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Introduction: Older classical Hodgkin lymphoma (cHL) patients are characterized by a significant reduced survival as compared to younger patients. In relapsed and refractory HL, prospective and retrospective studies showed that bendamustine monotherapy provided interesting efficacy with 30% of complete response with an acceptable toxicity profile. We developed the PVAB (Prednisone, Vinblastine, Doxorubicin, Bendamustine) regimen in first line therapy to improve prognosis of older HL with advanced stage. Methods: In this prospective phase II, we recruited newly diagnosed classical HL patients age of 61 years or older with an advanced stage (Ann Arbor stage III, IV, IIB with risk factors). Inclusion criteria were: ECOG performance status 0-2; adequate cardio-pulmonary function with LVEF ≥ 50%; adequate renal function with creatinine clearance ≥ 40 mL/min; HIV negative; For patients aged 70 years old and more, a Mini Nutritional Assessment (MNA) ≥ 17. Treatment consisted of 6 cycles of prednisone (40mg/m 2 D1-5), vinblastine (6mg/m 2, D1), doxorubicin (40mg/m 2, D1) and bendamustine (120mg/m 2, D1) every 21 days. The primary endpoint was the complete metabolic response (CMR) rate according to local review after 6 cycles of study treatment or at premature treatment discontinuation according to Lugano Classification. We presented the final analysis of the study with a median follow-up of 42 months (range, 0.5-63.8), with prognostic analyses for progression free survival (PFS) measured from the date of inclusion to the date of progression, relapse or death from any cause. Prognostic factors included baseline clinical and biological characteristics, geriatric assessments and 18F-FDG PET/CT metabolic parameters especially baseline total metabolic tumor volume (TMTV). Optimal thresholds for some parameters were calculated using X-Tile approach. Results: Between July 2015 and July 2018, 89 patients were included in 34 LYSA centers. The median age was 68 years (range, 61-88) with 35 patients ≥70 years old (39%). The main histological subtype was nodular sclerosis cHL (n=56, 63%) with 26 EBV associated cases (LMP1 staining). Ann Arbor stages were as follows: II (n=3, 3%), III (n=30, 34%), IV (n=56, 63%). B symptoms were present in 57% of patients; 70 patients (80%) had IPS≥3. The median of CIRS-G score was 3 (range, 0-12). Seventy-eight patients (88%) completed the 6 cycles of PVAB. Update results for toxicity showed that 28 patients (32%) presented at least one serious adverse event (SAE) in particular infections (n=13, 15%), blood (n=11, 12%) and cardiac disorders (n=4, 4.5%). The CMR rate according to local review corresponding to the primary endpoint of the study was 77.5% (95%CI, 67-86) with 69 patients in CMR. After central review of 79 available PET/CT images, the CMR rate was 78.5%. Thirty-one patients relapsed or progressed (35%). The 4-year PFS rate was 50% (95%CI, 39-61). For the 69 patients achieving CMR, the 4-year disease free survival (DFS) rate was 62.8% (95%CI, 49-74). Twenty-four patients (27%) died: 11 cHL (46%), 4 treatment toxicity (17%), 6 second cancers (25%), 3 other causes after treatment (infection, cardiac insufficiency, pulmonary embolism, 12%). The 4-year overall survival rate was 69% (95%CI, 57-79). In univariate analysis, altered ECOG PS, Ann Arbor stage IV, bulky disease (>7cm), B-symptoms, extra-nodal involvement (>1), bone or medullar involvement, liver involvement, albumin (≤30g/l), hemoglobin level (88mg/l), TMTV (>450ml) and number of medications non-related to HL (>5) were associated with PFS. In multivariate analysis, liver involvement (HR: 3.79; 95%CI,1.71-8.43; P=0.001), lymphopenia (HR: 3.04; 95%CI,1.54-6.01; P=0.001), CRP (HR: 3.37; 95%CI, 1.69-6.69; P=0.0005) and co-medications (HR: 2.85; 95%CI,1.44-5.66; P=0.003) were independently associated with PFS. Conclusions: PVAB regimen provided high CMR (77.5%) with acceptable toxicity for advanced stage cHL patient over 60 years. The 4-year PFS and OS rates were 50% and 69% respectively, these survival endpoints were influenced by not related-lymphoma events. Prognostic analyses showed that specific involved site (liver), biological parameters (lymphocyte count and CRP) and patient's comorbidity (co-medications) influenced independently PFS. Disclosures Ghesquieres: Celgene: Consultancy, Honoraria, Other: Travel, accommodation, expenses; Roche: Consultancy, Honoraria, Other: Travel, accommodation, expenses; Gilead Sciences: Consultancy, Honoraria, Other: Travel, accommodation, expenses; Mundipharma Research Limited: Consultancy, Honoraria; Takeda: Other: Travel, accommodation, expenses. Casasnovas: Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Gilead Kite: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; MSD: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; BMS: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; Abbvie: Consultancy, Honoraria. Jaccard: Janssen: Membership on an entity's Board of Directors or advisory committees; Pfizer: Honoraria; Abbvie: Honoraria. Laribi: Jansen: Research Funding; Novartis: Other: Personal Fees, Research Funding; Takeda: Other: Personal Fees, Research Funding; AbbVie: Other: Personal Fees, Research Funding; IQONE: Other: Personal Fees; Astellas Phama, Inc.: Other: Personal Fees; BeiGene: Other: Personal Fees; AstraZeneca: Other: Personal Fees; Le Mans Hospital: Research Funding. Morschhauser: BMS: Consultancy, Membership on an entity's Board of Directors or advisory committees; Servier: Consultancy; Incyte: Membership on an entity's Board of Directors or advisory committees; Chugai: Honoraria; Epizyme: Consultancy, Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; F. Hoffmann-La Roche Ltd: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Genentech, Inc.: Consultancy; Genmab: Membership on an entity's Board of Directors or advisory committees; AbbVie: Consultancy, Membership on an entity's Board of Directors or advisory committees; AstraZenenca: Membership on an entity's Board of Directors or advisory committees; Roche: Consultancy, Speakers Bureau; Janssen: Honoraria; Gilead: Consultancy, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees. Brice: Takeda: Consultancy, Honoraria, Research Funding; BMS: Honoraria; MSD: Honoraria. OffLabel Disclosure: Bendamustine is off-label drug use in Hodgkin lymphoma

Background: Immunochemotherapy induction followed by rituximab maintenance is the standard of care in previously untreated symptomatic follicular lymphoma (FL). The phase 3 RELEVANCE study of chemotherapy-free combination immunotherapy with lenalidomide and rituximab (R 2) showed promising activity comparable to standard rituximab + chemotherapy (R-chemo) options (Morschhauser, F and Fowler, NH, et al. N Engl J Med. 2018). Reported here are the results of the second interim analysis. Methods: RELEVANCE is a global, randomized, phase 3 trial (NCT01650701) of R 2 vs R-chemo followed by rituximab in patients with previously untreated grade 1-3a FL requiring therapy according to GELF criteria. Lenalidomide dose was 20 mg/d, d2-22/28 for 6-12 cycles (c), continued in responders at 10 mg/d for a total of 18 c. Rituximab dose was 375 mg/m 2 weekly c1 and d1 c2-6 and continued in responders for 12 additional c (q8wk). R-chemo was given per investigator's choice of standard R + cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP), R + bendamustine (R-B), or R-CVP, followed by 12 c of rituximab (q8wk). Co-primary endpoints were complete response (CR)/CR unconfirmed (CRu) at 120 wk and progression-free survival (PFS) by independent review committee (IRC) based on 1999 IWG criteria. The prespecified second interim analysis was done after 75% of total PFS events were reached. Results: 1030 patients with high tumor burden were randomized to R 2 (n = 513) and R-chemo (n = 517; 72% R-CHOP, 23% R-B, 5% R-CVP); baseline characteristics were similar in both groups. As of October 30, 2020, at median follow-up of 72 mo, 6-year PFS, according to IRC assessment using FDA censoring rules, was 60% for R 2 and 59% for R-chemo with a hazard ratio (HR) of 1.03 (95% CI, 0.84-1.27). Data according to investigator assessment and EMA censoring rules are shown in the table. Median PFS was not reached for both groups. CR/CRu rates at 120 wk by IRC was 48% for R 2 and 53% for R-chemo (P = 0.10). Secondary endpoints, including overall survival, event free survival, and time to next antilymphoma treatment, were also similar in both groups. 162 (32%) R 2 and 166 (32%) R-chemo patients experienced progression/relapse according to investigator assessment of which 107 and 99 patients received additional treatment(s), respectively. Histological transformation was documented in 13/513 patients the R 2 group and 11/517 patients in the R-chemo group over the 72 mo follow-up period. ORR and overall survival after subsequent treatment(s) for relapse/progression were similar in both groups. The overall safety profile in both groups was consistent with the 1st interim analysis. The number of patients with second primary malignancies (SPMs) were similar between both groups, occurring in 57 (11%) R 2-treated and 67 (13%) R-chemo-treated safety population patients. The total number of SPMs was 64 in the R 2 group and 87 in the R-chemo group, with invasive SPM accounting for 43 (67%) and 52 (60%), respectively. Grade 5 adverse events were reported in 9 (2%) R 2 and 6 (1%) R-chemo treated patients. Conclusions: R 2 continues to demonstrate comparable efficacy vs R-chemo in patients with previously untreated grade 1-3a FL requiring therapy with similar 6-year PFS (60% and 59%) and 6-year OS (89% in both groups). Also, response and overall survival after subsequent treatment were similar in both groups. The overall safety profile of both groups was consistent with the previous analysis, with no new safety signals detected. R 2 provides a chemo-free alternative to R-chemo based on immunotherapy/immunomodulation. Figure 1 Figure 1. Disclosures Morschhauser: Chugai: Honoraria; Gilead: Consultancy, Membership on an entity's Board of Directors or advisory committees; AstraZenenca: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; Genmab: Membership on an entity's Board of Directors or advisory committees; Incyte: Membership on an entity's Board of Directors or advisory committees; Servier: Consultancy; Genentech, Inc.: Consultancy; AbbVie: Consultancy, Membership on an entity's Board of Directors or advisory committees; BMS: Consultancy, Membership on an entity's Board of Directors or advisory committees; Roche: Consultancy, Speakers Bureau; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees; F. Hoffmann-La Roche Ltd: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria; Epizyme: Consultancy, Membership on an entity's Board of Directors or advisory committees. Nastoupil: Bayer: Honoraria; Denovo Pharma: Other: DSMC; Gilead/Kite: Honoraria, Research Funding; Janssen: Honoraria, Research Funding; TG Therapeutics: Honoraria, Research Funding; MorphoSys: Honoraria; Caribou Biosciences: Research Funding; Genentech: Honoraria, Research Funding; ADC Therapeutics: Honoraria; Pfizer: Honoraria, Research Funding; Novartis: Honoraria, Research Funding; IGM Biosciences: Research Funding; Takeda: Honoraria, Other: DSMC, Research Funding; Epizyme: Honoraria, Research Funding; Bristol Myers Squibb/Celgene: Honoraria, Research Funding. Feugier: Gilead: Consultancy, Honoraria; Abbvie: Consultancy, Honoraria; Amgen: Honoraria; Astrazeneca: Consultancy, Honoraria; Janssen: Consultancy, Honoraria. Palomba: Wolters Kluwer: Patents & Royalties; Lygenesis: Honoraria; Pluto: Honoraria; Ceramedix: Honoraria; Priothera: Honoraria; Nektar: Honoraria; Novartis: Consultancy; Seres: Honoraria, Other: Stock, Patents & Royalties, Research Funding; Rheos: Honoraria; Magenta: Honoraria; Juno: Patents & Royalties; BeiGene: Consultancy; Kite: Consultancy; WindMIL: Honoraria; Notch: Honoraria, Other: Stock; PCYC: Consultancy. Bachy: Kite, a Gilead Company: Honoraria; Novartis: Honoraria; Daiishi: Research Funding; Roche: Consultancy; Takeda: Consultancy; Incyte: Consultancy. Libby: Genentech: Research Funding; Janssen: Consultancy, Research Funding; BMS: Research Funding; GSK: Research Funding. Casasnovas: Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Gilead Kite: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; MSD: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; BMS: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; Abbvie: Consultancy, Honoraria. Flinn: Infinity Pharmaceuticals: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Curis: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Karyopharm Therapeutics: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Pfizer: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Novartis: Consultancy, Other: All consultancy and research funding payments made to Sarah Cannon Research Institute, Research Funding; Genentech: Consultancy, Other: All consultancy and research funding payments made to Sarah Cannon Research Institute, Research Funding; TG Therapeutics: Consultancy, Other: All consultancy and research funding payments made to Sarah Cannon Research Institute, Research Funding; Loxo: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; BeiGene: Consultancy, Other: All consultancy and research funding payments made to Sarah Cannon Research Institute, Research Funding; Agios: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Great Point Partners: Consultancy, Other: All consultancy payments made to Sarah Cannon Research Institute; Yingli Pharmaceuticals: Consultancy, Other: All consultancy payments made to Sarah Cannon Research Institute; Nurix Therapeutics: Consultancy, Other: All consultancy payments made to Sarah Cannon Research Institute; Kite, a Gilead Company: Consultancy, Other: All consultancy and research funding payments made to Sarah Cannon Research Institute, Research Funding; Janssen: Consultancy, Other: All consultancy and research funding payments made to Sarah Cannon Research Institute, Research Funding; Roche: Consultancy, Other: All consultancy and research funding payments made to Sarah Cannon Research Institute, Research Funding; ArQule: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Celgene: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Iksuda Therapeutics: Consultancy, Other: All consultancy payments made to Sarah Cannon Research Institute; Seagen: Consultancy, Other: All consultancy and research funding payments made to Sarah Cannon Research Institute, Research Funding; Forma Therapeutics: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Rhizen Pharmaceuticals: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Takeda: Consultancy, Other: All consultancy and research funding payments made to Sarah Cannon Research Institute, Research Funding; Constellation Pharmaceuticals: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Gilead Sciences: Consultancy, Other: All consultancy and research funding payments made to Sarah Cannon Research Institute, Research Funding; Pharmacyclics LLC, an AbbVie Company: Consultancy, Other: All consultancy and research funding payments made to Sarah Cannon Research Institute, Research Funding; IGM Biosciences: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Incyte: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Forty Seven: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Portola Pharmaceuticals: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Verastem: Consultancy, Other: All consultancy and research funding payments made to Sarah Cannon Research Institute, Research Funding; Unum Therapeutics: Consultancy, Other: All consultancy and research funding payments made to Sarah Cannon Research Institute, Research Funding; Acerta Pharma: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; AbbVie: Consultancy, Other: All Consultancy and Research Funding payments made to Sarah Cannon Research Institute, Research Funding; MorphoSys: Consultancy, Other: All consultancy and research funding payments made to Sarah Cannon Research Institute, Research Funding; AstraZeneca: Consultancy, Other: All consultancy and research funding payments made to Sarah Cannon Research Institute, Research Funding; Juno Therapeutics: Consultancy, Other: All consultancy and research funding payments made to Sarah Cannon Research Institute, Research Funding; Calithera Biosciences: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Merck: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Teva: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Trillium Therapeutics: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Triphase Research & Development Corp.: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Century Therapeutics: Consultancy, Other: All consultancy payments made to Sarah Cannon Research Institute; Hutchison MediPharma: Consultancy, Other: All consultancy payments made to Sarah Cannon Research Institute; Vincerx Pharma: Consultancy, Other: All consultancy payments made to Sarah Cannon Research Institute; Sarah Cannon Research Institute: Current Employment; Servier Pharmaceuticals: Consultancy, Other: All consultancy payments made to Sarah Cannon Research Institute; Yingli Pharmaceuticals: Consultancy, Other: All consultancy payments made to Sarah Cannon Research Institute; Seagen: Consultancy, Other: All consultancy payments made to Sarah Cannon Research Institute; Servier Pharmaceuticals: Consultancy, Other: All consultancy payments made to Sarah Cannon Research Institute; Unum Therapeutics: Consultancy, Other: All consultancy payments made to Sarah Cannon Research Institute, Research Funding; Johnson & Johnson: Current holder of individual stocks in a privately-held company; Seattle Genetics: Research Funding. Haioun: Amgen: Honoraria, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company); Roche: Consultancy, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company); Janssen-Cilag: Consultancy; Miltenyi Biotec: Consultancy; Takeda: Consultancy; Celgene: Consultancy, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company); Gilead Sciences: Consultancy, Honoraria; Servier/Pfizer: Honoraria; Novartis: Honoraria. Ysebaert: Abbvie, AstraZeneca, Janssen, Roche: Other: Advisory Board, Research Funding. Bartlett: Celgene: Research Funding; Bristol Myers Squibb: Research Funding; Forty Seven: Research Funding; Genentech: Research Funding; Janssen: Research Funding; Kite, a Gilead Company: Research Funding; Merck: Research Funding; Millennium: Research Funding; Pharmacyclics: Research Funding; Autolus: Research Funding; Seagen: Consultancy, Research Funding; Roche/Genentech: Consultancy; ADC Therapeutics: Consultancy, Research Funding. Brice: MSD: Honoraria; BMS: Honoraria; Takeda: Consultancy, Honoraria, Research Funding. Ribrag: Nanostring: Membership on an entity's Board of Directors or advisory committees; Roche: Membership on an entity's Board of Directors or advisory committees; PharmaMar: Honoraria, Membership on an entity's Board of Directors or advisory committees; Infinity Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees; GSK: Research Funding; Argen-X: Research Funding; Epizyme: Honoraria, Research Funding; Roche: Membership on an entity's Board of Directors or advisory committees; Gilead: Membership on an entity's Board of Directors or advisory committees; Astex Pharmaceuticals: Research Funding; AstraZeneca: Membership on an entity's Board of Directors or advisory committees; Bristol Myers Squibb: Membership on an entity's Board of Directors or advisory committees; MSD Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees; Servier: Consultancy, Membership on an entity's Board of Directors or advisory committees; Incyte: Membership on an entity's Board of Directors or advisory committees. Martin Garcia-Sancho: Celgene: Honoraria, Other: travel; Celgene/BMS: Consultancy; Janssen: Honoraria, Research Funding; Incyte: Consultancy; Takeda: Honoraria; Novartis: Consultancy; Kern Pharma: Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company); Eusa Pharma: Consultancy; Clinigen: Consultancy; Kyowa Kirin: Consultancy; Morphosys: Consultancy; Gilead: Consultancy, Honoraria; Servier: Consultancy, Honoraria, Other: Travel/Accommodations/Expenses; Roche: Consultancy, Honoraria, Other: Travel/Accommodations/Expenses. Lopez-Guillermo: Roche, Gilead/Kite, Celgene, Novartis, Janssen, AbbVie, Spectrum: Consultancy, Honoraria, Research Funding. Larouche: Gilead: Consultancy. Ando: Astellas Pharma: Honoraria; Celgene: Honoraria; Chugai Pharmaceutical: Research Funding; Kyowa Kirin: Research Funding; Novartis: Honoraria; Takeda Pharmaceutical: Research Funding. Maria: Roche: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company); Gilead: Membership on an entity's Board of Directors or advisory committees, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company), Research Funding; Astrazeneca: Research Funding; Janssen: Membership on an entity's Board of Directors or advisory committees, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company); Bristol Myers Squibb: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees; Abbvie: Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company). André: Johnson & Johnson: Research Funding; Roche: Other: Travel/accomodation/expenses, Research Funding; Incyte: Consultancy; Gilead: Consultancy, Other: Travel/Accommodations/Expenses; Karyopharm: Consultancy; Bristol-Myers-Squibb: Consultancy, Other: Travel/Accommodations/Expenses; AbbVie: Other: Travel/accomodation/expenses; Celgene: Other: Travel/accomodation/expenses; Takeda: Consultancy, Research Funding. Sehn: Genmab: Consultancy; Novartis: Consultancy; Debiopharm: Consultancy. Izutsu: Takeda: Honoraria, Research Funding; Symbio: Honoraria; Solasia: Research Funding; Pfizer: Research Funding; Ono Pharmaceutical: Honoraria, Research Funding; Novartis: Honoraria, Research Funding; MSD: Research Funding; Kyowa Kirin: Honoraria, Research Funding; Janssen: Honoraria, Research Funding; Incyte: Research Funding; Huya Biosciences: Research Funding; Genmab: Honoraria, Research Funding; Fuji Film Toyama Chemical: Honoraria; Eisai: Honoraria, Research Funding; Daiichi Sankyo: Honoraria, Research Funding; Chugai: Honoraria, Research Funding; Celgene: Honoraria, Research Funding; Beigene: Research Funding; Bayer: Research Funding; AstraZeneca: Honoraria, Research Funding; Yakult: Research Funding; Allergan Japan: Honoraria; AbbVie: Honoraria. Cartron: Roche, Celgene-BMS: Consultancy; Danofi, Gilead, Novartis, Jansen, Roche, Celgene-BMS, Abbvie, Takeda: Honoraria. Fowler: Bristol Myers Squibb, F. Hoffmann-La Roche Ltd, TG Therapeutics and Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding; BostonGene, Corp: Current Employment, Current holder of stock options in a privately-held company. Salles: Velosbio: Consultancy; Epizyme: Consultancy, Honoraria; Morphosys: Consultancy, Honoraria; Loxo: Consultancy; Regeneron: Consultancy, Honoraria; Novartis: Consultancy; Takeda: Consultancy; Incyte: Consultancy; Rapt: Consultancy; Kite/Gilead: Consultancy; Ipsen: Consultancy; Miltneiy: Consultancy; Genmab: Consultancy; Janssen: Consultancy; Genentech/Roche: Consultancy; Debiopharm: Consultancy; Allogene: Consultancy; BMS/Celgene: Consultancy; Beigene: Consultancy; Abbvie: Consultancy, Honoraria; Bayer: Honoraria.

Context The treatment of relapsed/refractory (R/R) diffuse large B-cell lymphoma (DLBCL) and mantle cell lymphoma (MCL) remains an area of unmet need. Combination therapies may improve treatment outcomes. Objectives Primary objective of a Phase 1/2 study (NCT03684694; Phase 1 part): Characterize the safety and tolerability of Lonca (an antibody-drug conjugate comprising a humanized anti-CD19 monoclonal antibody conjugated to a pyrrolobenzodiazepine dimer toxin) plus ibrutinib (a Bruton’s tyrosine kinase inhibitor) and identify the maximum tolerated dose (MTD) or the recommended Phase 2 dose and schedule. Secondary objective: Evaluate antitumor effects. Design Dose escalation and dose expansion, open-label, single-arm, combination study in patients (≥18 years) with R/R DLBCL or R/R MCL. Interventions MTD was determined during dose escalation as Lonca 60 µg/kg IV every 3 weeks (Q3W) for 2 cycles and oral ibrutinib 560 mg/day PO for up to 1 year. After disease assessment at Week 14, patients with partial response/stable disease may receive 2 additional Lonca cycles Q4W at Cycles 5–6. Results At data cut-off (January 4, 2021), 30 patients with DLBCL (non-germinal center B-cell [non-GCB] DLBCL 24; GCB DLBCL 6) and 7 with MCL received the MTD during Phase 1. Median patient age: 72 years (range 40–91); 28 (75.7%) had Stage 4 disease. Patients received a median of 2 (range 1–6) prior therapies. Patients received a median of 2 Lonca cycles (range 1–4) and 4 (range 1–14) ibrutinib cycles. Median treatment duration: 105 days (range 18–379). Treatment-emergent adverse events (TEAEs) occurred in 37/37 (100%) patients. Grade ≥3 TEAEs occurred in 24/37 (64.9%) patients; the most common (≥5%) were anemia (4 [10.8%]), neutropenia (4 [10.8%]), thrombocytopenia (2 [5.4%]), and fatigue (2 [5.4%]). TEAEs leading to treatment discontinuation occurred in 3 (8.1%) patients. Overall response rate (ORR; 36 evaluable patients) was 63.9% (complete response 36.1%; partial response 27.8%). ORR for non-GCB DLBCL, GCB DLBCL, all DLBCL, and MCL patients was 66.7%, 20.0%, 58.6%, and 85.7%, respectively. Conclusions Results indicate that Lonca 60 µg/kg plus ibrutinib 560 mg has encouraging antitumor activity with manageable toxicity in R/R DLBCL and R/R MCL. Research Funding ADC Therapeutics SA

International audience; In this retrospective multicentre study, we investigated the outcomes of elderly primary central nervous system lymphoma (PCNSL) patients (greater than or equal to65 years) who underwent high-dose chemotherapy followed by autologous stem cell transplantation (HDT-ASCT) at 11 centres between 2003 and 2016. End points included remission, progression-free survival (PFS), overall survival (OS) and treatment-related mortality. We identified 52 patients (median age 68.5 years, median Karnofsky Performance Status before HDT-ASCT 80%) who all underwent thiotepa-based HDT-ASCT. Fifteen patients (28.8%) received HDT-ASCT as first-line treatment and 37 (71.2%) received it as second or subsequent line. Remission status before HDT-ASCT was: CR 34.6%, PR 51.9%, stable disease 3.8% and progressive disease 9.6%. Following completion of HDT-ASCT, 36 patients (69.2%) achieved CR (21.2% first-line setting and 48.1% second or subsequent line setting) and 9 (17.3%) PR (5.8% first-line setting and 11.5% second or subsequent line setting). With a median follow-up of 22 months after HDT-ASCT, median PFS and OS were reached after 51.1 and 122.3 months, respectively. The 2-year PFS and OS rates were 62.0% and 70.8%, respectively. We observed two HDT-ASCT-associated deaths (3.8%). In selected elderly PCNSL patients, HDT-ASCT, using thiotepa-based conditioning regimes, is feasible and effective. Further prospective and comparative studies are warranted to further evaluate the role of HDT-ASCT in elderly PCNSL patients.

Background: ABP 798 is a proposed biosimilar to rituximab reference product (RP). Regulatory approval of biosimilars is based on a totality of evidence (TOE) approach which includes similarity in analytical characteristics (structural and functional), in mechanism of action (MoA) -clinical pharmacology, pharmacokinetics (PK), pharmacodynamics (PD), and in comparative clinical studies. Evidence from analytical, functional, clinical PK/PD, and efficacy and safety evaluations indicate that ABP 798 is similar to rituximab RP. Similarity of efficacy and safety in patients with non-Hodgkin lymphoma (NHL) was demonstrated in a randomized, double-blind, comparative clinical study in which the primary analysis was based on data from central, independent, and blinded assessments of disease and the sensitivity analysis was based on data using investigator assessments of disease. Here we present in vitro chemo synergy, preclinical in-vivo tumor efficacy data and show how the results of the sensitivity analysis using investigator assessments of the response rate from the NHL clinical study further add to the TOE supporting similarity of ABP 798 with the RP. Methods: In vitro synergy with chemotherapeutic agents was investigated by assessing the effect of docetaxel, gemcitabine, or doxorubicin with ABP 798 and rituximab RP in SU-DHL-6 cell lines and measured using the ATP-based cell viability endpoint (ATPLite). In vivo efficacy was assessed by evaluating the anti-tumor activity of ABP 798 and rituximab RP in NHL xenograft models in NOD/SCID mice using CD20-expressing RL and Raji cell lines. A sensitivity analysis was conducted to assess the robustness of the results of the primary efficacy endpoint of the proportion of patients with the best overall response of complete response, partial response, or unconfirmed complete response (ORR) in the NHL comparative clinical study using the investigator's assessment of disease on the full analysis set. Waterfall plots of the maximum percent reduction in the sum of the products of the greatest diameters (SPD) for index nodal lesions based on both the central, independent, blinded assessment of disease and the investigator's assessment of disease were used. Results: In vitro study results demonstrated synergistic activity of the combination of docetaxel and ABP 798 or the RP (synergy score = 6.35±0.69 [with ABP 798]; 6.79±0.12 [with RP]). In contrast, combinations with gemcitabine (synergy score = 2.68±0.20 [with ABP 798] and 2.54±0.29 [with RP]) or doxorubicin (synergy score = 1.95±0.56 [with ABP 79]) and 3.23±0.53 [with RP]) were additive. In RL cell lines, ABP 798 inhibited tumor growth similarly to rituximab RP, with no statistical difference between dose groups at 3 and 30 mg/kg (p = 0.951 and p = 0.996, respectively). In Raji cells, ABP 798 and rituximab RP significantly and similarly inhibited tumor growth when compared to an IgG1 isotype control (p < 0.001 for 3 and 30 µg/kg doses). ABP 798, at both dose levels, inhibited tumor growth similarly to rituximab RP by 27-41%, with no statistical difference. In the NHL comparative clinical study, risk difference (RD) of ORR with 1-sided 95% lower and upper confidence limits from the adjusted linear model was 7.7% (-3.2%, 18.6%) using central, blinded, independent assessments of the modified full analysis set based on randomized treatment assignment. The sensitivity analysis using investigator assessments of disease of the full analysis set of all randomized subjects based on the randomized treatment assignment received was RD = 0.5% (-7.8%, 8.8%). Waterfall plots of the maximum percent reduction in the SPD for index nodal lesions further demonstrate similarity of efficacy with central or local assessments of disease. Conclusions: In vitro and in vivo preclinical studies demonstrated chemo synergy and in vivo tumor efficacy. The sensitivity analysis of ORR using local assessments in the NHL comparative clinical study was consistent with results from the primary efficacy analysis; the maximum percent reduction in index nodal lesions was similar for central and local assessments of disease. These results further support that ABP 798 is similar to the RP across a range of efficacy evaluations as well as primary and secondary mechanisms of action and add additional supporting data to the TOE. Disclosures Niederwieser: Novartis: Speakers Bureau; Cellectis: Membership on an entity's Board of Directors or advisory committees; Daiichi: Research Funding; Amgen: Speakers Bureau. Hamm:Amgen: Consultancy. Cobb:Amgen: Consultancy. Thway:Amgen: Current Employment, Current equity holder in publicly-traded company. Forsyth:Amgen: Consultancy; Janssen Pharmaceuticals Australia: Honoraria, Membership on an entity's Board of Directors or advisory committees. Tucci:Amgen: Consultancy. Delwail:Amgen: Consultancy. Hajek:Janssen: Consultancy, Honoraria, Research Funding; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Consultancy, Honoraria, Research Funding; BMS: Consultancy, Honoraria, Research Funding; Novartis: Consultancy, Research Funding; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Abbvie: Consultancy, Honoraria; PharmaMar: Consultancy, Honoraria; Oncopeptides: Consultancy. Hanes:Amgen: Current Employment, Current equity holder in publicly-traded company.

Background: AcSé Pembrolizumab is a Phase 2, open-label, single-arm, multi-cohort, multicentric study investigating the efficacy and safety of pembrolizumab monotherapy in patients with advanced rare cancers (NCT03012620). Here, we report the first results of Pembrolizumab in the cohort of Primary Central Nervous System Lymphoma (PCNSL). Methods: Main inclusion criteria were: relapsed or refractory PCNSL after one or several lines of treatment including high dose Methotrexate based chemotherapy, pathologically confirmed diffuse large B cell lymphoma, age>18, HIV negative, concurrent steroid medication at a dose no greater than prednisone 20 mg/day or equivalent. Patients received pembrolizumab 200 mg IV as a 30-minute infusion on Day 1 of every 21-day cycles for a maximum of 2 years. The primary endpoint was the confirmed objective response rate according to IPCG at 84 day after the start of treatment. Secondary endpoints included best response (ORR), duration of response, progression-free survival (PFS), overall survival (OS), and safety. Analysis used all enrolled patients. Results: 50 patients suffering from PCNSL, including 9 primary vitreoretinal lymphoma (PVRL) were included from July, 2017 to October, 2019. Median age was 72 years (range: 43 to 83), Median PS (ECOG) was 1 (range 0-1). The median number of cycles was 4 (range 1-35). At 84 days from start of treatment, 6 patients responded (4 CR+2PR). Overall, 3 patients whose response was not assessed were considered as failures, and the rates of ORR (CR+PR), stable disease (SD), progressive disease (PD) were 26% (13/50, 8 CR + 5 PR), 10% (5/50), 58% (29/50), respectively. ORR was 29% (12/41) and 11% (1/9) in primary cerebral lymphoma and PVRL respectively. After a median follow-up of 6.7 months (range 0.2-27.4), median PFS was 2.6 months, with 6-month PFS of 29.8% and 6-month OS of 60.4%. In responders, median duration of response was estimated at 10 months (95%CI, 2.7 to 12.5). Grade III and IV toxicities related to the drug were observed in 4 patients (8%) and one patient (2%) respectively. No related toxic death was reported. Conclusion: Pembrolizumab shows moderate activity in relapsed/ refractory PCNSL with acceptable toxicity, supporting further studies evaluating its use in combination therapies. Disclosures Hoang-Xuan: BTG: Consultancy, Research Funding. Houot:Bristol-Myers Squibb: Honoraria; MSD: Honoraria; Gilead: Honoraria; Kite: Honoraria; Roche: Honoraria; Novartis: Honoraria; Janssen: Honoraria; Celgene: Honoraria. Schmitt:Celgene: Membership on an entity's Board of Directors or advisory committees; Roche, Janssen: Honoraria. Ahle:Roche: Honoraria; Novartis: Honoraria; Biogene: Honoraria; Abbvie: Honoraria; Sanofi: Honoraria. Bories:Abbvie: Consultancy; Celgen: Consultancy; Gilead: Consultancy; BMS: Honoraria; Novartis: Honoraria. Houillier:BTG: Consultancy.

Background: Mantle cell lymphoma (MCL) accounts for approximately 5-7% of non-Hodgkin lymphomas (NHL). Bruton's tyrosine kinase (BTK) inhibitors, eg ibrutinib, are indicated for treatment of adults with MCL who have received ≥1 prior therapy. Primary and acquired resistance to ibrutinib is common and linked with poor outcomes, and remains an unmet medical need. Parsaclisib, a potent, highly-selective, next-generation PI3Kδ inhibitor, demonstrated clinical activity in patients (pts) with relapsed or refractory (R/R) NHL. We report preliminary results for parsaclisib monotherapy in a cohort of pts with R/R MCL who were previously treated with ibrutinib in the open-label, phase 2 study CITADEL-205 (NCT03235544). Methods: Pts must be ≥18 years of age with pathologically confirmed MCL, R/R disease to the most recent treatment, documented cyclin D1 overexpression or t(11;14) translocation, have Eastern Cooperative Oncology Group performance status (ECOG PS) ≤2, and received 1 to 3 prior systemic treatments (including ibrutinib). Prior treatment with PI3Ki was prohibited. Pts were allocated to receive parsaclisib 20 mg once daily (QD) for 8 weeks followed by either 20 mg once weekly (weekly-dosing group [WG]) or 2.5 mg QD (daily-dosing group [DG]). Prophylaxis for Pneumocystis jirovecii pneumonia (PJP) was required. Objective response rate (ORR) was the primary endpoint; complete response rate (CRR), duration of response (DOR), progression-free survival (PFS), overall survival (OS), and safety and tolerability were secondary endpoints. All radiology-based endpoints were based on independent review. Results: From October 2017 to January 17, 2020 (data cut-off), 47 pts were treated (WG, n = 12; DG, n = 35). Enrollment is ongoing. At cut-off, 70% of pts had discontinued treatment, most commonly due to progressive disease (62%). Median exposure (range) was 2.2 (0.1-18.0) months. Median age was 70 years and 79% of pts were men. Median time since initial diagnosis was 4.7 years. Most pts (85%) had ECOG PS ≤1 and 51% had high-risk MCL International Prognostic Index. The median number of prior systemic therapies was 3; 38% of pts had prior hematopoietic stem cell transplant, and 38% were refractory to most recent systemic therapy. At data cut-off, 46 pts were evaluable for efficacy, including 12 in WG and 34 in DG (Table). Median follow-up (range) for this population was 10.2 months (1.5-25.9) overall and 7.6 months (1.5-25.9) for DG. ORR (95% confidence interval [CI]) and CRR were 28.3% (16.0-43.5) and 2.2%, respectively in all evaluable pts, and 35.3% (19.7-53.5) and 2.9%, respectively in DG. Median time to complete or partial response was 7.6 weeks. Median DOR (95% CI) was 7.3 months (0.2-not estimable) among all responders and 3.7 months (0.2-7.3) for DG. Median PFS (95% CI) was 3.65 months (1.9-3.9) overall and 3.65 months (1.9-5.5) for DG. Among 47 safety-evaluable pts, most common treatment-emergent adverse events (TEAEs) occurring in >10% of pts were anemia (19.1%), diarrhea (19.1%), neutropenia (14.9%), asthenia and cough (12.8% each), decreased appetite, dyspnea, fatigue, pyrexia and rash (10.6% each). Most common grade ≥3 TEAEs reported in ≥5% of pts included anemia (12.8%), neutropenia (10.6%), thrombocytopenia and rash (6.4% each). TEAEs leading to dose interruption or reduction occurred in 31.9% and 2.1% of pts, respectively. TEAEs leading to treatment discontinuation occurred in 2 (4.3%) pts (diarrhea and colitis). Serious TEAEs reported in ≥2 pts were diarrhea, dyspnea, peripheral swelling and pneumonia (4.3% each). Two pts experienced fatal TEAEs (one pt had general physical health deterioration and respiratory tract infection, deemed not related to treatment; one pt had pneumonia, neutropenia, and septic shock, deemed related to treatment and disease progression). New or worsening grade ≥3 laboratory test values of clinical interest occurring in ≥5% of pts included decreased neutrophils (14.9%), platelets (10.6%), and hemoglobin (8.5%); there were no grade ≥3 increases in alanine/aspartate aminotransferase. Conclusion: Preliminary efficacy data indicate that parsaclisib monotherapy is clinically active in this difficult-to-treat patient population. Treatment with parsaclisib had an acceptable safety profile and was generally well tolerated. Updated study results will be presented. Disclosures Zinzani: EUSA Pharma: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; AbbVie: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Gilead: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Kyowa Kirin: Consultancy, Speakers Bureau; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; ADC Therapeutics: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Immune Design: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Janssen: Consultancy, Honoraria, Speakers Bureau; Sandoz: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; BMS: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Servier: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Merck: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Portola: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Celltrion: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; MSD: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Verastem: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Incyte: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Immune Design: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Janssen-Cilag: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Kirin Kyowa: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; TG Therapeutics, Inc.: Honoraria, Speakers Bureau; Sanofi: Consultancy, Membership on an entity's Board of Directors or advisory committees; Eusapharma: Consultancy, Speakers Bureau. Delwail:Amgen: Consultancy. Paneesha:Bristol-Myers Squibb: Honoraria; Celgene: Honoraria; Gilead: Honoraria; Janssen: Honoraria; AbbVie: Honoraria. Rule:AstraZeneca: Consultancy; Celgene: Consultancy; Celltrion: Consultancy; Janssen Oncology: Consultancy, Research Funding, Speakers Bureau; Roche Pharma AG: Consultancy, Research Funding. Martin Garcia-Sancho:Roche, Celgene, Janssen, Servier, Gilead: Honoraria; Celgene, Eusa Pharma, Gilead, iQuone, Kyowa Kirin, Roche, Morphosys: Consultancy. Salles:Amgen: Honoraria; Bristol-Myers Squibb: Consultancy, Honoraria; Celgene: Consultancy, Honoraria, Research Funding; Gilead Sciences: Consultancy, Honoraria, Research Funding; Janssen: Consultancy, Honoraria; Novartis: Consultancy, Honoraria; Roche/Genentech: Consultancy, Honoraria, Other: Travel expenses, Research Funding; Servier: Consultancy, Honoraria; Acerta Pharma: Consultancy; Kite Pharma: Consultancy; Merck: Consultancy, Research Funding; Novimmune: Consultancy; Pfizer: Consultancy; Sanofi: Other. Sancho:Sandoz: Consultancy; Celltrion: Consultancy; Roche: Consultancy, Honoraria; Takeda: Honoraria; Novartis: Consultancy, Honoraria; Kern-Pharma: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; Gilead: Consultancy, Honoraria; Celgene: Consultancy, Honoraria; Bristol-Myers Squibb: Honoraria. Zheng:Incyte: Current Employment, Current equity holder in publicly-traded company. DeMarini:Incyte Corporation: Current Employment, Current equity holder in publicly-traded company. Jiang:Incyte Corporation: Current Employment, Current equity holder in publicly-traded company. Mehta:Seattle Genetics: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; TG Therapeutics: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Gelgene/BMS: Research Funding; Affimed: Research Funding; Merck: Research Funding; Kite/Gilead: Research Funding; Juno Parmaceuticals/BMS: Research Funding; Innate Pharmaceuticals: Research Funding; Oncotartis: Research Funding; Roche-Genentech: Research Funding; Incyte: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; fortyseven Inc/Gilead: Research Funding; Takeda: Research Funding.

ObjectiveReal-life studies on patients with primary CNS lymphoma (PCNSL) are scarce. Our objective was to analyze, in a nationwide population-based study, the current medical practice in the management of PCNSL.MethodsThe French oculo-cerebral lymphoma network (LOC) database prospectively records all newly diagnosed PCNSL cases from 32 French centers. Data of patients diagnosed between 2011 and 2016 were retrospectively analyzed.ResultsWe identified 1,002 immunocompetent patients (43% aged >70 years, median Karnofsky Performance Status [KPS] 60). First-line treatment was high-dose methotrexate-based chemotherapy in 92% of cases, with an increasing use of rituximab over time (66%). Patients 60 years of age, WBRT and HCT-ASCT consolidation were administered in only 9% and 2%, respectively. The complete response rate to initial chemotherapy was 50%. Median progression-free survival was 10.5 months. For relapse, second-line chemotherapy, HCT-ASCT, WBRT, and palliative care were offered to 55%, 17%, 10%, and 18% of patients, respectively. The median, 2-year, and 5-year overall survival was 25.3 months, 51%, and 38%, respectively (60 years: 15.4 months, 44%, and 28%). Age, KPS, sex, and response to induction CT were independent prognostic factors in multivariate analysis.ConclusionsOur study confirms the increasing proportion of elderly within the PCNSL population and shows comparable outcome in this population-based study with those reported by clinical trials, reflecting a notable application of recent PCNSL advances in treatment.

International audience; The clinicopathological characteristics of kidney infiltration in B-cell lymphoproliferative disorders remain poorly described. We retrospectively studied 52 adults with biopsy-proven malignant B-cell kidney infiltration, including Waldenström's macroglobulinemia (n=21), chronic lymphocytic leukemia (n=11), diffuse large B-cell lymphoma (DLBCL) (n=8), other lymphoma (n=11), and multiple myeloma (n=1). Kidney disease varied according to the underlying lymphoproliferative disorder. In DLBCL, malignant kidney infiltration was prominent, resulting in acute kidney injury (AKI, 75%) and kidney enlargement (88%). In the other types, associated immunoglobulin-related nephropathy (most commonly AL amyloidosis) was more common (45%), and chronic kidney disease with proteinuria was the primary presentation. All patients received chemotherapy. Over a median follow-up of 31 months, 20 patients died and 21 reached end-stage kidney disease. Renal response, achieved in 25 patients (48%), was associated with higher overall survival (97 vs. 37 months in non-renal responders). In univariate analysis, percentage of sclerotic glomeruli, kidney enlargement, and complete hematological response at 6 months were predictive of renal response. In multivariate analysis, concomitant immunoglobulin-related nephropathy was the sole independent predictor of poor renal outcome. In conclusion, clinical presentation of renal lymphomatous infiltration depends on the nature of the underlying lymphoproliferative disorder. In DLBCL, massive renal infiltration manifests with enlarged kidneys and AKI, and the diagnosis primarily relies on lymph node biopsy. In other B-cell lymphoproliferative disorders, the clinicopathological spectrum is more heterogeneous, with a high frequency of immunoglobulin-related nephropathy that may affect renal outcome; thus kidney biopsy is required for early diagnosis and prognostic assessment. © 2019 International Society of Nephrology

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.

BACKGROUND: Based on the encouraging activity and manageable safety profile observed in a phase 1 study, the ECHELON-2 trial was initiated to compare the efficacy and safety of brentuximab vedotin, cyclophosphamide, doxorubicin, and prednisone (A+CHP) versus cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) for the treatment of CD30-positive peripheral T-cell lymphomas.METHODS: ECHELON-2 is a double-blind, double-dummy, randomised, placebo-controlled, active-comparator phase 3 study. Eligible adults from 132 sites in 17 countries with previously untreated CD30-positive peripheral T-cell lymphomas (targeting 75% with systemic anaplastic large cell lymphoma) were randomly assigned 1:1 to receive either A+CHP or CHOP for six or eight 21-day cycles. Randomisation was stratified by histological subtype according to local pathology assessment and by international prognostic index score. All patients received cyclophosphamide 750 mg/m2 and doxorubicin 50 mg/m2 on day 1 of each cycle intravenously and prednisone 100 mg once daily on days 1 to 5 of each cycle orally, followed by either brentuximab vedotin 1·8 mg/kg and a placebo form of vincristine intravenously (A+CHP group) or vincristine 1·4 mg/m2 and a placebo form of brentuximab vedotin intravenously (CHOP group) on day 1 of each cycle. The primary endpoint, progression-free survival according to blinded independent central review, was analysed by intent-to-treat. This trial is registered with ClinicalTrials.gov, number NCT01777152.FINDINGS: Between Jan 24, 2013, and Nov 7, 2016, 601 patients assessed for eligibility, of whom 452 patients were enrolled and 226 were randomly assigned to both the A+CHP group and the CHOP group. Median progression-free survival was 48·2 months (95% CI 35·2-not evaluable) in the A+CHP group and 20·8 months (12·7-47·6) in the CHOP group (hazard ratio 0·71 [95% CI 0·54-0·93], p=0·0110). Adverse events, including incidence and severity of febrile neutropenia (41 [18%] patients in the A+CHP group and 33 [15%] in the CHOP group) and peripheral neuropathy (117 [52%] in the A+CHP group and 124 [55%] in the CHOP group), were similar between groups. Fatal adverse events occurred in seven (3%) patients in the A+CHP group and nine (4%) in the CHOP group.INTERPRETATION: Front-line treatment with A+CHP is superior to CHOP for patients with CD30-positive peripheral T-cell lymphomas as shown by a significant improvement in progression-free survival and overall survival with a manageable safety profile.FUNDING: Seattle Genetics Inc, Millennium Pharmaceuticals Inc, a wholly owned subsidiary of Takeda Pharmacuetical Company Limited, and National Institutes of Health National Cancer Institute Cancer Center.

International audience; We present results of a prospective, multicenter, phase II study evaluating rituximab, bendamustine, bortezomib and dexamethasone as first-line treatment for patients with mantle cell lymphoma aged 65 years or older. A total of 74 patients were enrolled (median age, 73 years). Patients received a maximum of six cycles of treatment at 28-day intervals. The primary objective was to achieve an 18-month progression-free survival rate of 65% or higher. Secondary objectives were to evaluate toxicity and the prognostic impact of mantle cell lymphoma prognostic index, Ki67 expression, [18F]fluorodeoxyglucose-positron emission tomography and molecular minimal residual disease, in peripheral blood or bone marrow. With a median follow-up of 52 months, the 24-month progression-free survival rate was 70%, hence the primary objective was reached. After six cycles of treatment, 91% (54/59) of responding patients were analyzed for peripheral blood residual disease and 87% of these (47/54) were negative. Four-year overall survival rates of the patients who did not have or had detectable molecular residual disease in the blood at completion of treatment were 86.6% and 28.6%, respectively (P

International audience; Recent studies suggest that psoriasis may be more severe in patients with nonalcoholic fatty liver disease, particularly in those with the inflammatory stage of steatohepatitis [nonalcoholic steatohepatitis (NASH)]. Herein, we investigated the impact of diet-induced steatohepatitis on the severity of imiquimod-induced psoriasiform dermatitis. Mice fed with a high-fat diet developed steatohepatitis reminiscent of human NASH with ballooning hepatocytes and significant liver fibrosis. Mice with steatohepatitis also displayed moderate cutaneous inflammation characterized by erythema, dermalinfiltrates of CD45(+) leukocytes, and a local production of IL-17A. Moreover, steatohepatitis was associated with an epidermal activation of caspase-1 and cutaneous overexpression of IL-1 beta. Imiquimod-induced psoriasiform dermatitis was exacerbated in mice with steatohepatitis as compared to animals fed with a standard diet. Scale formation and acanthosis were aggravated, in correlation with increased IL-17A and IL-22 expression in inflamed skins. Finally, intradermal injection of IL-17A in standard diet-fed mice recapitulated the cutaneous pathology of mice with steatohepatitis. The results show that high-fat diet induced steatohepatitis aggravates the inflammation in psoriasiform dermatitis, via the cutaneous production of IL-17A. In agreement with clinical data, this description of a novel extrahepatic manifestation of NASH should sensitize dermatologists to the screening and the management of fatty liver in psoriatic patients.

Autoimmune haemolytic anaemia (AIHA) in mantle cell lymphoma (MCL) is a rare but life-threatening complication. To date, there are no relevant data for treatment of AIHA in MCL. Ibrutinib, which has been approved for relapse/refractory MCL, is an immunomodulatory drug inhibiting Th2 activation and consequently the production of autoantibodies. We report a case of MCL with AIHA in which this form of anaemia was not controlled with the usual chemotherapy. Ibrutinib was used when MCL with AIHA relapsed, and it allowed rapid remission of AIHA and rapid discontinuation of steroid therapy.

8044 Background: ABP 798* is being developed as a biosimilar to rituximab, a CD20-directed cytolytic antibody. A randomized, double-blind, active-controlled study compared the efficacy, safety, and immunogenicity of ABP 798 with rituximab reference product (RP) in subjects with CD20-positive NHL; results of the final analysis are presented here. Methods: Adult subjects with grade 1, 2, or 3a follicular B-cell NHL and low tumor burden were randomized to receive intravenous ABP 798 or RP (375 mg/m2) once weekly for 4 weeks, then at weeks 12 and 20. The primary endpoint was risk difference (RD) of overall response rate (ORR) by week 28. Secondary endpoints included RD of ORR at week 12, pharmacokinetics, pharmacodynamics, safety, and immunogenicity. Results: 254/256 randomized subjects were treated with at least one infusion of ABP 798 (n = 128) or RP (n = 126); ORR by week 28, based on independent central blinded assessment of the modified full analysis set, was comparable between the ABP 798 and RP groups (78% vs. 70%, respectively). The 2-sided 90% confidence interval of RD of ORR (-1.4%; 16.8%) was within the pre-specified margin (-15%; 35.5%) thereby establishing clinical equivalence between ABP 798 and RP. This result was supported by analyses of the secondary efficacy endpoint of RD of ORR at week 12. In the two groups, the geometric least squares means for serum concentrations over time (e.g., week 12, pre-dose: ABP 798, 21.89 vs. RP, 20.57; week 12 post-dose: ABP 798, 201.30 vs. RP, 203.52) and the extent of B-cell depletion from day 1 to day 8 (ABP 798, 98.3% vs. RP, 98.3%) were similar. Frequency, type, and severity of adverse events (AEs) were comparable between ABP 798 and RP groups; grade ≥3 AEs were reported in 10.9% and 10.3% of subjects and serious AEs in 3.9% and 4.0%, respectively. Most common AEs were headache, fatigue, and nausea; the most common AE of interest was infusion reactions. No new or unexpected safety signals were observed. Binding and neutralizing anti-drug antibodies were comparable between groups. Conclusions: Results of this study demonstrated clinical similarity between ABP 798 and rituximab RP in subjects with CD20-positive NHL. *At the time of this submission, ABP 798 had not been approved by the FDA or any relevant regulatory agency and the indications are yet undetermined. Please consult ABP 798’s later approved label in the relevant country for information regarding the approved uses for ABP 798.

BACKGROUND AND PURPOSE: Perfusion and spectroscopic MR imaging provide noninvasive physiologic and metabolic characterization of tissues, which can help in differentiating brain tumors. We investigated the diagnostic role of perfusion and spectroscopic MR imaging using individual and combined classifiers of these modalities and assessed the added performance value that spectroscopy can provide to perfusion using optimal combined classifiers that have the highest differential diagnostic performance to discriminate lymphomas, glioblastomas, and metastases. MATERIALS AND METHODS: From January 2013 to January 2016, fifty-five consecutive patients with histopathologically proved lymphomas, glioblastomas, and metastases were included after undergoing MR imaging. The perfusion parameters (maximum relative CBV, maximum percentage of signal intensity recovery) and spectroscopic concentration ratios (lactate/Cr, Cho/NAA, Cho/Cr, and lipids/Cr) were analyzed individually and in optimal combinations. Differences among tumor groups, differential diagnostic performance, and differences in discriminatory performance of models with quantification of the added performance value of spectroscopy to perfusion were tested using 1-way ANOVA models, receiver operating characteristic analysis, and comparisons between receiver operating characteristic analysis curves using a bivariate χ2, respectively. RESULTS: The highest differential diagnostic performance was obtained with the following combined classifiers: maximum percentage of signal intensity recovery–Cho/NAA to discriminate lymphomas from glioblastomas and metastases, significantly increasing the sensitivity from 82.1% to 95.7%; relative CBV–Cho/NAA to discriminate glioblastomas from lymphomas and metastases, significantly increasing the specificity from 92.7% to 100%; and maximum percentage of signal intensity recovery–lactate/Cr and maximum percentage of signal intensity recovery–Cho/Cr to discriminate metastases from lymphomas and glioblastomas, significantly increasing the specificity from 83.3% to 97.0% and 100%, respectively. CONCLUSIONS: Spectroscopy yielded an added performance value to perfusion using optimal combined classifiers of these modalities, significantly increasing the differential diagnostic performances for these common brain tumors.

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

International audience; The benefit of radiotherapy (RT) after chemotherapy in limited-stage diffuse large B-cell lymphoma (DLBCL) remains controversial. We conducted a randomized trial in patients with nonbulky limited-stage DLBCL to evaluate the benefit of RT after rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP). Patients were stratified according to the modified International Prognostic Index, including lactate dehydrogenase, Eastern Cooperative Oncology Group performance status, age, and disease stage. The patients received 4 or 6 consecutive cycles of R-CHOP delivered once every 2 weeks, followed or not by RT at 40 Gy delivered 4 weeks after the last R-CHOP cycle. All patients were evaluated by fluorodeoxyglucose-positron emission tomography scans performed at baseline, after 4 cycles of R-CHOP, and at the end of treatment. The primary objective of the trial was event-free survival (EFS) from randomization. The trial randomly assigned 165 patients in the R-CHOP arm and 169 in the R-CHOP plus RT arm. In an intent-to-treat analysis with a median follow-up of 64 months, 5-year EFS was not statistically significantly different between the 2 arms, with 89% ± 2.9% in the R-CHOP arm vs 92% ± 2.4% in the R-CHOP plus RT arm (hazard ratio, 0.61; 95% confidence interval [CI], 0.3-1.2; = .18). Overall survival was also not different at 92% (95% CI, 89.5%-94.5%) for patients assigned to R-CHOP alone and 96% (95% CI, 94.3%-97.7%) for those assigned to R-CHOP plus RT ( = not significant). R-CHOP alone is not inferior to R-CHOP followed by RT in patients with nonbulky limited-stage DLBCL. This trial was registered at www.clinicaltrials.gov as #NCT00841945.