Publications by authors named "Emmanuelle Nicolas-Virelizier"

38 Publications

Cholesterol Granuloma: Unusual Pitfall for Hodgkin Lymphoma Evaluation With 18F-FDG PET/CT.

Clin Nucl Med 2021 Oct;46(10):e518-e520

Clinical Hematology, Centre Leon Berard, Lyon, France.

Abstract: Cholesterol granuloma (CG) is a foreign body-type granuloma that forms in response to cholesterol crystals. Its etiology and pathogenesis are unclear. 18F-FDG is not a tumor-specific agent. Fibroblasts, macrophages, and multinucleated giant cells also take up 18F-FDG. Like sarcoid granulomas or fibrous dysplasia, CG avidly takes up 18F-FDG and can mimic tumor involvement. We present 2 cases of histologically proven CG, which has been misinterpreted as active residual Hodgkin lymphoma lesion.
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http://dx.doi.org/10.1097/RLU.0000000000003740DOI Listing
October 2021

Individualised physical activity programme in patients over 65 years with haematological malignancies (OCAPI): protocol for a single-arm feasibility trial.

BMJ Open 2021 06 3;11(6):e046409. Epub 2021 Jun 3.

Département Prévention Cancer Environnement, Centre Léon Bérard, Lyon, France.

Introduction: Older adults with cancer suffer from the combined effects of ageing, cancer disease and treatment side effects. The main treatment for patients with haematological malignancies is chemotherapy, associated with significant toxicities. Chemotherapy can alter patients' physical function and quality of life which are often already diminished in older patients due to ageing and comorbidities. It therefore seems essential to develop and to evaluate interventions capable of preventing physical and psychosocial decline and its consequences. Promoting physical activity is a promising approach to improve physical function and quality of life in older adults with cancer, but there are limited data on the feasibility of such interventions among older patients with haematological malignancies, concomitant to chemotherapy.

Methods And Analysis: OCAPI (OnCogeriatric and Individualized Physical Activity) is a single-arm, interdisciplinary, prospective, interventional, feasibility study. It is intended to include 40 patients (20 patients with acute myeloid leukaemia and 20 patients with non-Hodgkin's lymphoma) over 65 years in an individualised 6-month physical activity programme. The programme consists of individually supervised exercise sessions with an increasing volume of physical activity either at home and/or in a laminar airflow room (depending on the disease and treatment regimen) followed by unsupervised sessions and phone follow-ups. Patients will receive an activity tracker during the 6 months of the programme. Evaluations will take place at inclusion and at 3, 6 and 12 months to assess the feasibility of the programme and to explore potential changes in physical, psychosocial and clinical outcomes. The results will generate preliminary data to implement a larger randomised controlled trial.

Ethics And Dissemination: The study protocol was approved by the French ethics committee (Comité de protection des personnes Est I, N°ID-RCB 2019-A01231-56, 12 July 2019). All participants will have to sign and date an informed consent form. The findings will be disseminated in peer-reviewed journals and academic conferences.

Trial Registration Number: NCT04052126.
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http://dx.doi.org/10.1136/bmjopen-2020-046409DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8183222PMC
June 2021

Intercontinental study on pre-engraftment and post-engraftment Gram-negative rods bacteremia in hematopoietic stem cell transplantation patients: Risk factors and association with mortality.

J Infect 2020 12 10;81(6):882-894. Epub 2020 Nov 10.

ICO-Hospital Universitari Germans Trias I Pujol, Badalona, Spain. Electronic address:

Objectives: We present here data on Gram-negative rods bacteremia (GNRB) rates, risk factors and associated mortality.

Methods: Data on GNRB episodes were prospectively collected in 65 allo-/67 auto-HSCT centers in 24 countries (Europe, Asia, Australia). In patients with and without GNRB, we compared: demography, underlying disease, HSCT-related data, center` fluoroquinolone prophylaxis (FQP) policy and accreditation status, and involvement of infection control team (ICT).

Results: The GNRB cumulative incidence among 2818 allo-HSCT was: pre-engraftment (pre-eng-allo-HSCT), 8.4 (95% CI 7-9%), post-engraftment (post-eng-allo-HSCT), 5.8% (95%CI: 5-7%); among 3152 auto-HSCT, pre-eng-auto-HSCT, 6.6% (95%CI: 6-7%), post-eng-auto-HSCT, 0.7% (95%CI: 0.4-1.1%). GNRB, especially MDR, was associated with increased mortality. Multivariate analysis revealed the following GNRB risk factors: (a) pre-eng-allo-HSCT: south-eastern Europe center location, underlying diseases not at complete remission, and cord blood source; (b) post-eng-allo-HSCT: center location not in northwestern Europe; underlying non-malignant disease, not providing FQP and never accredited. (c) pre-eng-auto-HSCT: older age, autoimmune and malignant (vs. plasma cell) disease, and ICT absence.

Conclusions: Benefit of FQP should be explored in prospective studies. Increased GNRB risk in auto-HSCT patients transplanted for autoimmune diseases is worrying. Infection control and being accredited are possibly protective against bacteremia. GNRB are associated with increased mortality.
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http://dx.doi.org/10.1016/j.jinf.2020.11.002DOI Listing
December 2020

Haematopoietic stem cell transplantation in adult soft-tissue sarcoma: an analysis from the European Society for Blood and Marrow Transplantation.

ESMO Open 2020 10;5(5):e000860

Internal Medicine and Medical Therapy, Università degli Studi di Pavia, Pavia, Lombardia, Italy.

Background: The role of high-dose chemotherapy with autologous stem cell transplantation (ASCT) in the treatment of soft-tissue sarcoma (STS) remains an unsettled issue. Prospective clinical trials failed to prove a benefit of the procedure but were limited by small and heterogeneous patient cohorts. Thus, it is unknown if ASCT may be a valuable treatment option in specific patient subgroups.

Methods: The purpose of this study was to investigate the value of ASCT according to histological subtype in STS patients who were registered in the European Society for Blood and Marrow Transplantation database between 1996 and 2016.

Results: Median progression-free (PFS) and overall survival (OS) in the entire cohort of 338 patients were 8.3 and 19.8 months, respectively, and PFS and OS at 5 years were 13% and 25%, respectively. Analysis of outcomes in different subgroups showed that younger age, better remission status before transplantation and melphalan-based preparative regimen were predictive of benefit from ASCT, whereas histology and grading had no statistically significant impact.

Conclusions: Outcomes after ASCT compared favorably to those of recent trials on conventional chemotherapies and targeted therapies in STS, including histology-tailored approaches. ASCT, thus, should be reinvestigated in clinical trials focusing on defined patient subgroups.
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http://dx.doi.org/10.1136/esmoopen-2020-000860DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7590345PMC
October 2020

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

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

Department of Hematology, Centre Léon Bérard, Lyon, France.

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

Bortezomib, Melphalan, and Dexamethasone for Light-Chain Amyloidosis.

J Clin Oncol 2020 10 30;38(28):3252-3260. Epub 2020 Jul 30.

Amyloidosis Research and Treatment Center "Fondazione Istituto di Ricovero e Cura a Carattere Scientifico Policlinico San Matteo," Pavia, Italy.

Purpose: Oral melphalan and dexamethasone (MDex) were considered a standard of care in light-chain (AL) amyloidosis. In the past decade, bortezomib has been increasingly used in combination with alkylating agents and dexamethasone. We prospectively compared the efficacy and safety of MDex and MDex with the addition of bortezomib (BMDex).

Methods: This was a phase III, multicenter, randomized, open-label trial. Patients were stratified according to cardiac stage. Patients with advanced cardiac stage (stage IIIb) amyloidosis were not eligible. The primary end point was hematologic response rate at 3 months. This trial is registered with ClinicalTrials.gov identifier NCT01277016.

Results: A total of 109 patients, 53 in the BMDex and 56 in the MDex group, received ≥ 1 dose of therapy (from January 2011 to February 2016). Hematologic response rate at 3 months was higher in the BMDex arm (79% 52%; = .002). Higher rates of very good partial or complete response rates (64% 39%; hazard ratio [HR], 2.47; 95% CI, 1.30 to 4.71) and improved overall survival, with a 2-fold decrease in mortality rate (HR, 0.50; 95% CI, 0.27 to 0.90), were observed in the BMDex arm. Grade 3 and 4 adverse events (the most common being cytopenia, peripheral neuropathy, and heart failure) were more common in the BMDex arm, occurring in 20% versus 10% of cycles performed.

Conclusion: BMDex improved hematologic response rate and overall survival. To our knowledge, this is the first time a controlled study has demonstrated a survival advantage in AL amyloidosis. BMDex should be considered a new standard of care for AL amyloidosis.
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http://dx.doi.org/10.1200/JCO.20.01285DOI Listing
October 2020

High mortality rate in cancer patients with symptoms of COVID-19 with or without detectable SARS-COV-2 on RT-PCR.

Eur J Cancer 2020 08 7;135:251-259. Epub 2020 Jun 7.

Centre Léon Bérard, 28 Rue Laënnec, 69373, Lyon Cedex 08, France; Université Claude Bernard Lyon I, France; Unicancer, Paris, France.

Background: Cancer patients presenting with COVID-19 have a high risk of death. In this work, predictive factors for survival in cancer patients with suspected SARS-COV-2 infection were investigated.

Methods: PRE-COVID-19 is a retrospective study of all 302 cancer patients presenting to this institute with a suspicion of COVID-19 from March 1st to April 25th 2020. Data were collected using a web-based tool within electronic patient record approved by the Institutional Review Board. Patient characteristics symptoms and survival were collected and compared in SARS-COV-2 real-time or reverse-transcriptase PCR (RT-PCR)-positive and RT-PCR-negative patients.

Results: Fifty-five of the 302 (18.2%) patients with suspected COVID-19 had detectable SARS-COV-2 with RT-PCR in nasopharyngeal samples. RT-PCR-positive patients were older, had more frequently haematological malignancies, respiratory symptoms and suspected COVID-19 pneumonia of computed tomography (CT) scan. However, respectively, 38% and 20% of SARS-COV-2 RT-PCR-negative patients presented similar respiratory symptoms and CT scan images. Thirty of the 302 (9.9%) patients died during the observation period, including 24 (80%) with advanced disease. At the median follow-up of 25 days after the first symptoms, the death rate in RT-PCR-positive and RT-PCR-negative patients were 21% and 10%, respectively. In both groups, independent risk factors for death were male gender, Karnofsky performance status <60, cancer in relapse and respiratory symptoms. Detection of SARS-COV-2 on RT-PCR was not associated with an increased death rate (p = 0.10). None of the treatment given in the previous month (including cytotoxics, PD1 Ab, anti-CD20, VEGFR2…) correlated with survival. The survival of RT-PCR-positive and -negative patients with respiratory symptoms and/or COVID-19 type pneumonia on CT scan was similar with a 18.4% and 19.7% death rate at day 25. Most (22/30, 73%) cancer patients dying during this period were RT-PCR negative.

Conclusion: The 30-day death rate of cancer patients with or without documented SARS-COV-2 infection is poor, but the majority of deaths occur in RT-PCR-negative patients.
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http://dx.doi.org/10.1016/j.ejca.2020.05.028DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7275994PMC
August 2020

Performance of CT Compared with F-FDG PET in Predicting the Efficacy of Nivolumab in Relapsed or Refractory Hodgkin Lymphoma.

Radiology 2020 06 14;295(3):651-661. Epub 2020 Apr 14.

From the Dept of Radiology, New York Presbyterian Hosp, Columbia Univ Medical Ctr, New York, NY (F.Z.M., L.D., A.C., L.H.S.); Dept of Radiology, Rangueil Univ Hosp, Toulouse, France (F.Z.M.); Dept of Radiology, First Affiliated Hosp of Nanjing Medical Univ, Nanjing, China (A.C.); Univ Lille, CHU Lille, EA 7365-GRITA-Groupe de Recherche sur les Formes Injectables et les Technologies Associées, Lille, France (F.M.); Dept of Hematology, Centre Henri Becquerel, Rouen, France (A.S.); Dept of Hematology, Paoli-Calmette Inst, Marseille, France (J.M.S.d.C.); Dept of Nuclear Medicine, Saint-Louis Hosp, AP-HP, Paris, France (L.V.); Dept of Hematology, Univ Hosp of Dijon, Dijon, France (O.C.); Dept of Hematology, Univ Hosp of Besançon, Besançon, France (A.C.); Dept of Hematology, Univ Hosp of Reims, Reims, France (A.D.); Dept of Hematology, Leon Berard Ctr, Lyon, France (E.N.V.); Dept of Hematology, Univ Hosp of Lyon, Lyon, France (H.G.); Dept of Hematology, Univ Hosp of Angers, Angers, France (M.P.M.M.); Dept of Hematology, Bergonie Inst, Bordeaux, France (A.S.); Dept of Hematology, Saint-Antoine Hosp, AP-HP, Paris, France (R.D.); Dept of Hematology, Univ Hosp of Bordeaux, Bordeaux, France (K.B.); Dept of Hematology, Institut Universitaire du Cancer Toulouse-Oncopole, Toulouse, France (C.B.); Dept of Hematology, Univ Hosp of Limoges, Limoges, France (M.T.); Dept of Hematology, Cochin Hosp, AP-HP, Paris, France (B.D.F.); Centre Antoine Lacassagne, Nice, France (F.P.); Dept of Nuclear Medicine, Institut Curie, Paris, France (R.D.S.); Dept of Hematology, Univ Hosp of Rennes, Rennes, France (G.M., R.H.); INSERM, U1236, Rennes, France (G.M., R.H.); and UMR1015, Institut Gustave Roussy, Université Paris Saclay, Villejuif 94800, France (L.D.).

Background CT and fluorine 18 (F) fluorodeoxyglucose (FDG) PET/CT performances following immune therapy are not well known in patients with relapsed or refractory Hodgkin lymphoma (RRHL). Purpose To compare CT and PET/CT for prognostic value of early response evaluation following nivolumab therapy. Materials and Methods This retrospective study included patients from 34 institutions who underwent early imaging response evaluation from July 2013 to April 2017. Three experienced readers classified imaging response by using Cheson et al and 2016 Lymphoma Response to Immunomodulatory Therapy Criteria as follows: complete (metabolic) response, partial (metabolic) response, stable disease or no metabolic response, or progressive (metabolic) disease. Primary CT and PET assessments were performed at a median of 2.0 months (interquartile range, 1.7-3.7 months) after nivolumab initiation. Kaplan-Meier analysis was used to determine the relationship of primary CT and PET assessment response categories to overall survival (OS). Agreements between primary and secondary imaging assessments were assessed by using κ analysis. Results A total of 45 patients (median age, 37 years; range, 18-77 years; 25 men) underwent a primary assessment using CT and PET/CT; 36 patients also underwent a subsequent assessment. Eleven patients (24%) died after a median follow-up of 21.2 months. CT and PET response categories were associated with OS ( = .03 for primary CT assessment; = .02 for primary PET assessment). There was no pseudoprogression at primary CT and PET assessments. At the primary assessment, response categories by using CT were reclassified by using PET in 44% (20 of 45) of patients. Among these, 55% (11 of 20) were reclassified to complete metabolic response (complete metabolic response rate: 29% [13 of 45 patients] vs complete response rate: 4% [two of 45 patients]), with a 2-year OS probability of 100%. At the secondary assessment, complete response rate using CT increased to 17% (six of 36 patients), hence a better agreement with PET (κ = 0.78; < .001). Conclusion Early CT and PET/CT at a median of 2 months after initiation of nivolumab predicted overall survival in relapsed or refractory Hodgkin lymphoma. Early PET detected additional patients with complete metabolic response. © RSNA, 2020 See also the editorial by Scott and Wang in this issue.
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http://dx.doi.org/10.1148/radiol.2020192056DOI Listing
June 2020

Composite and sequential lymphoma between classical Hodgkin lymphoma and primary mediastinal lymphoma/diffuse large B-cell lymphoma, a clinico-pathological series of 25 cases.

Br J Haematol 2020 04 6;189(2):244-256. Epub 2020 Feb 6.

Department of Haematology, Centre Hospitalier Lyon-Sud, Hospices Civils de Lyon, Pierre Bénite cedex, France.

Composite and sequential lymphomas involving both classical Hodgkin lymphoma (CHL) and primary mediastinal B-cell lymphoma (PMBCL) are rare phenomena. Beyond the relevant biological interest raised by these cases, treatments and outcome data are poorly covered in the recent literature. This retrospective analysis describes the pathological and clinical characteristics of 10 composite and 15 sequential cases included after a central pathological review. At diagnosis, 70% of the composite lymphomas presented a disseminated and extranodal disease. Among the 15 sequential lymphomas, 12 were CHL at first occurrence and three were PMBCL. Based on their clinical evolution, these sequential lymphomas could be divided into early (i.e., diagnosis of second lymphoma within a year) and late [(i.e., a second lymphoma occurrence occurring after a long period of complete remission]). All composite cases were alive in complete remission after a median follow-up of 34 months. If the early sequential lymphoma presented a particularly poor outcome with a median overall survival shorter than one year, the late cases were efficiently salvaged. Further molecular studies are needed to describe the underlying biology of these rare diseases, possibly representing the extreme of tumour cell plasticity found in grey-zone lymphoma.
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http://dx.doi.org/10.1111/bjh.16331DOI Listing
April 2020

CD8 T cells mediate ultraviolet A-induced immunomodulation in a model of extracorporeal photochemotherapy.

Eur J Immunol 2020 05 10;50(5):725-735. Epub 2020 Feb 10.

CIRI - Centre International de Recherche en Infectiologie, Team « Immunology of Skin Allergy and Vaccination », Inserm, U1111, Université Claude Bernard Lyon 1, CNRS, UMR5308, Ecole Normale Supérieure de Lyon, Lyon University, F-69007, Lyon, France.

Extracorporeal photochemotherapy (ECP) that takes advantage of the immunomodulatory effects of UV light has been extensively used for many years for the treatment of several T cell-mediated diseases, including graft-versus-host disease (GvHD) and systemic scleroderma. Immune mechanisms that lead to the establishment of T cell tolerance in ECP-treated patients remain poorly known. In this study, we have tested the effect of UV/psoralen-treated BM-derived dendritic cells, referred to as ECP-BMDCs on the outcome of an antigen-specific T cell-mediated reaction, that is, contact hypersensitivity (CHS), which is mediated by CD8 effector T cells (CD8 T ). The intravenous (i.v.) injection of antigen-pulsed ECP-BMDCs in recipient C57BL/6 mice induced specific CD8 T cells endowed with immunomodulatory properties (referred to as CD8 T ), which prevented the priming of CD8 T and the development of CHS, independently of conventional CD4 regulatory T cells. CD8 T mediated tolerance by inhibiting the migration and functions of skin DC and subsequently the priming of CD8 T . CD8 T displayed none of the phenotypes of the usual CD8 T regulatory cells described so far. Our results reveal an underestimated participation of CD8 T cells to ECP-induced immunomodulation that could explain the therapeutic effects of ECP in T cell-mediated diseases.
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http://dx.doi.org/10.1002/eji.201948318DOI Listing
May 2020

Clinical characteristics and outcomes of relapsed follicular lymphoma after autologous stem cell transplantation in the rituximab era.

Hematol Oncol 2020 Apr 30;38(2):137-145. Epub 2020 Jan 30.

Department of Hematology, Centre Hospitalier Lyon Sud, Université Claude Bernard Lyon 1, Pierre-Bénite, France.

High-dose chemotherapy followed by autologous stem cell transplantation (ASCT) is a therapeutic option for patients with relapsed follicular lymphoma (FL). The clinical characteristics and outcomes of FL relapse after ASCT in the rituximab era have not yet been fully elucidated. We retrospectively reviewed 414 FL patients treated with ASCT between 2000 and 2014 in four hematology departments. All patients received rituximab as a first-line treatment. We specifically analyzed the clinical characteristics, treatment strategies at relapse, and outcomes of 95 patients (23%) who relapsed after ASCT. The patients (median age, 57 y) received a median of two lines of therapy (range, 2-6) prior to ASCT, with 92% in complete response (CR) or partial response (PR) before ASCT. Histological transformation at relapse after ASCT was observed in 20% of the patients. Treatment at relapse after ASCT consisted of chemotherapy with or without rituximab (n = 45/90, 50%), targeted agents (18%), rituximab monotherapy (14%), or consolidation allogeneic transplantation after induction chemotherapy (12%) and radiotherapy (6%). After relapse, the median progression-free survival (PFS) and overall survival (OS) were 1 year (95% CI, 0.541-1.579) and 5.5 years (95% CI, 1.910-9.099), respectively. In the multivariate analysis, histological transformation (HT) was associated with OS (P = .044; HR 2.439; 95% CI, 1.025-5.806), and a high FLIPI score at relapse was associated with PFS (P = .028; HR 2.469; 95% CI, 1.104-5.521). This retrospective study showed that the period of PFS of patients who relapsed after ASCT is short. A biopsy should be performed for these patients to document the HT. Our results indicate that new treatment strategies will need to be developed for these patients.
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http://dx.doi.org/10.1002/hon.2713DOI Listing
April 2020

Early F-FDG PET/CT Response Predicts Survival in Relapsed or Refractory Hodgkin Lymphoma Treated with Nivolumab.

J Nucl Med 2020 05 18;61(5):649-654. Epub 2019 Oct 18.

Department of Radiology, New York Presbyterian Hospital, Columbia University Medical Center, New York, New York

Monoclonal antibodies (mAbs) against programmed cell death 1 (PD-1), such as nivolumab and pembrolizumab, are associated with high response rates in patients with relapsed or refractory classic Hodgkin lymphoma (HL). To date, no prognostic factor for overall survival (OS) has been established with these agents in HL. We examined whether the first early response assessment evaluated using F-FDG PET/CT may be associated with OS in this setting. This retrospective study included 45 patients from 34 institutions. In a masked, centralized review, 3 independent radiologists classified PET/CT scans obtained at a median of 2.0 mo (interquartile range, 1.7-3.7 mo) after nivolumab initiation using existing criteria (i.e., 2014 Lugano classification and 2016 LYRIC). Patients were classified according to 4 possible response categories: complete metabolic response (CMR), partial metabolic response (PMR), no metabolic response (NMR), or progressive metabolic disease (PMD). Because the OS of patients with NMR and PMR was similar, they were grouped together. OS was estimated using the Kaplan-Meier method and compared between groups using log-rank testing. Eleven patients (24%) died after a median follow-up of 21.2 mo. The classification was identical between Lugano and LYRIC because all 16 progression events classified as indeterminate response per LYRIC were confirmed on subsequent evaluations. Both Lugano and LYRIC classified patients as CMR in 13 cases (29%), PMD in 16 (36%), NMR in 4 (9%), and PMR in 12 (27%). The 2-y OS probability was significantly different in patients with PMD (0.53; 95% confidence interval [95%CI], 0.32-0.87), NMR or PMR (0.80; 95%CI, 0.63-1.00), and CMR (1.00; 95%CI, 1.00-1.00) in the overall population ( = 0.02, 45 patients), as well as according to a landmark analysis at 3 mo ( = 0.05, 32 patients). In relapsed or refractory HL patients treated with anti-PD-1 mAbs, the first early PET/CT assessment using either Lugano or LYRIC predicted OS and allowed early risk stratification, suggesting that PET/CT might be used to develop risk-adapted strategies.
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http://dx.doi.org/10.2967/jnumed.119.232827DOI Listing
May 2020

MRD response in relapsed/refractory FL after obinutuzumab plus bendamustine or bendamustine alone in the GADOLIN trial.

Leukemia 2020 02 28;34(2):522-532. Epub 2019 Aug 28.

Georgetown University Hospital, Washington, DC, USA.

We report assessment of minimal residual disease (MRD) status and its association with outcome in rituximab-refractory follicular lymphoma (FL) in the randomized GADOLIN trial (NCT01059630). Patients received obinutuzumab (G) plus bendamustine (Benda) induction followed by G maintenance, or Benda induction alone. Patients with a clonal marker (t[14;18] translocation and/or immunoglobulin heavy or light chain rearrangement) detected at study screening were assessed for MRD at mid-induction (MI), end of induction (EOI), and every 6-24 months post-EOI/discontinuation by real-time quantitative PCR. At MI, 41/52 (79%) patients receiving G-Benda were MRD-negative vs. 17/36 (47%) patients receiving Benda alone (p = 0.0029). At EOI, 54/63 (86%) patients receiving G-Benda were MRD-negative vs. 30/55 (55%) receiving Benda alone (p = 0.0002). MRD-negative patients at EOI had improved progression-free survival (HR, 0.33, 95% CI, 0.19-0.56, p < 0.0001) and overall survival (HR, 0.39, 95% CI, 0.19-0.78, p = 0.008) vs. MRD-positive patients, and maintained their MRD-negative status for longer if they received G maintenance than if they did not. These results suggest that the addition of G to Benda-based treatment during induction can significantly contribute to the speed and depth of response, and G maintenance in MRD-negative patients potentially delays lymphoma regrowth.
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http://dx.doi.org/10.1038/s41375-019-0559-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7214251PMC
February 2020

Obinutuzumab combined with lenalidomide for relapsed or refractory follicular B-cell lymphoma (GALEN): a multicentre, single-arm, phase 2 study.

Lancet Haematol 2019 Aug 8;6(8):e429-e437. Epub 2019 Jul 8.

Haematology Department, Centre Hospitalier Universitaire de Rennes, Rennes, France.

Background: Lenalidomide plus rituximab is approved to treat patients with relapsed or refractory follicular lymphoma. Obinutuzumab has been shown to enhance antibody-dependent cellular cytotoxicity, phagocytosis, and direct B-cell killing better than rituximab. Our aim was to determine the activity and safety of lenalidomide plus obinutuzumab in previously treated patients with relapsed or refractory follicular lymphoma.

Methods: In this multicentre, single-arm, phase 2 study, patients were enrolled from 24 Lymphoma Academic Research Organisation centres in France. Eligible patients (age ≥18 years) had histologically confirmed CD20-positive relapsed or refractory follicular lymphoma of WHO grade 1, 2, or 3a; an ECOG performance status of 0-2; and received at least one previous rituximab-containing therapy. Patients received oral lenalidomide (20 mg) plus intravenously infused obinutuzumab as induction therapy (1000 mg; six 28-day cycles), 1-year maintenance with lenalidomide (10 mg; 12 28-day cycles; days 2-22) plus obinutuzumab (1000 mg; alternate cycles), and 1-year maintenance with obinutuzumab (1000 mg; six 56-day cycles; day 1). The primary endpoint was the proportion of patients who achieved an overall response at induction end as per investigator assessment using the 1999 international working group criteria. The secondary endpoints were event-free survival, progression-free survival, overall survival, and safety. Analyses were per-protocol; the efficacy population included all patients who received at least one dose of both obinutuzumab and lenalidomide, and the safety population included all patients who received one dose of either investigational drug. The study is registered with ClinicalTrials.gov, number NCT01582776, and is ongoing but closed to accrual.

Findings: Between June 11, 2014, and Dec 18, 2015, 89 patients were recruited and 86 patients were evaluable for efficacy and 88 for safety. Median follow-up was 2·6 years (IQR 2·2-2·8). 68 (79%) of 86 evaluable patients (95% CI 69-87) achieved an overall response at induction end, meeting the prespecified primary endpoint. At 2 years, event-free survival was 62% (95% CI 51-72), progression-free survival 65% (95% CI 54-74), duration of response 70% (95% CI 57-79), and overall survival 87% (95% CI 78-93). Complete response was achieved by 33 (38%, 95% CI 28-50) of 86 patients at induction end, and the proportion of patients achieving a best overall response was 70 (81%, 95% CI 72-89) and 72 (84%, 74-91) of 86 patients during induction and treatment, respectively. The most common adverse events were asthenia (n=54, 61%), neutropenia (n=38, 43%), bronchitis (n=36, 41%), diarrhoea (n=35, 40%), and muscle spasms (n=34, 39%). Neutropenia was the most common toxicity of grade 3 or more; four (5%) patients had febrile neutropenia. 57 serious adverse events were reported in 30 (34%) of 88 patients. The most common serious adverse events were basal cell carcinoma (n=5, 6%), febrile neutropenia (n=4, 5%), and infusion-related reaction (n=3, 3%). One patient died due to treatment-related febrile neutropenia.

Interpretation: Our data shows that lenalidomide plus obinutuzumab is active in previously treated patients with relapsed or refractory follicular lymphoma, including those with early relapse, and has a manageable safety profile. Randomised trials of new immunomodulatory regimens, such as GALEN or using GALEN as a backbone, versus lenalidomide plus rituximab, are warranted.

Funding: Lymphoma Academic Research Organisation, and Celgene and Roche.
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http://dx.doi.org/10.1016/S2352-3026(19)30089-4DOI Listing
August 2019

[Management of CAR-T cell-related encephalopathy syndrome in adult and pediatric patients: Recommendations of the French Society of Bone Marrow transplantation and cellular Therapy (SFGM-TC)].

Bull Cancer 2020 Jan 13;107(1S):S12-S17. Epub 2019 Jun 13.

CHU de Lille, université de Lille, LIRIC, Inserm U995, 59000 Lille, France.

CAR-T cell-related encephalopathy syndrome (CRES) reflects the potential neurotoxicity of this therapeutic approach and must be considered in the presence of any neurological symptom after the infusion of the CAR-T. This is the second most common adverse event under this therapy and its incidence varies between 12 and 55%. The median time of the onset of the first neurologic symptoms is 4days after CAR-T infusion. The duration of CRES symptoms is generally between 2 and 4days, but late CRES may occur. Monitoring and diagnosis of CERS includes clinical exam, magnetic resonance imaging and electroencephalography. In addition to symptomatic treatments, corticosteroids represent the cornerstone of the high-grade CERS treatment. Drugs targeting IL-6 should be restricted to severe forms, especially those associated with cytokine release syndrome. The purpose of this workshop is to provide practical help in dealing with this complication.
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http://dx.doi.org/10.1016/j.bulcan.2019.05.001DOI Listing
January 2020

BAM conditioning before autologous transplantation for lymphoma: a study on behalf of the Francophone Society of Bone Marrow Transplantation and Cellular Therapy (SFGM-TC).

Ann Hematol 2019 Aug 20;98(8):1973-1980. Epub 2019 May 20.

Centre Hospitalo-Universitaire Tours, Tours, France.

High-dose chemotherapy before autologous transplantation is a therapeutic option as consolidation in primary or relapsed lymphoma. Even if BEAM conditioning is generally used, alternative conditioning regimens have been published. The purpose of this study was to assess the outcome of 177 adult patients with lymphoma whose conditioning treatment included a BAM (busulfan, aracytine, and melphalan) regimen. With a median follow-up of 17.4 months, 2-year estimates of overall survival and progression-free survival for the entire group were 87% and 70.5%, respectively. Mucositis was the main reported complications and infectious episodes were described in 80.2% of patients. According to multivariate analysis, high performance status and age at diagnosis were adverse factors for survival and increased the risk of disease relapse and death. Despite its limitations, this retrospective study suggests that BAM combination is a valid conditioning regimen in lymphoma patients, with an acceptable rate of toxicity.
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http://dx.doi.org/10.1007/s00277-019-03704-zDOI Listing
August 2019

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

[Management of cytokine release syndrome in adult and pediatric patients undergoing CAR-T cell therapy for hematological malignancies: Recommendation of the French Society of Bone Marrow and cellular Therapy (SFGM-TC)].

Bull Cancer 2019 Jan 17;106(1S):S102-S109. Epub 2019 Jan 17.

Institut de cancérologie Lucien-Neuwirth, département d'hématologie clinique, 108 Bis, avenue Albert-Raimond, 42271 Saint-Priest-en-Jarez, France. Electronic address:

The cytokine release syndrome (CRS) is the most common complication after adoptive immunotherapies such as chimeric antigen receptor T cells (CAR-T). The incidence varies from 30 to 100% depending on the CAR-T construct, cell doses and the underlying disease. Severe cases may involve 10 to 30% of patients. The triggering event is the activation of the CAR-T, after meeting with their target. The T cell activation leads to the release of effector cytokines, such as IFNγ, TNFα and IL2, that are responsible for the activating of monocyte/macrophage system, resulting in the production of pro-inflammatory cytokines, (including IL6, IFN-γ, IL10, MCP1) and associated with a significant elevation of CRP and ferritin. The CRS usually appears between 1 and 14days after the infusion of the cells and can last from 1 to 10days. Rare fatal cases have been reported in the literature. The first symptom is often a fever, sometimes very high, which must alert and reinforce the surveillance. In moderate forms, one can find fatigue, headache, rash, arthralgia and myalgia. T cell-related encephalopathy (CRES) syndrome may occur concomitantly. In case of aggravation, a vasoplegic shock associating capillary leakage and respiratory distress can occur. Close clinical monitoring is essential right from the injection to quickly detect the first symptoms. The treatment of severe forms, in addition to symptomatic management involves monoclonal antibodies targeting the IL6 or IL6 receptor, and sometimes steroids. Close cooperation with intensive care units is essential since 20 to 50% of patients require intensive care unit transfer.
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http://dx.doi.org/10.1016/j.bulcan.2018.12.001DOI Listing
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

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

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

Lysa, University Hospital, Lyon, France.

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

High-dose therapy and autologous stem cell transplantation in marginal zone lymphomas: a retrospective study by the EBMT Lymphoma Working Party and FIL-GITMO.

Br J Haematol 2018 09 9;182(6):807-815. Epub 2018 Jul 9.

Ospedale degli Infermi, Biella, Italy.

The role of autologous stem cell transplantation (ASCT) in patients with marginal zone lymphoma (MZL) is debatable. This study investigated the outcome and prognostic factors affecting the outcome of patients undergoing ASCT for MZL. Eligible patients had non-transformed nodal, extra-nodal (MALT) or splenic MZL (SMZL), aged ≥18 years, who underwent a first ASCT between1994 and 2013 and were reported to the European Society for Blood and Marrow Transplantation, Fondazione Italiana Linfomi or Gruppo Italiano Trapianto Di Midollo Osseo registries. The study included 199 patients, [111 MALT lymphoma, 55 nodal MZL (NMZL) and 33 SMZL]. Median age at transplantation was 56 years. The median number of prior therapies was 2 (range 1-8), including rituximab in 71%. 95% had chemosensitive disease. 89% received a chemotherapy-based high-dose regimen. There were no significant differences in patient and transplant characteristics between the 3 histological subtypes except for a lower percentage of patients previously treated with rituximab in the MALT sub-group and more transplants performed in recent years in the other sub-groups. After a median follow-up of 5 years, 5-year cumulative incidence of relapse/progression and non-relapse mortality were 38% and 9%, respectively. Five-year event-free survival (EFS) and overall survival (OS) were 53% and 73%, respectively. Five-year cumulative incidence of second malignancies was 6%. Multivariate analysis revealed age ≥65 years was associated with a shorter EFS and OS. In addition, patients with SMZL had a shorter OS than those with MALT. ASCT may provide clinical benefit in MZL patients who have failed multiple lines of chemoimmunotherapy.
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http://dx.doi.org/10.1111/bjh.15454DOI Listing
September 2018

Infradiaphragmatic Hodgkin lymphoma: a large series of patients staged with PET-CT.

Oncotarget 2017 Oct 19;8(49):85110-85119. Epub 2017 Jul 19.

Hématologie Clinique, CHU Le Bocage, Dijon, France.

Introduction: Infradiaphragmatic Hodgkin Lymphoma (IDHL) accounts for 3-11% of adult cases of stage I-II Hodgkin Lymphoma and the treatment strategy in IDHL is still heterogeneous. All previous published studies were conducted before the PET-CT era. PET may provide a more accurate evaluation of IDHL stage. The aim of this study was to analyze the clinical and biological characteristics of IDHL patients staged by CT scan or PET-CT in eight French hematology departments and their impact on outcomes in these patients.

Methods: Baseline clinical and biological data and outcomes in patients with a first diagnosis of stage I-II IDHL treated with ABVD +/- radiotherapy were retrospectively collected.

Results: Among the 99 patients included, 65 (66%) were staged with PET-CT. These patients were older (53 years vs 46 years, p=0.043), had lower ESR (27 vs 58mm, p=0.022), higher hemoglobin level (13.6 vs 12.8g/dL, p=0.015), less frequent Ann Arbor stage II (74% vs 91%) and less central adenopathy involvement (60% vs 82%, p=0.024). Treatment was chemotherapy alone in 55% of patients and the remaining patients received chemo-radiotherapy (CRT). Five-year PFS and OS rates in PET-CT-staged patients were 78% (95% CI 64-87) and 88% (95% CI 73-95), respectively, compared with 65% (p=0.225) and 82% (p=0.352) in CT-staged patients. The CRT strategy was associated with fewer relapses (p=0.027).

Conclusion: This study showed that the characteristics of CT-staged IDHL patients were less favorable than those of PET-CT-staged patients and indicated that CRT provided better PFS than did chemotherapy alone.
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http://dx.doi.org/10.18632/oncotarget.19389DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5689597PMC
October 2017

Rituximab, methotrexate, procarbazine, vincristine and intensified cytarabine consolidation for primary central nervous system lymphoma (PCNSL) in the elderly: a LOC network study.

J Neurooncol 2017 Jun 21;133(2):315-320. Epub 2017 Apr 21.

Service de Neurologie 2-Mazarin, Groupe Hospitalier Pitié-Salpêtrière, APHP, Sorbonne Universités UPMC Universités Paris VI, IHU, ICM, 47-83 boulevard de l'Hôpital, 75651, Paris Cedex 13, France.

Primary CNS lymphoma (PCNSL) is chemosensitive to high-dose methotrexate-based chemotherapy. However, responses in the elderly are short-lasting and outcome is poor. Given that radiotherapy and intensive chemotherapy expose elderly to severe toxicities, alternative consolidation approaches need to be evaluated. In this multicenter study, we retrospectively analyzed consecutive patients with newly-diagnosed PCNSL, aged >60, treated with a (R)-MPV-AAA regimen. The regimen consisted of three 28-day cycles of methotrexate (3.5 g/m D1, D15), procarbazine, vincristine, followed by three 28-day cycles of cytarabine consolidation (3 g/m D1-2). Addition of rituximab (375 mg/m D1) was optional. The results were compared with the historical MPV-A regimen. Ninety patients received the (R)-MPV-AAA regimen with (n = 39) or without (n = 51) rituximab. Median age was 68 and median KPS 60. 55% of patients achieved a complete response, 8% a partial response and 37% progressed. The median PFS was 10 months, the median OS 28.1 months. Toxicity was mainly hematological, with 54 and 51% of grade III-IV neutropenia and thrombopenia. The response rate was higher in patients receiving rituximab (77 vs. 53%; p = 0.03), whereas no difference was observed in terms of PFS or OS. When comparing the results to the historical MPV-A, there was no difference in terms of response rate, PFS or OS, but a higher rate of hematotoxicity. This study suggests that extending cytarabine consolidation after methotrexate-based chemotherapy does not improve the MPV-A efficacy but increases toxicity in the elderly. The addition of rituximab may improve the response rate, but its impact on final outcome remains unclear.
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http://dx.doi.org/10.1007/s11060-017-2435-7DOI Listing
June 2017

High-Dose Chemotherapy for Adult-Type Ovarian Granulosa Cell Tumors: A Retrospective Study of the European Society for Blood and Marrow Transplantation.

Int J Gynecol Cancer 2017 02;27(2):248-251

*Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori IRCCS, Meldola, Italy; †Centre Leon Berard, Lyon; and ‡EBMT Paris Office, Paris, France; §Universitatsklinikum Frankfurt, Frankfurt, Germany; ∥Hopital Tenon, Paris, France; ¶University Hospital Gasthuisberg, Leuven, Belgium; and #Hematology Unit, Ravenna Hospital, Ravenna; and **Ospedale di Busto Arsizio, Varese, Italy.

Objectives: A few small retrospective series reported results with salvage chemotherapy for malignant ovarian adult-type granulosa cell tumors (GCTs), whereas no data are available on high-dose chemotherapy (HDC) with hematopoietic progenitor cell support (HSCS) in these patients. The aim of this study was to analyze the available data of HDC for adult-type GCTs.

Methods: We conducted a retrospective analysis of ovarian cancer treated with salvage HDC registered with the European Society for Blood and Marrow Transplantation.

Results: Of 203 adult female patients with a diagnosis of nonepithelial ovarian cancer treated with salvage HDC with HSCS and registered with the European Society for Blood and Marrow Transplantation, 4 (2%) patients were affected by GCTs. All 4 patients had ovarian adult-type GCTs that relapsed/progressed after first-line chemotherapy. The conditioning regimens included a platinum agent in all 4 patients. Bone marrow recovery was promptly achieved; neither treatment-related deaths or life-threatening toxicities occurred. At a median follow-up of 8.5 months, all patients reported a progressive disease. The patient who underwent multicycle HDC enjoyed a long-term remission of 84 months before progression and is the only one alive after 94+ months.

Conclusions: We showed for the first time a case with long-lasting response to salvage multicycle HDC and HSCS in adult-type GCTs.
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http://dx.doi.org/10.1097/IGC.0000000000000882DOI Listing
February 2017

Utility of post-therapy brain surveillance imaging in the detection of primary central nervous system lymphoma relapse.

Eur J Cancer 2017 02 22;72:12-19. Epub 2016 Dec 22.

Centre Léon Bérard, Department of Hematology, Université Claude Bernard Lyon 1, Lyon, France; Department of Hematology, Centre Hospitalier Lyon Sud, Université Claude Bernard Lyon 1, Pierre-Bénite, France. Electronic address:

Background: The optimal follow-up strategy for primary central nervous system lymphoma (PCNSL) patients after first-line therapy is unclear. The goal of this study is to determine the utility of planned brain surveillance imaging in the detection of relapse in a retrospective cohort of PCNSL patients.

Methods: Patients were consecutive PCNSL cases treated in Leon Berard Cancer Centre, Lyon, France, from 1985 to 2011. Histology was diffuse large B-cell lymphoma in 94%. Patients were treated by methotrexate (92%) and cytarabine (63%) based-chemotherapy followed by radiotherapy for 108 patients (51%). Clinical records were reviewed for details at relapse and relationship to planned imaging. The imaging follow-up strategy was performed according to each treating physicians.

Results: Among 209 PCNSL patients, 127 complete response patients entered in post-treatment observation and 63 (50%) subsequently relapsed. Among the 125 evaluable patients, the majority of relapses (N = 49, 80%) was asymptomatic and identified before the planned brain imaging. Surveillance imaging detected relapses before symptoms in 12 patients who entered in post-therapy observation (10%). The median number of brain imaging during the follow-up was 7 (0-13). A total of 819 MRI/CT-scan were performed leading to the detection of 12 asymptomatic relapses. The one year OS rates were 41% and 58% for symptomatic and non-symptomatic relapses, respectively (P = 0.21).

Conclusion: The majority of PCNSL relapses occurred outside planned follow-up with no difference in patient outcome between symptomatic and asymptomatic relapses. The role of brain imaging for the detection of relapses in the follow-up of PCNSL patients remains to be clarified.
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http://dx.doi.org/10.1016/j.ejca.2016.10.036DOI Listing
February 2017

Early event status informs subsequent outcome in newly diagnosed follicular lymphoma.

Am J Hematol 2016 Nov 3;91(11):1096-1101. Epub 2016 Sep 3.

Department of Hematology, Oncology and Blood and Marrow Transplantation, University of Iowa, Iowa City, IA.

Recent advances in follicular lymphoma (FL) have resulted in prolongation of overall survival (OS). Here we assessed if early events as defined by event-free survival (EFS) at 12 and 24 months from diagnosis (EFS12/EFS24) can inform subsequent OS in FL. 920 newly diagnosed grade 1-3A FL patients enrolled on the University of Iowa/Mayo Clinic Lymphoma SPORE Molecular Epidemiology Resource (MER) from 2002-2012 were initially evaluated. EFS was defined as time from diagnosis to progression, relapse, re-treatment, or death due to any cause. OS was compared to age-and-sex-matched survival in the general US population using standardized mortality ratios (SMR) and 95% confidence intervals (CI). We used a cohort of 412 FL patients from two Lyon, France hospital registries for independent replication. Patients who failed to achieve EFS12 had poor subsequent OS (MER SMR = 3.72, 95%CI: 2.78-4.88; Lyon SMR = 8.74, 95%CI: 5.41-13.36). Conversely, patients achieving EFS12 had no added mortality beyond the background population (MER SMR = 0.73, 95%CI: 0.56-0.94, Lyon SMR = 1.02, 95%CI: 0.58-1.65). Patients with early events after immunochemotherapy had especially poor outcomes (EFS12 failure: MER SMR = 17.63, 95%CI:11.97-25.02, Lyon SMR = 19.10, 95%CI:9.86-33.36; EFS24 failure: MER SMR = 13.02, 95%CI:9.31-17.74, Lyon SMR = 7.22, 95%CI:4.13-11.74). In a combined dataset of all patients from both cohorts, baseline FLIPI was no longer informative in EFS12 achievers. Reassessment of patient status at 12 months from diagnosis in follicular lymphoma patients, or at 24 months in patients treated with immunochemotherapy, is a strong predictor of subsequent overall survival in FL. Early event status provides a simple, clinically relevant endpoint for studies assessing outcome in FL. Am. J. Hematol. 91:1096-1101, 2016. © 2016 Wiley Periodicals, Inc.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5073042PMC
http://dx.doi.org/10.1002/ajh.24492DOI Listing
November 2016

Impact of post-brentuximab vedotin consolidation on relapsed/refractory CD30+ Hodgkin lymphomas: a large retrospective study on 240 patients enrolled in the French Named-Patient Program.

Haematologica 2016 Apr 14;101(4):466-73. Epub 2016 Jan 14.

Hôpital Saint Louis AP-HP, Université Diderot, Paris, France.

Brentuximab vedotin was reported to be effective and safe against refractory/relapsed Hodgkin lymphoma in cohorts of between 12 to 102 patients. Herein we report our retrospective analysis of the French experience with brentuximab vedotin used alone to treat 240 refractory/relapsed Hodgkin lymphoma patients enrolled in a named patient program between 2011 and 2013. All patients had histologically documented CD30+ Hodgkin lymphoma; 74% had refractory disease or early relapses. After a median of 3 lines of chemotherapy, brentuximab vedotin was infused intravenously (1.8 mg/kg every 3 weeks). The primary endpoint was best response. Response at the end of treatment, its duration, survival data and toxicity profile were secondary endpoints. Patients received a median of 6 cycles; 68 underwent a consolidation thereafter. The best response was observed after a median of 4 cycles in 145 (60.4%) patients: 33.8% complete response/unconfirmed complete response, 26.7% partial response. Objective responses were observed as decreased (39.3%) in the 28 patients >60 years. The median response duration was 8.4 months. With median follow-up at 16.1 months, median progression-free survival was 6.8 months and this was significantly longer for patients transplanted after brentuximab vedotin (a median of 18,8 months); median overall survival was not reached. No death has been linked to brentuximab vedotin toxicity. The most common adverse events were peripheral sensory neuropathy (29.3%) and hematological toxicity. The results of this analysis support the previously reported brentuximab vedotin efficacy with manageable toxicity. Because of the short-term responses in most patients, a high-dose therapy with stem cell transplantation for responders should be considered as quickly as possible.
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http://dx.doi.org/10.3324/haematol.2015.134213DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5004383PMC
April 2016

Combination of romidepsin with cyclophosphamide, doxorubicin, vincristine, and prednisone in previously untreated patients with peripheral T-cell lymphoma: a non-randomised, phase 1b/2 study.

Lancet Haematol 2015 Apr 17;2(4):e160-5. Epub 2015 Mar 17.

Department of Hematology, Hospices Civils de Lyon and University Lyon 1, Lyon, France. Electronic address:

Background: Romidepsin is a histone deacetylase inhibitor approved in the USA for patients with recurrent or refractory peripheral T-cell lymphoma and has shown activity in this setting with mainly haematological and gastrointestinal toxicity. Although it has limited efficacy, cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) therapy is widely used for treatment of de-novo peripheral T-cell lymphoma. We aimed to assess the safety, tolerability, and activity of romidepsin combined with CHOP in patients with previously untreated disease.

Methods: We enrolled patients aged 18-80 years with histologically proven, previously untreated, peripheral T-cell lymphoma (Eastern Cooperative Oncology Group performance status ≤2) into a dose-escalation (phase 1b) and expansion (phase 2) study at nine Lymphoma Study Association centres in France. In the dose-escalation phase, we allocated consecutive blocks of three participants to receive eight 3 week cycles of CHOP (intravenous cyclophosphamide 750 mg/m(2), doxorubicin 50 mg/m(2), and vincristine 1.4 mg/m(2) [maximum 2 mg] on day 1 and oral prednisone 40 mg/m(2) on days 1-5) in association with varying doses of romidepsin. The starting dose was 10 mg/m(2) intravenously on days 1 and 8 of each cycle, and we used a 3 + 3 design. We assessed dose-limiting toxicities only during the first two cycles. The primary endpoint was to determine the recommended dose for the combination. For the phase 2 study, we aimed to increase the cohort of patients receiving the recommended dose to a total of 25 patients. Patients were assessed for safety outcomes at least twice per cycle according to the Common Terminology Criteria for Adverse Events, version 4.0. Safety analyses included all patients who received at least one dose of romidepsin and CHOP. This trial is registered at the European Clinical Trials Database (EudraCT), number 2010-020962-91 and ClinicalTrials.gov, number NCT01280526.

Findings: Between Jan 13, 2011, and May 21, 2013, we enrolled 37 patients (18 treated in phase 1b and 19 patients in phase 2). Three of six patients initially treated at 10 mg/m(2) had a dose-limiting toxicity. The dose-escalation committee decided to modify the study protocol to redefine dose-limiting toxicities with regard to haematological toxicity. Three patients were treated with 8 mg/m(2) of romidepsin, an additional three at 10 mg/m(2) (one dose-limiting toxicity), and six patients at 12 mg/m(2) (three dose-limiting toxicities). We chose romidepsin 12 mg/m(2) as the recommended dose for phase 2. Of the 37 patients treated, three had early cardiac events (two myocardial infarctions and one acute cardiac failure). No deaths were attributable to toxicity. 25 (68%) of 37 patients had at least one serious adverse event. Overall, the most frequent serious adverse events were febrile neutropenia (five [14%] of 37 patients), physical health deterioration (five [14%]), lung infection (four [11%]), and vomiting (three [8%]). 33 (89%) of patients had grade 3-4 neutropenia, and 29 (78%) had grade 3-4 thrombocytopenia.

Interpretation: Romidepsin can be combined with CHOP but this combination should now be tested in comparison to CHOP alone in a randomised trial.

Funding: Celgene.
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April 2015
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