and increased follicular dendritic cell meshwork. Analysis of 2 fresh skin samples confirmed the presence of CD3(-)CD4(+) T cells. Clonal T cells were detected in at least one tissue in 8 patients, including lymph nodes (n=4 of 4): the same clonal T cells were detected in blood and in at least one biopsy, with a maximum delay of 23 years between samples. In the majority of cases, circulating CD3(-)CD4(+) T cells were CD2(hi) (n=9 of 14), CD5(hi) (n=12 of 14), and CD7(-)(n=4 of 14) or CD7(low) (n=10 of 14). Angio-immunoblastic T-cell lymphoma can also present with CD3(-)CD4(+) T cells; despite other common histopathological and immunophenotypic features, CD10 expression and follicular helper T-cell markers were not detected in lymphoid variant of hypereosinophilic syndrome patients, except in both patients who developed angio-immunoblastic T-cell lymphoma, and only at T-cell lymphoma diagnosis. Taken together, persistence of tissular clonal T cells and histopathological features define CD3(-)CD4(+) lymphoid variant of hypereosinophilic syndrome as a peripheral indolent clonal T-cell lymphoproliferative disorder, which should not be confused with angio-immunoblastic T-cell lymphoma.
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http://dx.doi.org/10.3324/haematol.2014.118042DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5004425PMC
August 2015

Follow-up of post-transplant minimal residual disease and chimerism in childhood lymphoblastic leukaemia: 90 d to react.

Br J Haematol 2015 Apr 19;169(2):249-61. Epub 2014 Dec 19.

Department of Paediatric Haematology/oncology, University Hospital of Nancy, Nancy, France.

Relapse after transplantation is a major cause of treatment failure in paediatric acute lymphoblastic leukaemia (ALL). Here, we report the findings of a prospective national study designed to investigate the feasibility of immune intervention in children in first or subsequent remission following myeloablative conditioning. This study included 133 children who received a transplant for ALL between 2005 and 2008. Minimal Residual Disease (MRD) based on T cell receptor/immunoglobulin gene rearrangements was measured on days -30, 30, 90 and 150 post-transplantation. Ciclosporin treatment was rapidly discontinued and donor lymphocyte infusions (DLI) were programmed for patients with a pre- or post-transplant MRD status ≥10(-3) . Only nine patients received DLI. Pre- and post-transplant MRD status, and the duration of ciclosporin were independently associated with 5-year overall survival (OS), which was 62·07% for the whole cohort. OS was substantially higher in patients cleared of MRD than in those with persistent MRD (52·3% vs. 14·3%, respectively). Only pre-transplant MRD status (Hazard Ratio 2·57, P = 0·04) and duration of ciclosporin treatment (P < 0·001) were independently associated with relapse. The kinetics of chimerism were not useful for predicting relapse, whereas MRD monitoring up to 90 d post-transplantation was a valuable prognostic tool to guide therapeutic intervention.
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http://dx.doi.org/10.1111/bjh.13272DOI Listing
April 2015

[Systemic EBV+ T-cell lymphoproliferative disease of childhood].

Ann Pathol 2014 Aug 22;34(4):339-43. Epub 2014 Jul 22.

Institut de pathologie, CHRU de Lille, 2, avenue Oscar-Lambret, 59037 Lille cedex, France; Université Lille-Nord de France, 59000 Lille, France.

Systemic EBV+ T-cell lymphoproliferative disease of childhood is a recent entity described in the 2008 World Health Organisation tumours of haematopoietic system and lymphoid tissues as a clonal T-cell EBV+ systemic proliferation. It occurs after acute or chronic active EBV infection. We report the case of a caucasian, immunocompetent 12-year-old girl, with no particular history, who presented with hemophagocytic lymphohistiocytosis in the aftermath of an infectious mononucleosis. Main symptoms were multiple organ failure, hepatosplenomegaly and pancytopenia. Histopathology of peripheral lymph node and bone marrow revealed a T-cell, CD8+, EBV+ lymphoproliferation. An elevated viral load was detected in blood by PCR. The patient died within 3 weeks. Since most of the cases have been reported in Asia and South America, few cases still have been described in Europe. Unlike B-cell lymphoproliferation in immunocompromised individuals, T-cell EBV+ lymphoproliferation occurs in immunocompetent patients and seems to be the consequence of a proliferative disorder of EBV-infected T-cells, attributed to a cytotoxic T-cell response deficiency. These T-cell proliferations are more frequently immunoreactive for CD8 than CD4. A key feature of the diagnosis might be EBV viral load.
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http://dx.doi.org/10.1016/j.annpat.2014.04.009DOI Listing
August 2014

Calibration of BCR-ABL1 mRNA quantification methods using genetic reference materials is a valid strategy to report results on the international scale.

Clin Biochem 2014 Sep 8;47(13-14):1333-6. Epub 2014 Jun 8.

Laboratory of Hematology, University Hospital Saint-Louis, AP-HP, Paris, France; EA3518, University Paris Diderot, Paris, France. Electronic address:

Objectives: Until recently, diagnostic laboratories that wanted to report on the international scale had limited options: they had to align their BCR-ABL1 quantification methods through a sample exchange with a reference laboratory to derive a conversion factor. However, commercial methods calibrated on the World Health Organization genetic reference panel are now available. We report results from a study designed to assess the comparability of the two alignment strategies.

Design And Methods: Sixty follow-up samples from chronic myeloid leukemia patients were included. Two commercial methods calibrated on the genetic reference panel were compared to two conversion factor methods routinely used at Saint-Louis Hospital, Paris, and at Lille University Hospital. Results were matched against concordance criteria (i.e., obtaining at least two of the three following landmarks: 50, 75 and 90% of the patient samples within a 2-fold, 3-fold and 5-fold range, respectively).

Results: Out of the 60 samples, more than 32 were available for comparison. Compared to the conversion factor method, the two commercial methods were within a 2-fold, 3-fold and 5-fold range for 53 and 59%, 89 and 88%, 100 and 97%, respectively of the samples analyzed at Saint-Louis. At Lille, results were 45 and 85%, 76 and 97%, 100 and 100%, respectively. Agreements between methods were observed in the four comparisons performed.

Conclusion: Our data show that the two commercial methods selected are concordant with the conversion factor methods. This study brings the proof of principle that alignment on the international scale using the genetic reference panel is compatible with the patient sample exchange procedure. We believe that these results are particularly important for diagnostic laboratories wishing to adopt commercial methods.
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http://dx.doi.org/10.1016/j.clinbiochem.2014.05.067DOI Listing
September 2014

Fast multiclonal clusterization of V(D)J recombinations from high-throughput sequencing.

BMC Genomics 2014 May 28;15:409. Epub 2014 May 28.

Laboratoire d'Informatique Fondamentale de Lille (LIFL, UMR CNRS 8022, Université Lille 1) and Inria Lille - Cité scientifique - Bâtiment M3, 59655 Villeneuve d'Ascq, France.

Background: V(D)J recombinations in lymphocytes are essential for immunological diversity. They are also useful markers of pathologies. In leukemia, they are used to quantify the minimal residual disease during patient follow-up. However, the full breadth of lymphocyte diversity is not fully understood.

Results: We propose new algorithms that process high-throughput sequencing (HTS) data to extract unnamed V(D)J junctions and gather them into clones for quantification. This analysis is based on a seed heuristic and is fast and scalable because in the first phase, no alignment is performed with germline database sequences. The algorithms were applied to TR γ HTS data from a patient with acute lymphoblastic leukemia, and also on data simulating hypermutations. Our methods identified the main clone, as well as additional clones that were not identified with standard protocols.

Conclusions: The proposed algorithms provide new insight into the analysis of high-throughput sequencing data for leukemia, and also to the quantitative assessment of any immunological profile. The methods described here are implemented in a C++ open-source program called Vidjil.
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http://dx.doi.org/10.1186/1471-2164-15-409DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4070559PMC
May 2014

Oncogenetics and minimal residual disease are independent outcome predictors in adult patients with acute lymphoblastic leukemia.

Blood 2014 Jun 16;123(24):3739-49. Epub 2014 Apr 16.

Department of Hematology and.

With intensified pediatric-like therapy and genetic disease dissection, the field of adult acute lymphoblastic leukemia (ALL) has evolved recently. In this new context, we aimed to reassess the value of conventional risk factors with regard to new genetic alterations and early response to therapy, as assessed by immunoglobulin/T-cell receptor minimal residual disease (MRD) levels. The study was performed in 423 younger adults with Philadelphia chromosome-negative ALL in first remission (265 B-cell precursor [BCP] and 158 T-cell ALL), with cumulative incidence of relapse (CIR) as the primary end point. In addition to conventional risk factors, the most frequent currently available genetic alterations were included in the analysis. A higher specific hazard of relapse was independently associated with postinduction MRD level ≥10(-4) and unfavorable genetic characteristics (ie, MLL gene rearrangement or focal IKZF1 gene deletion in BCP-ALL and no NOTCH1/FBXW7 mutation and/or N/K-RAS mutation and/or PTEN gene alteration in T-cell ALL). These 2 factors allowed definition of a new risk classification that is strongly associated with higher CIR and shorter relapse-free and overall survival. These results indicate that genetic abnormalities are important predictors of outcome in adult ALL not fully recapitulated by early response to therapy. Patients included in this study were treated in the multicenter GRAALL-2003 and GRAALL-2005 trials. Both trials were registered at http://www.clinicaltrials.gov as #NCT00222027 and #NCT00327678, respectively.
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http://dx.doi.org/10.1182/blood-2014-01-547695DOI Listing
June 2014

Clinical value of pre-transplant minimal residual disease in childhood lymphoblastic leukaemia: the results of the French minimal residual disease-guided protocol.

Br J Haematol 2014 May 30;165(3):392-401. Epub 2014 Jan 30.

Department of Paediatric Haematology/Oncology, University Hospital of Rennes, Rennes, France.

Minimal residual disease (MRD) is a major predictive factor of the cure rate of acute lymphoblastic leukaemia (ALL). Haematopoietic cell transplantation is a treatment option for patients at high risk of relapse. Between 2005 and 2008, we conducted a prospective study evaluating the feasibility and efficacy of the reduction of immunosuppressive medication shortly after a non-ex vivo T depleted myeloablative transplantation. Immunoglobulin (Ig)H/T-cell receptor MRD 30 d before transplant could be obtained in 122 of the 133 cases of high-risk paediatric ALL enrolled. There were no significant demographic differences except remission status (first or second complete remission) between the 95 children with MRD <10(-3) and the 27 with MRD ≥10(-3) . Multivariate analysis identified sex match and MRD as being significantly associated with 5-year survival. MRD ≥10(-3) compromised the 5-year cumulative incidence of relapse (43·6 vs. 16·7%). Complete remission status and stem cell source did not modify the relationship between MRD and prognosis. Thus, pre-transplant MRD is still a major predictor of outcome for ALL. The MRD-guided strategy resulted in survival for 72·3% of patients with MRD<10(-3) and 40·4% of those with MRD ≥10(-3).
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http://dx.doi.org/10.1111/bjh.12749DOI Listing
May 2014
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