Publications by authors named "Pierre Sujobert"

63 Publications

Real-life targeted next-generation sequencing for lymphoma diagnosis over 1 year from the French Lymphoma Network.

Br J Haematol 2021 Mar 25. Epub 2021 Mar 25.

Pathology Department, Hospices Civils de Lyon, Centre Hospitalier Lyon-Sud, Pierre-Bénite, France.

As the impact of targeted next-generation sequencing (TNGS) on daily diagnosis has not been evaluated, we performed TNGS (46 genes) on lymphomas of unclear subtype following expert haematopathological review. The potential impact on patient care and modifications of final diagnosis were divided into major and minor changes according to the European Society of Medical Oncology (ESMO) guidelines. Among 229 patients [19 primary central nervous system lymphomas (PCNSL), 48 large B-cell lymphomas (LBCLs), 89 small BCLs (SBCLs), seven Hodgkin lymphomas (HL), 66 T-cell lymphomas], the overall concordance rate of histological and TNGS diagnosis was 89·5%. TNGS confirmed the histological diagnosis in 144 cases (62·9%), changed the diagnosis in 24 cases (10·5%) and did not help to clarify diagnosis in 61 cases (26·7%). Modifications to the final diagnosis had a clinical impact on patient care in 8·3% of cases. Diagnostic modifications occurred in all types of lymphoma except in PCNSL and HL; the modification rate was 14·6% in SBCL and 12·5% in LBCL. While comparing informative and uninformative cases, no differences were found in terms of DNA amplification, quality or depth of sequencing and biopsy type. The present study highlights that TNGS may directly contribute to a more accurate diagnosis in difficult-to-diagnose lymphomas, thus improving the clinical management in routine practice.
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http://dx.doi.org/10.1111/bjh.17395DOI Listing
March 2021

Genomic analysis of primary and secondary myelofibrosis redefines the prognostic impact of ASXL1 mutations: a FIM study.

Blood Adv 2021 Mar;5(5):1442-1451

Univ Angers, INSERM, CRCINA, Angers, France.

We aimed to study the prognostic impact of the mutational landscape in primary and secondary myelofibrosis. The study included 479 patients with myelofibrosis recruited from 24 French Intergroup of Myeloproliferative Neoplasms (FIM) centers. The molecular landscape was studied by high-throughput sequencing of 77 genes. A Bayesian network allowed the identification of genomic groups whose prognostic impact was studied in a multistate model considering transitions from the 3 conditions: myelofibrosis, acute leukemia, and death. Results were validated using an independent, previously published cohort (n = 276). Four genomic groups were identified: patients with TP53 mutation; patients with ≥1 mutation in EZH2, CBL, U2AF1, SRSF2, IDH1, IDH2, NRAS, or KRAS (high-risk group); patients with ASXL1-only mutation (ie, no associated mutation in TP53 or high-risk genes); and other patients. A multistate model found that both TP53 and high-risk groups were associated with leukemic transformation (hazard ratios [HRs] [95% confidence interval], 8.68 [3.32-22.73] and 3.24 [1.58-6.64], respectively) and death from myelofibrosis (HRs, 3.03 [1.66-5.56] and 1.77 [1.18-2.67], respectively). ASXL1-only mutations had no prognostic value that was confirmed in the validation cohort. However, ASXL1 mutations conferred a worse prognosis when associated with a mutation in TP53 or high-risk genes. This study provides a new definition of adverse mutations in myelofibrosis with the addition of TP53, CBL, NRAS, KRAS, and U2AF1 to previously described genes. Furthermore, our results argue that ASXL1 mutations alone cannot be considered detrimental.
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http://dx.doi.org/10.1182/bloodadvances.2020003444DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7948260PMC
March 2021

A French multicentric prospective prognostic cohort with epidemiological, clinical, biological and treatment information to improve knowledge on lymphoma patients: study protocol of the "REal world dAta in LYmphoma and survival in adults" (REALYSA) cohort.

BMC Public Health 2021 Mar 2;21(1):432. Epub 2021 Mar 2.

Inserm U1219 - EPICENE team, Université de Bordeaux, Bordeaux, France.

Background: Age-adjusted lymphoma incidence rates continue to rise in France since the early 80's, although rates have slowed since 2010 and vary across subtypes. Recent improvements in patient survival in major lymphoma subtypes at population level raise new questions about patient outcomes (i.e. quality of life, long-term sequelae). Epidemiological studies have investigated factors related to lymphoma risk, but few have addressed the extent to which socioeconomic status, social institutional context (i.e. healthcare system), social relationships, environmental context (exposures), individual behaviours (lifestyle) or genetic determinants influence lymphoma outcomes, especially in the general population. Moreover, the knowledge of the disease behaviour mainly obtained from clinical trials data is partly biased because of patient selection.

Methods: The REALYSA ("REal world dAta in LYmphoma and Survival in Adults") study is a real-life multicentric cohort set up in French areas covered by population-based cancer registries to study the prognostic value of epidemiological, clinical and biological factors with a prospective 9-year follow-up. We aim to include 6000 patients over 4 to 5 years. Adult patients without lymphoma history and newly diagnosed with one of the following 7 lymphoma subtypes (diffuse large B-cell, follicular, marginal zone, mantle cell, Burkitt, Hodgkin, mature T-cell) are invited to participate during a medical consultation with their hematologist. Exclusion criteria are: having already received anti-lymphoma treatment (except pre-phase) and having a documented HIV infection. Patients are treated according to the standard practice in their center. Clinical data, including treatment received, are extracted from patients' medical records. Patients' risk factors exposures and other epidemiological data are obtained at baseline by filling out a questionnaire during an interview led by a clinical research assistant. Biological samples are collected at baseline and during treatment. A virtual tumor biobank is constituted for baseline tumor samples. Follow-up data, both clinical and epidemiological, are collected every 6 months in the first 3 years and every year thereafter.

Discussion: This cohort constitutes an innovative platform for clinical, biological, epidemiological and socio-economic research projects and provides an opportunity to improve knowledge on factors associated to outcome of lymphoma patients in real life.

Trial Registration: 2018-A01332-53, ClinicalTrials.gov identifier: NCT03869619 .
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http://dx.doi.org/10.1186/s12889-021-10433-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7927409PMC
March 2021

Deep multi-instance learning using multi-modal data for diagnosis of lymphocytosis.

IEEE J Biomed Health Inform 2020 Nov 18;PP. Epub 2020 Nov 18.

We investigate the use of recent advances in deep learning and propose an end-to-end trainable multi-instance convolutional neural network within a mixture-of-experts formulation that combines information from two types of data---images and clinical attributes---for the diagnosis of lymphocytosis. The convolutional network learns to extract meaningful features from images of blood cells using an embedding level approach and aggregates them in order to associate them with lymphocytosis, while the mixture-of-experts model combines information from these images as well as clinical attributes to form an end-to-end trainable pipeline for multi-modal data. Our results demonstrate that even the convolutional network by itself is able to discover meaningful associations between the images and the diagnosis, indicating the presence of important unexploited information in the images. A repeatability study is performed to demonstrate that the mixture-of-experts formulation is shown to be more robust without loss of performance. The proposed methods are compared with different methods from literature based both on conventional radiomics and machine learning, and on recent deep learning models based on attention mechanisms. Our method reports a balanced accuracy of 85.41% and outperfroms the radiomics-based and attention-based approaches as well that of biologists which scored 79.44%, 82.89% and 77.07% respectively. These results give insights on the potentials of the applicability of the proposed method in clinical practice.
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http://dx.doi.org/10.1109/JBHI.2020.3038889DOI Listing
November 2020

A personalized approach to guide allogeneic stem cell transplantation in younger adults with acute myeloid leukemia.

Blood 2021 Jan;137(4):524-532

Université de Paris, Génomes, Biologie Cellulaire et Thérapeutique U944, INSERM, CNRS, Paris, France.

A multistage model instructed by a large dataset (knowledge bank [KB] algorithm) has recently been developed to improve outcome predictions and tailor therapeutic decisions, including hematopoietic stem cell transplantation (HSCT) in acute myeloid leukemia (AML). We assessed the performance of the KB in guiding HSCT decisions in first complete remission (CR1) in 656 AML patients younger than 60 years from the ALFA-0702 trial (NCT00932412). KB predictions of overall survival (OS) were superior to those of European LeukemiaNet (ELN) 2017 risk stratification (C-index, 68.9 vs 63.0). Among patients reaching CR1, HSCT in CR1, as a time-dependent covariate, was detrimental in those with favorable ELN 2017 risk and those with negative NPM1 minimal residual disease (MRD; interaction tests, P = .01 and P = .02, respectively). Using KB simulations of survival at 5 years in a scenario without HSCT in CR1 (KB score), we identified, in a similar time-dependent analysis, a significant interaction between KB score and HSCT, with HSCT in CR1 being detrimental only in patients with a good prognosis based on KB simulations (KB score ≥40; interaction test, P = .01). We could finally integrate ELN 2017, NPM1 MRD, and KB scores to sort 545 CR1 patients into 278 (51.0%) HSCT candidates and 267 (49.0%) chemotherapy-only candidates. In both time-dependent and 6-month landmark analyses, HSCT significantly improved OS in HSCT candidates, whereas it significantly shortened OS in chemotherapy-only candidates. Integrating KB predictions with ELN 2017 and MRD may thus represent a promising approach to optimize HSCT timing in younger AML patients.
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http://dx.doi.org/10.1182/blood.2020005524DOI Listing
January 2021

Commercial anti-CD19 CAR T cell therapy for patients with relapsed/refractory aggressive B cell lymphoma in a European center.

Am J Hematol 2020 11 25;95(11):1324-1333. Epub 2020 Aug 25.

Department of Hematology, Hospices Civils de Lyon, Lyon Sud Hospital, Pierre-Bénite, France.

Two autologous anti-CD19 chimeric antigen receptors (CAR) T cells (axicabtagene ciloleucel [axi-cel] and tisagenlecleucel [tisa-cel]) are commercially approved in Europe for relapsed/refractory (R/R) diffuse large B cell lymphoma (DLBCL). We performed a retrospective study to evaluate patterns of use, efficacy and safety for axi-cel and tisa-cel. Data from 70 patients who underwent apheresis for commercial CAR T cells between January 2018 and November 2019 in our institution were retrospectively collected. Sixty-one patients were infused. The median age at infusion was 59 years old (range 27-75 years). The median number of prior therapies was 3 (range, 2-6). The overall response rates (ORRs) at 1 month and 3 months were 63% and 45%, respectively, with 48% and 39% achieving a complete response (CR), respectively. After a median follow-up after infusion of 5.7 months, the median progression-free survival (PFS) was 3.0 months (95% CI, 2.8-8.8 months), and the median overall survival (OS) was 11.8 months (95% CI, 6.0-12.6 months). In multivariate analysis, factors associated with poor PFS were the number of previous lines of treatment before CAR T cells (≥4) (P = .010) and a C reactive protein (CRP) value >30 mg/L at the time of lymphodepletion (P < .001). Likewise, the only factor associated with a shorter OS was CRP >30 mg/L (P = .009). Cytokine release syndrome (CRS) of any grade occurred in 85% of patients, including 8% of patients with CRS of grade 3 or higher. Immune cell-associated neurotoxicity syndrome (ICANS) of any grade occurred in 28% of patients, including 10% of patients with ICANS of grade 3 or higher. Regarding efficacy and safety, no significant difference was found between axi-cel and tisa-cel. This analysis describes one of the largest real-life cohorts of patients treated with axi-cel and tisa-cel for R/R aggressive B cell lymphoma in Europe.
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http://dx.doi.org/10.1002/ajh.25951DOI Listing
November 2020

Clonal dominance is an adverse prognostic factor in acute myeloid leukemia treated with intensive chemotherapy.

Leukemia 2021 03 24;35(3):712-723. Epub 2020 Jun 24.

Service Hématologie Adultes, Hôpital Saint-Louis, Assistance Publique-Hôpitaux de Paris, F-75010, Paris, France.

Intra-tumor heterogeneity portends poor outcome in many cancers. In AML, a higher number of drivers worsens prognosis. The Shannon Index is a robust metric of clonal heterogeneity that accounts for the number of clones, but also their relative abundance. We show that a Shannon Index can be estimated from bulk sequencing, which is correlated (ρ = 0.76) with clonal diversity from single-colony genotyping. In a discovery cohort of 292 patients with sequencing of 43 genes, a higher number of drivers (HR = 1.18, P = 0.028) and a lower Shannon Index (HR = 0.68, P = 0.048), the latter reflecting clonal dominance, are independently associated with worse OS independently of European LeukemiaNet 2017 risk. These findings are validated in an independent cohort of 1184 patients with 111-gene sequencing (number of drivers HR = 1.16, P = 1 × 10, Shannon Index HR = 0.81, P = 0.007). By re-interrogating paired diagnosis/relapse exomes from 50 cytogenetically normal AMLs, we find clonal dominance at diagnosis to be correlated with the gain of a significantly higher number of mutations at relapse (P = 6 × 10), hence with clonal sweeping. Our results suggest that clonal dominance at diagnosis is associated with the presence of a leukemic phenotype allowing rapid expansion of new clones and driving relapse after chemotherapy.
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http://dx.doi.org/10.1038/s41375-020-0932-8DOI Listing
March 2021

Development of a Model for Chemical Screening Based on Collateral Sensitivity to Target BTK C481S Mutant.

Cancers (Basel) 2020 Apr 7;12(4). Epub 2020 Apr 7.

Cancer Research Center of Lyon, INSERM U1052 UMR CNRS 5286, Equipe labellisée Ligue Contre le Cancer, Université de Lyon, 69008 Lyon, France.

Targeted therapies have improved the outcome of cancer, but their efficacy is intrinsically limited by the emergence of subclones with a mutation in the gene encoding the target protein. A few examples of collateral sensitivity have demonstrated that the conformational changes induced by these mutations can create unexpected sensitivity to other kinase inhibitors, but whether this concept can be generalized is unknown. Here is described the development of a model to screen a library of kinase inhibitors for collateral sensitivity drugs active on the Bruton Tyrosine Kinase (BTK) protein with the ibrutinib resistance mutation C481S. First, we demonstrate that overexpression of the constitutively active mutant of BTK harboring the E41K mutation in Ba/F3 cells creates an oncogenic addiction to BTK. Then, we have exploited this phenotype to perform a screen of a kinase inhibitor library on cells with or without the ibrutinib resistance mutation. The BTK inhibitors showed the expected sensitivity profile, but none of the drugs tested had a specific activity against the C481S mutant of BTK, suggesting that extending the collateral sensitivity paradigm to all kinases targeted by cancer therapy might not be trivial.
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http://dx.doi.org/10.3390/cancers12040901DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7226254PMC
April 2020

Impact of using leader primers for IGHV mutational status assessment in chronic lymphocytic leukemia.

Leukemia 2020 08 29;34(8):2257-2259. Epub 2020 Jan 29.

Hospices Civils de Lyon, Service d'hématologie biologique, Centre Hospitalier Lyon Sud, Pierre-Bénite, France.

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http://dx.doi.org/10.1038/s41375-020-0716-1DOI Listing
August 2020

Vitamin D Receptor Controls Cell Stemness in Acute Myeloid Leukemia and in Normal Bone Marrow.

Cell Rep 2020 01;30(3):739-754.e4

INSERM UMR 1163, Laboratory of Cellular and Molecular Mechanisms of Hematological Disorders and Therapeutical Implications, 75015 Paris, France; Paris Descartes - Sorbonne Paris Cité University, Imagine Institute, 75015 Paris, France; CNRS ERL 8254, Laboratory of Cellular and Molecular Mechanisms of Hematological Disorders and Therapeutical Implications, 75015 Paris, France; Laboratory of Excellence GR-Ex, 75015 Paris, France.

Vitamin D (VD) is a known differentiating agent, but the role of VD receptor (VDR) is still incompletely described in acute myeloid leukemia (AML), whose treatment is based mostly on antimitotic chemotherapy. Here, we present an unexpected role of VDR in normal hematopoiesis and in leukemogenesis. Limited VDR expression is associated with impaired myeloid progenitor differentiation and is a new prognostic factor in AML. In mice, the lack of Vdr results in increased numbers of hematopoietic and leukemia stem cells and quiescent hematopoietic stem cells. In addition, malignant transformation of Vdr cells results in myeloid differentiation block and increases self-renewal. Vdr promoter is methylated in AML as in CD34 cells, and demethylating agents induce VDR expression. Association of VDR agonists with hypomethylating agents promotes leukemia stem cell exhaustion and decreases tumor burden in AML mouse models. Thus, Vdr functions as a regulator of stem cell homeostasis and leukemic propagation.
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http://dx.doi.org/10.1016/j.celrep.2019.12.055DOI Listing
January 2020

[Accreditation strategy for rare somatic molecular abnormalities detected or quantified by polymerase chain reaction: GBMHM recommendations].

Ann Biol Clin (Paris) 2019 12;77(6):681-684

Laboratoire d'hématologie, Hôpital Nord, Centre hospitalier universitaire de Saint-Étienne, Saint-Étienne, France.

In 2020, accreditation of molecular tests according to ISO 15189 is a requirement for all French medical laboratories. For many years, the GBMHM group (French Group of Molecular Biologists in Hematology) supports this approach through organization of external quality evaluation campaigns, and by publishing recommendations that have allowed the accreditation of the most frequent molecular tests for most laboratories. However, some molecular abnormalities concerns very few patients (and sometimes a single patient), and therefore cannot be evaluated in the same way, because of the lack of external quality controls or inter-laboratory comparisons. In order to allow the accreditation of these rare analyzes, the GBMHM proposes recommendations, based on the fact that analyzes using the same methodology than those already accredited by an extensive validation process, may be accredited without the need for full analytical validation. In particular, assays based on quantitative PCR or endpoint PCR may be accredited after verification of primer specificity, repeatability and/or reproducibility, and the determination of detection or linearity limits. These recommendations, by defining the validation approach for rare molecular abnormalities, make it possible to extend the requirement of accreditation for rare tests, to provide the best patient care.
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http://dx.doi.org/10.1684/abc.2019.1498DOI Listing
December 2019

Unclassifiable Isolated Monoclonal Lymphocytosis: Comprehensive Description of a Retrospective Cohort.

Cancers (Basel) 2019 Oct 4;11(10). Epub 2019 Oct 4.

Hospices Civils de Lyon, Centre Hospitalier Lyon Sud, Laboratoire d'hématologie, 69495 Pierre Bénite, France.

According to the World Health Organization (WHO) classification, the nosology of B-cell neoplasms integrates clinical, morphological, phenotypic, and genetic data. In this retrospective analysis, we identified 18 patients with isolated neoplastic lymphocytosis that could not be accurately classified within the WHO classification. Most of them were asymptomatic at the time of diagnosis and the evolution was relatively indolent, as only five patients required treatment after a median follow-up of 48 months. The neoplastic B-cells expressed CD5 in most cases, but the Royal Marsden Hospital score was strictly below 3. Trisomy 12 was the most frequent cytogenetic abnormality. High-throughput sequencing highlighted mutations found in both chronic lymphocytic leukemia (CLL) and marginal zone lymphoma (MZL). Similarly, the immunoglobulin heavy chain variable region repertoire was distinct from those reported in CLL or MZL. However, as treatment choice is dependent on the correct classification of the lymphoproliferative disorder, a histological diagnosis should be performed in case patients need to be treated.
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http://dx.doi.org/10.3390/cancers11101495DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6826630PMC
October 2019

[Follicular lymphoma: An update].

Presse Med 2019 Jul - Aug;48(7-8 Pt 1):850-858. Epub 2019 Aug 22.

Inserm U1052 CNRS 5286, centre de recherche en cancérologie de Lyon (CRCL), équipe « clinical and experimental models of lymphomagenesis », 69600 Lyon, France; Université de Lyon, université Claude-Bernard Lyon 1, faculté de médecine et de Maïeutique Lyon-Sud-Charles-Mérieux, 69600 Lyon, France; Groupement hospitalier Sud, hospices civils de Lyon, service d'hématologie clinique, 69310 Lyon, France. Electronic address:

Follicular lymphoma, the second most common lymphoma, is characterized by its slow growth and is often considered incurable in advanced stages. Progresses in biology have contributed to better understand the complex and successive mechanisms of development of this pathology, whose diagnosis is based on a lymph node biopsy. However, the prognosis of the patients is heterogeneous and several indexes have been proposed to identify groups of patients with a similar life expectancy, in order to guide the therapeutic choices. The treatment has been modified in the last 20 years by the emergence of anti-CD20 monoclonal antibodies which constitute, alone or in combination, of the cornerstone of therapeutic management. After staging using, in particular, 18-fluorodeoxyglucose positron emission tomography, the therapeutic strategy will be adapted for each patient, ranging from simple watchful waiting to a combination of chemotherapy and anti-CD20 antibodies. Relapses (which often require a new lymph node biopsy to eliminate a possible histological transformation into an aggressive lymphoma with poorer prognosis) remain common but are still accessible to effective therapeutic interventions. Thanks to these advances, the median life expectancy of patients with follicular lymphoma now exceeds 15 years.
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http://dx.doi.org/10.1016/j.lpm.2019.07.024DOI Listing
September 2019

Incidence and outcome of BCR-ABL mutated chronic myeloid leukemia patients who failed to tyrosine kinase inhibitors.

Cancer Med 2019 Sep 27;8(11):5173-5182. Epub 2019 Jul 27.

Groupe Fi-LMC, Hôpital Haut-Lévêque, Pessac, France.

Purpose: To assess the incidence of BCR-ABL kinase domain (KD) mutation detection and its prognostic significance in chronic phase chronic myeloid leukemia (CP-CML) patients treated with tyrosine kinase inhibitors (TKIs).

Patients And Methods: We analyzed characteristics and outcome of 253 CP-CML patients who had at least one mutation analysis performed using direct sequencing. Of them, 187 patients were early CP (ECP) and 66 were late CP late chronic phase (LCP) and 88% were treated with Imatinib as first-line TKI.

Results: Overall, 80 (32%) patients harbored BCR-ABL KD mutations. A BCR-ABL KD mutation was identified in 57% of patients, who progressed to accelerated or blastic phases (AP-BP), and 47%, 29%, 35%, 16% and 26% in patients in CP-CML at the time of mutation analysis who lost a complete hematologic response, failed to achieve or loss of a prior complete cytogenetic and major molecular response, respectively. Overall survival and cumulative incidence of CML-related death were significantly correlated with the disease phase whatever the absence or presence of a mutation was and for the latter the mutation subgroup (T315I vs P-loop vs non-T315I non-P-loop) (P<.001). Considering patients who were in CP at the time of mutation analysis, LCP mutated patients had a significantly worse outcome than ECP-mutated patients despite a lower incidence of T315I and P-loop mutations (P<.001). With a median follow-up from mutation analysis to last follow-up of 5 years, T315I and P-loop mutations were not associated with a worse outcome in ECP patients (P = .817).

Conclusion: Our results suggest that early mutation detection together with accessibility to 2nd and 3rd generation TKIs have reversed the worst outcome associated with BCR-ABL KD mutations whatever the mutation subgroup in CP-CML patients.
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http://dx.doi.org/10.1002/cam4.2410DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6718576PMC
September 2019

Prognostic Value of Genetic Alterations in Elderly Patients with Acute Myeloid Leukemia: A Single Institution Experience.

Cancers (Basel) 2019 Apr 22;11(4). Epub 2019 Apr 22.

Department of Hematology, Lyon-Sud Hospital, Hospices Civils de Lyon, 69495 Pierre Bénite, France.

Although the outcome in younger adults with acute myeloid leukemia (AML) has improved, the benefit associated with standard intensive chemotherapy in older patients remains debatable. In this study, we investigated the incidence and the prognostic significance of genetic characteristics according to treatment intensity in patients aged 60 years or older. On the 495 patients of our cohort, (25.2%), (23.7%) and (16.8%) were the most frequent molecular mutations found at diagnosis. In this elderly population, intensive chemotherapy seemed to be a suitable option in terms of early death and survival, except for normal karyotype (NK) patients and those aged over 70 within the adverse cytogenetic/molecular risk group. The mutation was systematically associated with an unfavorable outcome, independently of the ratio. NK genotype tends to confer a good prognosis in patients treated intensively. Regarding minimal residual disease prognostic value, overall survival was significantly better for patients achieving a 4 log reduction (median OS: 24.4 vs. 12.8 months, = 0.013) but did not reach statistical significance for progression free survival. This retrospective study highlights that intensive chemotherapy may not be the most appropriate option for each elderly patient and that molecular markers may help treatment intensity decision-making.
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http://dx.doi.org/10.3390/cancers11040570DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6520979PMC
April 2019

Cannibalistic acute myeloid leukemia with ZMYND11-MBTD1 fusion.

Blood 2019 04;133(16):1789

Hospices Civils de Lyon.

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http://dx.doi.org/10.1182/blood-2019-01-898619DOI Listing
April 2019

Molecular analysis of a CD19-negative diffuse large B-cell lymphoma.

Haematologica 2019 03 13;104(3):e114-e116. Epub 2018 Dec 13.

Cancer Research Center of Lyon, INSERM U1052 UMR CNRS 5286, Equipe labellisée Ligue Contre le Cancer, Université de Lyon

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http://dx.doi.org/10.3324/haematol.2018.203521DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6395315PMC
March 2019

Impact of NPM1 mutation subtypes on treatment outcome in AML: The Lyon-University Hospital experience.

Leuk Res 2019 01 29;76:29-32. Epub 2018 Nov 29.

Hospices Civils de Lyon, Department of Hematology, Lyon-Sud Hospital, Pierre-Bénite, France. Electronic address:

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http://dx.doi.org/10.1016/j.leukres.2018.11.016DOI Listing
January 2019

Finely-tuned regulation of AMP-activated protein kinase is crucial for human adult erythropoiesis.

Haematologica 2019 05 11;104(5):907-918. Epub 2018 Oct 11.

Institut Cochin, INSERM U1016

AMP-activated protein kinase (AMPK) is a heterotrimeric complex containing α, β, and γ subunits involved in maintaining integrity and survival of murine red blood cells. Indeed, α , and mice develop hemolytic anemia and the plasma membrane of their red blood cells shows elasticity defects. The membrane composition evolves continuously along erythropoiesis and during red blood cell maturation; defects due to the absence of Ampk could be initiated during erythropoiesis. We, therefore, studied the role of AMPK during human erythropoiesis. Our data show that AMPK activation had two distinct phases in primary erythroblasts. The phosphorylation of AMPK (Thr172) and its target acetyl CoA carboxylase (Ser79) was elevated in immature erythroblasts (glycophorin A), then decreased conjointly with erythroid differentiation. In erythroblasts, knockdown of the α1 catalytic subunit by short hairpin RNA led to a decrease in cell proliferation and alterations in the expression of membrane proteins (band 3 and glycophorin A) associated with an increase in phosphorylation of adducin (Ser726). AMPK activation in mature erythroblasts (glycophorin A), achieved through the use of direct activators (GSK621 and compound 991), induced cell cycle arrest in the S phase, the induction of autophagy and caspase-dependent apoptosis, whereas no such effects were observed in similarly treated immature erythroblasts. Thus, our work suggests that AMPK activation during the final stages of erythropoiesis is deleterious. As the use of direct AMPK activators is being considered as a treatment in several pathologies (diabetes, acute myeloid leukemia), this observation is pivotal. Our data highlighted the importance of the finely-tuned regulation of AMPK during human erythropoiesis.
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http://dx.doi.org/10.3324/haematol.2018.191403DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6518903PMC
May 2019

[Even the Warburg effect can be oxidized: metabolic cooperation and tumor development].

Med Sci (Paris) 2018 Aug-Sep;34(8-9):701-708. Epub 2018 Sep 19.

Équipe labellisée par la Ligue nationale contre le cancer, Clinical and experimental model of lymphomagenesis, Univ Lyon, Université Claude Bernard Lyon1, Inserm 1052, CNRS 5286, Centre Léon Bérard, Centre de recherche en cancérologie de Lyon, 165, chemin du Grand Revoyet, 69221 Oullins, France.

During tumor development, malignant cells rewire their metabolism to meet the biosynthetic needs required to increase their biomass and to overcome their microenvironment constraints. The sustained activation of aerobic glycolysis, also called Warburg effect, is one of these adaptative mechanisms. The progresses in this area of research have revealed the flexibility of cancer cells that alternate between glycolytic and oxidative metabolism to cope with their conditions of development while sharing their energetic resources. In this survey, we review these recent breakthroughs and discuss a model that likens tumor to an evolutive metabolic ecosystem. We further emphasize the ensuing therapeutic applications that target metabolic weaknesses of neoplastic cells.
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http://dx.doi.org/10.1051/medsci/20183408017DOI Listing
January 2019

What Does This Mutation Mean? The Tools and Pitfalls of Variant Interpretation in Lymphoid Malignancies.

Int J Mol Sci 2018 04 20;19(4). Epub 2018 Apr 20.

Cancer Research Center of Lyon, INSERM U1052 UMR CNRS 5286, Equipe labellisée LIGUE Contre le Cancer, 69008 Lyon, France.

High throughput sequencing (HTS) is increasingly important in determining cancer diagnoses, with subsequent prognostic and therapeutic implications. The biology of cancer is becoming increasingly deciphered and it is clear that therapy needs to be individually tailored. Whilst translational research plays an important role in lymphoid malignancies, few guidelines exist to guide biologists and routine laboratories through this constantly evolving field. In this article, we review the challenges of interpreting HTS in lymphoid malignancies and provide a toolkit to interpret single nucleotide variants obtained from HTS. We define the pre-analytical issues such as sequencing DNA obtained from formalin-fixed and paraffin-embedded tissue (FFPE), the acquisition of germline DNA, or the bioinformatic pitfalls, the analytical issues encountered and how to manage them. We describe the main constitutional and cancer databases, their characteristics and limitations, with an emphasis on variant interpretation in lymphoid malignancies. Finally, we discuss the challenges of predictions that one can make using in silico or in vitro modelling, pharmacogenomic screening, and the limits of those prediction tools. This description of the current status in genomic interpretation highlights the need for new large databases and international collaboration in the lymphoma field.
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http://dx.doi.org/10.3390/ijms19041251DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5979354PMC
April 2018

Knockdown of Human AMPK Using the CRISPR/Cas9 Genome-Editing System.

Methods Mol Biol 2018 ;1732:171-194

U1016, Institut Cochin, Inserm, Paris, France.

AMP-activated protein kinase (AMPK) is a critical energy sensor, regulating signaling networks involved in pathology including metabolic diseases and cancer. This increasingly recognized role of AMPK has prompted tremendous research efforts to develop new pharmacological AMPK activators. To precisely study the role of AMPK, and the specificity and activity of AMPK activators in cellular models, genetic AMPK inactivating tools are required. We report here methods for genetic inactivation of AMPK α1/α2 catalytic subunits in human cell lines by the CRISPR/Cas9 technology, a recent breakthrough technique for genome editing.
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http://dx.doi.org/10.1007/978-1-4939-7598-3_11DOI Listing
January 2019

A gene-expression profiling score for prediction of outcome in patients with follicular lymphoma: a retrospective training and validation analysis in three international cohorts.

Lancet Oncol 2018 04 20;19(4):549-561. Epub 2018 Feb 20.

Cancer Research Center of Lyon, INSERM U1052 UMR CNRS 5286, Lyon, France; Service d'Hématologie Clinique, Centre Hospitalier Lyon Sud, Hospices Civils de Lyon, Pierre-Bénite, France. Electronic address:

Background: Patients with follicular lymphoma have heterogeneous outcomes. Predictor models to distinguish, at diagnosis, between patients at high and low risk of progression are needed. The objective of this study was to use gene-expression profiling data to build and validate a predictive model of outcome for patients treated in the rituximab era.

Methods: A training set of fresh-frozen tumour biopsies was prospectively obtained from 160 untreated patients with high-tumour-burden follicular lymphoma enrolled in the phase 3 randomised PRIMA trial, in which rituximab maintenance was evaluated after rituximab plus chemotherapy induction (median follow-up 6·6 years [IQR 6·0-7·0]). RNA of sufficient quality was obtained for 149 of 160 cases, and Affymetrix U133 Plus 2.0 microarrays were used for gene-expression profiling. We did a multivariate Cox regression analysis to identify genes with expression levels associated with progression-free survival independently of maintenance treatment in a subgroup of 134 randomised patients. Expression levels from 95 curated genes were then determined by digital expression profiling (NanoString technology) in 53 formalin-fixed paraffin-embedded samples of the training set to compare the technical reproducibility of expression levels for each gene between technologies. Genes with high correlation (>0·75) were included in an L2-penalised Cox model adjusted on rituximab maintenance to build a predictive score for progression-free survival. The model was validated using NanoString technology to digitally quantify gene expression in 488 formalin-fixed, paraffin-embedded samples from three independent international patient cohorts from the PRIMA trial (n=178; distinct from the training cohort), the University of Iowa/Mayo Clinic Lymphoma SPORE project (n=201), and the Barcelona Hospital Clinic (n=109). All tissue samples consisted of pretreatment diagnostic biopsies and were confirmed as follicular lymphoma grade 1-3a. The patients were all treated with regimens containing rituximab and chemotherapy, possibly followed by either rituximab maintenance or ibritumomab-tiuxetan consolidation. We determined an optimum threshold on the score to predict patients at low risk and high risk of progression. The model, including the multigene score and the threshold, was initially evaluated in the three validation cohorts separately. The sensitivity and specificity of the score for the prediction of the risk of lymphoma progression at 2 years were assessed on the combined validation cohorts.

Findings: In the training cohort, the expression levels of 395 genes were associated with a risk of progression. 23 genes reflecting both B-cell biology and tumour microenvironment with correlation coefficients greater than 0·75 between the two technologies and sample types were retained to build a predictive model that identified a population at an increased risk of progression (p<0·0001). In a multivariate Cox model for progression-free survival adjusted on rituximab maintenance treatment and Follicular Lymphoma International Prognostic Index 1 (FLIPI-1) score, this predictor independently predicted progression (adjusted hazard ratio [aHR] of the high-risk group compared with the low-risk group 3·68, 95% CI 2·19-6·17 [p<0·0001]). The 5-year progression-free survival was 26% (95% CI 16-43) in the high-risk group and 73% (64-83) in the low-risk group. The predictor performances were confirmed in each of the individual validation cohorts (aHR comparing high-risk to low-risk groups 2·57 [95% CI 1·65-4·01] in cohort 1; 2·12 [1·32-3·39] in cohort 2; and 2·11 [1·01-4·41] in cohort 3). In the combined validation cohort, the median progression-free survival was 3·1 years (95% CI 2·4-4·8) in the high-risk group and 10·8 years (10·1-not reached) in the low-risk group (p<0·0001). The risk of lymphoma progression at 2 years was 38% (95% CI 29-46) in the high-risk group and 19% (15-24) in the low-risk group. In a multivariate analysis, the score predicted progression-free survival independently of anti-CD20 maintenance treatment and of the FLIPI score (aHR for the combined cohort 2·30, 95% CI 1·72-3·07).

Interpretation: We developed and validated a robust 23-gene expression-based predictor of progression-free survival that is applicable to routinely available formalin-fixed, paraffin-embedded tumour biopsies from patients with follicular lymphoma at time of diagnosis. Applying this score could allow individualised therapy for patients according to their risk category.

Funding: Roche, SIRIC Lyric, LYSARC, National Institutes of Health, the Henry J Predolin Foundation, and the Spanish Plan Nacional de Investigacion.
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http://dx.doi.org/10.1016/S1470-2045(18)30102-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5882539PMC
April 2018

Case report: Purulent transformation of granulocytic sarcoma: An unusual pattern of differentiation in acute promyelocytic leukemia.

Medicine (Baltimore) 2018 Feb;97(8):e9657

Department of Hematology, CHU UCL Namur, Belgium Department of Hematology Laboratory of Hematology Anatomopathology Department of Dermatology, Hospices Civils de Lyon, Centre Hospitalier Lyon Sud LBMC, ENS, CNRS UMR5239, Faculté de Médecine Lyon Sud, Pierre-Bénite, France.

Rationale: Acute promyelocytic leukemia (APL) is a curable subtype of acute myeloid leukemia. APL is currently treated with combination of all-trans retinoic acid (ATRA) and arsenic trioxide (ATO) resulting in the induction of apoptosis and differentiation of the leukemic cells. Differentiation syndrome (so-called ATRA syndrome) is the main life-threatening complication of induction therapy with these differentiating agents.

Patient Concerns: Herein, we report the case of a 49-year-old woman diagnosed with APL with, concomitantly, a bulky cutaneous lesion of 10 cm diameter with a red-to-purple background and a necrotic center, localized on her abdomen.

Diagnoses: After 10 days of treatment, the cutaneous lesion became purulent. Fluorescence in situ hybridization (FISH) analysis performed on this pus confirmed the presence of malignant features in the involved granulocytes proving their origin from the differentiation of leukemic APL cells, as all the analyzed nuclei showed 2 promyelocytic leukemia (PML)-retinoic acid receptor-a (RARA) fusions signals.

Intervention: The association by ATRA and ATO was continued.

Outcome: Eventually, the evolution was favorable with healing in three weeks.

Lessons: This case report therefore highlights the differentiation phenomenon of promyelocytic blasts within promyelocytic sarcoma with the ATRA-ATO combination and the efficacy of this drug association in resolving both the malignant sarcoma and a secondary local infection.
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http://dx.doi.org/10.1097/MD.0000000000009657DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5841987PMC
February 2018

When it rains, it pours.

Blood 2018 02;131(7):836

Hospices Civils de Lyon.

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http://dx.doi.org/10.1182/blood-2017-10-814087DOI Listing
February 2018