Brentuximab vedotin with AVD for stage II-IV HIV-related Hodgkin lymphoma (AMC 085): phase 2 results from an open-label, single arm, multicentre phase 1/2 trial.

BACKGROUND: Brentuximab vedotin in combination with doxorubicin, vinblastine, and dacarbazine (AVD) is approved in the upfront setting for advanced stage classical Hodgkin lymphoma (cHL). People living with HIV have been excluded from these studies. We aimed to understand the activity and safety of brentuximab vedotin-AVD in people living with HIV diagnosed with Hodgkin lymphoma, while focusing on HIV disease parameters and antiretroviral therapy (ART) interactions. METHODS: We present the phase 2 portion of a multicentre phase 1/2 study. Eligible patients were 18 years or older, had untreated stage II-IV HIV-associated cHL (HIV-cHL), a Karnofsky performance status of more than 30%, a CD4+ T-cell count of 50 cells per µL or more, were required to take ART, and were not on strong CYP3A4 or P-glycoprotein inhibitors. Patients were treated intravenously with 1·2 mg/kg of brentuximab vedotin (recommended phase 2 dose) with standard doses of AVD for six cycles on days 1 and 15 of a 28-day cycle. The primary endpoint of the phase 2 portion was 2-year progression-free survival (PFS), assessed in all eligible participants who began treatment. Accrual has been completed. This trial is registered at ClinicalTrials.gov, NCT01771107. FINDINGS: Between March 8, 2013, and March 7, 2019, 41 patients received study therapy with a median follow up of 29 months (IQR 16-38). 34 (83%) of 41 patients presented with stage III-IV and seven (17%) with stage II unfavourable HIV-cHL. 37 (90%) of 41 patients completed therapy, all 37 of whom achieved complete response. The 2-year PFS was 87% (95% CI 71-94) and the overall survival was 92% (78-97). The most common grade 3 or worse adverse events were peripheral sensory neuropathy (four [10%] of 41 patients), neutropenia (18 [44%]), and febrile neutropenia (five [12%]). One treatment-related death was reported, due to infection. INTERPRETATION: Brentuximab vedotin-AVD was highly active and had a tolerable adverse event rate in HIV-cHL and is an important therapeutic option for people with HIV-cHL. The complete reponse rate is encouraging and is possibly related to a unique aspect of HIV-cHL biology. Upcoming 5-year data will evaluate the sustainability of the outcomes obtained. FUNDING: National Institutes of Health and National Cancer Institute.

Central nervous system relapse in younger patients with diffuse large B-cell lymphoma: a LYSA and GLA/DSHNHL analysis.

Most patients with diffuse large B-cell lymphoma (DLBCL) can be cured with immunochemotherapy such as R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone). Patients with progression or relapse in the central nervous system (CNS) face dismal outcomes. The impact of more aggressive regimens used in frontline therapy has not been systematically investigated in this context. To this end, we analyzed a large cohort of 2203 younger patients with DLBCL treated on 10 German (German Lymphoma Alliance [GLA]/The German High Grade Non-Hodgkin's Lymphoma Study Group [DSHNHL]) and French (The Lymphoma Study Association [LYSA]) prospective phase 2 and 3 trials after first-line therapy with R-CHOP, R-CHOEP (R-CHOP + etoposide), dose-escalated R-CHOEP followed by repetitive stem cell transplantation (R-MegaCHOEP), or R-ACVBP (rituximab, doxorubicin, cyclophosphamide, vindesine, bleomycine, and prednisone) followed by consolidation including multiple drugs crossing the blood-brain barrier (BBB). Patients with DLBCL with an age-adjusted International Prognostic Index (aaIPI) of 0 to 1 showed very low cumulative incidence rates of CNS relapse regardless of first-line therapy and CNS prophylaxis (3-year cumulative incidences 0%-1%). Younger high-risk patients with aaIPI of 2 to 3 had 3-year cumulative incidence 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 = .118). Thus, for younger high-risk patients, frontline regimens incorporating agents crossing the BBB may reduce often fatal CNS relapse.

Economic burden in non-Hodgkin lymphoma survivors: The French Lymphoma Study Association SIMONAL cross-sectional study.

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.

Quality of life of survivors 1 year after the diagnosis of diffuse large B-cell lymphoma: a LYSA study.

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.

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.

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.

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

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.

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

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 (HRABVD vs BEACOPP  = 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.

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

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

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

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.

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

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.

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

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.

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.

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.

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

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.

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

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.

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

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 (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. RESULTS: DM patients presented with proximal and symmetrical muscle uptake. Differences in SUVPROX/SUVLIV and SUVMLT/SUVLIV ratios in DM subjects were significant (p < 0.001). SUVPROX/SUVMLT ratios in DM and their controls also differed significantly (p = 0.0012). The SUVPROX/SUVMLT 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 SUVPROX/SUVMLT 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 (SUVPROX) to SUV in musculus longissimus thoracis (SUVMLT) could be used to determine active DM. • Active disease is suspected for SUV PROX /SUV MLT ratios greater than 1.73.

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

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.

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

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.

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

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 GAPDHlow 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 GAPDHlow B cells and improve GAPDHlow B cell-lymphoma-bearing mice survival, while they are low or not efficient on GAPDHhigh B cell lymphomas. Ultimately, we selected four GAPDHlow 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.