Publications by authors named "Pierre Soubeyran"

94 Publications

Downregulation of Glutamine Synthetase, not glutaminolysis, is responsible for glutamine addiction in Notch1-driven acute lymphoblastic leukemia.

Mol Oncol 2021 May 13;15(5):1412-1431. Epub 2021 Feb 13.

Institut Européen de Chimie et Biologie, INSERM U1218, Université de Bordeaux, Pessac, France.

The cellular receptor Notch1 is a central regulator of T-cell development, and as a consequence, Notch1 pathway appears upregulated in > 65% of the cases of T-cell acute lymphoblastic leukemia (T-ALL). However, strategies targeting Notch1 signaling render only modest results in the clinic due to treatment resistance and severe side effects. While many investigations reported the different aspects of tumor cell growth and leukemia progression controlled by Notch1, less is known regarding the modifications of cellular metabolism induced by Notch1 upregulation in T-ALL. Previously, glutaminolysis inhibition has been proposed to synergize with anti-Notch therapies in T-ALL models. In this work, we report that Notch1 upregulation in T-ALL induced a change in the metabolism of the important amino acid glutamine, preventing glutamine synthesis through the downregulation of glutamine synthetase (GS). Downregulation of GS was responsible for glutamine addiction in Notch1-driven T-ALL both in vitro and in vivo. Our results also confirmed an increase in glutaminolysis mediated by Notch1. Increased glutaminolysis resulted in the activation of the mammalian target of rapamycin complex 1 (mTORC1) pathway, a central controller of cell growth. However, glutaminolysis did not play any role in Notch1-induced glutamine addiction. Finally, the combined treatment targeting mTORC1 and limiting glutamine availability had a synergistic effect to induce apoptosis and to prevent Notch1-driven leukemia progression. Our results placed glutamine limitation and mTORC1 inhibition as a potential therapy against Notch1-driven leukemia.
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http://dx.doi.org/10.1002/1878-0261.12877DOI Listing
May 2021

Perspectives on cancer care in older patients in France.

Ecancermedicalscience 2020 15;14:1103. Epub 2020 Sep 15.

Senior Oncology Unit, Medical Oncology Department, Gustave Roussy Cancer Campus, Chevilly-Larue 94550, France.

In France, cancer is the leading cause of death. Its incidence is increasing due to the growing population and longer life expectancy. Although older adults represent most new cases, they remain underrepresented in clinical trials. Their prognosis is often worse due to delayed diagnosis and multimorbidities. Geriatric oncology has made great strides worldwide, highlighted by important studies implementing geriatric assessment in clinical research and supported by the successive national cancer plans. This paper reviews the most important actions taken in France during the last decade to improve the management of older patients with cancer.
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http://dx.doi.org/10.3332/ecancer.2020.1103DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7532034PMC
September 2020

Palliative versus hospice care in patients with cancer: a systematic review.

BMJ Support Palliat Care 2020 Jul 17. Epub 2020 Jul 17.

Epicene Team, Inserm UMR 1219, Bordeaux Population Health Research Center, University of Bordeaux, Bordeaux, Aquitaine, France.

Background: Guidelines recommend an early access to specialised palliative medicine services for patients with cancer, but studies have reported a continued underuse. Palliative care facilities deliver early care, alongside antineoplastic treatments, whereas hospice care structures intervene lately, when cancer-modifying treatments stop.

Aim: This review identified factors associated with early and late interventions of specialised services, by considering the type of structures studied (palliative vs hospice care).

Design: We performed a systematic review, prospectively registered on PROSPERO (ID: CRD42018110063).

Data Sources: We searched Medline and Scopus databases for population-based studies. Two independent reviewers extracted the data and assessed the study quality using Joanna Briggs Institute critical appraisal checklists.

Results: The 51 included articles performed 67 analyses. Most were based on retrospective cohorts and US populations. The median quality scores were 19/22 for cohorts and 15/16 for cross-sectional studies. Most analyses focused on hospice care (n=37). Older patients, men, people with haematological cancer or treated in small centres had less specialised interventions. Palliative and hospice facilities addressed different populations. Older patients received less palliative care but more hospice care. Patients with high-stage tumours had more palliative care while women and patients with a low comorbidity burden received more hospice care.

Conclusion: Main disparities concerned older patients, men and people with haematological cancer. We highlighted the challenges of early interventions for older patients and of late deliveries for men and highly comorbid patients. Additional data on non-American populations, outpatients and factors related to quality of life and socioeconomic status are needed.
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http://dx.doi.org/10.1136/bmjspcare-2020-002195DOI Listing
July 2020

Triarylpyridine Compounds and Chloroquine Act in Concert to Trigger Lysosomal Membrane Permeabilization and Cell Death in Cancer Cells.

Cancers (Basel) 2020 Jun 18;12(6). Epub 2020 Jun 18.

Institut Bergonié, INSERM U1218, Université de Bordeaux, 33000 Bordeaux, France.

Lysosomes play a key role in regulating cell death in response to cancer therapies, yet little is known on the possible role of lysosomes in the therapeutic efficacy of G-quadruplex DNA ligands (G4L) in cancer cells. Here, we investigate the relationship between the modulation of lysosomal membrane damage and the degree to which cancer cells respond to the cytotoxic effects of G-quadruplex ligands belonging to the triarylpyridine family. Our results reveal that the lead compound of this family, promotes the enlargement of the lysosome compartment as well as the induction of lysosome-relevant mRNAs. Interestingly, the combination of and chloroquine (an inhibitor of lysosomal functions) led to a significant induction of lysosomal membrane permeabilization coupled to massive cell death. Similar effects were observed when chloroquine was added to three new triarylpyridine derivatives. Our findings thus uncover the lysosomal effects of triarylpyridines compounds and delineate a rationale for combining these compounds with chloroquine to increase their anticancer effects.
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http://dx.doi.org/10.3390/cancers12061621DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7352983PMC
June 2020

Taking care of older patients with cancer in the context of COVID-19 pandemic.

Lancet Oncol 2020 05 14;21(5):e236. Epub 2020 Apr 14.

Department of Medical Oncology, Institut Bergonié, Université de Bordeaux, Inserm U1218, 33076 Bordeaux Cedex, France. Electronic address:

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http://dx.doi.org/10.1016/S1470-2045(20)30229-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7156244PMC
May 2020

Management and outcome of primary CNS lymphoma in the modern era: An LOC network study.

Neurology 2020 03 6;94(10):e1027-e1039. Epub 2020 Jan 6.

From Service de Neurologie 2-Mazarin, Sorbonne Université, IHU, ICM (C. Houillier, A.A., D.D., H.D., D.G., B.A., K.H.-X.), Service d'Hématologie (S. Choquet), Service de Neuro-Radiologie (N.M.-D.), Service d'Ophtalmologie (V.T.), Service de Médecine Nucléaire (A.K.), Service de Neuro-Pathologie (K.M.), Service d'Anatomie et Cytologies Pathologiques (F.C.), Service de Radiothérapie (L.F.), Service d'Hémato-Biologie (M.L.G.-T., M.C.), and Service de Neurochirurgie (B.M., M.P.), APHP, Groupe Hospitalier Pitié-Salpêtrière, Paris; Service d'Hématologie (C. Soussain), Institut Curie, Site Saint-Cloud; Service d'Hématologie (H.G.), CHU Lyon Sud; Service d'Hématologie (P.S., A.S.), Institut Bergonié, Bordeaux; Service de Neuro-Oncologie (O. Chinot), Aix-Marseille Université, CNRS, INP, AP-HM, CHU de la Timone, Marseille; Service de Neurologie (L.T., M.B.), CHU de Nancy; Service d'Hématologie (R.H.), Inserm U1236 Université de Rennes 1 (T.L.), CHU de Rennes; Service de Neurologie (G.A.), Hôpitaux Civils, Colmar; Service d'Hématologie (G.D.), CHU de Caen; Service d'Oncologie Médical (P.A.), Institut de Cancérologie de l'Ouest, Saint Herblain; Service d'Hématologie (C.M.-C.), CHU de Clermont-Ferrand; Service de Neurologie (A.A.), CHU de Toulouse; Service d'Oncologie Hématologique et de Thérapie Cellulaire (V.D.), CHU de Poitiers, INSERM, CIC 1402, Centre d'Investigation Clinique, Université de Poitiers; Service d'Oncologie Médicale (M.F.), Institut du Cancer de Montpellier Val d'Aurelle; Service d'Hématologie (F.J.), Centre Henri Becquerel, Rouen; Service d'Hématologie (A.C.), CHU de Besançon; Service d'Hématologie (M.P.M.-M.), CHU d'Angers; Service d'Hématologie (F.M., E.B.), CHRU de Lille; Service d'Hématologie (O. Casasnovas), CHU de Dijon; Service d'Onco-Hématologie (R.G.), CHU de Grenoble; Service d'Hématologie (L.M.F.), CHU de Strasbourg; Service d'Hématologie (J.A.), CHU de Limoges; Service d'Hématologie (J.-P.M.), CHU d'Amiens; Service d'Hématologie (A.T.), CHU de Brest; Service de Neurologie (C.C.) and Service d'Hématologie (A.W.), CHU de Nîmes; Clinique Courlancy (P.C.), Reims; Service d'Hématologie (J.T.), Hôpital Cochin, APHP, Paris; Service d'Hématologie Clinique (K.L.), Centre Hospitalier, Le Mans; Service d'Hématologie (C. Serrier), Centre Hospitalier de Perpignan; Service d'Hématologie (C. Haioun), Hôpital Henri Mondor, Créteil, APHP; Service d'Hématologie Clinique (S. Chebrek), Centre Hospitalier d'Avignon; Service d'Hématologie (J.O.B.), CHU de Clermont-Ferrand; Service d'Hématologie (L.O.), Institut Universitaire du Cancer de Toulouse; Service de Neuro-Oncologie (E.T.), Aix-Marseille Univ, CNRS, INP, AP-HM, CHU de la Timone; Service d'Ophtalmologie (N.C.), Institut Curie, Université Paris V Descartes et PSL (Paris Science et Lettre), Paris; and Service d'Hématologie et Thérapie Cellulaire (E.G.), Centre d'Investigations Cliniques INSERM U1517, Centre Hospitalier Universitaire, Université de Tours, France.

Objective: Real-life studies on patients with primary CNS lymphoma (PCNSL) are scarce. Our objective was to analyze, in a nationwide population-based study, the current medical practice in the management of PCNSL.

Methods: The French oculo-cerebral lymphoma network (LOC) database prospectively records all newly diagnosed PCNSL cases from 32 French centers. Data of patients diagnosed between 2011 and 2016 were retrospectively analyzed.

Results: We identified 1,002 immunocompetent patients (43% aged >70 years, median Karnofsky Performance Status [KPS] 60). First-line treatment was high-dose methotrexate-based chemotherapy in 92% of cases, with an increasing use of rituximab over time (66%). Patients <60 years of age received consolidation treatment in 77% of cases, consisting of whole-brain radiotherapy (WBRT) (54%) or high-dose chemotherapy with autologous stem cell transplantation (HCT-ASCT) (23%). Among patients >60 years of age, WBRT and HCT-ASCT consolidation were administered in only 9% and 2%, respectively. The complete response rate to initial chemotherapy was 50%. Median progression-free survival was 10.5 months. For relapse, second-line chemotherapy, HCT-ASCT, WBRT, and palliative care were offered to 55%, 17%, 10%, and 18% of patients, respectively. The median, 2-year, and 5-year overall survival was 25.3 months, 51%, and 38%, respectively (<60 years: not reached [NR], 70%, and 61%; >60 years: 15.4 months, 44%, and 28%). Age, KPS, sex, and response to induction CT were independent prognostic factors in multivariate analysis.

Conclusions: Our study confirms the increasing proportion of elderly within the PCNSL population and shows comparable outcome in this population-based study with those reported by clinical trials, reflecting a notable application of recent PCNSL advances in treatment.
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http://dx.doi.org/10.1212/WNL.0000000000008900DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7238921PMC
March 2020

Development of a self-reported version of the G8 screening tool.

J Geriatr Oncol 2019 11 30;10(6):926-930. Epub 2019 Aug 30.

Department of Geriatric Medicine, Diakonessenhuis Utrecht, The Netherlands.

Introduction: The G8 is a widely used frailty screening tool in patients with cancer that was designed to be completed by healthcare professionals. A patient-reported version would enable a broader application. Aim of this study was to develop a self-reported version of the G8 and to assess its agreement with the original G8.

Materials And Methods: A self-reported version of the G8 was developed with the aid of communication specialists. Patients aged ≥ 70 years from two different study populations were included: 1. Patients with cancer and 2. Patients visiting the geriatric outpatient clinic. The original G8 was completed by an oncology nurse or clinical research assistant and patients completed the self-reported G8. Patients were blinded to results of the original G8. Kappas were calculated to measure the agreement between the self-reported and original G8 for both the individual items as well as for the cut-off for potential frailty (≤14).

Results: 161 patients participated, of whom 104 had cancer (65%). Patients with cancer more frequently completed all items than geriatric patients (all items completed in 94% versus 72%, p < 0.001). The agreement for potential frailty was substantial for patients with cancer (Kappa 0.63) and poor for geriatric patients (Kappa 0.05).

Conclusion: Completion of the self-reported G8 is feasible and agreement of its outcome with the original G8 outcome is sufficient for patients with cancer but not for geriatric patients. The self-reported G8 may therefore be a useful alternative to the original G8 in older patients with cancer.
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http://dx.doi.org/10.1016/j.jgo.2019.08.011DOI Listing
November 2019

A genome-wide association study identifies susceptibility loci for primary central nervous system lymphoma at 6p25.3 and 3p22.1: a LOC Network study.

Neuro Oncol 2019 08;21(8):1039-1048

(i) National Institute of Health and Medical Research (Inserm) U 1127, Paris, France, (ii) National Center for Scientific Research, Joint Research Unit 7225, Paris, France, (iii) Brain and Spine Institute (ICM), Paris, France, and (iv) Sorbonne University, Pierre and Marie Curie University, Paris 6, Paris, France.

Background: Primary central nervous system lymphoma (PCNSL) is a rare form of extra-nodal non-Hodgkin lymphoma. PCNSL is a distinct subtype of non-Hodgkin lymphoma, with over 95% of tumors belonging to the diffuse large B-cell lymphoma (DLBCL) group. We have conducted a genome-wide association study (GWAS) on immunocompetent patients to address the possibility that common genetic variants influence the risk of developing PCNSL.

Methods: We performed a meta-analysis of 2 new GWASs of PCNSL totaling 475 cases and 1134 controls of European ancestry. To increase genomic resolution, we imputed >10 million single nucleotide polymorphisms using the 1000 Genomes Project combined with UK10K as reference. In addition we performed a transcription factor binding disruption analysis and investigated the patterns of local chromatin by Capture Hi-C data.

Results: We identified independent risk loci at 3p22.1 (rs41289586, ANO10, P = 2.17 × 10-8) and 6p25.3 near EXOC2 (rs116446171, P = 1.95 x 10-13). In contrast, the lack of an association between rs41289586 and DLBCL suggests distinct germline predisposition to PCNSL and DLBCL. We found looping chromatin interactions between noncoding regions at 6p25.3 (rs11646171) with the IRF4 promoter and at 8q24.21 (rs13254990) with the MYC promoter, both genes with strong relevance to B-cell tumorigenesis.

Conclusion: To our knowledge this is the first study providing insight into the genetic predisposition to PCNSL. Our findings represent an important step in defining the contribution of common genetic variation to the risk of developing PCNSL.
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http://dx.doi.org/10.1093/neuonc/noz088DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6682213PMC
August 2019

[Clinical trials and elderly patients with cancer, the Geriatric Core Dataset (G-Code) tool].

Soins Gerontol 2019 May - Jun;24(137):35-37

Ucogir d'Aquitaine, Institut Bergonié, SIRIC BRIO, 229 cours de l'Argonne, 33000 Bordeaux, France.

Faced with the lack of evidence-based medicine concerning the efficacy and tolerance of cancer treatments in the extremely heterogeneous elderly population, and with no standardised geriatric evaluation in geriatric oncology clinical trials, the intergroup Dialog set itself the objective of establishing a minimal standardised geriatric evaluation for clinical trials. The evaluation must be simple, short and effective. It must comprise validated and reproducible measurement tools. The Geriatric Core Dataset, made up of seven items, has been formalised and validated by national and international experts.
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http://dx.doi.org/10.1016/j.sger.2019.03.010DOI Listing
July 2019

A systematic review on the association of the G8 with geriatric assessment, prognosis and course of treatment in older patients with cancer.

J Geriatr Oncol 2019 11 8;10(6):847-858. Epub 2019 May 8.

Department of Geriatric Medicine, Diakonessenhuis Utrecht, The Netherlands.

Aim: The aim of this systematic review is to summarise all available data on the use of the G8 screening tool in geriatric oncology, focusing on the diagnostic accuracy of the G8 to predict the presence of impairments on geriatric assessment (GA) and on its association with different clinical outcomes (survival, course of treatment and patient-centred outcomes).

Methods: A systematic search in MEDLINE and EMBASE for studies on the use of the G8 in older patients with cancer.

Results: The literature search identified 8987 reports, of which 54 publications from 46 studies were included (including 18 conference abstracts). 19 studies compared the diagnostic characteristics of the G8 with GA. Median sensitivity and specificity of the G8 for frailty on GA were respectively: 85% and 64%. Out of the 24 studies addressing the association of the G8 with survival, 15 (63%) found the G8 was associated with survival. Six out of fourteen studies (43%) reporting on treatment-related complications found an association between G8 scores and risk of complications. Treatment completion, health care utilisation and patient-centred outcomes were investigated less frequently.

Conclusion: The G8 is a useful diagnostic tool to identify older patients with cancer who require full GA and is associated with survival and treatment-related complications. Future prospective studies should investigate whether the G8 is predictive for other relevant clinical outcomes such as treatment completion and patient-centred outcomes.
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http://dx.doi.org/10.1016/j.jgo.2019.04.016DOI Listing
November 2019

Determinants of functional decline in older adults experiencing cancer (the INCAPAC study).

J Geriatr Oncol 2019 11 20;10(6):913-920. Epub 2019 Mar 20.

Univ. Bordeaux, Inserm, Bordeaux Population Health Research Center, Epicene team, UMR 1219, F-33000 Bordeaux, France; Clinical and Epidemiological Research Unit, INSERM CIC1401, Institut Bergonie, Comprehensive Cancer Center, F-33000 Bordeaux, France.

Background: Previous studies have reported on the higher risk of functional decline among older patients with cancer. However, few have focused on factors of functional decline in older persons with cancer and are mainly hospital-based and focus on consequences of cancer treatment. The aim of the study was to identify determinants of functional decline in older subjects with cancer in a population-based study.

Methods: Using cancer registries, we identified older subjects (age ≥ 65 years) with cancer in three prospective cohort studies from Gironde, a French department. Functional status was measured using the Instrumental Activities of Daily Living (IADL) and the basic Activities of Daily Living (ADL) scales, and functional decline was measured between cancer pre- and post-diagnosis visits. Studied variables were demographic and socioeconomic (age at diagnosis, sex, living alone, education), cancer-related (stage at diagnosis, treatment received), smoking status, health-related (polypharmacy, depressive symptomatology), and geriatric-specific (cognitive impairment or dementia). Analyses were performed using logistic regression models.

Results: Age (≥85 years), cognitive impairment or dementia, and advanced stage at diagnosis were associated with a higher risk of ADL limitations, whether considering death or not. Age (≥85 years), education and polypharmacy were associated with a higher risk of ADL and/or IADL limitations.

Conclusions: We identified factors that could impact on ADL and/or IADL limitations in older patients with cancer. The information on these determinants is useful in clinical settings to identify patients with cancer at high risk of functional decline.
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http://dx.doi.org/10.1016/j.jgo.2019.03.006DOI Listing
November 2019

Role of Calcium Signaling in GA101-Induced Cell Death in Malignant Human B Cells.

Cancers (Basel) 2019 Mar 1;11(3). Epub 2019 Mar 1.

Institut Bergonié, Comprehensive Cancer Centre, F-33000 Bordeaux, France.

GA101/obinutuzumab is a novel type II anti-CD20 monoclonal antibody (mAb), which is more effective than rituximab (RTX) in preclinical and clinical studies when used in combination with chemotherapy. Ca signaling was shown to play a role in RTX-induced cell death. This report concerns the effect of GA101 on Ca signaling and its involvement in the direct cell death induced by GA101. We reveal that GA101 triggered an intracellular Ca increase by mobilizing intracellular Ca stores and activating Orai1-dependent Ca influx in non-Hodgkin lymphoma cell lines and primary B-Cell Chronic Lymphocytic Leukemia (B-CLL) cells. According to the cell type, Ca was mobilized from two distinct intracellular compartments. In Raji, BL2, and B-CLL cells, GA101 induced a Ca release from lysosomes, leading to the subsequent lysosomal membrane permeabilization and cell death. Inhibition of this calcium signaling reduced GA101-induced cell death in these cells. In SU-DHL-4 cells, GA101 mobilized Ca from the endoplasmic reticulum (ER). Inhibition of ER replenishment, by blocking Orai1-dependent Ca influx, led to an ER stress and unfolded protein response (UPR) which sensitized these cells to GA101-induced cell death. These results revealed the central role of Ca signaling in GA101's action mechanism, which may contribute to designing new rational drug combinations improving its clinical efficacy.
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http://dx.doi.org/10.3390/cancers11030291DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6468563PMC
March 2019

Radiotherapy or Autologous Stem-Cell Transplantation for Primary CNS Lymphoma in Patients 60 Years of Age and Younger: Results of the Intergroup ANOCEF-GOELAMS Randomized Phase II PRECIS Study.

J Clin Oncol 2019 04 20;37(10):823-833. Epub 2019 Feb 20.

3 Institut Curie, Site Saint-Cloud, Saint-Cloud, France.

Purpose: To determine the efficacy and toxicity of chemoimmunotherapy followed by either whole-brain radiotherapy (WBRT) or intensive chemotherapy and autologous stem-cell transplantation (ASCT) as a first-line treatment of primary CNS lymphoma (PCNSL).

Patients And Methods: Immunocompetent patients (18 to 60 years of age) with untreated PCNSL were randomly assigned to receive WBRT or ASCT as consolidation treatment after induction chemotherapy consisting of two cycles of R-MBVP (rituximab 375 mg/m day (D) 1, methotrexate 3 g/m D1; D15, VP16 100 mg/m D2, BCNU 100 mg/m D3, prednisone 60 mg/kg/d D1-D5) followed by two cycles of R-AraC (rituximab 375 mg/m D1, cytarabine 3 g/m D1 to D2). Intensive chemotherapy consisted of thiotepa (250 mg/m/d D9; D8; D7), busulfan (8 mg/kg D6 through D4), and cyclophosphamide (60 mg/kg/d D3; D2). WBRT delivered 40 Gy (2 Gy/fraction). The primary end point was 2-year progression-free survival. Cognitive outcome was the main secondary end point. Analysis was intention to treat in a noncomparative phase II trial.

Results: Between October 2008 and February 2014, 140 patients were recruited from 23 French centers. Both WBRT and ASCT met the predetermined threshold (among the first 38 patients in each group, at least 24 patients were alive and disease free at 2 years). The 2-year progression-free survival rates were 63% (95% CI, 49% to 81%) and 87% (95% CI, 77% to 98%) in the WBRT and ASCT arms, respectively. Toxicity deaths were recorded in one and five patients after WBRT and ASCT, respectively. Cognitive impairment was observed after WBRT, whereas cognitive functions were preserved or improved after ASCT.

Conclusion: WBRT and ASCT are effective consolidation treatments for patients with PCNSL who are 60 years of age and younger. The efficacy end points tended to favor the ASCT arm. The specific risk of each procedure should be considered.
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http://dx.doi.org/10.1200/JCO.18.00306DOI Listing
April 2019

Modulation of the ATM/autophagy pathway by a G-quadruplex ligand tips the balance between senescence and apoptosis in cancer cells.

Nucleic Acids Res 2019 04;47(6):2739-2756

Institut Bergonié, Université de Bordeaux, INSERM U1218, F-33076 Bordeaux, France.

G-quadruplex ligands exert their antiproliferative effects through telomere-dependent and telomere-independent mechanisms, but the inter-relationships among autophagy, cell growth arrest and cell death induced by these ligands remain largely unexplored. Here, we demonstrate that the G-quadruplex ligand 20A causes growth arrest of cancer cells in culture and in a HeLa cell xenografted mouse model. This response is associated with the induction of senescence and apoptosis. Transcriptomic analysis of 20A treated cells reveals a significant functional enrichment of biological pathways related to growth arrest, DNA damage response and the lysosomal pathway. 20A elicits global DNA damage but not telomeric damage and activates the ATM and autophagy pathways. Loss of ATM following 20A treatment inhibits both autophagy and senescence and sensitizes cells to death. Moreover, disruption of autophagy by deletion of two essential autophagy genes ATG5 and ATG7 leads to failure of CHK1 activation by 20A and subsequently increased cell death. Our results, therefore, identify the activation of ATM by 20A as a critical player in the balance between senescence and apoptosis and autophagy as one of the key mediators of such regulation. Thus, targeting the ATM/autophagy pathway might be a promising strategy to achieve the maximal anticancer effect of this compound.
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http://dx.doi.org/10.1093/nar/gkz095DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6451122PMC
April 2019

The prognostic value of G8 for functional decline.

J Geriatr Oncol 2019 11 9;10(6):921-925. Epub 2019 Jan 9.

Department of Medical Oncology, Institut Bergonié, Bordeaux, France; Université de Bordeaux, France; Inserm UMR1218, France. Electronic address:

Purpose: Clinical experience suggests that functional decline (FD) during treatment may have a major adverse impact on outcome. Geriatric assessment of older patients before cancer treatment is usually based on use of a screening tool (such as G8) followed by comprehensive geriatric assessment (CGA). However, many oncology teams cannot implement geriatric oncology management due to non-availability of geriatricians. Consequently, we decided to evaluate whether a procedure using G8 and routinely available factors could help oncologists foresee the outcome in patients ≥70: we firstly evaluated whether functional decline is a determinant of early death, then searched for predictors of early functional decline (measured before initiation of the second cycle of chemotherapy), including G8 but voluntarilly excluding CGA.

Methods: We tested the value of clinical, biological factors and early FD to predict early death on a cohort of 292 patients (≥70 years) treated with first-line chemotherapy. We then used a logistic regression model to search for pretreatment predictors of FD, including the same factors and G8 but excluding CGA.

Results: FD occurred in 48 patients. In multivariate analyses, early FD (OR = 4.13, 95% CI [1.89; 9.04], p < .01), disease extension (OR = 4.55, 95% CI [1.96; 10.57]; p < .01), and being male (OR = 2.59, 95% CI [1.12; 5.97], p = .02) were significant prognostic factors for early death; G8 was the only significant factor associated with FD (OR = 4.38, 95% CI [1.28; 14.92], p = .018).

Conclusions: FD has an important prognostic significance in patients ≥70 treated with chemotherapy, and G8 predicts for its occurrence. These data reinforce the routine use of G8 in the management of these patients.
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http://dx.doi.org/10.1016/j.jgo.2018.12.004DOI Listing
November 2019

Calcium Independent Effect of Orai1 and STIM1 in Non-Hodgkin B Cell Lymphoma Dissemination.

Cancers (Basel) 2018 Oct 26;10(11). Epub 2018 Oct 26.

Department of Life and Health Sciences, University of Bordeaux, F-33076 Bordeaux, France.

Ca release-activated Ca channels, composed of Orai1 and STIM1 (stromal interaction molecule 1) proteins, are the main Ca entry mechanism in lymphocytes. Their role in cell migration and metastasis is demonstrated in solid cancers but it remains elusive in malignant hemopathies. Diffuse large B cell lymphoma (DLBCL) is characterized by the dissemination of neoplastic B cells throughout the organism which is under the control of chemokines such as Stromal Derived Factor 1 (SDF-1) and its receptor CXCR4. CXCR4 activation triggers a complex intracellular signaling including an increase in intracellular Ca concentration whose role is still unclear. Using pharmacological and genetic approaches, we revealed that STIM1 and Orai1 were responsible for Ca influx induced by SDF-1. Furthermore, we provide in vitro and in vivo evidence that they are necessary for basal or SDF-1-induced DLBCL cell migration which is independent of Ca entry. We identify that they act as effectors coupling RhoA and ROCK dependent signaling pathway to MLC2 phosphorylation and actin polymerization. Finally, we revealed an alteration of Orai1 and STIM1 expression in extra-nodal DLBCL. Thus, we discovered a novel Ca-independent but Orai1 and STIM1-dependent signaling pathway involved in basal and CXCR4 dependent cell migration, which could be relevant for DLBCL physiopathology.
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http://dx.doi.org/10.3390/cancers10110402DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6267368PMC
October 2018

Bendamustine and rituximab in elderly patients with low-tumour burden follicular lymphoma. Results of the LYSA phase II BRIEF study.

Br J Haematol 2018 10 16;183(1):76-86. Epub 2018 Aug 16.

Lysa, University Hospital, Lyon, France.

The treatment of low-tumour burden follicular lymphoma (LTBFL) remains a challenge. Rituximab-based strategies may be improved by adding chemotherapy. This Lymphoma Study Association multicentre phase II study assessed rituximab and bendamustine in 63 patients with untreated LTBFL who were aged over 60 years old and had a follicular lymphoma International Prognostic Index (FLIPI) score ≥2. Induction comprised 4 weekly cycles of rituximab 375 mg/m intravenously combined with 2 cycles of bendamustine 90 mg/m days 1-2 with a 28-day interval, followed by twelve cycles of 375 mg/m rituximab maintenance therapy every 8 weeks. The primary endpoint was complete response (CR)/unconfirmed CR (CRu), at 12 weeks. Median age was 67·4 years and median FLIPI was 3. Ultimately, 18 patients (29%) had high tumour burden according to Groupe d'Etude des Lymphomes Folliculaires criteria. The 12-week CR/CRu rate was 54·0% and the overall response rate was 93·7%. Surprisingly, 3 patients died during maintenance (2 sepsis, 1 neoplasm). Progression-free survival was 85·4% at 24 months. In LTBFL patients with FLIPI ≥2, two cycles of rituximab and bendamustine result in a CR rate of 54·0%. However, the treatment-related deaths observed do not allow this regimen to be recommended for LTBFL patients aged over 60 years. EudraCT: 2010-020757-14; ClinicalTrials.gov: NCT01313611.
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http://dx.doi.org/10.1111/bjh.15513DOI Listing
October 2018

mTOR Inhibition via Displacement of Phosphatidic Acid Induces Enhanced Cytotoxicity Specifically in Cancer Cells.

Cancer Res 2018 09 27;78(18):5384-5397. Epub 2018 Jul 27.

Institut de Chimie des Substances Naturelles, CNRS UPR 2301, Gif-sur-Yvette, France.

The mTOR is a central regulator of cell growth and is highly activated in cancer cells to allow rapid tumor growth. The use of mTOR inhibitors as anticancer therapy has been approved for some types of tumors, albeit with modest results. We recently reported the synthesis of ICSN3250, a halitulin analogue with enhanced cytotoxicity. We report here that ICSN3250 is a specific mTOR inhibitor that operates through a mechanism distinct from those described for previous mTOR inhibitors. ICSN3250 competed with and displaced phosphatidic acid from the FRB domain in mTOR, thus preventing mTOR activation and leading to cytotoxicity. Docking and molecular dynamics simulations evidenced not only the high conformational plasticity of the FRB domain, but also the specific interactions of both ICSN3250 and phosphatidic acid with the FRB domain in mTOR. Furthermore, ICSN3250 toxicity was shown to act specifically in cancer cells, as noncancer cells showed up to 100-fold less sensitivity to ICSN3250, in contrast to other mTOR inhibitors that did not show selectivity. Thus, our results define ICSN3250 as a new class of mTOR inhibitors that specifically targets cancer cells. ICSN3250 defines a new class of mTORC1 inhibitors that displaces phosphatidic acid at the FRB domain of mTOR, inducing cell death specifically in cancer cells but not in noncancer cells. .
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http://dx.doi.org/10.1158/0008-5472.CAN-18-0232DOI Listing
September 2018

Determinants of cancer treatment and mortality in older cancer patients using a multi-state model: Results from a population-based study (the INCAPAC study).

Cancer Epidemiol 2018 08 25;55:39-44. Epub 2018 May 25.

Univ. Bordeaux, Inserm, Bordeaux Population Health Research Center, Epicene team, UMR 1219, F-33000 Bordeaux, France; Clinical and Epidemiological Research Unit, INSERM CIC1401, Institut Bergonié, Comprehensive Cancer Center, F-33000 Bordeaux, France.

Introduction: Several studies have reported disparities in the care management and survival of older cancer patients. The aim of our study was to identify determinants of treatment administration in this population of cancer patients aged over 65 years taking into account competing risks of death.

Methods: The INCAPAC study is a population-based study. Four cancer registries and three prospective cohort studies on older subjects (age ≥65 years) from Gironde, a French department, were merged to identify older cancer patients. We used a non-parametric multi-state model including three states (cancer, treatment and all-cause death). This model allowed studying determinants of treatment administration (all treatments including curative, symptomatic and palliative treatments) and mortality considering that patients can move from cancer state to death state, either directly or through the treatment phase. Studied variables were demographic and socioeconomic-, cancer-, health-, and geriatric-related.

Results: A total of 450 patients were included in the analyses. They were mainly aged 85 and over, men and educated. Among included patients, 372 (83%) received cancer treatment. In the final multivariate model, dementia was associated with a lower likelihood of receiving cancer treatment (HR = 0.68, 95% CI = 0.47-0.99). In treated patients, age, sex, comorbidities, dependency and stage at diagnosis were associated to all-cause mortality, and in untreated patients, diagnosis of dementia and stage at diagnosis were associated to mortality.

Conclusion: Further studies are necessary to understand the impact of geriatric impairments on treatment administration and to develop clinical practice guidelines.
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http://dx.doi.org/10.1016/j.canep.2018.04.013DOI Listing
August 2018

Impact of geriatric assessment for the therapeutic decision-making of breast cancer: results of a French survey. AFSOS and SOFOG collaborative work.

Breast Cancer Res Treat 2018 Apr 14;168(2):433-441. Epub 2017 Dec 14.

Department of Medical Oncology, Lyon Sud University Hospital, Hospices Civils de Lyon and Lyon University, Pierre-Bénite, France.

Background: Cancer management in the elderly is often considered as suboptimal, highly variable, and rarely evidence-based. Data are needed to understand decision-making processes in this population.

Materials And Methods: A survey was performed in France to describe decision-making in gynaecologic patients over 70. It followed a three-step method: (1) 101 representative physicians questioned about treatment decision criteria; (2) simplified individual data were collected; (3) as well as detailed data patients receiving chemotherapy. This analysis refers to breast cancer subgroup of patients.

Results: Main decision criteria were performance status, comorbidities, and renal function. In adjuvant setting, the main concern was life expectancy, whereas it was quality of life in metastatic setting. Of the 631 patients entered in the simplified analysis, 41% had been evaluated by a geriatrician, 67% received chemotherapy. In the detailed analysis, patients older than 75 were more likely to receive a monochemotherapy and to be treated with weekly/divided dose. In adjuvant setting, respectively, 19, 55, and 26% of the patients were treated with regimen validated in the elderly, validated in a younger population, and not validated. A G-CSF was prescribed in 48% of the patients, as primary prophylaxis in 78 and in 41% of patients with a risk of febrile neutropenia < 10%.

Conclusion: Geriatric covariates become an increasing concern in the decision-making process. This survey also suggests an insufficient use of validated chemotherapy regimens. To date, age remains a risk factor for heterogeneity in oncologic practice justifying a persistent effort for elaborating and disclosing specific recommendations.
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http://dx.doi.org/10.1007/s10549-017-4607-8DOI Listing
April 2018

R-CHOP 14 with or without radiotherapy in nonbulky limited-stage diffuse large B-cell lymphoma.

Blood 2018 01 23;131(2):174-181. Epub 2017 Oct 23.

Hematology and Cell Therapy Department, CIC INSERM U1415, CHU de Poitiers, and CIC INSERM 1402, Université de Poitiers, Poitiers, France.

The benefit of radiotherapy (RT) after chemotherapy in limited-stage diffuse large B-cell lymphoma (DLBCL) remains controversial. We conducted a randomized trial in patients with nonbulky limited-stage DLBCL to evaluate the benefit of RT after rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP). Patients were stratified according to the modified International Prognostic Index, including lactate dehydrogenase, Eastern Cooperative Oncology Group performance status, age, and disease stage. The patients received 4 or 6 consecutive cycles of R-CHOP delivered once every 2 weeks, followed or not by RT at 40 Gy delivered 4 weeks after the last R-CHOP cycle. All patients were evaluated by fluorodeoxyglucose-positron emission tomography scans performed at baseline, after 4 cycles of R-CHOP, and at the end of treatment. The primary objective of the trial was event-free survival (EFS) from randomization. The trial randomly assigned 165 patients in the R-CHOP arm and 169 in the R-CHOP plus RT arm. In an intent-to-treat analysis with a median follow-up of 64 months, 5-year EFS was not statistically significantly different between the 2 arms, with 89% ± 2.9% in the R-CHOP arm vs 92% ± 2.4% in the R-CHOP plus RT arm (hazard ratio, 0.61; 95% confidence interval [CI], 0.3-1.2; = .18). Overall survival was also not different at 92% (95% CI, 89.5%-94.5%) for patients assigned to R-CHOP alone and 96% (95% CI, 94.3%-97.7%) for those assigned to R-CHOP plus RT ( = not significant). R-CHOP alone is not inferior to R-CHOP followed by RT in patients with nonbulky limited-stage DLBCL. This trial was registered at www.clinicaltrials.gov as #NCT00841945.
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http://dx.doi.org/10.1182/blood-2017-07-793984DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5757680PMC
January 2018

Sociodemographic, socioeconomic, and clinical determinants of survival in patients with cancer: A systematic review of the literature focused on the elderly.

J Geriatr Oncol 2018 01 10;9(1):6-14. Epub 2017 Oct 10.

Univ. Bordeaux, Inserm, Bordeaux Population Health Research Center, Epicene team, UMR 1219, F-33000 Bordeaux, France; Clinical and Epidemiological Research Unit, INSERM CIC1401, Institut Bergonie, Comprehensive Cancer Center, F-33000 Bordeaux, France.

Studies on cancer survival have revealed disparities not only between the elderly and their younger counterparts, but also among the elderly themselves. The aim of this work was to identify sociodemographic, socioeconomic, clinical, and care-related determinants of survival or mortality in older patients with cancer by a systematic synthesis of the literature. Understanding these factors is of great value for guiding health policies and programs aimed at reducing cancer survival disparities. We conducted a search of MEDLINE and SCOPUS databases under PRISMA guidelines. Results were limited to articles published in English and French from 2005 to 2015, and focused on elderly patients with cancer. The article selection was performed in a stepwise fashion: title, abstract, and full-text selection. Studied determinants and results of each article were synthesized. Forty-five articles were eligible and included in the study. We observed different ways of measuring socioeconomic status, comorbidities, and treatment among studies. Cancer-specific and overall survival were the main studied outcomes. Advanced age, low income, low socioeconomic status, presence of comorbidities, advanced stage, and poor tumor grade were found to be associated with lower survival or higher mortality. On the other hand, female gender and being married were predictive of increased survival or lower mortality. The next logical step is to carry out studies on elderly patients from different countries and to incorporate pertinent factors in a unique model. Moreover, specific geriatric health impairments should be taken into account in further research because of their association with survival.
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http://dx.doi.org/10.1016/j.jgo.2017.07.007DOI Listing
January 2018

Rational therapeutic choice for older patients with lymphoma.

Curr Opin Oncol 2017 Sep;29(5):322-327

aDepartment of Hematology, Institut Jules Bordet (ULB), Brussels, Belgium bDepartment of Medical Oncology, Institut Bergonié, Bordeaux, France.

Purpose Of Review: The choice for an optimal treatment in older lymphoma patients is a real challenge for hemato-oncologists. They have to treat a potentially curative lymphoma, and concomitantly protect their patients from unacceptable toxicities. Some recommendations are provided for the major subtypes of lymphomas including the antitumoral treatment and primarily the optimal supportive care.

Recent Findings: All the recent literature data converge to say that the approach of an older patient with a malignant hemopathy is a multistep procedure. This process comprises the appraisal of life expectancy of the patient with or without the disease, the prognostic factors of the tumor, the functional, physiological and cognitive functions evaluation, the socio-economical environment and the patient's expectancy in terms of quality of life. Major progresses have been achieved in the management of diffuse large B cell lymphoma and mantle cell lymphoma in patients up to 80 and above 80 years old.

Summary: With all these information in hands, the hematologist will decide if the treatment's objective is the standard treatment with optimal supportive care (fit patients), tailor-made adapted chemotherapy (unfit patients) or preservation of quality of life (frail patients).
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http://dx.doi.org/10.1097/CCO.0000000000000394DOI Listing
September 2017

Immune checkpoint inhibitors and elderly people: A review.

Eur J Cancer 2017 09 6;82:155-166. Epub 2017 Jul 6.

Department of Medical Oncology, Hôpital Saint-André, Bordeaux University Hospital-CHU Bordeaux, France; University of Bordeaux, Bordeaux, France; Clinical Investigational Center, CIC, INSERM CIC 1401, Bordeaux University Hospital, Bordeaux, France.

Immune checkpoint inhibitors, including targeting programmed cell death 1, programmed cell death ligand 1, and cytotoxic T lymphocyte antigen 4 pathways, are a new type of cancer treatment. This approach of targeting the immune system has demonstrated dramatic efficacy for several cancers, and various drugs have been approved by health authorities and are used in clinical practice. Elderly patients (≥65 years) represent most of the cancers diagnosed and deaths by age group, with an increase expected over the next decade. However, this subgroup of patients is under-represented in clinical trials. Ageing is also associated with a decrease in the effectiveness of the immune system and in alterations to it. Few specific trials have been carried out for immunotherapy in elderly people, with most patients considered to be fit. In this review, we discuss the impact of ageing and immunosenescence on immune system functions, and we assess the safety and efficacy of immune checkpoint inhibitors in elderly patients, principally from the data of pivotal clinical trials with subgroup analysis. Tolerance in elderly patients seems similar to younger people, but efficacy seems different between younger and elderly patients according to the type of cancer, some showing no difference and others less efficacy in the elderly subgroup. However, the numbers in elderly groups are small and more investigation is needed, with specific clinical trials for elderly cancer patients.
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http://dx.doi.org/10.1016/j.ejca.2017.05.044DOI Listing
September 2017

mTORC1 inhibition in cancer cells protects from glutaminolysis-mediated apoptosis during nutrient limitation.

Nat Commun 2017 01 23;8:14124. Epub 2017 Jan 23.

Institut Européen de Chimie et Biologie, INSERM U1218, Université de Bordeaux, 2 Rue Robert Escarpit, Pessac 33607, France.

A master coordinator of cell growth, mTORC1 is activated by different metabolic inputs, particularly the metabolism of glutamine (glutaminolysis), to control a vast range of cellular processes, including autophagy. As a well-recognized tumour promoter, inhibitors of mTORC1 such as rapamycin have been approved as anti-cancer agents, but their overall outcome in patients is rather poor. Here we show that mTORC1 also presents tumour suppressor features in conditions of nutrient restrictions. Thus, the activation of mTORC1 by glutaminolysis during nutritional imbalance inhibits autophagy and induces apoptosis in cancer cells. Importantly, rapamycin treatment reactivates autophagy and prevents the mTORC1-mediated apoptosis. We also observe that the ability of mTORC1 to activate apoptosis is mediated by the adaptor protein p62. Thus, the mTORC1-mediated upregulation of p62 during nutrient imbalance induces the binding of p62 to caspase 8 and the subsequent activation of the caspase pathway. Our data highlight the role of autophagy as a survival mechanism upon rapamycin treatment.
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http://dx.doi.org/10.1038/ncomms14124DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5264013PMC
January 2017

Patterns of response and relapse in primary CNS lymphomas after first-line chemotherapy: imaging analysis of the ANOCEF-GOELAMS prospective randomized trial.

Neuro Oncol 2017 03;19(3):422-429

APHP, Sorbonne Universités, UPMC Univ Paris 06, Service de neurologie Mazarin, Groupe Hospitalier Pitié-Salpêtrière, Paris, France.

Background: Our aim was to review MRI characteristics of patients with primary CNS lymphoma (PCNSL) enrolled in a randomized phase II trial and to evaluate their potential prognostic value and patterns of relapse, including T2 fluid attenuated inversion recovery (FLAIR) MRI abnormalities.

Methods: Neuroimaging findings in 85 patients with PCNSL enrolled in a prospective trial were reviewed blinded to outcomes. MRI characteristics and responses according to International PCNSL Collaborative Group (IPCG) criteria were correlated with progression-free survival (PFS) and overall survival (OS).

Results: Multivariate analysis showed that objective response at 2 months (P < .001) and at end of treatment (P = .015) were predictors of prolonged OS. Infratentorial location (P = .008) and large (>11.4 cm3) enhancing tumor volume (P = .006) were associated with poor OS and PFS, respectively. Ratio of change in product of largest diameters at early MRI evaluation but not timing of complete response achievement (early vs delayed) was prognostic for OS. Sixty-nine patients relapsed. Relapse in the brain (n = 52) involved an initial enhancing site, a different site, or both in 46%, 40%, and 14% of patients, respectively. At baseline, non-enhancing T2-FLAIR hypersignal lesions distant from the enhancing tumor site were detected in 18 patients. These lesions markedly decreased (>50%) in 16 patients after chemotherapy, supporting their neoplastic nature. Of these patients, 10/18 relapsed, half (n = 5) in the initially non-enhancing T2-FLAIR lesions.

Conclusions: Baseline tumor size and infratentorial localization are of prognostic value in PCNSL. Our findings provide evidence that non-enhancing FLAIR abnormalities may add to overall tumor burden, suggesting that response criteria should be refined to incorporate evaluation of T2-weighted/FLAIR sequences.
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http://dx.doi.org/10.1093/neuonc/now238DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5464299PMC
March 2017

Consolidation anti-CD22 fractionated radioimmunotherapy with Y-epratuzumab tetraxetan following R-CHOP in elderly patients with diffuse large B-cell lymphoma: a prospective, single group, phase 2 trial.

Lancet Haematol 2017 Jan 8;4(1):e35-e45. Epub 2016 Dec 8.

Institut Bergonié, Cancer Centre, and University of Bordeaux, Bordeaux, France.

Background: Radioimmunotherapy represents a potential option as consolidation after chemoimmunotherapy in patients with diffuse large B-cell lymphoma who are not candidates for transplantation. We aimed to assess activity and toxicity of fractionated radioimmunotherapy using anti-CD22 Y-epratuzumab tetraxetan as consolidation after front-line induction chemoimmunotherapy in untreated elderly patients with diffuse large B-cell lymphoma.

Methods: We did a prospective, single-group, phase 2 trial at 28 hospitals in France, with patients recruited from 17 hospitals. Eligible patients were aged 60-80 years with bulky stage 2-3 or stage 3-4 CD20-positive diffuse large B-cell lymphoma, previously untreated, and not eligible for transplantation. Patients received six cycles of R-CHOP (rituximab [375 mg/m], cyclophosphamide [750 mg/m], doxorubicin [50 mg/m], and vincristine [1·4 mg/m, up to 2 mg] all on day 1, and prednisone [40 mg/m] daily for 5 days), administered every 14 days. 6-8 weeks after R-CHOP, responders received two doses of 15 mCi/m (555 MBq/m) Y-epratuzumab tetraxetan administered 1 week apart. The primary endpoint was 2 year event-free survival in all registered eligible patients who received at least 1 day of study treatment; the safety analysis was done in the same population. This trial is registered with ClinicalTrials.gov, number NCT00906841.

Findings: Between Oct 22, 2008, and Dec 16, 2010, we recruited 75 patients, of whom four (5%) were excluded after central pathology review; hence, 71 (95%) patients were included in the analysis. All patients started induction treatment; 57 (80%) received radioimmunotherapy. With a median follow-up of 37 months (IQR 30-44), the estimated 2 year event-free survival was 75% (95% CI 63-84). Radioimmunotherapy toxicity consisted of grade 3-4 thrombocytopenia in 48 (84%) of 57 patients and neutropenia in 45 (79%) of 57 patients. One patient developed myelodysplastic syndrome 28 months after receiving radioimmunotherapy and one patient developed acute myeloid leukaemia 5 months after receiving radioimmunotherapy.

Interpretation: Fractionated radioimmunotherapy with Y-epratuzumab tetraxetan might be appropriate for response consolidation after induction chemotherapy in older patients with advanced diffuse large B-cell lymphoma, but further comparative studies are needed.

Funding: Immunomedics, Amgen, Canceropôle Grand Ouest, the GOELAMS/LYSA group and the French National Agency for Research (Investissements d'Avenir).
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http://dx.doi.org/10.1016/S2352-3026(16)30168-5DOI Listing
January 2017

Walking a tightrope: clinical use of ibrutinib in mantle cell lymphoma in the elderly.

Hematology Am Soc Hematol Educ Program 2016 Dec;2016(1):432-436

Department of Medical Oncology, Institut Bergonie, Bordeaux, France.

Representative clinical case. A 74-year-old male patient was diagnosed with stage 3 mantle cell lymphoma in 2012. Because he was ineligible for intensive treatment (age, previous myocardial infarction [MI]), he received rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) chemoimmunotherapy for 6 cycles (reaching complete response) and then rituximab maintenance (RM) for 2 years. One year after the end of RM, he relapsed with disseminated disease. He was started on ibrutinib 560 mg/day. Two weeks after the start of ibrutinib, he developed grade 3 diarrhea that required interruption of ibrutinib. Two weeks after the regular dose was restarted (month 3), the patient had repeated bleeding (patient was receiving aspirin for previous MI) and had to stop ibrutinib again. Because the patient was in partial response (PR) with lack of disease-associated symptoms, he was restarted on ibrutinib 280 mg/day with no further adverse events, and he had maintained PR at last follow-up (month 9 on ibrutinib).
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http://dx.doi.org/10.1182/asheducation-2016.1.432DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6142482PMC
December 2016