Publications by authors named "Luc-Matthieu Fornecker"

42 Publications

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

The landscape of copy number variations in classical Hodgkin lymphoma: a joint KU Leuven and LYSA study on cell-free DNA.

Blood Adv 2021 04;5(7):1991-2002

Department of Human Genetics and.

The low abundance of Hodgkin/Reed-Sternberg (HRS) cells in lymph node biopsies in classical Hodgkin lymphoma (cHL) complicates the analysis of somatic genetic alterations in HRS cells. As circulating cell-free DNA (cfDNA) contains circulating tumor DNA (ctDNA) from HRS cells, we prospectively collected cfDNA from 177 patients with newly diagnosed, mostly early-stage cHL in a monocentric study at Leuven, Belgium (n = 59) and the multicentric BREACH study by Lymphoma Study Association (n = 118). To catalog the patterns and frequencies of genomic copy number aberrations (CNAs), cfDNA was sequenced at low coverage (0.26×), and data were analyzed with ichorCNA to yield read depth-based copy number profiles and estimated clonal fractions in cfDNA. At diagnosis, the cfDNA concentration, estimated clonal fraction, and ctDNA concentration were significantly higher in cHL cases than controls. More than 90% of patients exhibited CNAs in cfDNA. The most frequent gains encompassed 2p16 (69%), 5p14 (50%), 12q13 (50%), 9p24 (50%), 5q (44%), 17q (43%), 2q (41%). Losses mostly affected 13q (57%), 6q25-q27 (55%), 4q35 (50%), 11q23 (44%), 8p21 (43%). In addition, we identified loss of 3p13-p26 and of 12q21-q24 and gain of 15q21-q26 as novel recurrent CNAs in cHL. At diagnosis, ctDNA concentration was associated with advanced disease, male sex, extensive nodal disease, elevated erythrocyte sedimentation rate, metabolic tumor volume, and HRS cell burden. CNAs and ctDNA rapidly diminished upon treatment initiation, and persistence of CNAs was associated with increased probability of relapse. This study endorses the development of ctDNA as gateway to the HRS genome and substrate for early disease response evaluation.
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http://dx.doi.org/10.1182/bloodadvances.2020003039DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8045498PMC
April 2021

Temporal multiomic modeling reveals a B-cell receptor proliferative program in chronic lymphocytic leukemia.

Leukemia 2021 05 8;35(5):1463-1474. Epub 2021 Apr 8.

Laboratoire d'ImmunoRhumatologie Moléculaire, INSERM UMR-S1109, LabEx Transplantex, Plateforme Genomax, Fédération de Médecine Translationnelle de Strasbourg (FMTS), Université de Strasbourg, Strasbourg, France.

B-cell receptor (BCR) signaling is crucial for the pathophysiology of most mature B-cell lymphomas/leukemias and has emerged as a therapeutic target whose effectiveness remains limited by the occurrence of mutations. Therefore, deciphering the cellular program activated downstream this pathway has become of paramount importance for the development of innovative therapies. Using an original ex vivo model of BCR-induced proliferation of chronic lymphocytic leukemia cells, we generated 108 temporal transcriptional and proteomic profiles from 1 h up to 4 days after BCR activation. This dataset revealed a structured temporal response composed of 13,065 transcripts and 4027 proteins, comprising a leukemic proliferative signature consisting of 430 genes and 374 proteins. Mathematical modeling of this complex cellular response further highlighted a transcriptional network driven by 14 early genes linked to proteins involved in cell proliferation. This group includes expected genes (EGR1/2, NF-kB) and genes involved in NF-kB signaling modulation (TANK, ROHF) and immune evasion (KMO, IL4I1) that have not yet been associated with leukemic cells proliferation. Our study unveils the BCR-activated proliferative genetic program in primary leukemic cells. This approach combining temporal measurements with modeling allows identifying new putative targets for innovative therapy of lymphoid malignancies and also cancers dependent on ligand-receptor interactions.
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http://dx.doi.org/10.1038/s41375-021-01221-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8102193PMC
May 2021

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

BMC Public Health 2021 03 2;21(1):432. Epub 2021 Mar 2.

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

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

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

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

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

Microenvironment Remodeling and Subsequent Clinical Implications in Diffuse Large B-Cell Histologic Variant of Richter Syndrome.

Front Immunol 2020 14;11:594841. Epub 2020 Dec 14.

Inserm UMRS1256 Nutrition-Génétique et Exposition aux Risque Environnementaux (N-GERE), Université de Lorraine, Nancy, France.

Introduction: Richter Syndrome (RS) is defined as the development of an aggressive lymphoma in the context of Chronic Lymphocytic Leukemia (CLL), with a Diffuse Large B-Cell Lymphoma (DLBCL) histology in 95% cases. RS genomic landscape shares only a few features with DLBCLs and is marked by a wide spectrum of cytogenetic abnormalities. Little is known about RS microenvironment. Therapeutic options and efficacy are limited, leading to a 12 months median overall survival. The new targeted treatments usually effective in CLL fail to obtain long-term remissions in RS.

Methods: We reviewed available PubMed literature about RS genomics, PD-1/PD-L1 (Programmed Death 1/Programmed Death Ligand 1) pathway triggering and subsequent new therapeutic options.

Results: Data from about 207 patients from four landmark papers were compiled to build an overview of RS genomic lesions and point mutations. A number of these abnormalities may be involved in tumor microenvironment reshaping. T lymphocyte exhaustion through PD-L1 overexpression by tumor cells and subsequent PD-1/PD-L1 pathway triggering is frequently reported in solid cancers. This immune checkpoint inhibitor is also described in B lymphoid malignancies, particularly CLL: PD-1 expression is reported in a subset of prolymphocytes from the CLL lymph node proliferation centers. However, there is only few data about PD-1/PD-L1 pathway in RS. In RS, PD-1 expression is a hallmark of recently described « Regulatory B-cells », which interact with tumor microenvironment by producing inhibiting cytokines such as TGF-β and IL-10, impairing T lymphocytes anti-tumoral function. Based upon the discovery of high PD-1 expression on tumoral B lymphocyte from RS, immune checkpoint blockade therapies such as anti-PD-1 antibodies have been tested on small RS cohorts and provided heterogeneous but encouraging results.

Conclusion: RS genetic landscape and immune evasion mechanisms are being progressively unraveled. New protocols using targeted treatments such as checkpoint inhibitors as single agents or in combination with immunochemotherapy are currently being evaluated.
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http://dx.doi.org/10.3389/fimmu.2020.594841DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7767850PMC
June 2021

A fixed-duration, measurable residual disease-guided approach in CLL: follow-up data from the phase 2 ICLL-07 FILO trial.

Blood 2021 02;137(8):1019-1023

Department of Hematology, Avicenne Hospital, AP-HP, Bobigny, France.

Trials assessing first-line, fixed-duration approaches in chronic lymphocytic leukemia (CLL) are yielding promising activity, but few long-term data are available. We report follow-up data from a phase 2 trial (ICLL07 FILO) in previously untreated, medically fit patients (N = 135). Patients underwent obinutuzumab-ibrutinib induction for 9 months; then, following evaluation (N = 130 evaluable), those in complete remission and with bone marrow measurable residual disease (BM MRD) <0.01% (n = 10) received ibrutinib for 6 additional months; those in partial remission and/or with BM MRD ≥0.01%, the majority (n = 120), also received 4 cycles of immunochemotherapy (fludarabine/cyclophosphamide-obinutuzumab). Beyond end of treatment, responses were assessed every 3 month and peripheral blood MRD every 6 months. At median follow-up 36.7 months from treatment start, progression-free and overall survival rates (95% confidence interval) at 3 years were 95.7% (92.0% to 99.5%) and 98% (95.1% to 100%), respectively. Peripheral blood MRD <0.01% rates were 97%, 96%, 90%, 84%, and 89% at months 16, 22, 28, 34, and 40, respectively. No new treatment-related or serious adverse event occurred beyond end of treatment. Thus, in previously untreated, medically fit patients with CLL, a fixed-duration (15 months), MRD-guided approach achieved high survival rates, a persistent MRD benefit beyond the end of treatment, and low long-term toxicity. This trial was registered at www.clinicaltrials.gov as #NCT02666898.
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http://dx.doi.org/10.1182/blood.2020008164DOI Listing
February 2021

Diagnosis and Treatment of Chronic Lymphocytic Leukemia: Recommendations of the French CLL Study Group (FILO).

Hemasphere 2020 Oct 23;4(5):e473. Epub 2020 Sep 23.

CHU de Caen Normandie, Caen, France.

As a result of significant recent developments, the management of patients with chronic lymphocytic leukemia (CLL) is changing, and new therapeutic options will continue to emerge in the near future. The recommendations of the French Innovative Leukemia Organization (FILO-CLL) group presented here are intended to provide practical recommendations for physicians taking care of CLL patients, taking into account the availability of both biological tests and therapies in daily practice in France at the time of publication. This text details the documented information and guidelines on diagnosis, indications for treatment, infectious complications and therapeutic strategies in frontline and relapsed CLL as well as in particular conditions such as autoimmune cytopenia or Richter syndrome.
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http://dx.doi.org/10.1097/HS9.0000000000000473DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7523785PMC
October 2020

Impact of TP53 mutations in acute myeloid leukemia patients treated with azacitidine.

PLoS One 2020 1;15(10):e0238795. Epub 2020 Oct 1.

Laboratoire d'Hématologie, Centre Hospitalier Universitaire de Toulouse, Institut Universitaire du Cancer de Toulouse Oncopole, Toulouse, France.

Hypomethylating agents are a classical frontline low-intensity therapy for older patients with acute myeloid leukemia. Recently, TP53 gene mutations have been described as a potential predictive biomarker of better outcome in patients treated with a ten-day decitabine regimen., However, functional characteristics of TP53 mutant are heterogeneous, as reflected in multiple functional TP53 classifications and their impact in patients treated with azacitidine is less clear. We analyzed the therapeutic course and outcome of 279 patients treated with azacitidine between 2007 and 2016, prospectively enrolled in our regional healthcare network. By screening 224 of them, we detected TP53 mutations in 55 patients (24.6%), including 53 patients (96.4%) harboring high-risk cytogenetics. The identification of any TP53 mutation was associated with worse overall survival but not with response to azacitidine in the whole cohort and in the subgroup of patients with adverse karyotype. Stratification of patients according to three recent validated functional classifications did not allow the identification of TP53 mutated patients who could benefit from azacitidine. Systematic TP53 mutant classification will deserve further exploration in the setting of patients treated with conventional therapy and in the emerging field of therapies targeting TP53 pathway.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0238795PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7529302PMC
November 2020

Lomustine is beneficial to older AML with ELN2017 adverse risk profile and intermediate karyotype: a FILO study.

Leukemia 2021 05 18;35(5):1291-1300. Epub 2020 Sep 18.

Clinical Hematology, Bordeaux University Hospital, Bordeaux University, Inserm 1035, Bordeaux, France.

We previously reported the benefit of lomustine addition to conventional chemotherapy in older acute myeloid leukemias with nonadverse chromosomal aberrations in the LAM-SA 2007 randomized clinical trial (NCT00590837). A molecular analysis of 52 genes performed in 330 patients included in this trial, 163 patients being treated with lomustine in combination with idarubicin and cytarabine and 167 without lomustine, identified 1088 mutations with an average of 3.3 mutations per patient. NPM1, FLT3, and DNMT3A were the most frequently mutated genes. A putative therapeutic target was identified in 178 patients (54%). Among five molecular classifications analyzed, the ELN2017 risk classification has the stronger association with the clinical evolution. Patients not treated with lomustine have an expected survival prognosis in agreement with this classification regarding the overall and event-free survivals. In strong contrast, lomustine erased the ELN2017 classification prognosis. The benefit of lomustine in nonadverse chromosomal aberrations was restricted to patients with RUNX1, ASXL1, TP53, and FLT3-ITD/NPM1 mutations in contrast to the intermediate and favorable ELN2017 patients. This post-hoc analysis identified a subgroup of fit elderly AML patients with intermediate cytogenetics and molecular markers who may benefit from lomustine addition to intensive chemotherapy.
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http://dx.doi.org/10.1038/s41375-020-01031-1DOI Listing
May 2021

Bendamustine-EAM versus BEAM regimen in patients with mantle cell lymphoma undergoing autologous stem cell transplantation in the frontline setting: a multicenter retrospective study from Lymphoma Study Association (LYSA) centers.

Bone Marrow Transplant 2020 06 17;55(6):1076-1084. Epub 2020 Jan 17.

Department of Clinical Hematology, Caen University Hospital, F-14000, Caen, France.

The combination of carmustine, etoposide, cytarabine, and melphalan (BEAM) as conditioning regimen prior to autologous stem-cell transplantation (ASCT) remains the standard of care for patients with mantle cell lymphoma (MCL) who are eligible for transplantation. The replacement of carmustine with bendamustine (BeEAM) was described as a promising alternative in non-Hodgkin lymphoma. The aim of this retrospective study was to compare the BeEAM with the BEAM regimen in MCL patients in the frontline setting. Sixty and 108 patients were included in the BeEAM and the BEAM groups, respectively. At 3 years, progression-free survival (PFS) was significantly higher in the BeEAM than in the BEAM group (84% [73-96] vs. 63% [51-79], p = 0.03). The overall survival was not statistically different between the two groups (p = 0.2). In multivariable analysis, BeEAM regimen remained associated with higher PFS (HR = 0.377, 95% CI, 0.146-0.970; p = 0.043). Subgroup analyses in patients treated with prior rituximab-aracytine induction alone showed that BeEAM improved the PFS compared with BEAM regimen (p = 0.04). Despite the high rate of acute renal failure KDIGO III (32%), treatment-related mortality was not increased with the BeEAM regimen. A prospective randomized trial will be necessary to confirm the beneficial effect of the BeEAM regimen in MCL patients undergoing ASCT.
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http://dx.doi.org/10.1038/s41409-020-0783-yDOI Listing
June 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

Prevalence of and mutations in a real-life CLL cohort still on ibrutinib after 3 years: a FILO group study.

Blood 2019 08 26;134(7):641-644. Epub 2019 Jun 26.

Groupe de Hôpitaux Universitaires Paris Seine-Saint-Denis (GHUPSSD), Assistance Publique-Hôpitaux de Paris (AP-HP), Bobigny, France.

Mutational analyses performed following acquired ibrutinib resistance have suggested that chronic lymphocytic leukemia (CLL) progression on ibrutinib is linked to mutations in Bruton tyrosine kinase () and/or phospholipase Cγ2 () genes. Mutational information for patients still on ibrutinib is limited. We report a study aimed to provide a "snapshot" of the prevalence of mutations in a real-life CLL cohort still on ibrutinib after at least 3 years of treatment. Of 204 patients who initiated ibrutinib via an early-access program at 29 French Innovative Leukemia Organization (FILO) centers, 63 (31%) were still on ibrutinib after 3 years and 57 provided a fresh blood sample. Thirty patients had a CLL clone ≥0.5 × 10/L, enabling next-generation sequencing (NGS); and mutations were detected in 57% and 13% of the NGS samples, respectively. After median follow-up of 8.5 months from sample collection, the presence of a mutation was significantly associated with subsequent CLL progression ( = .0005 vs no mutation). Our findings support that mutational analysis should be considered in patients receiving ibrutinib who have residual clonal lymphocytosis, and that clinical trials are needed to evaluate whether patients with a mutation may benefit from an early switch to another treatment.
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http://dx.doi.org/10.1182/blood.2019000854DOI Listing
August 2019

High-dose therapy with autologous stem cells transplantation in Bing-Neel syndrome: A retrospective analysis of 14 cases.

Am J Hematol 2019 09 10;94(9):E227-E229. Epub 2019 Jun 10.

Department of Hematology, Hôpital Pitié-Salpêtrière, APHP, Paris, France.

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http://dx.doi.org/10.1002/ajh.25547DOI Listing
September 2019

Evaluation of the effects of chemotherapy on brain glucose metabolism in children with Hodgkin's lymphoma.

Ann Nucl Med 2019 Aug 13;33(8):564-569. Epub 2019 May 13.

Service de Biophysique Et de Médecine Nucléaire, Hôpitaux Universitaires de Strasbourg, Hôpital de Hautepierre, 1, Avenue Molière, 67098, Strasbourg Cedex 09, France.

Objective: Chemobrain is a recently proposed pathological entity. F-FDG PET/CT can show objective abnormalities to explain brain disorders caused by chemotherapy, although no study has investigated these phenomena in children to date. The main objective of the present study was to examine quantitatively the effects of chemotherapy on brain metabolism in a homogeneous population of children treated for Hodgkin's lymphoma using 18F-FDG PET/CT.

Methods: In this retrospective study, we included 20 children, newly diagnosed with Hodgkin's lymphoma, who underwent F-FDG PET/CT at initial staging and at least one PET/CT in follow-up. The SPM12 software provided t-maps to show the difference in metabolism between these PET/CTs. The statistical maps were analyzed with xjView software to identify the brain regions associated with the clusters detected.

Results: Altered glucose metabolism was found in the frontal, cingular, and temporoinsular regions after two cycles of chemotherapy. Results in children were compared to a group of 35 adults. For the same statistical threshold, the extent and depth of the metabolic alterations were less in the adult group than in children.

Conclusions: F-FDG PET/CT is useful in providing objective data to explain brain disorders caused by chemotherapy. This could lead to better care and should be compared to neuropsychological test results.
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http://dx.doi.org/10.1007/s12149-019-01363-8DOI Listing
August 2019

Multi-omics dataset to decipher the complexity of drug resistance in diffuse large B-cell lymphoma.

Sci Rep 2019 01 29;9(1):895. Epub 2019 Jan 29.

Laboratoire de Spectrométrie de Masse BioOrganique (LSMBO), IPHC, Université de Strasbourg, CNRS UMR 7178, Strasbourg, France.

The prognosis of patients with relapsed/refractory (R/R) diffuse large B-cell lymphoma (DLBCL) remains unsatisfactory and, despite major advances in genomic studies, the biological mechanisms underlying chemoresistance are still poorly understood. We conducted for the first time a large-scale differential multi-omics investigation on DLBCL patient's samples in order to identify new biomarkers that could early identify patients at risk of R/R disease and to identify new targets that could determine chemorefractoriness. We compared a well-characterized cohort of R/R versus chemosensitive DLBCL patients by combining label-free quantitative proteomics and targeted RNA sequencing performed on the same tissues samples. The cross-section of both data levels allowed extracting a sub-list of 22 transcripts/proteins pairs whose expression levels significantly differed between the two groups of patients. In particular, we identified significant targets related to tumor metabolism (Hexokinase 3), microenvironment (IDO1, CXCL13), cancer cells proliferation, migration and invasion (S100 proteins) or BCR signaling pathway (CD79B). Overall, this study revealed several extremely promising biomarker candidates related to DLBCL chemorefractoriness and highlighted some new potential therapeutic drug targets. The complete datasets have been made publically available and should constitute a valuable resource for the future research.
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http://dx.doi.org/10.1038/s41598-018-37273-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6351558PMC
January 2019

BCR-associated factors driving chronic lymphocytic leukemia cells proliferation ex vivo.

Sci Rep 2019 01 24;9(1):701. Epub 2019 Jan 24.

Laboratoire d'ImmunoRhumatologie Moléculaire, INSERM UMR-S1109, LabEx Transplantex, Fédération de Médecine Translationnelle de Strasbourg (FMTS), Université de Strasbourg, Strasbourg, France.

A chronic antigenic stimulation is believed to sustain the leukemogenic development of chronic lymphocytic leukemia (CLL) and most of lymphoproliferative malignancies developed from mature B cells. Reproducing a proliferative stimulation ex vivo is critical to decipher the mechanisms of leukemogenesis in these malignancies. However, functional studies of CLL cells remains limited since current ex vivo B cell receptor (BCR) stimulation protocols are not sufficient to induce the proliferation of these cells, pointing out the need of mandatory BCR co-factors in this process. Here, we investigated benefits of several BCR co-stimulatory molecules (IL-2, IL-4, IL-15, IL-21 and CD40 ligand) in multiple culture conditions. Our results demonstrated that BCR engagement (anti-IgM ligation) concomitant to CD40 ligand, IL-4 and IL-21 stimulation allowed CLL cells proliferation ex vivo. In addition, we established a proliferative advantage for ZAP70 positive CLL cells, associated to an increased phosphorylation of ZAP70/SYK and STAT6. Moreover, the use of a tri-dimensional matrix of methylcellulose and the addition of TLR9 agonists further increased this proliferative response. This ex vivo model of BCR stimulation with T-derived cytokines is a relevant and efficient model for functional studies of CLL as well as lymphoproliferative malignancies.
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http://dx.doi.org/10.1038/s41598-018-36853-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6345919PMC
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

Tuberculosis and atypical mycobacterial infections in ruxolitinib-treated patients with primary or secondary myelofibrosis or polycythemia vera.

Int J Infect Dis 2019 Mar 11;80:134-136. Epub 2019 Jan 11.

Department of Oncology and Haematology, Hôpitaux Universitaires de Strasbourg, Strasbourg, France; Université de Strasbourg, Inserm UMR-S1113/IRFAC, Strasbourg, France.

Ruxolitinib is a JAK-1/JAK-2 inhibitor indicated for the treatment of polycythemia vera and primary or secondary myelofibrosis. Only one patient (0.2%) was diagnosed with tuberculosis among the 485 patients receiving ruxolitinib in the four pivotal trials. Fourteen cases of tuberculosis have since been reported. We observed two (3%) mycobacterial infections (one due to Mycobacterium tuberculosis and one due to Mycobacterium avium complex) in our cohort of 65 patients receiving ruxolitinib. This observation suggests that the rate of mycobacterial infection might be higher than that observed in the pivotal trials and that atypical mycobacterial infections can also occur.
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http://dx.doi.org/10.1016/j.ijid.2019.01.002DOI Listing
March 2019

Aplastic anemia in the elderly: a nationwide survey on behalf of the French Reference Center for Aplastic Anemia.

Haematologica 2019 02 27;104(2):256-262. Epub 2018 Sep 27.

French Reference Center for Aplastic Anemia, CHU Saint Louis, Paris.

Aplastic anemia is a rare but potentially life-threatening disease that may affect older patients. Data regarding the treatment of aplastic anemia in this ageing population remains scarce. We conducted a retrospective nationwide multicenter study in France to examine current treatments for aplastic anemia patients over 60 years old. Our aims were to evaluate efficacy and tolerance, and to analyze predictive factors for response and survival. Over the course of a decade, 88 patients (median age 68.5 years) were identified in 19 centers, with a median follow up of 2.7 years; 21% had very severe and 36% severe aplastic anemia. We analyzed 184 treatment lines, mostly involving the standard combination of anti-thymocyte globulin and cyclosporine-A (33%), which was also the most frequent first-line treatment (50%). After first-line therapy, 32% of patients achieved a complete response, and 15% a partial response. Responses were significantly better in first line and in patients with good performance status, as well as in those that had followed an anti-thymocyte globulin and cyclosporine-A regimen (overall response rate of 70% after first-line treatment). All treatments were well tolerated by patients, including over the age of 70. Three-year survival was 74.7% (median 7.36 years). Age, Charlson comorbidity index and very severe aplastic anemia were independently associated with mortality. Age, per se, is not a limiting factor to aplastic anemia treatment with anti-thymocyte globulin and cyclosporine-A; this regimen should be used as a first-line treatment in elderly patients if they have a good performance status and low comorbidity index score.
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http://dx.doi.org/10.3324/haematol.2018.198440DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6355477PMC
February 2019

Improved Survival by Adding Lomustine to Conventional Chemotherapy for Elderly Patients With AML Without Unfavorable Cytogenetics: Results of the LAM-SA 2007 FILO Trial.

J Clin Oncol 2018 Nov 27;36(32):3203-3210. Epub 2018 Sep 27.

Arnaud Pigneux and Pierre-Yves Dumas, Bordeaux University Hospital, Bordeaux University, INSERM 1035; Louis-Rachid Salmi, Ariane Mineur, and Julien Asselineau, Bordeaux University Hospital, Bordeaux; Marie C. Béné, and Jacques Delaunay, Nantes University Hospital, Nantes; Caroline Bonmati, Nancy University Hospital, Nancy; Romain Guièze, Clermont-Ferrand University Hospital, Clermont Ferrand; Isabelle Luquet, Eric Delabesse, and Christian Récher, Toulouse University Hospital, Toulouse; Pascale Cornillet-Lefebvre, Reims University Hospital, Reims; Jean-Christophe Ianotto, Brest University Hospital, Brest; Mario Ojeda-Uribe, Mulhouse Regional Hospital, Mulhouse; Mathilde Hunault and Norbert Ifrah, Angers University Hospital and INSERM U 892/CNRS 6299, Angers; Anne Banos, Cote Basque General Hospital, Bayonne; Luc Matthieu Fornecker, Strasbourg University Hospital, Strasbourg; Marc Bernard, Rennes University Hospital, Rennes; Eric Jourdan, Nîmes University Hospital, Nîmes; Norbert Vey, Institut Paoli Calmettes, Marseilles; Hacene Zerazhi, Avignon General Hospital, Avignon; Yosr Hishri, Montpellier University Hospital, Montpellier; Roselyne Delepine, Tours University Hospital, Tours; and Jean-Yves Cahn, Grenoble University Hospital, Grenoble, France.

Purpose: Acute myeloid leukemia (AML) in elderly patients has a poor prognosis. In an attempt to improve outcome for these patients, the prospective open-label phase III LAM-SA 2007 (Adding Lomustine to Chemotherapy in Older Patients With Acute Myelogenous Leukemia (AML), and Allogeneic Transplantation for Patients From 60 to 65 Years Old) trial randomly assigned patients to a standard induction regimen with lomustine added or to a consolidation regimen with cytarabine and idarubicin.

Patients And Methods: Adults age 60 years or older with previously untreated AML who were fit to receive intensive chemotherapy and who were without unfavorable cytogenetics received standard chemotherapy with lomustine (idarubicin, cytarabine, and lomustine [ICL]) or without (idarubicin and cytarabine [IC]). The primary objective of the study was overall survival (OS); secondary objectives were response rate, cumulative incidence of relapse (CIR), event-free survival (EFS), and safety.

Results: From February 2008 to December 2011, 459 patients were enrolled. Comparing patients in the IC and ICL arms, complete response or complete response with incomplete recovery was achieved in 74.9% versus 84.7% ( = .01). The proportional hazards assumption was rejected for OS ( = .02), which led us to consider two separate time intervals: during and after induction. There was no significant difference between the two arms during induction, although induction deaths were 3.7% versus 7.7%, respectively ( = .11). However, significantly better results were observed after induction with an improved 2-year OS of 56% in the ICL arm versus 48% in the IC arm ( = .02). At 2 years, EFS was improved at 41% in the ICL arm versus 26% in the IC arm ( = .01). The CIR at 2 years was 41.2% in the ICL arm versus 60.9% in the IC arm ( = .003). Grade 3 and 4 toxicities, mostly hematologic, were significantly higher in the ICL arm ( = .04), and fewer patients required a second treatment after ICL.

Conclusion: Adding lomustine to standard chemotherapy significantly improved the outcome of elderly patients with AML.
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http://dx.doi.org/10.1200/JCO.2018.78.7366DOI Listing
November 2018

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

Imaging spectrum of Bing-Neel syndrome: how can a radiologist recognise this rare neurological complication of Waldenström's macroglobulinemia?

Eur Radiol 2019 Jan 19;29(1):102-114. Epub 2018 Jun 19.

From the 2nd Radiology Department, University Hospital of Strasbourg, Avenue Molière 1, 67098, Strasbourg, France.

Objectives: Bing-Neel syndrome (BNS) is a rare neurological complication of Waldenström's macroglobulinemia. The aim of this study is to describe the spectrum of radiological manifestations of this syndrome and their prevalence in order to facilitate its early diagnosis.

Methods: Twenty-four patients with BNS were diagnosed between 1994 and 2016 in eight centres in France. We retrospectively examined the medical records of these patients as well as the corresponding literature, focusing on imaging studies. Recorded data were statistically analysed and radiological findings described.

Results: The mean age of our patients was 62.4 years (35-80 years). The vast majority of patients were men, with a male to female ratio of 9:1. Findings included parenchymal or meningeal involvement or both. The most common finding was leptomeningeal infiltration, either intracranial or spinal, with a prevalence reaching 70.8%. Dural involvement was present in 37.5% of patients. In 41.7% (10/24) of patients, there was parenchymal involvement with a higher prevalence of brain comparing to medullar involvement (33.3% and 23.1% respectively). High T2 signal of the parenchyma was identified in 41.7% of patients and high signal in diffusion was evident in 25% of them. Intraorbital or periorbital involvement was also detected in four cases. A proposition regarding the appropriate imaging protocol completed our study.

Conclusion: BNS's diagnosis remains challenging. Central nervous system MRI findings in the setting of known or suspected Waldenström's macroglobulinemia appear to be highly suggestive of BNS and appropriate imaging protocols should be implemented for their depiction.

Key Points: • Diagnosis of Bing-Neel syndrome (BNS) remains challenging and recent expert recommendations include MRI in the diagnostic criteria for the syndrome. • The most common radiological manifestations of BNS are leptomeningeal/dural infiltration or parenchymal involvement of brain or spinal cord, but many atypical forms may exist with various presentations. • Appropriate imaging protocol for BNS should include enhanced MRI studies of both brain and spine.
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http://dx.doi.org/10.1007/s00330-018-5543-7DOI Listing
January 2019

Tandem haematopoietic stem cell transplantation for High Risk relapsed/refractory Hodgkin Lymphoma: a LYSA study.

Br J Haematol 2018 05 2;181(3):341-349. Epub 2018 Apr 2.

Hopital Saint Louis, Paris, France.

Tandem stem cell transplantation (SCT) is an option for high-risk relapsed/refractory Hodgkin Lymphoma (HL) patients. We evaluated the tolerance/efficacy of double autologous or autologous SCT (ASCT) followed by allogenic SCT (alloSCT) in 120 HL patients prospectively registered on a French nationwide database. Median age was 26 (14-56) years. Complete remission rate was 60%, including 33% after a single line, and another 27% after two or more salvage regimens. Partial response rate was 32%, and 8% suffered treatment failure. Overall, 115 (96%) patients underwent a first ASCT, and 73 (61%) had a tandem SCT, including alloSCT in 44 (60%) and ASCT in 29 (40%). The median follow-up was 43 months (4.8-73.7 months). The two-year progression-free survival rate for the whole population and for patients receiving tandem transplant was 56% (95% confidence interval [CI]: 46-65%) and 71% (95% CI: 49-84%), respectively. Among tandem transplants, we observed 20 deaths (17%), 10 of which were transplant-related (6 alloSCT and 4 ASCT). We suggest that tandem SCT is efficient in high-risk relapsed/refractory HL patients, although transplant-related mortality remains high. The benefit of tandem SCT should be balanced with the efficacy of Brentuximab vedotin-based post-transplant consolidative strategies in high-risk relapsed/refractory HL patients.
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http://dx.doi.org/10.1111/bjh.15184DOI Listing
May 2018

Better outcome with haploidentical over HLA-matched related donors in patients with Hodgkin's lymphoma undergoing allogeneic haematopoietic cell transplantation-a study by the Francophone Society of Bone Marrow Transplantation and Cellular Therapy.

Bone Marrow Transplant 2018 04 12;53(4):400-409. Epub 2018 Jan 12.

Department of Haematology, Liège University Hospital, Liège, Belgium.

The question of the best donor type between haploidentical (HAPLO) and matched-related donors (MRD) for patients with advanced HL receiving an allogeneic hematopoietic cell transplantation (allo-HCT) is still debated. Given the lack of data comparing these two types of donor in the setting of non-myeloablative (NMA) or reduced-intensity (RIC) allo-HCT, we performed a multicentre retrospective study using graft-vs.-host disease-free relapse-free survival (GRFS) as our primary endpoint. We analysed the data of 151 consecutive HL patients who underwent NMA or RIC allo-HCT from a HAPLO (N  =  61) or MRD (N  =  90) between January 2011 and January 2016. GRFS was defined as the probability of being alive without evidence of relapse, grade 3-4 acute GVHD or chronic GVHD. In multivariable analysis, MRD donors were independently associated with lower GRFS compared to HAPLO donors (HR  =  2.95, P   < 0.001). Disease status at transplant other than CR was also associated with lower GRFS in multivariable analysis (HR  =  1.74, P  =  0.01). In addition, the administration of ATG was independently linked to higher GRFS (HR  =  0.52, P  =  0.009). In summary, we observed significantly higher GRFS in HL patients receiving an allo-HCT using the HAPLO PT-Cy platform compared to MRD.
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http://dx.doi.org/10.1038/s41409-017-0018-zDOI Listing
April 2018

Rituximab after Autologous Stem-Cell Transplantation in Mantle-Cell Lymphoma.

N Engl J Med 2017 09;377(13):1250-1260

From Service d'Hématologie Clinique (S.L.G., T.G.), Service d'Anatomopathologie (A.M.), and Service d'Hématologie Biologique (M.C.B.), Hôtel-Dieu Centre Hospitalier Universitaire (CHU) de Nantes, and Centre de Recherche en Cancérologie et Immunologie (S.L.G., M.C.B.) and Faculté de Médecine (S.L.G.), Université de Nantes, Nantes, Hemato-Oncologie, Assistance Publique-Hôpitaux de Paris (APHP), Hôpital Saint-Louis, Université Diderot Sorbonne Paris-Cité (C.T.), Université Descartes (C.T.), Département d'Hématologie, Faculté de Médecine, Université Paris-Sud (V.R.), Département d'Anatomopathologie (D.C.) and Département d'Hématologie (O.H.), Necker Hospital, APHP, Sorbonne Paris-Cité, and INSERM Unité 1163 et Centre National de la Recherche Scientifique (CNRS) Équipe de Recherche Labellisée 8654, Imagine Institute (O.H.), Paris, Département d'Hématologie, Institut Universitaire du Cancer-Oncopole de Toulouse, Toulouse (L.O.), Service d'Hématologie Clinique et Thérapie Cellulaire, CHU de Bordeaux, Bordeaux (K.B.), Service d'Hématologie et Thérapie Cellulaire, CHU de Tours, Tours (C.D.), Service d'Hématologie, CHU d'Amiens, Amiens (G.D.), INSERM, Gustave Roussy Cancer Campus, Université Paris-Saclay, Villejuif (V.R.), Département d'Hématologie, CHU de Nancy, Nancy (P.F.), INSERM Unité 954, Vandoeuvre (P.F.), Service d'Hématologie Clinique, CHU de Dijon, and INSERM Unité Mixte de Recherche 1231, Dijon (O.C.), Service d'Hématologie, Centre Hospitalier d'Avignon, Avignon (H.Z.), Lymphoid Malignancies Unit, Hôpital Henri Mondor, APHP, Créteil (C.H.), Service d'Hématologie du Centre Hospitalier de Vendée, La Roche-sur-Yon (H.M.), Service Hématologie Clinique (R.H.) and Département d'Hématologie (T.L.), CHU de Rennes, INSERM Unité 917 (R.H.), and INSERM Unité 1236 (T.L.), Rennes, Département d'Hematology, Centre Henri-Becquerel et Université de Normandie Unité 1245, Rouen (F.J., H.T.), Service d'Hématologie Clinique Adulte et de Thérapie Cellulaire, CHU de Clermont-Ferrand et Université Clermont Auvergne, Clermont-Ferrand (O.T.), Service d'Hématologie, Clinique Victor Hugo, Le Mans (K.L.D.), Department of Hematology, Université de Lille, Groupe de Recherche sur les Formes Injectables et les Technologies Associées, and CHU de Lille, Lille (F.M.), Département d'Hématologie Clinique, CHU de Montpellier, CNRS UMR 5235, Montpellier (G.C.), Service d'Oncologie et d'Hématologie, Hôpitaux Universitaires de Strasbourg, Strasbourg (L.-M.F.), INSERM 1209, CNRS UMR 5309, Faculté de Médecine, Université Grenoble Alpes (M.C., R.G.), Institute for Advanced Biosciences (M.C.), and Laboratoire de Génétique Onco-hématologie (M.C.) and Faculté de Médecine (R.G.), CHU de Grenoble Alpes, Grenoble, Service d'Hématologie, Hospices Civils de Lyon, Centre Hospitalier Lyon Sud, Pierre-Bénite (G.S.), and Université Claude Bernard Lyon 1 and Cancer Research Center of Lyon, INSERM 1052 CNRS 5286 Lyon, Lyon (G.S.) - all in France; and Département d'Hématologie, Cliniques Universitaires Saint-Luc-Université Catholique de Louvain, Brussels (E.V.D.N.).

Background: Mantle-cell lymphoma is generally incurable. Despite high rates of complete response after initial immunochemotherapy followed by autologous stem-cell transplantation, patients have relapses. We investigated whether rituximab maintenance therapy at a dose of 375 mg per square meter of body-surface area administered every 2 months for 3 years after transplantation would prolong the duration of response.

Methods: In a phase 3 trial involving 299 patients who were younger than 66 years of age at diagnosis, we randomly assigned 240 patients to receive rituximab maintenance therapy or to undergo observation after autologous stem-cell transplantation (120 patients per group); 59 patients did not undergo randomization. The primary end point was event-free survival (with an event defined as disease progression, relapse, death, allergy to rituximab, or severe infection) after transplantation among patients who underwent randomization.

Results: After four courses of immunochemotherapy induction (rituximab, dexamethasone, cytarabine, and a platinum derivative [R-DHAP]), the overall response rate was 89%, and the complete response rate 77%. Transplantation was performed in 257 patients. The median follow-up from randomization after transplantation was 50.2 months (range, 46.4 to 54.2). Starting from randomization, the rate of event-free survival at 4 years was 79% (95% confidence interval [CI], 70 to 86) in the rituximab group versus 61% (95% CI, 51 to 70) in the observation group (P=0.001). The rate of progression-free survival at 4 years was 83% (95% CI, 73 to 88) in the rituximab group versus 64% (95% CI, 55 to 73) in the observation group (P<0.001). The rate of overall survival was 89% (95% CI, 81 to 94) in the rituximab group versus 80% (95% CI, 72 to 88) in the observation group (P=0.04). According to a Cox regression unadjusted analysis, the rate of overall survival at 4 years was higher in the rituximab group than in the observation group (hazard ratio for death, 0.50; 95% CI, 0.26 to 0.99; P=0.04).

Conclusions: Rituximab maintenance therapy after transplantation prolonged event-free survival, progression-free survival, and overall survival among patients with mantle-cell lymphoma who were younger than 66 years of age at diagnosis. (Funded by Roche and Amgen; LyMa ClinicalTrials.gov number, NCT00921414 .).
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http://dx.doi.org/10.1056/NEJMoa1701769DOI Listing
September 2017

Effect of Azithromycin on Airflow Decline-Free Survival After Allogeneic Hematopoietic Stem Cell Transplant: The ALLOZITHRO Randomized Clinical Trial.

JAMA 2017 08;318(6):557-566

APHP, Hématologie-Transplantation Hôpital St Louis, Université Denis Diderot and INSERM UMR 1160, Paris, France.

Importance: Bronchiolitis obliterans syndrome has been associated with increased morbidity and mortality after allogeneic hematopoietic stem cell transplant (HSCT). Previous studies have suggested that azithromycin may reduce the incidence of post-lung transplant bronchiolitis obliterans syndrome.

Objective: To evaluate if the early administration of azithromycin can improve airflow decline-free survival after allogeneic HSCT.

Design, Setting, And Participants: The ALLOZITHRO parallel-group trial conducted in 19 French academic transplant centers and involving participants who were at least 16 years old, had undergone allogeneic HSCT for a hematological malignancy, and had available pretransplant pulmonary function test results. Enrollment was from February 2014 to August 2015 with follow-up through April 26, 2017.

Interventions: Patients were randomly assigned to receive 3 times a week either 250 mg of azithromycin (n = 243) or placebo (n = 237) for 2 years, starting at the time of the conditioning regimen.

Main Outcomes And Measures: The primary efficacy end point was airflow decline-free survival at 2 years after randomization. Main secondary end points were overall survival and bronchiolitis obliterans syndrome at 2 years.

Results: Thirteen months after enrollment, the independent data and safety monitoring board detected an unanticipated imbalance across blinded groups in the number of hematological relapses, and the treatment was stopped December 26, 2016. Among 480 randomized participants, 465 (97%) were included in the modified intention-to-treat analysis (mean age, 52 [SD, 14] years; 75 women [35%]). At the time of data cutoff, 104 patients (22%; 54 azithromycin vs 50 placebo) had experienced an airflow decline; 138 patients (30%) died (78 azithromycin vs 60 placebo). Two-year airflow decline-free survival was 32.8% (95% CI, 25.9%-41.7%) with azithromycin and 41.3% (95% CI, 34.1%-50.1%) with placebo (unadjusted hazard ratio [HR], 1.3; 95% CI, 1.02-1.70; P = .03). Of the 22 patients (5%) who experienced bronchiolitis obliterans syndrome, 15 (6%) were in the azithromycin group and 7 (3%) in the placebo group (P = .08). The azithromycin group had increased mortality, with a 2-year survival of 56.6% (95% CI, 50.2%-63.7%) vs 70.1% (95% CI, 64.2%-76.5%) in the placebo group (unadjusted HR, 1.5; 95% CI, 1.1-2.0; P = .02). In a post hoc analysis, the 2-year cumulative incidence of hematological relapse was 33.5% (95% CI, 27.3%-39.7%) with azithromycin vs 22.3% (95% CI, 16.4%-28.2%) with placebo (unadjusted cause-specific HR, 1.7; 95% CI, 1.2-2.4; P = .002).

Conclusions And Relevance: Among patients undergoing allogeneic HSCT for hematological malignancy, early administration of azithromycin resulted in worse airflow decline-free survival than did placebo; these findings are limited by early trial termination. The potential for harm related to relapse requires further investigation.

Trial Registration: clinicaltrials.gov Identifier: NCT01959100.
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http://dx.doi.org/10.1001/jama.2017.9938DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5817485PMC
August 2017
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