Publications by authors named "Nicolas Mounier"

122 Publications

Rituximab plus gemcitabine and oxaliplatin (R-GemOx) in refractory/relapsed diffuse large B-cell lymphoma: a real-life study in patients ineligible for autologous stem-cell transplantation.

Leuk Lymphoma 2021 Mar 25:1-8. Epub 2021 Mar 25.

Lymphoid Malignancies Unit, Hôpital Henri Mondor, AP-HP, Créteil, France.

There is no established standard treatment for relapsed/refractory (R/R) diffuse large B-cell lymphoma (DLBCL) in patients who are not eligible to receive an intensive treatment. The combination of rituximab gemcitabine and oxaliplatin (R-GemOx) is widely used in this population but data are scarce. We retrospectively collected the data of 196 patients with R/R DLBCL treated with R-GemOx in two French centers over a period of 15 years. The median age of the population was 72 years (range, 24-89), 63% of the patients had an international prognostic index of 3 or higher and 57% were refractory to the last treatment. At the end of R-GemOx treatment, 33% of the patients obtained a complete response. The median progression-free survival (PFS) of the population was 5 months and the median overall survival (OS) was 10 months. Several factors were predictors of unfavorable survival: age over 75 years, international prognostic index of 2 or higher, refractory disease and de novo DLBCL. The median PFS and OS of the patients who obtained a complete response were 22 months and 40 months, respectively. The most significant toxicities were grade 3-4 hematological toxicities (31% of patients). Given its efficacy and tolerability, R-GemOx can be used in patients ineligible for intensive treatment and serve as a basis for new regimen combinations.
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http://dx.doi.org/10.1080/10428194.2021.1901090DOI Listing
March 2021

Prospective evaluation of blood Epstein-Barr virus DNA load and antibody profile in HIV-related non-Hodgkin lymphomas.

AIDS 2021 05;35(6):861-868

Centre Hospitalier de Versailles, Service d'Hémato-Oncologie, Université Versailles Saint Quentin en Yvelines, Université Paris-Saclay, Le Chesnay.

Objectives: The value of Epstein-Barr virus (EBV) biomarkers on the prognosis of HIV-related non-Hodgkin's lymphoma (NHL) has been poorly explored in the combined antiretroviral therapy (cART) era.

Design: We evaluated EBV DNA load and EBV antibodies in HIV-NHL patients enrolled in the French ANRS-CO16 Lymphovir Cohort between 2008 and 2015.

Methods: Whole blood and plasma EBV DNA load and serological profiles were analyzed in 76 HIV-infected patients at diagnosis of NHL and 6 months after the initiation of chemotherapy.

Results: Prechemotherapy whole blood (WB) and plasma EBV DNA loads were positive for 80 and 45% of HIV-NHL patients, respectively. Pretreatment WB EBV DNA positivity was associated with a positive plasma HIV-1 RNA load (relative risk (RR), 4.42 [1.33; 14.72]) and plasma EBV DNA positivity with EBV in situ detection (RR 10.62 [2.38; 47.49]). Following chemotherapy, the proportions of patients with positive WB or plasma EBV DNA declined from 81 to 23% (P < 0.0001) and from 43 to 8% (P < 0.0001), respectively. Estimated 2-year progression-free survival did not differ according to prechemotherapy WB positivity (82% versus 67%, P = 0.15) or plasma EBV DNA positivity (76% versus 81%, P  = 0.52).

Conclusions: The plasma EBV DNA load correlates with in situ EBV detection. The WB EBV DNA load correlates with HIV load. WB and plasma EBV DNA loads at NHL diagnosis do not constitute prognostic markers for HIV-NHL patients in the modern cART era.
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http://dx.doi.org/10.1097/QAD.0000000000002839DOI Listing
May 2021

Favorable outcome of HIV-associated Burkitt lymphoma in the modern combined antiretroviral therapy era.

Eur J Cancer 2020 10 4;138:189-192. Epub 2020 Sep 4.

Unit of Hematology-Oncology, Versailles Hospital, Le Chesnay, France; Université Versailles Saint Quentin en Yvelines, Université Paris-Saclay, Communauté Paris-Saclay, Paris, France; INSERM U1018, Centre pour La Recherche en Epidémiologie et Sante des Populations (CESP), Equipe Générations et Santé, Gustave Roussy, Villejuif, France. Electronic address:

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http://dx.doi.org/10.1016/j.ejca.2020.07.033DOI Listing
October 2020

Long-term overall survival and toxicities of ABVD vs BEACOPP in advanced Hodgkin lymphoma: A pooled analysis of four randomized trials.

Cancer Med 2020 09 25;9(18):6565-6575. Epub 2020 Jul 25.

Department of Onco-Haematology, Archet Hospital, Nice, France.

Purpose: We explored the potential overall survival (OS) benefit of bleomycin, etoposide, doxorubicin (Adriamycin), cyclophosphamide, vincristine (Oncovin), procarbazine, and prednisone (BEACOPP) over doxorubicin (Adriamycin), bleomycin, vinblastine, and dacarbazine (ABVD) in a pooled analysis of four randomized trials.

Patients And Methods: Primary objective was to evaluate the OS impact of BEACOPP using individual patient data. Secondary objectives were progression-free survival (PFS), secondary cancers, and use of autologous stem cell transplantation (ASCT).

Results: About 1227 patients were included. The 7-year OS was 84.3% (95% CI 80.8-87.2) for ABVD vs 87.7% (95% CI 84.5-90.2) for BEACOPP. Two follow-up periods were identified based on survival curves and hazard ratio (HR) over time. For the first 18 months, there was no difference. For the second period of ≥18 months, ABVD patients had a higher death risk (HR  = 1.59; 95% CI 1.09-2.33). A Cox model stratified by trial and evaluating the effect of treatment and International Prognostic Index (IPI) score as fixed effects showed that both were statistically significant (treatment, P = .0185; IPI score, P = .0107). The 7-year PFS was 71.1% (95% CI 67.1-74.6) for ABVD vs 81.1% (95% CI 77.5-84.2) for BEACOPP (P < .001). After ABVD, 25 secondary cancers (4.0%) were reported with no myelodysplasia (MDS)/acute myeloid leukemia (AML) compared to 36 (6.5%) after BEACOPP, which included 13 patients with MDS/AML. Following ABVD, 86 patients (13.8%) received ASCT vs 39 (6.4%) for BEACOPP.

Conclusions: This analysis showed a slight improvement in OS for BEACOPP and confirmed a PFS benefit. Frontline use of BEACOPP instead of ABVD increased secondary leukemia incidence but halved the requirement for ASCT.
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http://dx.doi.org/10.1002/cam4.3298DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7520354PMC
September 2020

Cancer incidence in the vicinity of a waste incineration plant in the Nice area between 2005 and 2014.

Environ Res 2020 09 20;188:109681. Epub 2020 May 20.

Université Côte d'Azur, Public Health Department, Centre Hospitalier Universitaire de Nice, France.

Introduction: Few studies on cancer incidence have been conducted since the adoption of the EU 2000/76/EC waste incineration directive which aimed to limit dioxin emission levels to less than 0.1 ng TEQ/m before December 31, 2005.

Objective: To measure cancer incidence among the population exposed to atmospheric emissions from the waste incineration plant near the town of Nice (South-Eastern France), compared to the unexposed population of the Alpes-Maritimes department (A-M).

Methods: All primary invasive cancers and haematological malignancies diagnosed among AM residents between 2005 and 2014 were recorded. The exposed surface was modeled on an average dioxin deposition model ≥4.25 ng/m/year. Each case was geolocated and assigned to one of 36 predefined geographic units of exposed area, or one of 462 units in the unexposed area. The adjusted incidence rate, the standardized incidence ratio and the Comparative Morbidity Figure were calculated for two periods: 2005-2009/2010-2014.

Results: We recorded 80,865 new cancers in the A-M population. Between 2005 and 2009, we observed a higher incidence among exposed women of acute myeloid leukaemia, myelodysplastic syndromes and myeloma and, among exposed men, of soft tissue sarcomas, myeloma and lung cancer. Between 2010 and 2014, there was no excess incidence among women, while among men incidence of myeloma and lung cancer remained higher.

Conclusion: Only among men, the incidence of myeloma and lung cancer remained higher in the exposed area during the second period. The EU directive resulting in the limitation of atmospheric emissions from incinerators could explain the decrease in incidence of cancers with protracted latency. Consideration of other risk factors and further data collection will be necessary to validate this hypothesis.
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http://dx.doi.org/10.1016/j.envres.2020.109681DOI Listing
September 2020

Acadesine Circumvents Azacitidine Resistance in Myelodysplastic Syndrome and Acute Myeloid Leukemia.

Int J Mol Sci 2019 12 25;21(1). Epub 2019 Dec 25.

INSERM U1065, Université Côte d'Azur, C3M, 06204 Nice, France.

Myelodysplastic syndrome (MDS) defines a group of heterogeneous hematologic malignancies that often progresses to acute myeloid leukemia (AML). The leading treatment for high-risk MDS patients is azacitidine (Aza, Vidaza), but a significant proportion of patients are refractory and all patients eventually relapse after an undefined time period. Therefore, new therapies for MDS are urgently needed. We present here evidence that acadesine (Aca, Acadra), a nucleoside analog exerts potent anti-leukemic effects in both Aza-sensitive (OCI-M2S) and resistant (OCI-M2R) MDS/AML cell lines in vitro. Aca also exerts potent anti-leukemic effect on bone marrow cells from MDS/AML patients ex-vivo. The effect of Aca on MDS/AML cell line proliferation does not rely on apoptosis induction. It is also noteworthy that Aca is efficient to kill MDS cells in a co-culture model with human medullary stromal cell lines, that mimics better the interaction occurring in the bone marrow. These initial findings led us to initiate a phase I/II clinical trial using Acadra in 12 Aza refractory MDS/AML patients. Despite a very good response in one out 4 patients, we stopped this trial because the highest Aca dose (210 mg/kg) caused serious renal side effects in several patients. In conclusion, the side effects of high Aca doses preclude its use in patients with strong comorbidities.
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http://dx.doi.org/10.3390/ijms21010164DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6981810PMC
December 2019

Hepatitis C virus or hepatitis B virus coinfection and lymphoma risk in people living with HIV.

AIDS 2020 03;34(4):599-608

Sorbonne Universités, INSERM, UPMC Université Paris 06, Institut Pierre Louis d'épidémiologie et de Santé Publique (IPLESP UMRS1136), Paris.

Objective: Chronic hepatitis C virus (HCV) and hepatitis B virus (HBV) infections are associated with increased risks of lymphomas in the non-HIV setting. Their impacts on HIV-associated lymphomas deserved further studies in the modern combined antiretroviral therapy (cART) era.

Design: We evaluated the associations between HCV, HBV and HIV-related lymphomas in the Lymphovir-ANRS-CO16 cohort.

Methods: Prevalence of HCV seropositivity and chronic HBV infections were compared with those observed in the French Hospital Database on HIV (FHDH-ANRS-CO4).

Results: Between 2008 and 2015, 179 patients with HIV-related lymphomas from 32 French hospitals were enrolled, 69 had Hodgkin's lymphoma (39%), and 110 non-Hodgkin's lymphoma (NHL) (61%). The prevalence of HCV infection was higher in patients with NHL than in the FHDH-ANRS-CO4 [26 versus 14%, odd ratio (OR): 2.15; 95% confidence interval (1.35-3.32)] whereas there was no association between Hodgkin's lymphoma and chronic HCV infection. Chronic HBV infection was not associated with NHL in our cohort with a prevalence of 5 versus 7% in FHDH-ANRS-CO4 but tended to be associated with Hodgkin's lymphoma [prevalence of 14%, OR: 2.16 (0.98-4.27)]. Chronic HCV infection tended to pejoratively impact 2-year overall survival in patients with NHL: 72% [57%, 91%] versus 82% [74%, 91%], hazard ratio: 2.14 [0.95-4.84]. In contrast, chronic HBV infection did not correlate with outcome.

Conclusion: In the modern cART era, chronic HCV infection is associated with an increased risk of NHL in PLWHIV and tends to pejoratively impact overall survival. HBV infection is not associated with the risk of NHL but with a borderline increase of Hodgkin's lymphoma risk.
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http://dx.doi.org/10.1097/QAD.0000000000002461DOI Listing
March 2020

Lenalidomide maintenance for diffuse large B-cell lymphoma patients responding to R-CHOP: quality of life, dosing, and safety results from the randomised controlled REMARC study.

Br J Haematol 2020 04 8;189(1):84-96. Epub 2019 Nov 8.

Paracelsus Medical University Salzburg, Salzburg Cancer Research Institute, Salzburg, Austria.

Lenalidomide maintenance therapy prolonged progression-free survival (PFS) versus placebo in elderly patients with diffuse large B-cell lymphoma (DLBCL) responding to induction chemotherapy in the phase 3 REMARC study. This subpopulation analysis assessed the impact of lenalidomide maintenance and treatment-emergent adverse events (TEAEs) on health-related quality of life (HRQOL). Global health status (GHS), and physical functioning and fatigue subscales were evaluated in patients who completed the European Organisation for Research and Treatment of Cancer quality-of-life questionnaire-C30 v3.0. The impact of TEAEs classified post hoc as subjective (patients can feel) or observable (only measurable by physicians) on dose reductions and discontinuations was assessed. Among 457 patients (lenalidomide, n = 229; placebo, n = 228), mean (standard deviation) GHS was similar between treatment arms [68·2 (20·7) Versus 72·0 (17·8)] at randomisation and remained similar during maintenance. Patients receiving lenalidomide experienced no meaningful changes in GHS, physical functioning, or fatigue. Observable TEAEs were more common (81·1% Versus 66·3%) and more likely to lead to dose reductions, than subjective TEAEs in both arms. PFS was superior in the lenalidomide arm regardless of dose reduction. Lenalidomide maintenance prolonged PFS and did not negatively impact HRQOL in patients with DLBCL despite TEAEs being more common, when compared with placebo.
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http://dx.doi.org/10.1111/bjh.16300DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7154674PMC
April 2020

In situ BCL2 expression is an independent prognostic factor in HIV-associated DLBCL, a LYMPHOVIR cohort study.

Br J Haematol 2020 02 29;188(3):413-423. Epub 2019 Aug 29.

Unit of Haematology-Oncology, Centre Hospitalier Versailles, Le Chesnay, France.

The prognostic value of cell of origin (COO) classification and BCL2 expression is not well established in diffuse large B-cell lymphoma (DLBCL) patients with human immunodeficiency virus (HIV) infection in the recent era. Phenotypic patterns were determined by immunohistochemistry (IHC) of pathological samples from patients with HIV-associated DLBCL prospectively enrolled in the French AIDS and Viral Hepatitis CO16 Lymphovir cohort between 2008 and 2015. Molecular subgroup classification into germinal centre B-cell (GCB) and non-GCB subtypes was determined using the Hans algorithm. Among 52 samples of systemic DLBCL subjected to centralized pathological analysis, 25 of the 42 tested for BCL2 expression were positive. Samples were further classified into GCB (n = 19) and non-GCB (n = 16) subtypes and 17 remained unclassified. In multivariable analysis, BCL2 expression was an independent pejorative prognostic biomarker [4-year progression-free survival (PFS): 52% for BCL2 vs. 88% for BCL2 , P = 0·02] and tended to reduce 4-year overall survival (OS) (63% for BCL2 vs. 88% for BCL2 , P = 0·06). The difference between CGB and non-GCB subtypes on PFS and OS did not reach significance (4-year PFS: 79% for GCB vs. 53% for non-GCB, P = 0·24 and 4-year OS: 78% for GCB vs. 69% for non-GCB, P = 0·34). BCL2 expression determined by IHC is an independent pejorative prognostic biomarker in HIV-associated DLBCL in the recent era. This supports the investigation of new therapeutic strategies in patients with BCL2 expression.
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http://dx.doi.org/10.1111/bjh.16176DOI Listing
February 2020

Fatigue level changes with time in long-term Hodgkin and non-Hodgkin lymphoma survivors: a joint EORTC-LYSA cross-sectional study.

Health Qual Life Outcomes 2019 Jul 2;17(1):115. Epub 2019 Jul 2.

Centre de Traitement des Données du Cancéropôle Nord-Ouest, Plateforme de Recherche Clinique Ligue Contre le Cancer, Centre François Baclesse, 3 Avenue Général Harris, 14076, Caen, Cedex 5, France.

Background: Long-term lymphoma survivors often complain of persistent fatigue that remains unexplained. While largely reported in Hodgkin lymphoma (HL), long-term fatigue is poorly documented in non-Hodgkin lymphomas (NHL). Data collected in two cohort studies were used to illustrate the fatigue level changes with time in the two populations.

Methods: Two cross-sectional studies were conducted in 2009-2010 (HL) and in 2015 (NHL) in survivors enrolled in European Organisation for Research and Treatment of Cancer (EORTC) Lymphoma Group and Lymphoma Study Association (LYSA) trials. The same protocol and questionnaires were used in both studies including the Multidimensional Fatigue Inventory (MFI) tool to assess fatigue and a checklist of health disorders. Multivariate linear regression models were used in the two populations separately to assess the influence of time since diagnosis and primary treatment, age, gender, education level, cohabitation status, obesity and health disorders on fatigue level changes. Fatigue level changes were compared to general population data.

Results: Overall, data of 2023 HL and 1619 NHL survivors with fatigue assessment available (99 and 97% of cases, respectively) were analyzed. Crude levels of fatigue were similar in the two populations. Individuals who reported health disorders (61% of HL and 64% of NHL) displayed higher levels of fatigue than those who did not (P <  0.001). HL survivors showed increasing fatigue level with age while in NHL survivors mean fatigue level remained constant until age 70 and increased beyond. HL survivors showed fatigue changes with age higher than those of the general population with health disorders while NHL survivors were in between those of the general population with and without health disorders.

Conclusions: Among lymphoma survivors progressive increase of fatigue level with time since treatment completion is a distinctive feature of HL. Our data suggest that changes in fatigue level are unlikely to only depend on treatment complications and health disorders. Investigations should be undertaken to identify which factors including biologic mechanisms could explain why a substantial proportion of survivors develop high level of fatigue.
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http://dx.doi.org/10.1186/s12955-019-1186-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6604328PMC
July 2019

Clinical value of a [18F]-FDG PET-CT muscle-to-muscle SUV ratio for the diagnosis of active dermatomyositis.

Eur Radiol 2019 Dec 27;29(12):6708-6716. Epub 2019 Jun 27.

Service de Médecine Interne, CH d'Antibes-Juan-les-Pins, Antibes, France.

Objective: To study a muscle-to-muscle standardised uptake value (SUV) ratio with FDG-PET/CT (FDG-PET) as a marker for the detection of disease activity in dermatomyositis (DM).

Methods: Patients with DM (n = 24) who met the European Neuro-Muscular Centre diagnostic criteria were retrospectively identified over a 3-year period through a national survey. Muscle biopsy was performed in all patients. Maximum SUV was measured in proximal muscles (SUV) that had the highest radiotracer uptake on visual grading as well as in the musculus longissimus thoracis (SUV), whereas mean SUV was measured for the liver (SUV). Muscle-to-liver SUV ratios for either muscle group were compared and a SUV/SUV ratio was calculated. SUV/SUV of DM patients were compared with age- and sex-matched control subjects (n = 24) with melanoma who had received FDG-PET scans.

Results: DM patients presented with proximal and symmetrical muscle uptake. Differences in SUV/SUV and SUV/SUV ratios in DM subjects were significant (p < 0.001). SUV/SUV ratios in DM and their controls also differed significantly (p = 0.0012). The SUV/SUV ratio threshold between DM subjects and controls was 1.73 with a sensitivity of 50% (CI95%, 29.1 to 70.9%) and specificity at 83.3% (CI95%, 62.6 to 95.3%). When amyopathic DM patients were removed from the analysis, specificity was increased to 95% (CI95%, 75.1 to 99.9%) with a likelihood ratio of 10 and an AUC of 83.4% (CI95%, 71.4 to 95.4%).

Conclusion: A muscle-to-muscle SUV/SUV ratio with a cut-off value of 1.73 in FDG-PET imaging might serve as a non-invasive marker to determine disease activity in dermatomyositis.

Key Points: • [18F]-FDG PET-scanner standardised uptake value (SUV) could reflect disease activity in dermatomyositis (DM). • A ratio of SUV in proximal muscles (SUV) to SUV in musculus longissimus thoracis (SUV) could be used to determine active DM. • Active disease is suspected for SUV /SUV ratios greater than 1.73.
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http://dx.doi.org/10.1007/s00330-019-06302-9DOI Listing
December 2019

Epstein-Barr virus biomarkers have no prognostic value in HIV-related Hodgkin lymphoma in the modern combined antiretroviral therapy era.

AIDS 2019 05;33(6):993-1000

INSERM U1184, Center for Immunology of Viral Infections and Autoimmune Diseases, Le Kremlin Bicêtre Unité d'Hémato-Oncologie, Centre Hospitalier de Versailles, Le Chesnay, France.

Objectives: Epstein-Barr virus (EBV) has been implicated in lymphomagenesis of HIV-related classical Hodgkin lymphoma (HIV-cHL). The utility of EBV molecular and serological biomarkers has scarcely been examined in HIV-cHL in the recent combined antiretroviral therapy (cART) era.

Design: We evaluated EBV DNA load and a panel of EBV antibodies in HIV-cHL patients prospectively enrolled in the French ANRS-CO16 Lymphovir cohort between 2008 and 2015.

Methods: Pretreatment whole blood, plasma EBV DNA load and serological profiles were analysed in 63 HIV-infected patients diagnosed with cHL. For the 42 patients with available material, comparisons were performed between values at diagnosis and 6 months after the initiation of chemotherapy.

Results: Pretreatment whole blood and plasma EBV DNA loads were positive in 84 and 59% of HIV-cHL patients, respectively. Two-year progression-free survival estimates did not differ between the patients with pretreatment whole blood (n = 53) or plasma (n = 37) EBV DNA(+) and the patients with pretreatment whole blood (n = 10) or plasma (n = 26) EBV DNA(-) (92 vs. 80% or 89 vs. 92%, P = 0.36 and 0.47, respectively). At diagnosis, 47% of patients harboured an EBV reactivation serological profile. Following chemotherapy, whole blood and plasma EBV DNA levels significantly declined from medians of 1570 [interquartile range, 230-3760) and 73 (0-320) copies/ml to 690 (0-1830) and 0 (0-0) copies/ml, respectively (P = 0.02 and P < 0.0001, respectively]. Anti-EBV IgG antibody level significantly dropped at 6-month follow-up (P = 0.004).

Conclusion: Whole blood and plasma EBV DNA loads do not constitute prognostic markers in HIV-cHL patients in the modern cART era.
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http://dx.doi.org/10.1097/QAD.0000000000002129DOI Listing
May 2019

Long-term fatigue in survivors of non-Hodgkin lymphoma: The Lymphoma Study Association SIMONAL cross-sectional study.

Cancer 2019 07 22;125(13):2291-2299. Epub 2019 Mar 22.

French Center on eHealth, North-West Region Data Processing Center and French National League Against Cancer Clinical Research Platform, Caen, France.

Background: Long-term survivors of non-Hodgkin lymphoma (NHL) must cope with treatment complications and late toxicities that affect their health-related quality of life. Little is known about the risk-to-benefit ratio of new agents like rituximab. The impact of treatment regimens and health disorders on long-term fatigue levels was investigated in a cross-sectional study.

Methods: Two self-administered questionnaires, the 20-item Multidimensional Fatigue Inventory (MFI-20) and a Life Situation Questionnaire, were mailed in 2015 to NHL survivors enrolled onto 12 successive clinical studies (1993-2010) conducted by the Lymphoma Study Association. Private addresses were obtained for 3317 survivors, of whom 1671 (50%) returned the questionnaires. Severe fatigue was defined as MFI-20 scores ≥60 on dimension scales scored from 0 to 100. Linear regression models were used to assess factors that were linked to increased fatigue levels.

Results: The study population included 906 men and 765 women, and the median age was 64 years (age range, 24-95 years). Overall, 811 survivors had received cyclophosphamide, doxorubicin, vincristine, prednisone (CHOP)-like chemotherapy, 518 had received high-dose CHOP, and 342 had undergone upfront autologous stem cell transplantation; 829 survivors also had received rituximab. In total, 1100 survivors (66%) reported 1 or more late health disorders. Severe fatigue was reported by 602 survivors (37%). Increased fatigue levels were associated (P < .001) with increased age, obesity, and the presence of health disorders, but not with initial treatment or rituximab.

Conclusions: The survey confirms that high proportions long-term NHL survivors have severe fatigue. The results suggest that initial treatment and the receipt of rituximab have no influence on the development of long-term fatigue.
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http://dx.doi.org/10.1002/cncr.32040DOI Listing
July 2019

GAPDH Expression Predicts the Response to R-CHOP, the Tumor Metabolic Status, and the Response of DLBCL Patients to Metabolic Inhibitors.

Cell Metab 2019 06 28;29(6):1243-1257.e10. Epub 2019 Feb 28.

CHU Dinant Godinne, UcL Namur, Yvoir, Belgium.

Diffuse large B cell lymphoma (DLBCL) is a heterogeneous disease treated with anti-CD20-based immuno-chemotherapy (R-CHOP). We identified that low levels of GAPDH predict a poor response to R-CHOP treatment. Importantly, we demonstrated that GAPDH lymphomas use OxPhos metabolism and rely on mTORC1 signaling and glutaminolysis. Consistently, disruptors of OxPhos metabolism (phenformin) or glutaminolysis (L-asparaginase) induce cytotoxic responses in GAPDH B cells and improve GAPDH B cell-lymphoma-bearing mice survival, while they are low or not efficient on GAPDH B cell lymphomas. Ultimately, we selected four GAPDH DLBCL patients, who were refractory to all anti-CD20-based therapies, and targeted DLBCL metabolism using L-asparaginase (K), mTOR inhibitor (T), and metformin (M) (called KTM therapy). Three out of the four patients presented a complete response upon one cycle of KTM. These findings establish that the GAPDH expression level predicts DLBCL patients' response to R-CHOP treatment and their sensitivity to specific metabolic inhibitors.
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http://dx.doi.org/10.1016/j.cmet.2019.02.002DOI Listing
June 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

LAMP2 expression dictates azacytidine response and prognosis in MDS/AML.

Leukemia 2019 06 3;33(6):1501-1513. Epub 2019 Jan 3.

Université Côte d'Azur, Nice, France.

Chaperone-mediated autophagy (CMA) is a highly selective form of autophagy. During CMA, the HSC70 chaperone carries target proteins endowed with a KFERQ-like motif to the lysosomal receptor LAMP2A, which then translocate them into lysosomes for degradation. In the present study, we scrutinized the mechanisms underlying the response and resistance to Azacytidine (Aza) in MDS/AML cell lines and bone marrow CD34 blasts from MDS/AML patients. In engineered Aza-resistant MDS cell lines and some AML cell lines, we identified a profound defect in CMA linked to the absence of LAMP2A. LAMP2 deficiency was responsible for Aza resistance and hypersensitivity to lysosome and autophagy inhibitors. Accordingly, gain of function of LAMP2 in deficient cells or loss of function in LAMP2-expressing cells rendered them sensitive or resistant to Aza, respectively. A strict correlation was observed between the absence of LAMP2, resistance to Aza and sensitivity to lysosome inhibitors. Low levels of LAMP2 expression in CD34 blasts from MDS/AML patients correlated with lack of sensitivity to Aza and were predictive of poor overall survival. We propose that CD34/LAMP2 patients at diagnosis or who become CD34/LAMP2 during the course of treatment with Aza might benefit from a lysosome inhibitor already used in the clinic.
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http://dx.doi.org/10.1038/s41375-018-0336-1DOI Listing
June 2019

Lenalidomide in combination with R-CHOP (R2-CHOP) as first-line treatment of patients with high tumour burden follicular lymphoma: a single-arm, open-label, phase 2 study.

Lancet Haematol 2018 Sep;5(9):e403-e410

Hospices Civils de Lyon, Centre Hospitalier Lyon-Sud, INSERM1052, University of Lyon, Pierre-Benite, France.

Background: Immunochemotherapy with rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) is a standard front-line treatment for follicular lymphoma. The combination of lenalidomide and rituximab has shown high efficacy in relapsed or refractory and untreated follicular lymphoma. We aimed to evaluate the safety and activity of the combination of lenalidomide and R-CHOP (R2-CHOP) in previously untreated patients with high burden follicular lymphoma.

Methods: This single-arm, open-label, multicentre, phase 2 trial was done in 16 hospitals in France, all of which were Lymphoma Study Association (LYSA) sites. Eligible patients were aged 18-70 years and had previously untreated CD20-positive follicular lymphoma of grade 1, 2, or 3a; at least one high tumour burden criterion according to Groupe d'Etude des Lymphomes Folliculaires criteria; an Eastern Cooperative Oncology Group performance status score of 2 or less; and a minimum life expectancy of more than 3 months. Patients received induction therapy with six cycles of R2-CHOP every 3 weeks (one cycle involved standard R-CHOP on days 1-5, and 25 mg oral lenalidomide per day on days 1-14), followed by two rituximab infusions at 3-week intervals. The total treatment schedule was 24 weeks. Patients who achieved a complete or partial response to induction therapy received maintenance therapy consisting of one rituximab infusion every 8 weeks for 2 years. The primary outcome was the proportion of patients who achieved a complete response (complete response and complete response unconfirmed), according to International Workshop to Standardize Response Criteria, at the end of induction treatment. Safety was assessed in all patients who completed treatment. This trial is registered with ClinicalTrials.gov, number NCT01393756, and is closed to accrual.

Findings: Between Dec 21, 2010, and Jan 25, 2012, 80 patients were enrolled, and 68 (85%) completed six cycles of R2-CHOP. At the end of the induction phase, 59 patients achieved a complete response (74%, 95% CI 63-83). 55 patients achieved a complete response at 30 months from enrolment (69%, 57-78). The most frequent adverse event was grade 4 neutropenia in 52 (65%) patients. The most frequent non-haematological side-effects included grade 1-2 sensory neuropathy in 28 (35%) patients and grade 1-2 transient rash in 27 (34%) patients. Four patients died during the study period; none of these deaths were judged to be related to treatment.

Interpretations: Lenalidomide in combination with R-CHOP had an acceptable safety profile and showed anti-cancer activity in patients with previously untreated high burden follicular lymphoma. A future comparative study showing evidence of a survival advantage would be necessary for this combination to be proposed as a treatment for follicular lymphoma.

Funding: French Ministry of Health, Celgene Corporation, and Amgen France.
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http://dx.doi.org/10.1016/S2352-3026(18)30131-5DOI Listing
September 2018

Central nervous system relapse in patients over 80 years with diffuse large B-cell lymphoma: an analysis of two LYSA studies.

Cancer Med 2018 03 23;7(3):539-548. Epub 2018 Feb 23.

APHP, Hôpital Saint-Louis, Hemato-Oncologie, Paris, France.

CNS relapse is reported in 2-5% of diffuse large B-cell lymphoma (DLBCL) patients, dramatically decreasing overall survival (OS). Very few studies address incidence and risk factors of CNS relapse in very elderly patients, a challenging population to treat given their commonly associated comorbidities. A retrospective analysis was performed of 270 DLBCL patients >80 years treated between 2004 and 2013 in two multicentre phase II LYSA trials (LNH03-7B, LNH09-7B) evaluating the addition of rituximab or ofatumumab to mini-CHOP as front-line therapy. No patients received CNS prophylaxis. CNS relapse was evaluated according to cumulative incidence, patient characteristics, risk factors, and survival. Median age was 83 years (range: 79-95). After a median follow-up of 28.7 months, eight patients had CNS relapse (3.0%). Median time between inclusion and CNS relapse was 19.2 months (range: 3.2-32.6). Patients survived a median of 1.5 months after CNS relapse (range: 0.4-4.1). Median OS from relapse was significantly lower in CNS relapse patients (1.5 months, 95% CI: 0.4-3.5) compared to patients with non-CNS relapse (6.6 months; 95% CI: 4.6-11.9). No baseline characteristics were associated with CNS relapse. The proportion of patients with CNS disease did not differ significantly between patients with low-intermediate risk according to CNS-IPI and patients with high risk (3% vs. 2.8%, P = 1.00). CNS relapse cumulative incidence in very elderly treatment-naive patients is 1.8% at 2 years and is associated with poor survival. This population had a long median time to CNS relapse. Absence of prophylaxis did not strongly impact CNS relapse incidence.
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http://dx.doi.org/10.1002/cam4.1139DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5852369PMC
March 2018

VEGF, is predictor for survival in activated B-cell-like diffuse large B-cell lymphoma and is related to an immune response gene signature conserved in cancers.

Oncotarget 2017 Oct 19;8(53):90808-90824. Epub 2017 Jul 19.

Paris Diderot University, Sorbonne Paris Cité, Paris, France.

Tumor microenvironment including endothelial and immune cells plays a crucial role in tumor progression and has been shown to dramatically influence cancer survival. In this study, we investigated the clinical relevance of the gene expression of key mediators of angiogenesis, VEGF isoforms 121, 165, and 189, and their receptors (VEGFR-1 and R-2) in a cohort of patients ( = 37) with relapsed/refractory diffuse large B-cell lymphoma (DLBCL) from the Collaborative Trial in Relapsed Aggressive Lymphoma (CORAL). In patients with ABC-like DLBCL, but not in patients with GCB-like DLBCL, low expression was associated with a significantly better survival than in those with high level: 4-year overall survival at 100% vs 36% ( = .011), respectively. A specific gene signature including 57 genes was correlated to expression level and was analyzed using a discovery process in 1,842 GSE datasets of public microarray studies. This gene signature was significantly expressed in other cancer datasets and was associated with immune response. In conclusion, low expression level was significantly associated with a good prognosis in relapsed/refractory ABC-like DLBCL, and with a well-conserved gene-expression profiling signature related to immune response. These findings pave the way for rationalization of drugs targeting immune response in refractory/relapsed ABC-like DLBCL.
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http://dx.doi.org/10.18632/oncotarget.19385DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5710886PMC
October 2017

Outcomes for HIV-associated diffuse large B-cell lymphoma in the modern combined antiretroviral therapy era.

AIDS 2017 11;31(18):2493-2501

aUnit of Hematology-Oncology, Centre Hospitalier de Versailles, Le ChesnaybUniversité Versailles Saint Quentin en Yvelines, Université Paris-Saclay, Communauté Paris-Saclay, PariscINSERM U1018, Centre pour la Recherche en Epidémiologie et Santé des Populations (CESP), Equipe 'Générations et Santé' Gustave Roussy, VillejuifdSorbonne Universités, INSERM, UPMC Univ Paris 06, Institut Pierre Louis d'épidémiologie et de Santé Publique (IPLESP UMRS1136), PariseUniversité Paris Sud, Faculté de médecine Paris Sud, Le Kremlin-BicêtrefPathology Unit, AP-HP, Hôpitaux Paris Sud Site Béclère, ClamartgInfectious Diseases Unit, CHU Toulouse, ToulousehInternal Medicine and Infectious Diseases Unit, CHU Bordeaux, INSERM U1219, Université de Bordeaux, BordeauxiInfectious Diseases Unit, AP-HP CHU Saint-Antoine, ParisjHIV Infection Unit, Hôpitaux Universitaires, StrasbourgkU1037, CRCT, University Toulouse III Paul SabatierlDepartment of Hematology, Institut Universitaire du Cancer (IUC), ToulousemDepartment of Hematology, AP-HP, CHU Pitié-Salpétrière, ParisnInternal Medicine Unit, AP-HP, Hôpitaux Paris Sud, Le Kremlin-BicêtreoClinical Immunology Unit, AP-HP, Hôpitaux Paris Sud Site Béclère, ClamartpDepartment of Hematology, AP-HP CHU Saint-Antoine, ParisqDepartment of Hematology, AP-HM, Assistance Publique Hôpitaux de Marseille, MarseillerImmunology Unit, AP-HP, Hôpitaux Paris Sud, Le Kremlin-BicêtresDepartment of Hematology, AP-HP, Hôpital Necker Enfants Malades, ParistHematology Unit, Centre Hospitalier Universitaire-Dijon, DijonuDepartment of Onco-Hematology, Archet Hospital, Nice, France.

Objective: Non-Hodgkin's lymphoma (NHL) remains among the most frequent malignancies in persons living with HIV (PLWHIV). Survival among patients with HIV-associated diffuse large B-cell lymphoma (DLBCL), the most frequent NHL subtype, has improved markedly in recent years. We aimed to analyze characteristics and outcomes of DLBCL in HIV-infected patients in the era of modern combined antiretroviral therapy (cART).

Design: PLWHIV with lymphoma were prospectively enrolled in the French ANRS-CO16 Lymphovir cohort between 2008 and 2015. We compared the patients treated with R-CHOP) (rituximab, cyclophosphamide, daunorubicin, vin-cristine, prednisolone) with HIV-negative DLBCL patients enrolled simultaneously in the R-CHOP arms of Lymphoma Study Association trials.

Results: Among 110 PLWHIV with NHL, 52 (47%) had systemic DLBCL. These 52 cases had frequent extranodal disease (81%), poor performance status (35%) and advanced age-adjusted international prognostic index (aaIPI) (58%), and were mainly treated with R-CHOP (n = 44, 85%). Their median CD4 T-cell count was 233 cells/μl, and 79% of patients were on cART. The 2-year overall and progression-free survival rates were both 75% (95% confidence interval: 64%, 88%). Factors associated with progression or death in univariate analysis were poor performance status [hazard ratio: 3.3 (1.2, 8.9)], more than one extranodal site [hazard ratio: 3.4 (1.1, 10.5)] and an advanced aaIPI [hazard ratio: 3.7 (1.0, 13.1)]. Progression-free survival after R-CHOP therapy did not differ from that of the HIV-negative counterparts (P = 0.11).

Conclusion: In the recent cART era, despite frequent high-risk features, the 2-year overall survival of HIV-DLBCL patients reaches 75%. Outcomes after R-CHOP therapy are similar to those of HIV-negative patients with similar aaIPI.
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http://dx.doi.org/10.1097/QAD.0000000000001652DOI Listing
November 2017

[Conduct of epidemiologic studies in French cancer survivors: Methods, difficulties encountered and solutions provided. Lessons learned from the SIMONAL study on long-term toxicities after non-Hodgkin lymphoma treatment].

Bull Cancer 2017 Mar 15;104(3):221-231. Epub 2017 Feb 15.

CHU de Nice, hôpital l'Archet 1, service d'onco-hématologie, 151, route Saint-Antoine-Ginestière, 06202 Nice, France. Electronic address:

Introduction: Since the introduction of targeted therapies, specific lymphoma mortality has decreased. Possible long-term toxicities, however, are not known yet. This article describes the implementation of the SIMONAL study that investigates the hypothesis of an overconsumption of care after lymphoma treatment with a 10-year follow-up.

Methods: After the mandatory regulatory steps (CCTIRS and CNIL) the vital status and address of 5247 patients treated in 131 French centers were retrieved using a secure web portal, in order to send a quality of life after lymphoma questionnaire. After an additional vital status validation request at the center for epidemiologic research and population health (CESP), the questionnaires were sent. Double data entry was performed on the collected data and a request to access data from France's public health insurance scheme information system (SNIIRAM) was formulated.

Results: Retrieval of the addresses via the portal has been slow and multiple reminders were needed. The CESP identified 9.4 % additional deaths not known by the treatment centers. Of the 3391 questionnaires sent, the response rate was 50%. A comparison between the responders and non-responders revealed no demographic differences but showed that the responders were more often treated with targeted drugs as they were included in more recent trials.

Discussion: Logistic and information technology (IT) aspects rendered the implementation of the SIMONAL study more complex, time consuming and costly. However, using the collected data, many future research questions will be addressed.
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http://dx.doi.org/10.1016/j.bulcan.2017.01.007DOI Listing
March 2017

Reply to C.F. Hess et al.

J Clin Oncol 2017 01 28;35(3):374. Epub 2016 Oct 28.

Patrice P. Carde, Gustave Roussy Cancer Campus, Villejuif, France; Michael Grynberg, Hôpital Jean Verdier, Bondy, France; Catherine Poirot, Hôpital Saint Louis, Paris, France; Bengt Glimelius, Uppsala University Hospital, Uppsala, Sweden; and Nicolas Mounier, L'Archet Hospital, Nice, France.

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http://dx.doi.org/10.1200/JCO.2016.69.7995DOI Listing
January 2017

Mobile applications in oncology: is it possible for patients and healthcare professionals to easily identify relevant tools?

Ann Med 2016 11 27;48(7):509-515. Epub 2016 Jun 27.

a Oncology Hematology Department , Louis Pasteur Hospital , Chartres Le Coudray , France.

Aim: Mobile applications represent promising tools in management of chronic diseases, both for patients and healthcare professionals, and especially in oncology. Among the large number of mobile health (mhealth) applications available in mobile stores, it could be difficult for users to identify the most relevant ones. This study evaluated the business model and the scientific validation for mobile applications related to oncology.

Methods: A systematic review was performed over the two major marketplaces. Purpose, scientific validation, and source of funding were evaluated according to the description of applications in stores. Results were stratified according to targeted audience (general population/patients/healthcare professionals).

Results: Five hundred and thirty-nine applications related to oncology were identified: 46.8% dedicated to healthcare professionals, 31.5% to general population, and 21.7% to patients. A lack of information about healthcare professionals' involvement in the development process was noted since only 36.5% of applications mentioned an obvious scientific validation. Most apps were free (72.2%) and without explicit support by industry (94.2%).

Conclusions: There is a need to enforce independent review of mhealth applications in oncology. The economic model could be questioned and the source of funding should be clarified. Meanwhile, patients and healthcare professionals should remain cautious about applications' contents. Key messages A systematic review was performed to describe the mobile applications related to oncology and it revealed a lack of information on scientific validation and funding. Independent scientific review and the reporting of conflicts of interest should be encouraged. Users, and all health professionals, should be aware that health applications, whatever the quality of their content, do not actually embrace such an approach.
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http://dx.doi.org/10.1080/07853890.2016.1195010DOI Listing
November 2016

Relapsed diffuse large B-cell lymphoma present different genomic profiles between early and late relapses.

Oncotarget 2016 Dec;7(51):83987-84002

Inserm U954, Faculty of Medicine, Nancy, France.

Despite major advances in first-line treatment, a significant proportion of patients with diffuse large B-cell lymphoma (DLBCL) will experience treatment failure. Prognosis is particularly poor for relapses occurring less than one year after the end of first-line treatment (early relapses/ER) compared to those occurring more than one year after (late relapses/LR). To better understand genomic alterations underlying the delay of relapse, we identified copy number variations (CNVs) on 39 tumor samples from a homogeneous series of patients included in the Collaborative Trial in Relapsed Aggressive Lymphoma (CORAL) prospective study. To identify CNVs associated with ER or LR, we devised an original method based on Significance Analysis of Microarrays, a permutation-based method which allows control of false positives due to multiple testing. Deletions of CDKN2A/B (28%) and IBTK (23%) were frequent events in relapsed DLBCLs. We identified 56 protein-coding genes and 25 long non-coding RNAs with significantly differential CNVs distribution between ER and LR DLBCLs, with a false discovery rate < 0.05. In ER DLBCLs, CNVs were related to transcription regulation, cell cycle and apoptosis, with duplications of histone H1T (31%), deletions of DIABLO (26%), PTMS (21%) and CK2B (15%). In LR DLBCLs, CNVs were related to immune response, with deletions of B2M (20%) and CD58 (10%), cell proliferation regulation, with duplications of HES1 (25%) and DVL3 (20%), and transcription regulation, with MTERF4 deletions (20%). This study provides new insights into the genetic aberrations in relapsed DLBCLs and suggest pathway-targeted therapies in ER and LR DLBCLs.
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http://dx.doi.org/10.18632/oncotarget.9793DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5356640PMC
December 2016

Eight Cycles of ABVD Versus Four Cycles of BEACOPPescalated Plus Four Cycles of BEACOPPbaseline in Stage III to IV, International Prognostic Score ≥ 3, High-Risk Hodgkin Lymphoma: First Results of the Phase III EORTC 20012 Intergroup Trial.

J Clin Oncol 2016 06 25;34(17):2028-36. Epub 2016 Apr 25.

Patrice Carde and Christophe Ferme, Gustave Roussy Cancer Campus, Villejuif; Pauline Brice, Hopital St. Louis, Paris; Olivier Casasnovas and Denis Caillot, Centre Hospitalier Universitaire (CHU) de Dijon, Dijon; Isabelle Gaillard, CHU Henri Mondor, Creteil; Serge Bologna, Centre Hospitalier Regional Universitaire (CHR) de Nancy, Nancy; Frank Morschhauser, CHR de Lille, Lille; Bertrand Coiffier, CHU de Lyon, Lyon; Nicolas Mounier, Hopital de L'Archet, Nice, France; Matthias Karrasch and Catherine Fortpied, European Organisation for Research and Treatment of Cancer Headquarters, Brussels, Belgium; Hussein Khaled, National Cancer Institute, Cairo, Egypt; Pieternella Johanna Lugtenburg, Erasmus Medical Center Cancer Institute, Rotterdam, the Netherlands; Igor Aurer, University Hospital Centre Zagreb, Zagreb, Croatia; Ralph Meyer, Juravinski Cancer Centre, Hamilton, Ontario; Matthew Seftel, Cancer Care Manitoba, Winnipeg, Manitoba, Canada; Max Wolf, Peter MacCallum Cancer Institute, East Melbourne, Victoria, Australia; Bengt Glimelius, Uppsala University, Uppsala, Sweden; and Anna Sureda, Hospital de la Santa Creu i Sant Pau, Barcelona, Spain.

Purpose: To compare patients with high-risk stage III to IV Hodgkin lymphoma (HL) in the phase III European Organisation for Research and Treatment of Cancer 20012 Intergroup trial (Comparison of Two Combination Chemotherapy Regimens in Treating Patients With Stage III or Stage IV Hodgkin's Lymphoma) who were randomly assigned to either doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD) or to bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, and prednisone (BEACOPP).

Patients And Methods: Patients with clinical stage III or IV HL, International Prognostic Score of 3 or higher, and age 60 years or younger received ABVD for eight cycles (ABVD8) or escalated-dose BEACOPP (BEACOPPescalated) for four cycles followed by baseline BEACOPP (BEACOPPbaseline) for four cycles (BEACOPP4+4) without radiotherapy. Primary end points were event-free survival (EFS), treatment discontinuation, no complete response (CR) or unconfirmed complete response (CRu) after eight cycles, progression, relapse, or death. Secondary end points were CR rate, overall survival (OS), quality of life, secondary malignancies, and disease-free survival in CR/CRu patients.

Results: Between 2002 and 2010, 549 patients were randomly assigned to ABVD8 (n = 275) or BEACOPP4+4 (n = 274). Other characteristics included median age, 35 years; male, 75%; stage IV, 74%; "B" symptoms, 81%; and International Prognostic Score ≥ 4, 59%. WHO performance status was 0 (34%), 1 (48%), or 2 (17%). Median follow-up was 3.6 years. CR/CRu was 82.5% in both arms. At 4 years, EFS was 63.7% for ABVD8 versus 69.3% for BEACOPP4+4 (hazard ratio [HR], 0.86; 95% CI, 0.64 to 1.15; P = .312); disease-free survival was 85.8% versus 91.0% (HR, 0.59; 95% CI, 0.33 to 1.06; P = .076), and OS was 86.7% versus 90.3% (HR, 0.71; 95% CI, 0.42 to 1.21; P = .208). Death as a result of toxicity occurred in six and five patients, early discontinuation (before cycle 5) in 12 and 26 patients, treatment crossovers in five and 10 patients, and secondary malignancies in eight and 10 patients in the ABVD8 and BEACOPP4+4 arms, respectively.

Conclusion: ABVD8 and BEACOPP4+4 resulted in similar EFS and OS in patients with high-risk advanced-stage HL. Because BEACOPP4+4 did not demonstrate a favorable effectiveness or toxicity ratio compared with ABVD8, treatment burden, immediate and late toxicities, and associated costs must be considered before selecting one of these regimens on which to build future treatment strategies.
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http://dx.doi.org/10.1200/JCO.2015.64.5648DOI Listing
June 2016

Central nervous system involvement in AIDS-related lymphomas.

Br J Haematol 2016 06 7;173(6):857-66. Epub 2016 Apr 7.

Albert Einstein College of Medicine/Montefiore Medical Center, Bronx, NY, USA.

Central nervous system (CNS) involvement is reportedly more common in acquired immunodeficiency syndrome (AIDS)-related lymphomas (ARL). We describe factors and outcomes associated with CNS involvement at baseline (CNS(B) ) and relapse (CNS(R) ) in 886 patients with newly diagnosed ARL. Of 886 patients, 800 received either intrathecal (IT) therapy for CNS(B) or IT prophylaxis. CNS(B) was found in 13%. CNS(B) was not associated with reduced overall survival (OS). There was no difference in the prevalence of CNS(B) between the pre-combination antiretroviral therapy (cART) and cART eras. 5·3% of patients experienced CNS(R) at a median of 4·2 months after diagnosis (12% if CNS(B) ; 4% if not). Median OS after CNS(R) was 1·6 months. On multivariate analysis, only CNS(B) [hazard ratio (HR) 3·68, P = 0·005] and complete response to initial therapy (HR 0·14, P < 0·0001) were significantly associated with CNS(R) . When restricted to patients without CNS(B) , IT CNS prophylaxis with 3 vs. 1 agent did not significantly impact the risk of CNS(R) . Despite IT CNS prophylaxis, 5% of patients experienced CNS(R) . Our data confirms that CNS(R) in ARL occurs early and has a poor outcome. Complete response to initial therapy was associated with a reduced frequency of CNS(R) . Although CNS(B) conferred an increased risk for CNS(R) , it did not impact OS.
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http://dx.doi.org/10.1111/bjh.13998DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4900917PMC
June 2016

Nodular lymphocyte predominant Hodgkin lymphoma: a Lymphoma Study Association retrospective study.

Haematologica 2015 Dec 1;100(12):1579-86. Epub 2015 Oct 1.

Department of Medical Oncology, Gustave Roussy, Villejuif, France

Nodular lymphocyte predominant Hodgkin lymphoma represents a distinct entity from classical Hodgkin lymphoma. We conducted a retrospective study to investigate the management of patients with nodular lymphocyte predominant Hodgkin lymphoma. Clinical characteristics, treatment and outcome of adult patients with nodular lymphocyte predominant Hodgkin lymphoma were collected in Lymphoma Study Association centers. Progression-free survival (PFS) and overall survival (OS) were analyzed, and the competing risks formulation of a Cox regression model was used to control the effect of risk factors on relapse or death as competing events. Among 314 evaluable patients, 82.5% had early stage nodular lymphocyte predominant Hodgkin lymphoma. Initial management consisted in watchful waiting (36.3%), radiotherapy (20.1%), rituximab (8.9%), chemotherapy or immuno-chemotherapy (21.7%), combined modality treatment (12.7%), or radiotherapy plus rituximab (0.3%). With a median follow-up of 55.8 months, the 10-year PFS and OS estimates were 44.2% and 94.9%, respectively. The 4-year PFS estimates were 79.6% after radiotherapy, 77.0% after rituximab alone, 78.8% after chemotherapy or immuno-chemotherapy, and 93.9% after combined modality treatment. For the whole population, early treatment with chemotherapy or radiotherapy, but not rituximab alone (Hazard ratio 0.695 [0.320-1.512], P=0.3593) significantly reduced the risk of progression compared to watchful waiting (HR 0.388 [0.234-0.643], P=0.0002). Early treatment appears more beneficial compared to watchful waiting in terms of progression-free survival, but has no impact on overall survival. Radiotherapy in selected early stage nodular lymphocyte predominant Hodgkin lymphoma, and combined modality treatment, chemotherapy or immuno-chemotherapy for other patients, are the main options to treat adult patients with a curative intent.
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http://dx.doi.org/10.3324/haematol.2015.133025DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4666334PMC
December 2015

High Risk Features Contrast With Favorable Outcomes in HIV-associated Hodgkin Lymphoma in the Modern cART Era, ANRS CO16 LYMPHOVIR Cohort.

Clin Infect Dis 2015 Nov 29;61(9):1469-75. Epub 2015 Jul 29.

Sorbonne Universités, UPMC Univ Paris 06 INSERM, UMR_S 1136, Institut Pierre Louis d'épidémiologie et de Santé Publique, Paris.

Background: Human immunodeficiency virus (HIV) infection is associated with a high risk of classical Hodgkin's lymphoma (cHL) in the combined antiretroviral therapy (cART) era.

Methods: We analyzed the characteristics and outcome of HIV-associated cHL diagnosed in the modern cART era. The French ANRS-CO16 Lymphovir cohort enrolled 159 HIV-positive patients with lymphoma, including 68 (43%) with cHL. HIV-HL patients were compared with a series of non-HV-infected patients consecutively diagnosed with HL.

Results: Most patients (76%) had Ann-Arbor stages III-IV and 96% of patients were treated with ABVD. At diagnosis, median CD4 T-cell count was 387/µL and 94% of patients were treated with cART. All patients received cART after diagnosis. Five patients died from early progression (n = 2), sepsis (1) or after relapse (2). Two additional patients relapsed during follow-up. Two-year overall and progression free survivals (PFS) were 94% [95% CI, 89%, 100%] and 89% [82%, 97%], respectively. The only factor associated with progression or death was age with a relative risk of 8.1 [1.0; 67.0] above 45 years. The PFS of Lymphovir patients appeared similar to PFS of HIV-negative patients, 86% [82%, 90%], but patients with HIV infection displayed higher risk features than HIV-negative patients.

Conclusions: Although high-risk features still predominate in HIV-HL, the prognosis of these patients, treated with cART and mainly ABVD, has markedly improved in the modern cART era and is now similar to non-HIV-infected patients.
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http://dx.doi.org/10.1093/cid/civ627DOI Listing
November 2015
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