Publications by authors named "Adrian Tempescul"

58 Publications

Identification of altered cell signaling pathways using proteomic profiling in stable and progressive chronic lymphocytic leukemia.

J Leukoc Biol 2021 Jul 20. Epub 2021 Jul 20.

Univ Brest, INSERM, UMR1227, B Lymphocytes and Autoimmunity, Brest, France.

Chronic lymphocytic leukemia (CLL) is characterized by significant biologic and clinical heterogeneity. This study was designed to explore CLL B-cells' proteomic profile in order to identify biologic processes affected at an early stage and during disease evolution as stable or progressive. Purified B cells from 11 untreated CLL patients were tested at two time points by liquid chromatography-tandem mass spectrometry. Patients included in the study evolved to either progressive (n = 6) or stable disease (n = 5). First, at an early stage of the disease (Binet stage A), based on the relative abundance levels of 389 differentially expressed proteins (DEPs), samples were separated into stable and progressive clusters with the main differentiating factor being the RNA splicing pathway. Next, in order to test how the DEPs affect RNA splicing, a RNA-Seq study was conducted showing 4217 differentially spliced genes between the two clusters. Distinct longitudinal evolutions were observed with predominantly proteomic modifications in the stable CLL group and spliced genes in the progressive CLL group. Splicing events were shown to be six times more frequent in the progressive CLL group. The main aberrant biologic processes controlled by DEPs and spliced genes in the progressive group were cytoskeletal organization, Wnt/β-catenin signaling, and mitochondrial and inositol phosphate metabolism with a downstream impact on CLL B-cell survival and migration. This study suggests that proteomic profiles at the early stage of CLL can discriminate progressive from stable disease and that RNA splicing dysregulation underlies CLL evolution, which opens new perspectives in terms of biomarkers and therapy.
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http://dx.doi.org/10.1002/JLB.4HI0620-392RDOI Listing
July 2021

Gonadal Function Recovery in Patients With Advanced Hodgkin Lymphoma Treated With a PET-Adapted Regimen: Prospective Analysis of a Randomized Phase III Trial (AHL2011).

J Clin Oncol 2021 Jun 22:JCO2100068. Epub 2021 Jun 22.

Department of Haematology, University Hospital F Mitterrand and Inserm UMR1231, Dijon, France.

Purpose: The prospective, randomized AHL2011 trial demonstrated that the use of the doxorubicin, bleomycin, vinblastine, and dacarbazine regimen (ABVD) after two cycles of bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, and prednisone (BEACOPP) in early responders on the basis of a positron emission tomography (PET)-driven strategy was safe and minimized toxicity compared with standard 6 BEACOPP cycles. This substudy investigated the benefit of this strategy in gonadal function and fertility in patients under 45 years old.

Methods: Ovarian function was assessed by serum measurement of follicle-stimulating hormone (FSH), estradiol, and anti-müllerian hormone in women, and semen analysis, FSH, and testosterone levels were used to evaluate testicular function in men at baseline, end of treatment, and during 5 years of follow-up.

Results: A total of 145 women and 424 men, enrolled between May 19, 2011, and April 29, 2014, were included. The risk of premature ovarian insufficiency (FSH > 24 IU/L) and of having a low ovarian reserve (anti-müllerian hormone < 0.5 ng/mL) was reduced after treatment in the PET-driven group (odds ratio [OR], 0.20; 95% CI, 0.08 to 0.50; = .001 and OR, 0.15; 95% CI, 0.04 to 0.56, = .005, respectively). Both parameters were correlated with age and dose of alkylating agents. However, no significant differences were observed in terms of pregnancy rates. Men in the PET-driven group had a higher recovery rate of sperm parameters after treatment compared with the standard BEACOPP group, as well as a lower risk of severe testicular damage (OR, 0.26; 95% CI, 0.13 to 0.5; < .0001) and a higher likelihood of achieving pregnancy (OR, 3.7; 95% CI, 1.4 to 9.3; = .004).

Conclusion: Although both treatments affected ovarian reserve and spermatogenesis, the PET-driven strategy decreased the risk of gonadal dysfunction and infertility in advanced Hodgkin lymphoma.
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http://dx.doi.org/10.1200/JCO.21.00068DOI Listing
June 2021

Intravenous high-dose methotrexate based systemic therapy in the treatment of isolated primary vitreoretinal lymphoma: An LOC network study.

Am J Hematol 2021 07 3;96(7):823-833. Epub 2021 May 3.

Ophthalmology, Centre Hospitalier Universitaire de Brest, Brest, France.

The treatment of primary vitreoretinal lymphoma (PVRL) remains controversial regarding the use of local, systemic, or combined treatments. The aim of this study was to analyze the efficacy and toxicity of intravenous high-dose methotrexate (IV HD-MTX) based systemic therapy in a uniformly treated population of PVRL patients. From a nationwide French database, we retrospectively selected 59 patients (median age: 70 years, median Karnofsky Performance Status: 90%) with isolated PVRL at diagnosis who received first-line treatment with HD-MTX between 2011 and 2018. 8/59 patients also received a local treatment. No deaths or premature discontinuations of MTX due to toxicity were reported. A complete response was obtained in 40/57 patients after chemotherapy. Before treatment, IL-10 was elevated in the aqueous humor (AH) or in the vitreous in 89% of patients. After treatment, AH IL-10 was undetectable in 87% of patients with a CR/uCR/PR and detectable in 92% of patients with PD/SD. After a median follow-up of 61 months, 42/59 (71%) patients had relapsed, including 29 isolated ocular relapses as the first relapse and a total of 22 brain relapses. The median overall survival, progression-free survival, ocular-free survival and brain-free survival were 75, 18, 29 and 73 months, respectively. IV HD-MTX based systemic therapy as a first-line treatment for isolated PVRL is feasible, with acceptable toxicity, even in an elderly population. This strategy seems efficient to prevent brain relapse with prolonged overall survival. However, the ocular relapse rate remains high. New approaches are needed to improve local control of this disease, and ocular assessment could be completed by monitoring AH IL-10.
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http://dx.doi.org/10.1002/ajh.26199DOI Listing
July 2021

MicroRNAs Associated With a Good Prognosis of Acute Myeloid Leukemia and Their Effect on Macrophage Polarization.

Front Immunol 2020 15;11:582915. Epub 2021 Jan 15.

Department of Hematology, Iuliu Haţieganu University of Medicine and Pharmacy, Cluj-Napoca, Romania.

Acute myeloid leukemia (AML) is an aggressive myeloid malignancy with poor outcomes despite very intensive therapeutic approaches. For the majority of patients which are unfit and treated less intensively, the prognosis is even worse. There has been unspectacular progress in outcome improvement over the last decades and the development of new approaches is of tremendous interest. The tumor microenvironment is credited with an important role in supporting cancer growth, including leukemogenesis. Macrophages are part of the tumor microenvironment and their contribution in this setting is increasingly being deciphered, these cells being credited with a tumor supporting role. Data on macrophage role and polarization in leukemia is scarce. MicroRNAs (miRNAs) have a role in the post-transcriptional regulation of gene expression, by impending translation and promoting degradation of messenger RNAs. They are important modulators of cellular pathways, playing major roles in normal hematopoietic differentiation. miRNA expression is significantly correlated with the prognosis of hematopoietic malignancies, including AML. Oncogenic miRNAs correlate with poor prognosis, while tumor suppressor miRNAs, which inhibit the expression of proto-oncogenes, are correlated with a favorable prognosis. miRNAs are proposed as biomarkers for diagnosis and prognosis and are regarded as therapeutic approaches in many cancers, including AML. miRNAs with epigenetic or modulatory activity, as well as with synergistic activity with chemotherapeutic agents, proved to be promising therapeutic targets in experimental, pre-clinical approaches. The clinical availability of emerging compounds with mimicking or suppressor activity provides the opportunity for future therapeutic targeting of miRNAs. The present paper is focusing on miRNAs which, according to current knowledge, favorably impact on AML outcomes, being regarded as tumor suppressors, and reviews their role in macrophage polarization. We are focusing on miRNA expression in the setting of AML, but data on correlations between miRNA expression and macrophage polarization is mostly coming from studies involving normal tissue.
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http://dx.doi.org/10.3389/fimmu.2020.582915DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7845488PMC
June 2021

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

Prognostic Value of Baseline Total Metabolic Tumor Volume Measured on FDG PET in Patients With Richter Syndrome.

Clin Nucl Med 2020 Feb;45(2):118-122

Univ Rennes, Department of Nuclear Medicine, CLCC Eugène Marquis, Inserm, LTSI-UMR 1099 Research Unit, Rennes, France.

Purpose: We evaluated the prognostic value of baseline total metabolic tumor volume (TMTV) measured using pretreatment FDG PET for patients with transformation of chronic lymphocytic leukemia (CLL) into diffuse large B-cell lymphoma (DLBCL).

Methods: A total of 28 patients with transformation of CLL into DLBCL who had undergone FDG PET before treatment were retrospectively reviewed. Univariate and multivariate analysis of conventional clinicopathologic variables (sex, age, World Health Organization performance status score, International Prognostic Index score, Binet stage, lactate dehydrogenase serum level [LDH], platelet count, presence or not of prior therapies for CLL, the time from CLL to Richter syndrome, Ann Arbor stage, Bulky or not) and metabolic parameters (SUVmax, SUVmean, TMTV, and total lesion glycolysis) at the time of the transformation of CLL into DLBCL were tested for overall survival (OS).

Results: Of the 28 patients, 14 patients (50%) died during the follow-up period. Low platelet count, World Health Organization performance status score >1, high LDH, and high TMTV were found to be significant prognostic factors for OS on univariate analysis. The 5-year estimates of OS were 63% in the low metabolic burden group (TMTV ≤1200 cm) and 0% in the high metabolic burden group (TMTV >1200 cm). Multivariate analysis revealed that only high LDH was a significant predictor after adjustment for other variables of OS.

Conclusions: TMTV extracted from FDG PET at the time of the transformation of CLL into DLBCL is a predictor of OS.
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http://dx.doi.org/10.1097/RLU.0000000000002879DOI Listing
February 2020

A case of IgE myeloma transformed into IgE-producing plasma cell leukaemia.

Biochem Med (Zagreb) 2020 Feb 15;30(1):010801. Epub 2019 Dec 15.

Department of Biochemistry and Pharmaco-Toxicology, Martinique University Hospital, Fort-de-France, France.

This is a case report of a challenging diagnosis of IgE monoclonal gammopathy of undetermined significance, which transformed into myeloma, then transformed into IgE-producing plasma cell leukaemia in a 71-year-old male who was followed in Brest, France, from 2015 to 2019. The IgE-producing variant is the rarest sub-type of multiple myeloma, and plasma cell leukaemia is considered to be the rarest and the most aggressive of human monoclonal gammopathies. In November 2015, hypogammaglobulinemia was detected during a systematic check-up. A kappa light chain monoclonal gammopathy was first diagnosed due to an increase of the free kappa/lambda light chains ratio. No monoclonal immunoglobulin was detected by either serum protein electrophoresis (Capillarys 2, Sebia, Issy-les-Moulineaux, France) or immunofixation (Hydrasys 2, Sebia, Issy-les-Moulineaux, France). In June 2018, a blood smear led to the diagnosis of plasma cell leukaemia. A monoclonal peak was detected and identified as IgE-kappa. Analysis of an archival sample taken three years earlier, revealed the presence of a monoclonal IgE, which had been missed at diagnosis. Chemotherapy with bortezomib and dexamethasone was introduced. The patient survived 10 months after the diagnosis of leukaemia. This case shows that an abnormal free light chain ratio should be considered as a possible marker of IgE monoclonal gammopathy even in the absence of a solitary light chain revealed by immunofixation. In addition, the use of an undiluted serum may increase the sensitivity of the immunofixation for the detection of IgE monoclonal gammopathies compared to the 1:3 dilution recommended by the manufacturer.
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http://dx.doi.org/10.11613/BM.2020.010801DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6904968PMC
February 2020

A simplified frailty scale predicts outcomes in transplant-ineligible patients with newly diagnosed multiple myeloma treated in the FIRST (MM-020) trial.

Leukemia 2020 01 19;34(1):224-233. Epub 2019 Aug 19.

Hôpital Saint-Louis, Paris, France.

Patients with multiple myeloma are generally older and vary in fitness levels, which may influence the clinical benefit of treatment. Patients from the large, phase 3 FIRST trial in newly diagnosed multiple myeloma (NDMM) were retrospectively investigated to determine outcomes based on frailty using scores for age, Charlson Comorbidity Index (CCI), and Eastern Cooperative Oncology Group performance status (ECOG PS), instead of the EQ-5D quality-of-life questionnaire, as previously reported. ECOG PS (n = 1618) was investigated in frailty groups: frail (49%) and nonfrail (51%). Frail patients experienced worse progression-free and overall survival vs nonfrail patients. Prognostic assessment was improved when combining frailty and International Staging System stage (I/II vs III). Frail patients had a higher risk of developing grade 3/4 treatment-emergent adverse events. Treatment effects observed in the FIRST trial were confirmed per frailty group and per frailty and ISS group. The use of this ECOG PS-containing frailty scale as a predictive measure of clinical outcomes in patients with transplant-ineligible NDMM is supported by data from the FIRST trial. This score, based on age, CCI, and ECOG PS, can be easily replicated and may help design future myeloma studies in frail or nonfrail elderly patients.
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http://dx.doi.org/10.1038/s41375-019-0539-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7214253PMC
January 2020

Complement System: a Neglected Pathway in Immunotherapy.

Clin Rev Allergy Immunol 2020 Apr;58(2):155-171

Inserm UMR1227, B lymphocytes and autoimmunity, University of Brest, Brest, France.

Approved for the treatment of autoimmune diseases, hematological malignancies, and solid cancers, several monoclonal antibodies (mAb) make use of complement in their mechanism of action. Such an assessment is based on comprehensive investigations that used mouse models, in vitro studies, and analyses from patients at initiation (basal level to highlight deficiencies) and after treatment initiation (mAb impact on complement), which have further provided key insights into the importance of the complement activation and/or complement deficiencies in mAb activity. Accordingly, new approaches can now be developed with the final objective of increasing the clinical efficacy of mAb. These improvements include (i) the concurrent administration of fresh frozen plasma during mAb therapy; (ii) mAb modifications such as immunoglobulin G subclass switching, Fc mutation, or IgG hexamerization to improve the fixation and activation of C1q; (iii) optimization of the target recognition to induce a higher complement-dependent cytotoxicity (CDC) and/or complement-dependant cellular cytotoxicity (CDCC); and (iv) the control of soluble and cellular complement inhibitors.
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http://dx.doi.org/10.1007/s12016-019-08741-0DOI Listing
April 2020

Long-term efficacy of anti-PD1 therapy in Hodgkin lymphoma with and without allogenic stem cell transplantation.

Eur J Cancer 2019 07 10;115:47-56. Epub 2019 May 10.

Department of Hematology, University Hospital of Rennes, Rennes, France; INSERM, U1236, Rennes, France. Electronic address:

Introduction: Long-term efficacy of anti-PD1 therapy and the need for a consolidation with allogenic haematopoietic stem cell transplantation (allo-HSCT) remain unclear in patients with relapsed/refractory (R/R) Hodgkin lymphoma (HL).

Methods: We retrospectively analysed 78 patients with R/R HL treated with nivolumab in the French Early Access Program and compared their outcomes according to subsequent allo-HSCT.

Results: After a median follow-up of 34.3 months, the best overall response rate was 65.8%, including 38.2% complete responses (CRs). The median progression-free survival (PFS) was 12.1 months. Patients reaching a CR upon nivolumab had a significantly longer PFS than those reaching a partial response (PR) (median = not reached vs 9.3 months, p < 0.001). In our cohort, 13 patients who responded (i.e. in CR or PR) to nivolumab monotherapy underwent consolidation with allo-HSCT. Among responding patients, none of those who underwent subsequent allo-HSCT (N = 13) relapsed, whereas 62.2% of those who were not consolidated with allo-HSCT (N = 37) relapsed (p < 0.001). There was no difference in overall survival (OS) between the two groups. Five of 6 patients who were not in CR at the time of transplantation (4 PRs and 1 progressive disease) converted into a CR after allo-HSCT.

Conclusion: Most patients with R/R HL treated with anti-PD1 monotherapy eventually progressed, notably those who did not achieve a CR. Patients undergoing consolidation with allo-HSCT after anti-PD1 therapy experienced prolonged disease-free survival compared with non-transplanted patients, but this difference did not translate into a benefit in OS. This information should be considered when evaluating the risk/benefit ratio of allo-HSCT after anti-PD1 therapy.
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http://dx.doi.org/10.1016/j.ejca.2019.04.006DOI Listing
July 2019

STIM1 at the plasma membrane as a new target in progressive chronic lymphocytic leukemia.

J Immunother Cancer 2019 04 23;7(1):111. Epub 2019 Apr 23.

INSERM U1227 B lymphocytes and autoimmunity, University of Brest, Brest, France.

Background: Dysregulation in calcium (Ca) signaling is a hallmark of chronic lymphocytic leukemia (CLL). While the role of the B cell receptor (BCR) Ca pathway has been associated with disease progression, the importance of the newly described constitutive Ca entry (CE) pathway is less clear. In addition, we hypothesized that these differences reflect modifications of the CE pathway and Ca actors such as Orai1, transient receptor potential canonical (TRPC) 1, and stromal interaction molecule 1 (STIM1), the latter being the focus of this study.

Methods: An extensive analysis of the Ca entry (CE) pathway in CLL B cells was performed including constitutive Ca entry, basal Ca levels, and store operated Ca entry (SOCE) activated following B cell receptor engagement or using Thapsigargin. The molecular characterization of the calcium channels Orai1 and TRPC1 and to their partner STIM1 was performed by flow cytometry and/or Western blotting. Specific siRNAs for Orai1, TRPC1 and STIM1 plus the Orai1 channel blocker Synta66 were used. CLL B cell viability was tested in the presence of an anti-STIM1 monoclonal antibody (mAb, clone GOK) coupled or not with an anti-CD20 mAb, rituximab. The Cox regression model was used to determine the optimal threshold and to stratify patients.

Results: Seeking to explore the CE pathway, we found in untreated CLL patients that an abnormal CE pathway was (i) highly associated with the disease outcome; (ii) positively correlated with basal Ca concentrations; (iii) independent from the BCR-PLCγ2-InsPR (SOCE) Ca signaling pathway; (iv) supported by Orai1 and TRPC1 channels; (v) regulated by the pool of STIM1 located in the plasma membrane (STIM1); and (vi) blocked when using a mAb targeting STIM1. Next, we further established an association between an elevated expression of STIM1 and clinical outcome. In addition, combining an anti-STIM1 mAb with rituximab significantly reduced in vitro CLL B cell viability within the high STIM1 CLL subgroup.

Conclusions: These data establish the critical role of a newly discovered BCR independent Ca entry in CLL evolution, provide new insights into CLL pathophysiology, and support innovative therapeutic perspectives such as targeting STIM1 located at the plasma membrane.
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http://dx.doi.org/10.1186/s40425-019-0591-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6480884PMC
April 2019

Apoptotic resistance in chronic lymphocytic leukemia and therapeutic perspectives.

Crit Rev Clin Lab Sci 2019 08 6;56(5):321-332. Epub 2019 May 6.

c Laboratory of Immunology and Immunotherapy , Brest University Medical School Hospital , Brest , France.

Increased resistance to apoptosis represents a key oncogenic mechanism in chronic lymphocytic leukemia (CLL) that has been attributed to the upregulation of the anti-apoptotic B cell lymphoma 2 (Bcl-2) family members. Such an observation was associated with the development of molecules inhibiting Bcl-2 activity, and among them, BH3-mimetics represent a novel class of therapeutic compounds. In 2016, venetoclax became the first approved oral inhibitor of Bcl-2, and it has been used with success in patients with CLL who present with a 17p deletion or mutations and in those who have received at least one prior therapy. However, its mechanism for controlling relapses, and its optimal use in terms of duration and combinations with other drugs, remain unknown. Therefore, this review focuses on the mechanisms controlling apoptosis, CLL B cell strategies to prevent apoptosis including in response to BH3-mimetics, and arguments supporting the use of BH3-mimetics in association with other therapies in order to limit compensatory mechanisms.
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http://dx.doi.org/10.1080/10408363.2019.1600468DOI Listing
August 2019

Rapid and complete response to idelalisib in a case of Richter syndrome.

Onco Targets Ther 2019 13;12:1181-1184. Epub 2019 Feb 13.

Department of Hematology, Brest University Medical School Hospital, Brest, France,

Richter syndrome (RS) is an aggressive lymphoma arising on the back of chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL) and is the most common B-cell malignancy in the Western world. In the majority of cases, RS presents an activated B cell (ABC) phenotype of diffuse large B-cell lymphoma (DLBCL). From the therapeutic point of view, selective inhibition of PI3Kδ with idelalisib represents a valuable addition to available treatment options for patients with CLL/SLL, many of whom do not respond to or cannot tolerate chemoimmunotherapy. However, to our knowledge, there have been no prospective studies evaluating idelalisib efficacy in a DLBCL-ABC form of RS. Here, we present a case of a DLBCL-ABC form of RS achieving a complete response at 3 weeks after initiating idelalisib and rituximab therapy for six cycles. This response was maintained during the idelalisib monotherapy, but the patient relapsed rapidly after treatment was withdrawn, because of a grade three immune colitis that developed at 10 months of treatment. This report demonstrates that idelalisib is highly effective in RS and provides an attractive option in this aggressive disease. This agent could meet an unmet need by providing a treatment option with a tolerable safety profile for elderly patients with RS.
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http://dx.doi.org/10.2147/OTT.S187459DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6389009PMC
February 2019

The regulatory capacity of B cells directs the aggressiveness of CLL.

Oncoimmunology 2019;8(3):1554968. Epub 2018 Dec 12.

UMR1227, Lymphocytes B et Autoimmunité, Univ Brest, INSERM, Brest, France.

Chronic lymphocytic leukemia (CLL) is associated with abnormal T-cell responses responsible for defective anti-tumor activities. Intriguingly, CLL B cells share phenotypical characteristics with regulatory B (Breg) cells suggesting that they might negatively control the T-cell activation and immune responses. We elaborated an co-culture system with T cells to evaluate the Breg capacities of CLL B cells following innate Toll-like receptor 9 (TLR9) engagement. We demonstrated that B cells from half of the patients exhibited regulatory capacities, whilst B cells from the remaining patients were unable to develop a Breg function. The T cell sensitivities of all patients were normal suggesting that defective Breg activities were due to intrinsic CLL B cell deficiencies. Thus, TLR-dedicated gene assays highlighted differential signature of the TLR9 negative regulation pathway between the two groups of patients. Furthermore, correlations of the doubling time of lymphocytosis, the time to first treatment, the mutational status of IgVH and the Breg functions indicate that patients with efficient Breg activities have more aggressive CLL than patients with defective Breg cells. Our observations may open new approaches for adjusting therapeutic strategies targeting the Breg along with the evolution of the disease.
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http://dx.doi.org/10.1080/2162402X.2018.1554968DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6350696PMC
December 2018

17p deletion strongly influences rituximab elimination in chronic lymphocytic leukemia.

J Immunother Cancer 2019 01 29;7(1):22. Epub 2019 Jan 29.

Laboratory of Immunology and Immunotherapy, Brest University Medical School Hospital, Brest, France.

Chronic lymphocytic leukemia (CLL) is the most common type of leukemia and the anti-CD20 monoclonal antibody, rituximab, represents the therapeutic gold standard for more than 2 decades in this pathology, when used in combination with chemotherapy. However, some patients experience treatment resistance or rapid relapses, and in particular, those harboring a 17p/TP53 deletion (del(17p)). This resistance could be explained by a chemo-resistance, but it could also result from the direct impact of del(17p) on the pharmacokinetics of rituximab, which represents the aim of the present study. Accordingly, 44 CLL patients were included in the study, and among them 9 presented a del(17p). Next, a total of 233 rituximab sera were selected for a pharmacokinetic study and analyzed in a two-compartment model showing important differences when del(17p) CLL patients were compared with non-del(17p) patients treated with rituximab and chemotherapy: (1) clearance of rituximab was faster; (2) central volume of rituximab distribution V1 (peripheral blood) was reduced while peripheral volume V2 (lymphoid organs and tissues) was increased; and (3) the rate of rituximab elimination (Kout) was faster. In contrast, the group with a better prognosis harboring isolated del(13q) presented a slower rate of elimination (Kout). Pharmacokinetic parameters were independent from the other factors tested such as age, sex, chemotherapy regimen (fludarabine/cyclophosphamide versus bendamustine), IGHV mutational status, and FCGR3A 158VF status. In conclusion, this study provides an additional argument to consider that del(17p) is effective not only to control chemoresistance but also monoclonal antibody activity, based on higher rituximab turnover.
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http://dx.doi.org/10.1186/s40425-019-0509-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6352369PMC
January 2019

PET-adapted treatment for newly diagnosed advanced Hodgkin lymphoma (AHL2011): a randomised, multicentre, non-inferiority, phase 3 study.

Lancet Oncol 2019 02 15;20(2):202-215. Epub 2019 Jan 15.

LYSA Imaging, Hôpital H Mondor, Creteil, France.

Background: Increased-dose bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, and prednisone (BEACOPP) improves progression-free survival in patients with advanced Hodgkin lymphoma compared with doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD), but is associated with increased risks of haematological toxicity, secondary myelodysplasia or leukaemia, and infertility. We investigated whether PET monitoring during treatment could allow dose de-escalation by switching regimen (BEACOPP to ABVD) in early responders without loss of disease control compared with standard treatment without PET monitoring.

Methods: AHL2011 is a randomised, non-inferiority, phase 3 study done in 90 centres across Belgium and France. Eligible patients were aged 16-60 years and had newly diagnosed Hodgkin lymphoma, excluding nodular lymphocyte predominant subtype, an Eastern Cooperative Oncology Group performance status score less than 3, a life expectancy of at least 3 months, an Ann Arbor disease stage III, IV, or IIB with mediastinum-to-thorax ratio of 0·33 or greater than or extranodal localisation, and had received no previous treatment for Hodgkin lymphoma. Randomisation was unmasked and done centrally by the permuted block method. Patients were randomly assigned to standard treatment (BEACOPP given every 21 days for six cycles) or PET-driven treatment. All patients received two cycles of upfront BEACOPP, after which PET assessment was done (PET2). In the standard treatment group, PET2 patients completed two additional cycles of BEACOPP induction therapy irrespective of PET2 findings. In the PET-driven treatment group, patients with positive PET2 scans received the further two cycles of BEACOPP and those with a negative PET2 scan switched to two cycles of ABVD for the remaining induction therapy. In both treatment groups, PET at the end of induction therapy was used to decide whether to continue with consolidation therapy in those with negative scans or start salvage therapy in patients with positive scans (either two cycles of ABVD in PET2-negative patients in the PET-driven arm or two cycles of BEACOPP). BEACOPP consisted of bleomycin 10 mg/m and vincristine 1·4 mg/m intravenously on day 8, etoposide 200 mg/m intravenously on days 1-3, doxorubicin 35 mg/m and cyclophosphamide 1250 mg/m intravenously on day 1, 100 mg/m oral procarbazine on days 1-7, and 40 mg/m oral prednisone on days 1-14. ABVD was given every 28 days (doxorubicin 25 mg/m, bleomycin 10 mg/m, vinblastine 6 mg/m, and dacarbazine 375 mg/m intravenously on days 1 and 15). The primary endpoint was investigator-assessed progression-free survival. Non-inferiority analyses were done by intention to treat and per protocol. The study had a non-inferiority margin of 10%, to show non-inferiority of PET-guided treatment versus standard care with 80% power and an alpha of 2·5% (one-sided). This study is registered with ClinicalTrials.gov, number NCT01358747.

Findings: From May 19, 2011, to April 29, 2014, 823 patients were enrolled-413 in the standard care group and 410 in the PET-driven group. 346 (84%) of 410 patients in the PET-driven treatment group were assigned to receive ABVD and 51 (12%) to continue receiving BEACOPP after PET2. With a median follow-up of 50·4 months (IQR 42·9-59·3), 5-year progression-free survival by intention to treat was 86·2%, 95% CI 81·6-89·8 in the standard treatment group versus 85·7%, 81·4-89·1 in the PET-driven treatment group (hazard ratio [HR] 1·084, 95% CI 0·737-1·596; p=0·65) and per protocol the values were 86·7%, 95% CI 81·9-90·3 and 85·4%, 80·7-89·0, respectively (HR 1·144, 0·758-1·726; p=0·74). The most common grade 3-4 adverse events were leucopenia (381 [92%] in the standard treatment group and 387 [95%] in the PET-driven treatment group), neutropenia (359 [87%] and 366 [90%]), anaemia (286 [69%] vs 114 [28%]), thrombocytopenia (271 [66%] and 163 [40%]), febrile neutropenia (145 [35%] and 93 [23%]), infections (88 [22%] and 47 [11%]), and gastrointestinal disorders (49 [11%] and 48 [11%]). Serious adverse events related to treatment were reported in 192 (47%) patients in the standard treatment group and 114 (28%) in the PET-driven treatment group, including infections (84 [20%] of 412 vs 50 [12%] of 407) and febrile neutropenia (21 [5%] vs 23 [6%]). Six (1%) patients in the standard care group died from treatment-related causes (two from septic shock, two from pneumopathy, one from heart failure, and one from acute myeloblastic leukaemia), as did two (<1%) in the PET-driven treatment group (one from septic shock and one from acute myeloblastic leukaemia).

Interpretation: PET after two cycles of induction BEACOPP chemotherapy safely guided treatment in patients with advanced Hodgkin lymphoma and allowed the use of ABVD in early responders without impairing disease control and reduced toxicities. PET staging allowed accurate monitoring of treatment in this trial and could be considered as a strategy for the routine management of patients with advanced Hodgkin lymphoma.

Funding: Programme Hospitalier de Recherche Clinique.
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http://dx.doi.org/10.1016/S1470-2045(18)30784-8DOI Listing
February 2019

A phase 2 study of rituximab, bendamustine, bortezomib and dexamethasone for first-line treatment of older patients with mantle cell lymphoma.

Haematologica 2019 01 31;104(1):138-146. Epub 2018 Aug 31.

Hematology Department, Catherine de Sienne Clinic, Nantes.

We present results of a prospective, multicenter, phase II study evaluating rituximab, bendamustine, bortezomib and dexamethasone as first-line treatment for patients with mantle cell lymphoma aged 65 years or older. A total of 74 patients were enrolled (median age, 73 years). Patients received a maximum of six cycles of treatment at 28-day intervals. The primary objective was to achieve an 18-month progression-free survival rate of 65% or higher. Secondary objectives were to evaluate toxicity and the prognostic impact of mantle cell lymphoma prognostic index, Ki67 expression, [F]fluorodeoxyglucose-positron emission tomography and molecular minimal residual disease, in peripheral blood or bone marrow. With a median follow-up of 52 months, the 24-month progression-free survival rate was 70%, hence the primary objective was reached. After six cycles of treatment, 91% (54/59) of responding patients were analyzed for peripheral blood residual disease and 87% of these (47/54) were negative. Four-year overall survival rates of the patients who did not have or had detectable molecular residual disease in the blood at completion of treatment were 86.6% and 28.6%, respectively (<0.0001). Neither the mantle cell lymphoma index, nor fluorodeoxyglucose-positron emission tomography nor Ki67 positivity (cut off of ≥30%) showed a prognostic impact for survival. Hematologic grade 3-4 toxicities were mainly neutropenia (51%), thrombocytopenia (35%) and lymphopenia (65%). Grade 3-4 non-hematologic toxicities were mainly fatigue (18.5%), neuropathy (15%) and infections. In conclusion, the tested treatment regimen is active as frontline therapy in older patients with mantle cell lymphoma, with manageable toxicity. Minimal residual disease status after induction could serve as an early predictor of survival in mantle cell lymphoma. .
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http://dx.doi.org/10.3324/haematol.2018.191429DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6312036PMC
January 2019

Resistance to complement activation, cell membrane hypersialylation and relapses in chronic lymphocytic leukemia patients treated with rituximab and chemotherapy.

Oncotarget 2018 Aug 3;9(60):31590-31605. Epub 2018 Aug 3.

U1227 B Lymphocytes and Autoimmunity, Université de Brest, INSERM, IBSAM, Labex IGO, Networks IC-CGO and REpiCGO from 'Canceropole Grand Ouest, Brest, France.

The anti-CD20-specific monoclonal antibody rituximab (RTX), in combination with chemotherapy, is commonly used for primary treatment in chronic lymphocytic leukemia (CLL). However, relapses remain important and activation of the complement pathway is one of the mechanisms by which RTX generates the destruction of B cells directly by complement-dependent cytotoxicity (CDC), or indirectly by antibody-dependent cellular phagocytosis. In this study, the RTX capacity to induce CDC was established in 69 untreated CLL patients, this cohort including 34 patients tested before the initiation of RTX-chemotherapy. CDC-resistance to RTX predicts lower response rates to RTX-chemotherapy and shorter treatment free survival. Furthermore, the predictive value of CDC-resistance was independent from the clinical, cytogenetic and FcγR3A V158F polymorphism status. In contrast, CLL cell resistance to CDC predominates in IGHV unmutated patients and was related to an important α2-6 sialyl transferase activity, which in turn increases cell surface α2-6 hypersialylation. Suspected factors associated with resistance to CDC (CD20, CD55, CD59, factor H, GM1, and sphingomyelin) were not differentially expressed or recruited between the two CLL groups. Altogether, results provide evidence that testing RTX capacity to induce CDC represents an independent predictive factor of therapeutic effects of RTX, and that α2-6 hypersialylation in CLL cells controls RTX response through the control of the complement pathway. At a time when CLL therapy is moving towards chemo-free treatments, further experiments are required to determine whether performing an initial assay to appreciate CLL CDC resistance might be useful to select patients.
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http://dx.doi.org/10.18632/oncotarget.25657DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6114972PMC
August 2018

Preserved lenalidomide efficacy in a recurrent isolated subcutaneous mantle cell lymphoma relapse.

J BUON 2018 Jan-Feb;23(1):273-274

Iuliu Hatieganu University of Medicine and Pharmacy, Cluj- Napoca, Romania.

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September 2019

DNA demethylation marks in chronic lymphocytic leukemia: it is time to let the cat out of the bag.

Future Sci OA 2018 Feb 3;4(2):FSO265. Epub 2017 Nov 3.

U1227 B Llymphocytes & Autoimmunity, University of Brest, INSERM, IBSAM, Brest, France.

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http://dx.doi.org/10.4155/fsoa-2017-0120DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5778384PMC
February 2018

Non-adherence to treatment with cytoreductive and/or antithrombotic drugs is frequent and associated with an increased risk of complications in patients with polycythemia vera or essential thrombocythemia (OUEST study).

Haematologica 2018 04 15;103(4):607-613. Epub 2017 Dec 15.

Fédération Inter Hospitalière d'Immuno-Hématologie de Bretagne Occidentale (FIHBO), France

The purpose of this study was to identify the incidence, causes and impact of non-adherence to oral and subcutaneous chronic treatments for patients with polycythemia vera or essential thrombocythemia. Patients receiving cytoreductive drugs for polycythemia vera or essential thrombocythemia were recruited at our institution ( registry). They completed a one-shot questionnaire designed by investigators ( study). Data about complications (thrombosis, transformation and death) at any time in the patient's life (before diagnosis, up until consultation and after the completion of the questionnaire) were collected. Sixty-five (22.7%) of 286 patients reported poor adherence (<90%) to their treatment with cytoreductive drugs and 46/255/18%) also declared non-adherence to antithrombotic drugs. In total, 85/286 patients (29.7%) declared they did not adhere to their treatment. Missing an intake was rare and was mostly due to forgetfulness especially during occupational travel and holidays. Patients who did not adhere to their treatment were characterized by younger age, living alone, having few medications but a high numbers of pills and determining their own schedule of drug intake. Having experienced thrombosis or hematologic evolution did not influence the adherence rate. Non-adherence to oral therapy was associated with a higher risk of phenotypic evolution (7.3 1.8%, =0.05). For patients treated for polycythemia vera or essential thrombocythemia, non-adherence to cytoreductive and/or antithrombotic therapies is frequent and is influenced by age, habitus and concomitant treatments, but not by disease history or treatment side effects. Phenotypic evolution seems to be more frequent in the non-adherent group.
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http://dx.doi.org/10.3324/haematol.2017.180448DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5865440PMC
April 2018

Combining cytogenetic and epigenetic approaches in chronic lymphocytic leukemia improves prognosis prediction for patients with isolated 13q deletion.

Clin Epigenetics 2017 28;9:122. Epub 2017 Nov 28.

U1227 B lymphocytes and autoimmunity, University of Brest, INSERM, IBSAM, Labex IGO, networks IC-CGO and REpiCGO from "Canceropole Grand Ouest", Brest, France.

Background: Both defective DNA methylation and active DNA demethylation processes are emerging as important risk factors in chronic lymphocytic leukemia (CLL). However, associations between 5-cytosine epigenetic markers and the most frequent chromosomal abnormalities detected in CLL remain to be established.

Methods: CLL patients were retrospectively classified into a cytogenetic low-risk group (isolated 13q deletion), an intermediate-risk group (normal karyotype or trisomy 12), and a high-risk group (11q deletion, 17p deletion, or complex karyotype [≥ 3 breakpoints]). The two 5-cytosine derivatives, 5-methylcytosine (5-mCyt) and 5-hydroxymethylcytosine (5-hmCyt), were tested by ELISA ( = 60), while real-time quantitative PCR was used for determining transcriptional expression levels of and ( = 24).

Results: By using global DNA methylation/demethylation levels, in the low-risk disease group, two subgroups with significantly different clinical outcomes have been identified (median treatment-free survival [TFS] 45 versus > 120 months for 5-mCyt,  = 0.0008, and 63 versus > 120 months for 5-hmCyt,  = 0.04). A defective 5-mCyt status was further associated with a higher percentage of 13q deleted nuclei (> 80%), thus suggesting an acquired process. When considering the cytogenetic intermediate/high-risk disease groups, an association of 5-mCyt status with lymphocytosis ( = 0.0008) and the lymphocyte doubling time ( = 0.04) but not with TFS was observed, as well as a reduction of , , and transcripts.

Conclusions: Combining cytogenetic studies with 5-mCyt assessment adds accuracy to CLL patients' prognoses and particularly for those with 13q deletion as a sole cytogenetic abnormality.
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http://dx.doi.org/10.1186/s13148-017-0422-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5704505PMC
July 2018

Alterations in DNA methylation/demethylation intermediates predict clinical outcome in chronic lymphocytic leukemia.

Oncotarget 2017 Sep 9;8(39):65699-65716. Epub 2017 Aug 9.

U1227 B Lymphocytes and Autoimmunity, University of Brest, INSERM, IBSAM, Labex IGO, Networks IC-CGO and REpiCGO from Cancéropôle Grand Ouest, Brest, France.

Cytosine derivative dysregulations represent important epigenetic modifications whose impact on the clinical outcome in chronic lymphocytic leukemia (CLL) is incompletely understood. Hence, global levels of 5-methylcytosine (5-mCyt), 5-hydroxymethylcytosine (5-hmCyt), 5-carboxylcytosine (5-CaCyt) and 5-hydroxymethyluracil were tested in purified B cells from CLL patients ( = 55) and controls ( = 17). The DNA methylation 'writers' (DNA methyltransferases []), 'readers' (methyl-CpG-binding domain []), 'editors' (ten-eleven translocation []) and 'modulators' () were also evaluated. Accordingly, patients were stratified into three subgroups. First, a subgroup with a global deficit in cytosine derivatives characterized by hyperlymphocytosis, reduced median progression free survival (PFS = 52 months) and shorter treatment free survival (TFS = 112 months) was identified. In this subgroup, major epigenetic modifications were highlighted including a reduction of 5-mCyt, 5-hmCyt, 5-CaCyt associated with , and downregulation. Second, the cytosine derivative analysis revealed a subgroup with a partial deficit (PFS = 84, TFS = 120 months), mainly affecting DNA demethylation (5-hmCyt reduction, induction). Third, a subgroup epigenetically similar to controls was identified (PFS and TFS > 120 months). The prognostic impact of stratifying CLL patients within three epigenetic subgroups was confirmed in a validation cohort. In conclusion, our results suggest that dysregulations of cytosine derivative regulators represent major events acquired during CLL progression and are independent from mutational status.
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http://dx.doi.org/10.18632/oncotarget.20081DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5630365PMC
September 2017

Immune checkpoint blockade: the role of PD-1-PD-L axis in lymphoid malignancies.

Onco Targets Ther 2017 28;10:2349-2363. Epub 2017 Apr 28.

Department of Hematology, Iuliu Hatieganu University of Medicine and Pharmacy, Cluj-Napoca, Romania.

The co-inhibitory receptor programmed cell death (PD)-1, expressed by immune effector cells, is credited with a protective role for normal tissue during immune responses, by limiting the extent of effector activation. Its presently known ligands, programmed death ligands (PD-Ls) 1 and 2, are expressed by a variety of cells including cancer cells, suggesting a role for these molecules as an immune evasion mechanism. Blocking of the PD-1-PD-L signaling axis has recently been shown to be effective and was clinically approved in relapsed/refractory tumors such as malignant melanoma and lung cancer, but also classical Hodgkin's lymphoma. A plethora of trials exploring PD-1 blockade in cancer are ongoing. Here, we review the role of PD-1 signaling in lymphoid malignancies, and the latest results of trials investigating PD-1 or PD-L1 blocking agents in this group of diseases. Early phase studies proved very promising, leading to the clinical approval of a PD-1 blocking agent in Hodgkin's lymphoma, and Phase III clinical studies are either planned or ongoing in most lymphoid malignancies.
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http://dx.doi.org/10.2147/OTT.S133385DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5417656PMC
April 2017

Biosimilars of filgrastim in autologous stem cell transplantation: certain differences for myeloma patients only.

Leuk Lymphoma 2017 09 7;58(9):1-3. Epub 2017 Feb 7.

a Service d'Hématologie , Institut de Cancéro-Hématologie, Hôpital Morvan, CHRU de Brest , Brest Cedex , France.

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http://dx.doi.org/10.1080/10428194.2017.1285025DOI Listing
September 2017

Relapsed chronic lymphocytic leukemia retreated with rituximab: interim results of the PERLE study.

Leuk Lymphoma 2017 06 9;58(6):1366-1375. Epub 2017 Feb 9.

q Hématologie, CHU Robert Debré , Reims , France.

This prospective non-interventional study assessed the management of relapsed/refractory CLL after one or two treatments with rituximab, and retreatment with a rituximab-based regimen. An interim analysis was performed at the end of the induction period in 192 evaluable patients. Median age was 72 years [35-89], first relapse (55%), and second relapse (45%). Rituximab administered during first (68%), second (92%), or both treatment lines (20%). R-bendamustine administered in 56% of patients, R-purine analogs (21%), and R-alkylating agents (19%). The overall response rate (ORR) was 74.6%, in favor of R-purine analogs (90%), R-bendamustine (75%), and R-alkylating agents (69%). Lower ORR in Del 17p patients (43%) and third time rituximab (31%). Most frequent adverse events were hematological (23% patients) including neutropenia (11%) and infections (12%); grade 3/4 AEs (23% patients), mainly hematological (18%); death during induction treatment (7%). This first large study focusing on relapsed/refractory CLL patients retreated with rituximab-based regimens is still ongoing.
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http://dx.doi.org/10.1080/10428194.2016.1243673DOI Listing
June 2017

Atypical aleukemic presentation of large granular lymphocytic leukemia: a case report.

Onco Targets Ther 2017 19;10:31-34. Epub 2016 Dec 19.

Department of Hematology, Iuliu Hatieganu University of Medicine and Pharmacy, Cluj-Napoca, Romania; Department of Hematology, Ion Chiricuta Oncology Institute, Cluj-Napoca.

Large granular lymphocytic leukemia (LGLL) is a rare lymphoproliferative disorder of transformed natural killer or T-cells attributed to chronic exposure to the proinflammatory cytokine IL-15. Diagnosis of the majority of T-cell LGLL is established by documenting clonal large granular lymphocytes (LGLs) in peripheral blood, by morphology and immunophenotype. The proteasome inhibitor bortezomib is known to target molecular pathways downstream of the IL-15 receptor signaling and has been proposed as a therapy in these patients. We report an uncommon presentation of LGLL with chronic neutropenia lacking typical blood LGLs, which failed to respond to bortezomib but obtained a very good partial remission with a classical methotrexate regimen.
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http://dx.doi.org/10.2147/OTT.S115892DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5182032PMC
December 2016

Prognostic value of interim FDG PET-CT in patients older than 60 years with diffuse large B-cell lymphoma treated by PMitCEBO plus Rituximab: comparison between Deauville 5-point scale and International Harmonization Project criteria.

Q J Nucl Med Mol Imaging 2016 Nov 30. Epub 2016 Nov 30.

Department of Haematology, University Hospital of Brest, Brest, France -

Background: Advanced age is an independent poor prognostic factor of diffuse large B-cell lymphoma. PMitCEBO is an alternative to CHOP to decrease side effects in elderly patients. Many studies have shown prognostic value of an interim FDG PET-CT to predict survival. A recent consensus (ICML, Lugano 2013) has suggested using the 5-point scale Deauville criteria instead of those of the international harmonization project (IHP) to visually assess the response on interim PET. The objective of this study was to evaluate the prognostic value of an interim FDG PET-CT in patients older than 60 with treated DLBCL and to compare IHP and 5-PS Deauville visual interpretation to predict survival.

Methods: Forty-eight patients (mean age 73.2±5.2 years) treated by R- PMitCEBO for DLBCL undergoing FDG PET-CT before and after 3 cycles of treatment were retrospectively included. Event-free survival and overall survival were determined by Kaplan Meier method and compared with interim PET-CT results using IHP and 5-PS Deauville criteria.

Results: Interim PET results using 5-PS Deauville criteria were significantly correlated with EFS (p<0.0001) and OS (p=0.001) whereas they were moderately correlated with EFS (p=0.046) and not with OS (p=0.106) using IHP criteria. The 2-years EFS and OS rates were respectively 86.5% and 89.2% for patients in 1-3 score group and 27.3% and 36.4% for patients in ≥ 4 score group using Deauville criteria.

Conclusions: Our results confirmed the prognostic value of an interim PET- CT in elderly patients with DLBCL and the better performance of the 5-PS Deauville criteria.
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November 2016

Isolated Cardiac Richter Syndrome: a Case Report.

Ann Hematol 2017 Jan 3;96(1):147-149. Epub 2016 Oct 3.

Department of Hematology, CHRU Morvan, 2 Foch Avenue, 29200, Brest, France.

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http://dx.doi.org/10.1007/s00277-016-2834-4DOI Listing
January 2017
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