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BACKGROUND No study has focused on the economic burden in non-Hodgkin lymphoma (NHL) survivors, even though this knowledge is essential. This study reports on health care resource use and associated health care costs as well as related factors in a series of 1671 French long-term NHL survivors. METHODS Health care costs were measured from the payer perspective. Only direct medical costs (medical consultations, outpatient treatments, hospitalizations, and medical transport) in the past 12 months were included (reference year 2015). Multiple linear regression was used to search for explanatory factors of health care costs. RESULTS In total, 1100 survivors (66%) reported having used at least 1 health care resource, and 867 (52%) reported having used at least 1 outpatient treatment. After the authors accounted for missing data, the mean health care cost was estimated at €702 ± €2221. Hospitalizations and outpatient treatments were the main cost drivers. Sensitivity analyses confirmed the robustness of the results. For the 1100 survivors who reported using at least 1 health care resource, the mean health care cost was €1067 ± €2268. Several factors demonstrated statistically significant relationships with health care costs. For instance, cardiovascular disorders increased costs by 66% ± 16%. In contrast, rituximab or autologous stem cell transplantation as initial therapy had no effect on health care costs. CONCLUSIONS The consideration of economic constraints in health care is now a reality. This retrospective study reports on a better understanding of health care resource use and associated health care costs as well as related factors. It may help health care professionals in their ongoing efforts to design person-centered health care pathways.

The majority of patients with diffuse large B-cell lymphoma (DLBCL) can be cured with immunochemotherapy comprising rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP). Patients suffering progression or relapse in the central nervous system (CNS) face dismal outcomes. The impact of more aggressive regimens used in front-line therapy has not systematically been investigated in this context. To this end, we analyzed a large cohort of 2203 younger DLBCL patients treated on ten German and French prospective phase II and III trials following first-line therapy with R-CHOP, R-CHOEP (R-CHOP + etoposide), dose-escalated R-CHOEP followed by repetitive stem cell transplantation (R-MegaCHOEP), or rituximab, doxorubicin, cyclophosphamide, vindesine, bleomycine, prednisone (R-ACVBP) followed by consolidation including multiple drugs crossing the blood-brain-barrier (BBB). DLBCL patients with age-adjusted International Prognostic Index (aaIPI) of 0–1 showed very low cumulative incidence (CI) rates of CNS relapse regardless of first-line therapy and CNS prophylaxis (3-year CI 0% − 1%). Younger high-risk patients with aaIPI of 2–3 had 3-year CI rates of 1.6% and 4% after R-ACVBP plus consolidation or R-(Mega)CHO(E)P, respectively (Hazard Ratio 2.4 (95% confidence interval: 0.8–7.4), p = 0.118). Thus, for younger high-risk patients, front-line regimens incorporating multiple agents crossing the BBB may reduce often fatal CNS relapse.

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). 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 (SUVPROX) that had the highest radiotracer uptake on visual grading as well as in the musculus longissimus thoracis (SUVMLT), whereas mean SUV was measured for the liver (SUVLIV). Muscle-to-liver SUV ratios for either muscle group were compared and a SUVPROX/SUVMLT ratio was calculated. SUVPROX/SUVMLT of DM patients were compared with age- and sex-matched control subjects (n = 24) with melanoma who had received FDG-PET scans. DM patients presented with proximal and symmetrical muscle uptake. Differences in SUVPROX/SUVLIV and SUVMLT/SUVLIV ratios in DM subjects were significant (p

Health-related quality of life (HRQoL) is a multidimensional concept including physical, emotional, social, and cognitive functions, disease symptoms, and side effects of treatment. Differences in HRQoL due to gender, existence of comorbidities, and number of chemotherapy cycles are little explored in diffuse large B-cell lymphoma (DLBCL) survivors. Our objective was to investigate whether differences in HRQoL in function of these factors exist 1 year after the diagnosis of DLBCL. One hundred and one patients, enrolled in the RT3 (Real-Time Tailored Therapy) Study, answered self-administrated European Organization for Research and Treatment of Cancer Quality of Life Questionnaire Core 30 (EORTC QLQ-C30), EORTC High-Grade Non-Hodgkin Lymphoma (NHL-HG29), Hospital Anxiety and Depression Scale (HADS), Post Traumatic Growth Inventory (PTGI), and Multidimensional Fatigue Inventory (MFI) questionnaires. Adjusted means of scores were calculated in multivariate linear regression models. Fifty-seven survivors (mean age of 58.5 years) answered all questionnaires. Women have significantly higher scores of posttraumatic growth and lower physical functioning than men (P < 0.04). Survivors with comorbidities have increased physical fatigue and symptom burden, increased emotional impact, mental fatigue and depression, and reduced physical functioning and global health status (all P < 0.05). A greater number of cycles of chemotherapy increase the level of symptoms (pain, neuropathy, and dyspnoea; P < 0.05). The various aspects related to HRQoL should be discussed with DLBCL patients and investigated, with the aim of developing strategies to ensure appropriate psychosocial and supportive care and to improve the HRQoL in these patients. Supplementary Information The online version contains supplementary material available at 10.1007/s00277-021-04689-4.

International audience; 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.

International audience; 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.

Summary 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.

Dose-dense induction and up-front consolidation with autologous stem cell transplantation (ASCT) remain controversial issues when treating patients with high-risk diffuse large B-cell lymphoma. GELA designed a randomized phase 2 trial evaluating the efficacy of either rituximab, doxorubicin, cyclophosphamide, vindesine, bleomycin, prednisone (R-ACVBP) or rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone (R-CHOP14) induction and a positron emission tomography (PET)-driven ASCT or standard immunochemotherapy (SIC) consolidation in age-adjusted international prognosis index 2 (aaIPI2)-aaIPI3 patients. PET was performed at baseline, after 2 (PET2) and 4 (PET4) induction cycles, and centrally assessed using international harmonization project (IHP) criteria. PET2-/PET4- patients were assigned SIC, PET2+/PET4- patients were assigned ASCT, and PET4+ patients were treated with the investigator's choice. The primary end-point was the 2007 international working group complete response (CR) rate after induction. Change in maximum standard uptake value (ΔSUVmax) after PET assessment was explored. Two hundred eleven patients were randomly assigned to R-ACVBP (n = 109) or R-CHOP14 (n = 102). PET4-/CR rates were 53%/47% with R-ACVBP and 41%/39% with R-CHOP14 (CR 95% confidence interval [CI], 38%-67% and 28%-54%, respectively; P = .076). Consolidation in the R-ACVBP and R-CHOP14 groups was SIC in 26% and 23% of patients and ASCT in 28% and 18% of patients, respectively. PET4 positivity was higher with R-CHOP14 vs R-ACVBP (54% vs 41%; P = .08), leading to more salvage therapy (37% vs 26%; P = .07) and lower event-free survival (EFS; 4-year EFS, 31% vs 43%; P 70% was associated with better outcome (4-year PFS, 84% vs 35%; 4-year OS, 91% vs 57%; P < .0001), whatever the consolidation. Superiority of R-ACVBP over R-CHOP14 was not established, as IHP criteria did not properly reflect disease control. ΔSUVmax may help better select patients needing an alternative to SIC, including ASCT.

// Julien Broseus 1,2,* , Samia Mourah 3,4,5,* , Gerard Ramstein 6 , Sophie Bernard 7 , Nicolas Mounier 8 , Wendy Cuccuini 9 , Philippe Gaulard 10,11 , Christian Gisselbrecht 7,12 , Josette Briere 13 , Remi Houlgatte 1,14,** and Catherine Thieblemont 3,7 1 Inserm U954, Faculty of Medicine, University of Lorraine, Nancy, France 2 University Hospital of Nancy, Hematology Laboratory, Nancy, France 3 Paris Diderot University, Sorbonne Paris Cite, Paris, France 4 APHP, Saint Louis University Hospital, Pharmacology-Biologic Laboratory, Paris, France 5 Inserm UMRS 976, France 6 LS2N - DUKe, University of Nantes, Nantes, France 7 APHP, Saint-Louis University Hospital, Hemato-Oncology, Paris, France 8 University Hospital of L’archet, Nice, France 9 APHP, Saint-Louis University Hospital, Hematology Laboratory, Paris, France 10 Department of Pathology, APHP, Henri Mondor University Hospital, Creteil, France 11 Inserm U955, University Paris-Est, Creteil, France 12 Lymphoma Study Association, Pierre-Benite, France 13 Department of Pathology, APHP, Saint-Louis University Hospital, Paris, France 14 University Hospital of Nancy, DRCI, Nancy, France * Julien Broseus and Samia Mourah have contributed equally to this work ** Catherine Thieblemont and Remi Houlgatte have contributed equally to this work Correspondence to: Catherine Thieblemont, email: // Remi Houlgatte, email: // Keywords : ABC, like DLBCL, angiogenesis, immune response, cancer Received : June 12, 2017 Accepted : July 03, 2017 Published : July 19, 2017 Abstract 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 ( n = 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 VEGF 121 expression was associated with a significantly better survival than in those with high VEGF 121 level: 4-year overall survival at 100% vs 36% ( p = .011), respectively. A specific gene signature including 57 genes was correlated to VEGF 121 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 VEGF 121 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.

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.

Introduction Few studies on cancer incidence have been conducted since the EU 2000/76/EC Waste incineration directive. Objective To measure cancer incidence among the population exposed to atmospheric emissions from the Ariane waste incineration plant near Nice, in the Alpes-Maritimes (AM), compared to the unexposed AM population. Methods All primary invasive cancers and malignant haematological conditions diagnosed among AM residents from 01/01/2005 to 31/12/2014 recorded by the CRISAPPACA Cancer Observatory, public and private hospitals and the ONCOPACA-Corsica Network were included. The exposed area, based on an average dioxin deposition model, was that with a concentration ≥4.25ng/m2/year. Each case was geolocated and assigned to a predefined geographic unit (IRIS): 36 units in the exposed area, 462 in the unexposed area. The adjusted incidence rate, the standardized incidence ratio (SIR) and the Comparative Morbidity Figure (CMF) were calculated for two periods: 2005-2009/2010-2014. Results We recorded 80,865 new cancers in the AM population (1,083,974 residents; 87,462 exposed). For the 2005-2009 period, among exposed women, excess SIR were recorded of acute myeloid leukaemia (SIR = 1.81 [1.03-2.93]), myelodysplastic syndromes (SIR = 2.58 [1.70-3.76]) and myeloma (SIR = 1.64 [1.09-2.37]); in exposed men, of soft tissue sarcomas (SIR = 1.65 [1.05-2, 48]), myeloma (SIR = 2.04 [1.39-2.90]) and lung cancer (SIR = 1.19 [1.03-1.36]). For the 2010-2014 period, there was no excess SIR among women, while among men an excess SIR of myeloma (SIR = 1.76 [1.21-2.47]) and lung cancer (SIR = 1.24 [1.08-1.41]) was observed. Conclusions The higher incidence of myeloma and lung cancer in both periods can be explained by their long latency and by other risk factors. The EU Directive appears to have resulted in limiting atmospheric emissions from the incinerator. Study funded by the Nice Côte d’Azur Metropolis and with the support of the South-PACA Regional Health Agency. Key messages Few studies on cancer incidence have been conducted since the EU 2000/76/EC Waste incineration directive. The EU Directive appears to have resulted in limiting atmospheric emissions from the incinerator.

International audience; 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.

7543 Background: Central nervous system (CNS) relapse occurs in 2-6% of DLBCL patients (pts) increasing to 10% or more in high-risk groups. Intrathecal (IT) or intravenous high-dose methotrexate (HD MTX) have limited if any prophylactic impact on CNS relapse. To address the role of systemic first-line therapy in pts tolerating intensified strategies (R-ACVBP, R-(Mega)CHOEP, R-CHO(E)P), we compared CNS relapses occurring in a large cohort of pts ≤60 years. Methods: We conducted a retrospective analysis including previously untreated pts with DLBCL by central review, age 18-60 years, from multicenter clinical trials conducted by LYSA and GLA/DSHNHL (Table). We assessed the risk of CNS relapse in matched cohorts based on the aaIPI. Results: A total of 2203 pts were included. Median age was 47 years (18-60). 455 pts were treated with R-ACVBP, 444 with R-(Mega)CHOEP, 1304 with R-CHOP. Distribution of CNS IPI was not significantly different comparing R-ACVBP to R-CHO(E)P groups within aaIPI categories (Table). PFS and OS were comparable according to treatment within aaIPI groups, also adjusted for prognostic factors. No CNS events occured during observation time of 3 years in pts with aaIPI 0. In pts with aaIPI 1, no CNS event occured in the R-ACVPB arm, the 3y-cumulative incidence of CNS relapse for pts treated with R-CHO(E)P group was 1.0% (95%CI 0.3-1.7). In pts with aaIPI 2,3 and intermediate/high CNS IPI, four (1.6%) treated with R-ACVBP experienced relapse in the CNS compared to 15 (3.9%) pts treated with R-(Mega)CHO(E)P (3y-cumulative incidence 1.6% (95%CI 0-3.2) vs. 4.0% (95%CI 2.0-6.0). Conclusions: CNS relapse was extremely rare in younger DLBCL pts with aaIPI 0 or 1; prophylactic measures are not warranted. In pts with aaIPI 2,3 (and intermediate/high CNS-IPI), only 4 (1.6%) CNS relapses were seen with the R-ACVBP while 15 (3.9%) relapses did occur after R-(Mega)CHO(E)P. This analysis underlines the important role of the systemic therapy in controling CNS relapse.[Table: see text]

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.

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/m3 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/m2/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.

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.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.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.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).Whole blood and plasma EBV DNA loads do not constitute prognostic markers in HIV-cHL patients in the modern cART era.

International audience; Background: Increased-dose bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, and prednisone (BEACOPPescalated) 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 (BEACOPPescalated 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 (BEACOPPescalated given every 21 days for six cycles) or PET-driven treatment. All patients received two cycles of upfront BEACOPPescalated, after which PET assessment was done (PET2). In the standard treatment group, PET2 patients completed two additional cycles of BEACOPPescalated induction therapy irrespective of PET2 findings. In the PET-driven treatment group, patients with positive PET2 scans received the further two cycles of BEACOPPescalated 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 BEACOPPescalated). BEACOPPescalated consisted of bleomycin 10 mg/m2 and vincristine 1·4 mg/m2 intravenously on day 8, etoposide 200 mg/m2 intravenously on days 1-3, doxorubicin 35 mg/m2 and cyclophosphamide 1250 mg/m2 intravenously on day 1, 100 mg/m2 oral procarbazine on days 1-7, and 40 mg/m2 oral prednisone on days 1-14. ABVD was given every 28 days (doxorubicin 25 mg/m2, bleomycin 10 mg/m2, vinblastine 6 mg/m2, and dacarbazine 375 mg/m2 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 BEACOPPescalated 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 (

International audience; 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(low) 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(low) B cells and improve GAPDH(low) B cell-lymphoma-bearing mice survival, while they are low or not efficient on GAPDH(high) B cell lymphomas. Ultimately, we selected four GAPDH(low) 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.

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., SCOPUS: ar.j, info:eu-repo/semantics/published

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

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+/LAMP2Low patients at diagnosis or who become CD34+/LAMP2Low during the course of treatment with Aza might benefit from a lysosome inhibitor already used in the clinic.

Non-Hodgkin lymphoma (NHL) patients failing second-line regimens have three potential therapeutic avenues; a third-line regimen in the perspective of HDT/ASCT consolidation, a novel drug (if availa...

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.

Patients with the most common aggressive AIDS-related non-Hodgkin lymphomas can expect improved outcomes approaching those of immunocompetent patients in the contemporary era. When treated with appropriate antilymphoma therapy, these improvements apply to every subgroup of patients, including those with low CD4 counts and high-risk disease. Background We undertook the present analysis to examine the shifting influence of prognostic factors in HIV-positive patients diagnosed with aggressive non-Hodgkin lymphoma (NHL) over the last two decades. Patients and methods We carried out a pooled analysis from an existing database of patients with AIDS-related lymphoma. Individual patient data had been obtained prior from prospective phase II or III clinical trials carried out between 1990 until 2010 in North America and Europe that studied chemo(immuno)therapy in HIV-positive patients diagnosed with AIDS-related lymphomas. Studies had been identified by a systematic review. We analyzed patient-level data for 1546 patients with AIDS-related lymphomas using logistic regression and Cox proportional hazard models to identify the association of patient-, lymphoma-, and HIV-specific variables with the outcomes complete response (CR), progression-free survival, and overall survival (OS) in different eras: pre-cART (1989–1995), early cART (1996–2000), recent cART (2001–2004), and contemporary cART era (2005–2010). Results Outcomes for patients with AIDS-related diffuse large B-cell lymphoma and Burkitt lymphoma improved significantly over time, irrespective of baseline CD4 count or age-adjusted International Prognostic Index (IPI) risk category. Two-year OS was best in the contemporary era: 67% and 75% compared with 24% and 37% in the pre-cART era (P Conclusions Our results demonstrate a significant improvement of CR rate and survival for all patients with AIDS-related lymphomas. Effective HIV-directed therapies reduce the impact of HIV-related prognostic factors on outcomes and allow curative antilymphoma therapy for the majority of patients with aggressive NHL.

International audience; 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/mu l, 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. Copyright (C) 2017 Wolters Kluwer Health, Inc. All rights reserved.

Deregulated expression of glycolytic enzymes contributes not only to the increased energy demands of transformed cells but also has non-glycolytic roles in tumors. However, the contribution of these non-glycolytic functions in tumor progression remains poorly defined. Here, we show that elevated expression of glyceraldehyde-3-phosphate dehydrogenase (GAPDH), but not of other glycolytic enzymes tested, increased aggressiveness and vascularization of non-Hodgkin's lymphoma. Elevated GAPDH expression was found to promote nuclear factor-κB (NF-κB) activation via binding to tumor necrosis factor receptor-associated factor-2 (TRAF2), enhancing the transcription and the activity of hypoxia-inducing factor-1α (HIF-1α). Consistent with this, inactive mutants of GAPDH failed to bind TRAF2, enhance HIF-1 activity or promote lymphomagenesis. Furthermore, elevated expression of gapdh mRNA in biopsies from diffuse large B-cell non-Hodgkin's lymphoma patients correlated with high levels of hif-1α, vegf-a, nfkbia mRNA and CD31 staining. Collectively, these data indicate that deregulated GAPDH expression promotes NF-κB-dependent induction of HIF-1α and has a key role in lymphoma vascularization and aggressiveness.

Resume L’infection par le VIH est associee a une augmentation du risque de cancer, qu’il soit classant sida (maladie de Kaposi, lymphomes non hodgkinien, cancer du col uterin) ou non-classant sida. Si l’avenement des traitements antiretroviraux hautement actifs a diminue l’incidence des lymphomes non hodgkinien et de la maladie de Kaposi, les cancers non classants, tels que le cancer broncho-pulmonaire, l’hepatocarcinome, le cancer du canal anal ou bien les cancers cutanes, restent une cause importante de morbidite et de mortalite dans la population infectee par le VIH. La presentation clinique est souvent differente de celle de la population non infectee par le VIH, avec parfois un diagnostic plus tardif, une pathologie plus agressive et des comorbidites associees telles que l’immunodepression, responsables d’un pronostic souvent plus pejoratif. De nombreuses etudes se sont interessees au traitement de ces neoplasies associees a l’infection VIH, mais il n’existe pas encore a l’heure actuelle de recommandations precises sur le plan therapeutique. Une attention toute particuliere est a porter sur les interactions entre les traitements antiretroviraux et la chimiotherapie notamment via le cytochrome P 450. A ce titre, un reseau de soins appartenant au groupe des «cancers rares» dont le cœur de l’organisation repose sur une reunion de concertation pluridisciplinaire nationale (CANCERVIH) a ete mis en place en 2013grâce a l’Institut national du cancer (INCa). L’objectif de cette revue est de presenter une actualite scientifique concernant certains cancers associes a l’infection par le VIH, dans leurs aspects cliniques et dans la specificite de leur prise en charge therapeutique.

// Thomas Cluzeau 1,2,3,4,6,* , Alix Dubois 1,2,3,4,* , Arnaud Jacquel 1,2,3,4 , Frederic Luciano 1,2,3,4 , Aline Renneville 5 , Claude Preudhomme 5 , Jean Michel Karsenti 6 , Nicolas Mounier 6 , Pierre Rohrlich 6 , Sophie Raynaud 7 , Bernard Mari 8 , Guillaume Robert 1,2,3,4 and Patrick Auberger 1,2,3,4,6 1 INSERM U1065, Mediterranean Center for Molecular Medicine (C3M), Nice, France 2 INSERM U1065, Team 2: Cell Death, Differentiation, Inflammation and Cancer 3 Equipe labellisee par la Ligue Nationale Contre le Cancer (2011-2013), Paris, France 4 University of Nice, Nice, France 5 Laboratory of Hematology, Biology and Pathology Center, CHRU of Lille, Lille, France 6 Department of Clinical hematology and Transplantation, CHU of Nice, Nice, France 7 Oncohematology laboratory, CHU of Nice, Nice, France 8 Molecular and Cellular Pharmacology Institute, CNRS, Sophia-Antipolis, France * These authors participated equally to this work Correspondence: Patrick Auberger, email: // Keywords : MDS, AML, Azacitidine, Polyploidy, TET2, ASLX1 Received : May 5, 2014 Accepted : May 26, 2014 Published : May 27, 2014 Abstract In the present study, we provide a comparative phenotypic and genotypic analysis of azacitidine-sensitive and resistant SKM-1 cell lines. Morphologically, SKM1-R exhibited increase in cell size that accounts for by enhanced ploidy in a majority of cells as shown by cell cycle and karyotype analysis. No specific Single Nucleotide Polymorphism (SNP) alteration was found in SKM1-R cells compared to their SKM1-S counterpart. Comparative pangenomic profiling revealed the up-regulation of a panel of genes involved in cellular movement, cell death and survival and down-regulation of genes required for cell to cell signaling and free radical scavenging in SKM1-R cells. We also searched for mutations frequently associated with myelodysplastic syndromes (MDS) and found that both cell lines harbored mutations in TET2, ASLX1 and TP53. Collectively, our data show that despite their different morphological and phenotypic features, SKM1-S and SKM1-R cells exhibited similar genotypic characteristics. Finally, pangenomic profiling identifies new potential pathways to be targeted to circumvent AZA-resistance. In conclusion, SKM1-R cells represent a valuable tool for the validation of new therapeutic intervention in MDS.

Les tumeurs primitives mediastinales representent un ensemble heterogene d’etiologies neoplasiques ou benignes. Le processus diagnostique favorise est l’approche « topographique » ou une masse est caracterisee par ses aspects iconographiques et en fonction du compartiment dans lequel elle se trouve. La prise en charge necessite une approche rigoureuse et multidisciplinaire conciliant les differentes techniques d’imagerie avec les donnees biologiques, et parfois meme des methodes chirurgicales. L’utilisation de l’imagerie nucleaire permet de preciser certaines etiologies ou d’en realiser le bilan d’extension.

Introduction: There is no standard treatment of refractory or relapsed (R/R) patients (pts) with DLBCL ineligible for autologous stem-cell transplantation (ASCT). However, R-GemOx is widely used in these circumstances. We here report the results of a retrospective analysis of a cohort of patient treated in two academic centers in France. The main objectives were to evaluate the activity and safety profile of this regimen in a large series of R/R DLBCL pts in a real life setting. Methods: Patients selected had to have de novo or transformed DLBCL, R/R after at least one line of treatment containing doxorubicin and rituximab, to be ineligible for ASCT and to have received at least one cycle of R-GEMOX. Rituximab 375 mg/m2 was administered on D1, gemcitabine 1000 mg/m2 on D2 and oxaliplatin 100 mg/m2 on D2 as previously described (Mounier N. et al. Haematologica 2013; 98:1726-31). Cycles were given every 2 weeks and 8 cycles were planned if at least a partial response (PR) was obtained after 4 cycles. Results: Between May 2002 and May 2017, 196 pts were treated. Baseline characteristics were: median age: 72 y (range, 24-89), international prognostic index (IPI) 3-5: 63%, refractory state to last treatment (tx): 42%, history of indolent lymphoma: 45%, prior ASCT: 16%. The median number of previous line was 1 (range 1-7) with 112 pts having received R-GemOx in second line. One hundred and thirty-six pts received at least 4 cycles, 86 pts completed 6 cycles and 61 pts 8 cycles. After 4 cycles, the overall response rate (ORR) according to IWC (Cheson 1999 or 2007) was 54 % and the complete response (CR) rate was 23 %. At the end of treatment, the ORR and CR rates were 38 % and 33 %, respectively. With a median follow-up of 22 months, median (m) progression-free survival (PFS) and overall survival (OS) were 5 and 10 months (mo), respectively. mOS was significantly longer in case of prior history of indolent lymphoma (21 vs 8 mo, p < 0.001), age Summary/Conclusion: This real life study of R/R DLBCL, confirms the activity and safety of R-GemOx. This combination represents a platform to be combined with targeted therapies as it is currently proposed with nivolumab in the phase 3 NIVEAU trial (NCT03366272) and planned with polatuzumab vedotin (POLARGO trial). However, facing this very high unmet medical need, new approaches including CAR T-cells should also be considered in this patient population. Disclosures Belhadj: Janssen: Honoraria; Celgene: Honoraria, Other: personal fees from Celgene, personal fees from Amgen, personal fees from Takeda, personal fees from Janssen, outside the submitted work; Takeda: Honoraria; Amgen: Honoraria. Le Bras:Pfizer: Other: Travel grant; Takeda: Research Funding; Jansen: Other: Travel grant. Jardin:amgen: Honoraria; Servier: Honoraria; celgene: Honoraria; roche: Honoraria; janssen: Honoraria. Tilly:Roche: Consultancy; Celgene: Consultancy, Research Funding; Astra-Zeneca: Consultancy; Karyopharm: Consultancy; BMS: Honoraria; Janssen: Honoraria; Gilead: Honoraria; merck: Honoraria; servier: Honoraria; roche: Membership on an entity's Board of Directors or advisory committees. Haioun:F. Hoffmann-La Roche Ltd: Honoraria; Novartis: Honoraria; Janssen: Honoraria; Gilead: Honoraria; Amgen: Honoraria; Celgene: Honoraria; Servier: Honoraria; Miltenyi: Honoraria; Takeda: Honoraria.

Introduction: Patients (pts) with HIV have a 6-fold increased risk of developing classic Hodgkin lymphoma (cHL) over the general population. The outcome of frontline therapy for HIV-associated cHL (HIV-cHL) using doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD) is similar to the non-HIV population. However, pts with advanced stage cHL continue to have a 30% chance of refractory/relapsed disease with ABVD. Brentuximab vedotin (BV) is an anti-CD30 antibody drug conjugate that selectively induces apoptosis of CD30+ cells. The FDA approved BV with AVD (BV-AVD) after the Echelon-1 (E1) study for advanced stage disease demonstrated improved modified progression free survival (mPFS) at 2 years compared with standard ABVD: 82% vs. 77%. Pts with HIV were excluded from both relapsed/refractory and frontline BV trials. Here we present the final results of the phase 2 trial of BV-AVD in previously untreated HIV-associated cHL, an AIDS Malignancy Consortium/LYSA collaboration (ClinicalTrials.gov ID: NCT01771107). Methods: Forty-one pts were treated on days 1 and 15 of 6, 28 day cycles, with 1.2mgs/kg of BV in combination with doxorubicin 25 mg/m2, vinblastine 6 mg/m2, and dacarbazine 375 mg/m2 (AVD). Eligibility criteria included untreated cHL stage II-IV, CD4 + T-cell counts ≥50 cells/mm3, and initiation of combined antiretroviral therapy (cART) at least 1 week prior to therapy. Ritonavir, zidovidine, cobisistat, and other strong CYP3A4 or P-glycoprotein inhibitors were excluded with a washout of at least 1 week being required. Hematopoietic growth factor was mandated. The primary objective was 2 year PFS. The sample size was based on providing an estimate of the PFS with a 95% CI +/- 10% under the assumption of a 2 year progression free survival (PFS) estimate of 85%. Secondary objectives included toxicity, effects on CD4/CD8 + T-cells, HIV-1 viral load, prognostic significance of post C2 and end of treatment PET-CT. Results: Forty-one pts (93% men) were treated with a median age of 48y (range 24-67). Pts presented with stage II (17%), III (27%), and IV (56%) disease. Two year PFS estimate in the overall population (N=41) was 86% (95% CI: .74, .98). The 2-year overall survival (OS) estimate was 92% (95% CI: 0.83, 1.0) with 3 deaths at the time of analysis, including 1 which was a treatment related death (Figure 1A). For pts with advanced disease (N=34), the 2-year PFS estimate was 87% (95% CI: 0.76, 0.99) with an OS estimate of 90% (95% CI: 0.8, 1.00) (Figure 1B). Safety profiles were quite similar to the BV-AVD arm in the E1 study of the pts who received growth factor. Neuropathy was higher in our study compared to E1, (49% vs. 29% for any grade, P=0.01; 9.8% vs. 5% for G3/4, p=0.06). G3 Neutropenia was greater in AMC 085 compared to E1 BV-AVD arm with growth factor: 57% vs. 29% (p Conclusions: BV-AVD in stage II-IV HIV-cHL was efficacious although neutropenia and neuropathy were increased compared to the non-HIV population. The 2-year PFS estimate was 86% for the entire cohort and 87% for advanced stage HIV-cHL. Major interactions with strong CYP3A4 inhibitors lead to toxicity and must be avoided. The etiology of the CD4 increase is under investigation and may have implications for future therapy. Disclosures Rudek: Cullinan Apollo: Research Funding; Taiho: Research Funding; RenovoRX: Research Funding; Celgene: Research Funding. Barta:Mundipharma: Honoraria; Celgene: Research Funding; Janssen: Membership on an entity's Board of Directors or advisory committees; Takeda: Research Funding; Seattle Genetics: Honoraria, Research Funding; Bayer: Consultancy, Research Funding; Mundipharma: Honoraria; Merck: Research Funding; Celgene: Research Funding; Janssen: Membership on an entity's Board of Directors or advisory committees. Noy:Medscape: Honoraria; Janssen: Consultancy; Prime Oncology: Honoraria; NIH: Research Funding; Pharamcyclics: Research Funding; Raphael Pharma: Research Funding. OffLabel Disclosure: Brentuximab Vedotin has been approved for the upfront treatment of advanced stage cHL in combination with AVD though not specifically approved for use in patients infected with HIV or stage 2 cHL.

In diffuse large B-cell lymphoma (DLBCL), the age-adjusted International Prognostic Index (aaIPI) score is currently used to predict patient outcomes and to choose the best therapeutic treatment. Body mass index (BMI) and gender are occasionally sited as prognostic factors; however, their value has never been studied in a large series of patients included in prospective clinical trials in the rituximab era. To assess the impact of BMI and gender on OS and PFS independently of the aaIPI score, we pooled 985 patients that were prospectively included in GELA studies and uniformly treated with R-CHOP. Univariate analysis indicated that high aaIPI and male gender were associated with a worse PFS, whereas high (>25) or low (

Limited comparative data exist for the treatment of HIV-associated non-Hodgkin lymphoma. We analyzed pooled individual patient data for 1546 patients from 19 prospective clinical trials to assess treatment-specific factors (type of chemotherapy, rituximab, and concurrent combination antiretroviral [cART] use) and their influence on the outcomes complete response (CR), progression free survival (PFS), and overall survival (OS). In our analysis, rituximab was associated with a higher CR rate (odds ratio [OR] 2.89; P < .001), improved PFS (hazard ratio [HR] 0.50; P < .001), and OS (HR 0.51; P < .0001). Compared with cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP), initial therapy with more dose-intense regimens resulted in better CR rates (ACVBP [doxorubicin, cyclophosphamide, vindesine, bleomycin and prednisolone]: OR 1.70; P < .04), PFS (ACVBP: HR 0.72; P = .049; "intensive regimens": HR 0.35; P < .001) and OS ("intensive regimens": HR 0.54; P < .001). Infusional etoposide, prednisone, infusional vincristine, infusional doxorubicin, and cyclophosphamide (EPOCH) was associated with significantly better OS in diffuse large B-cell lymphoma (HR 0.33; P = .03). Concurrent use of cART was associated with improved CR rates (OR 1.89; P = .005) and trended toward improved OS (HR 0.78; P = .07). These findings provide supporting evidence for current patterns of care where definitive evidence is unavailable.

Current advances in the biology of cancer and emergence of new tools for genome analysis have opened clinical perspectives in oncology, generally termed as ‘personalized medicine’. This broad term must encompass previous well-proven strategies, such as pharmacogenetics- and pharmacokinetics-based dosing, with more recently introduced pharmacogenomics approaches, all applied as a means to tailor treatment to a given patient presenting with a given tumor. Despite outstanding results in lung cancer, colorectal cancer and melanoma, only a few predictive biomarkers are currently justified in routine clinical practice. Overall, there is a persistent gap between the growing number of identified deregulated pathways or genetic mutations, both at the tumor and the constitutional levels, and their actual implementation at the bedside as part of clinical routine. This article underlines these limitations and covers several issues that may explain the discrepancy between the plethora of published data about emerging biomarkers, and the relative scarcity of tests eventually reaching a clinically validated application. The main identified difficulties concern invasive and costly prospective biomarker studies and the issue of tumor heterogeneity. Finally, early trial designs for targeted therapies as well as those for conventional cytotoxics may not necessarily address the right questions by skipping critical end points. Proposed solutions point out the use of liquid biopsies and systems biology approaches, for an easier implementation of personalized medicine at the bedside.

How Relevant Is Treatment-Related Infertility for Individual Treatment Selection in Hodgkin Lymphoma? : Reply

First-line escalated BEACOPP does not hinder stem cell collection and transplantation strategy in patients with relapsed/refractory Hodgkin's lymphoma