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Background: Diagnostic-to-treatment interval (DTI) was recently described as a strong prognostic factor for newly diagnosed systemic diffuse large B-cell lymphoma patients (DLBCL) with an improvement of event-free survival (EFS) for patients with a longer DTI. These results have some implications for patient selection and result interpretations in clinical trials. This association has not been previously evaluated in DLBCL Primary CNS Lymphoma (PCNSL) patients who also present a clinically aggressive disease. Patients and Methods: The cohort constited of all consecutive DLBCL PCNSL patients treated in two Hematology Departments of the University of Lyon between 1984 and 2018 (N=244). All patients had DLBCL histology at diagnosis, obtained by brain biopsy (N=235, 96%), vitrectomy (N=4, 2%) or CSF evaluation (N=5, 2%). As first line treatments, all patients but 5 (2%) received high-dose (HD) methotrexate-based chemotherapy, associated with intra-venous rituximab for 154 patients (63%) and HD cytarabine for 182 patients (75%). Consolidation treatment by whole-brain radiotherapy was performed in seventy-six patients (31%). DTI was defined as the number of days between the date of diagnosis (i.e. biopsy) and the date of treatment initiation. Association between DTI and patient characteristics was assessed by chi-square tests or Student t-tests. EFS was defined from the start of therapy to progression, relapse, or death from any cause. As we previously described, prognostic factors such as age and performance status (PS) demonstrate a time-dependent effect on overall survival (OS) in PCNSL limiting the validity of traditional Cox proportional hazard models. We thus used a piecewise Cox model to allow assessment of prognostic effect over different time periods. All survival analyses were done in univariate and multivariate settings and stratified on rituximab use during first-line therapy. Results: With a median follow-up of 73.5 months, the 5-year EFS and OS rates were 31.6% and 48.4% for whole cohort, respectively. Median DTI was 16 days (range, 1 to 67 days). Short DTI (≤16 days) was associated with a poor PS (ECOG PS 2-4, 53.3% versus 38.5%), altered Karnofsky score ( 16 days, respectively (Figure 1). Using a standard cox model, in univariate analyses, PS (2-4 vs. 0-1) (HR: 1.40, 95%CI, 1.00 - 1.94, P=0.045) and age (per 10-year increase) (HR: 1.19, 95%CI, 1.05-1.36, P=0.006) were associated with EFS but not DTI (≤ or > 16 days) (HR: 0.80, P=0.19), deep involvement (HR: 0.97, P=0.85) and LDH level (HR=1.02, P=0.91). In multivariate analysis, only age was associated with EFS (HR: 1.27, 95%CI, 1.11-1.46, P=0.001). Using a piecewise Cox model over two periods of time (before and after 12 months), we confirmed in multivariate analyses, the time varying effect of PS and age on EFS with a high-risk period before 12 months and no prognostic effect after 12 months (Table 1). We also observed a time-dependent effect for DTI as shown by a significant interaction with time (P=0.02) (Table 1). Indeed, longer DTI was not associated with EFS before 12 months (HR: 1.14, 95%CI, 0.74-1.76, P=0.56) however, it had a strong protective effect after 12 months (HR: 0.44, 95%CI, 0.24-0.86, P=0.02). Conclusions: In this large cohort of DLBCL PCNSL, a short DTI was mainly associated with poor PS at diagnosis. We confirmed that prognostic factors for PCNSL outcome such as age and PS had time-varying effects with a good predictability of EFS only before 12 months. However, DTI allows prediction of long-term EFS (>12 months) after first line treatment. These results could be related to different biological patterns of tumor aggressiveness. If confirmed in independent PCNSL cohorts, DTI should also be taken in consideration for patient selection and the interpretation of clinical trial results especially for long-term outcome. Disclosures Karlin: Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel support, personal fees; Sanofi: Honoraria; Celgene/Bristol-Myers Squibb: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel support; AbbVie: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel support; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel support, personal fees; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel support, personal fees; GlaxoSmithKline: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Other: Personal fees. Salles:Autolus: Consultancy, Membership on an entity's Board of Directors or advisory committees; Amgen: Honoraria, Other: Educational events; BMS: Honoraria; Merck: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Educational events; Novartis, Servier, AbbVie, Karyopharm, Kite, MorphoSys: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Educational events; Roche, Janssen, Gilead, Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Educational events; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Educational events; Epizyme: Consultancy, Honoraria. Bachy:Amgen: Research Funding; Roche, Gilead: Consultancy; Beigene: Membership on an entity's Board of Directors or advisory committees; Roche, Celgene, Amgen, Janssen, Gilead, Novartis, Sanofi: Honoraria.

Background: Zanubrutinib is a selective next-generation Bruton tyrosine kinase (BTK) inhibitor designed to have high specificity for BTK and minimize off-target effects (J Med Chem 2019;62:7923-40). Data from several phase 2 CLL trials assessing BCL-2 and BTK inhibitor combination treatment suggested that undetectable minimal residual disease (uMRD)-driven fixed-duration combination treatment was tolerable and enabled durable responses after treatment discontinuation (JAMA Oncol 2021;1649.; EHA 2021 S147). However, a limited number of patients with the high-risk feature, deletion of chromosome 17p13.1 [del(17p)], have been included in these studies. Preliminary data from Arm C of the SEQUOIA trial suggested that zanubrutinib monotherapy was active (18-mo progression-free survival: 90.6%) and well-tolerated in CLL/SLL patients with del(17p) (ASH 2020 1306). Here, we present early results for patients with TN del(17p) CLL/SLL receiving zanubrutinib + venetoclax in Arm D of the SEQUOIA trial (NCT03336333). Methods: SEQUOIA is an open-label, global, multicenter, phase 3 study that includes a nonrandomized cohort (Arm D) of patients with TN del(17p) CLL/SLL (Blood 2020;136 [supplement 1]:24-5). Patients in Arm D were treated with zanubrutinib (160 mg twice daily) for 3 mos followed by zanubrutinib (same dosing) + venetoclax (ramp-up cycle followed by 400 mg once daily) combination treatment for 12-24 cycles until progressive disease (PD), unacceptable toxicity, or achievement of uMRD at 7% aberrant nuclei present. Initial safety and tolerability of zanubrutinib + venetoclax was assessed, including the risk of tumor lysis syndrome (TLS) both at baseline and prior to initiation of venetoclax. Responses for CLL and SLL were investigator-assessed per modified iwCLL criteria (Blood 2008;111:5446-56; J Clin Oncol 2012;30:2820-2) and Lugano criteria (J Clin Oncol 2014;32:3059-68), respectively. Bone marrow exams to confirm a suspected complete response (CR) or CR with incomplete hematological recovery were required starting at the end of Cycle 9. Results: As of 1 JUN 2021 (data cutoff), 35 of approximately 80 planned patients with centrally confirmed del(17p) were enrolled. Median follow-up was 9.7 mos. In the safety analysis population (n=35), 94.3% had CLL and high-risk characteristics including Binet stage C (51.5%), bulky disease ≥5 cm (42.9%), unmutated immunoglobulin heavy chain variable locus (85.3%, n=34), median del(17p) frequency of 81.5%, and elevated β 2-microglobulin (71.4%). At data cutoff, 29 patients had started combination therapy and 27 patients completed ramp-up venetoclax dosing. Thirty-two patients remained on study treatment and 3 patients ended treatment due to withdrawal of consent, PD, or adverse event (AE of lung cancer), all n=1. The patient with lung cancer had lung nodules present at screening and died due to lung adenocarcinoma. AEs and serious AEs were reported in 29 patients (82.9%) and 4 patients (11.4%), respectively. AEs reported in ≥10% of patients included diarrhea (n=5), neutropenia (n=5), fatigue (n=4), nausea (n=4), and petechiae (n=4). Thirteen patients (37.1%) had grade ≥3 AEs; most frequently neutropenia (n=4) and diarrhea (n=2). One patient with ongoing grade 2 atrial fibrillation at baseline reported grade 3 atrial fibrillation on study. To date, no AEs of TLS have been reported. At baseline, the TLS risk categories were high, medium, and low in 12 (34.3%), 22 (62.9%), and 1 (2.9%) patients, compared with 0 (0%), 21 (67.7%), and 10 (32.3%) patients, respectively, prior to initiation of venetoclax. For the 31 patients who reached the initial efficacy assessment at 3 mos after starting zanubrutinib, the overall response rate was 96.8% (30/31); one patient reported PD after having an initial partial response while on combination therapy. Conclusion: Preliminary safety data with the 9.7-mo median follow-up suggest that zanubrutinib + venetoclax was generally well tolerated in this high-risk population, with no new safety signals identified and no TLS reported. Enrollment is ongoing; updated safety, efficacy, and biomarker data will be presented. Figure 1 Figure 1. Disclosures Tedeschi: AbbVie: Honoraria, Other: Advisory Board and Travel, Accommodations, Expenses, Speakers Bureau; Janssen: Honoraria, Other: Advisory Board and Travel, Accommodations, Expenses, Speakers Bureau; BeiGene: Honoraria, Other: Advisory Board, Speakers Bureau; AstraZeneca: Honoraria, Other: Advisory Board, Speakers Bureau. Ferrant: Janssen: Other: Travel, Accommodations, Expenses; AbbVie: Honoraria, Other: Travel, Accommodations, Expenses; AstraZeneca: Honoraria. Flinn: Calithera Biosciences: 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; Triphase Research & Development Corp.: Other: All 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; Portola Pharmaceuticals: Other: All 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; Genentech: 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; Kite, a Gilead Company: Consultancy, Other: All consultancy and 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; Incyte: 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; Forty Seven: 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; Janssen: Consultancy, Other: All consultancy and research funding payments made to Sarah Cannon Research Institute, Research Funding; Yingli Pharmaceuticals: Consultancy, Other: All consultancy payments made to Sarah Cannon Research Institute; Loxo: 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; Rhizen Pharmaceuticals: 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; Trillium Therapeutics: Other: All 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; Verastem: Consultancy, Other: All consultancy and 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; TG Therapeutics: 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; Nurix Therapeutics: Consultancy, Other: All consultancy payments made to Sarah Cannon Research Institute; Gilead Sciences: Consultancy, Other: All consultancy and 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; Forma Therapeutics: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Seagen: 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; AstraZeneca: 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; MorphoSys: Consultancy, Other: All consultancy and 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; Infinity Pharmaceuticals: 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; Constellation 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; Acerta Pharma: 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; 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. Tam: Roche: Consultancy, Honoraria; Novartis: Honoraria; Pharmacyclics: Honoraria; Janssen: Consultancy, Honoraria, Research Funding; Loxo: Consultancy; AbbVie: Consultancy, Honoraria, Research Funding; BeiGene: Consultancy, Honoraria. Ghia: Acerta/AstraZeneca: Consultancy, Honoraria, Research Funding; AbbVie: Consultancy, Honoraria, Research Funding; ArQule/MSD: Consultancy, Honoraria; Celgene/Juno/BMS: Consultancy, Honoraria; BeiGene: Consultancy, Honoraria; Gilead: Consultancy, Research Funding; Janssen: Consultancy, Honoraria, Research Funding; Roche: Consultancy, Honoraria; Sunesis: Research Funding; AstraZeneca: Consultancy, Honoraria, Research Funding. Robak: Biogen, Abbvie, Octapharma, Janssen: Honoraria, Other: Advisory board; AstraZeneca, Abbvie, Janssen, Octapharma, Gilead,Oncopeptides AB, Pharmacyclics, Pfizer, GlaxoSmithKline, Biogen: Research Funding; Medical University of Lodz: Current Employment. Brown: MEI Pharma: Consultancy; Bristol-Myers Squib/Juno/Celegene: Consultancy; Pfizer: Consultancy; Abbvie: Consultancy; Sun: Research Funding; Gilead: Research Funding; Rigel: Consultancy; Catapult: Consultancy; Eli Lilly and Company: Consultancy; Genentech/Roche: Consultancy; Novartis: Consultancy; Invectys: Other: Data Safety Monitoring Committee Service; Beigene: Consultancy; Nextcea: Consultancy; Morphosys AG: Consultancy; TG Therapeutics: Research Funding; Acerta/Astra-Zeneca: Consultancy; Janssen: Consultancy; SecuraBio: Research Funding; Loxo/Lilly: Research Funding. Ramakrishnan: BeiGene: Current Employment, Current equity holder in publicly-traded company, Divested equity in a private or publicly-traded company in the past 24 months, Other: Travel, Accommodations, Expenses. Tian: AbbVie: Ended employment in the past 24 months; BeiGene: Current Employment. Kuwahara: BeiGene: Current Employment, Current equity holder in publicly-traded company, Divested equity in a private or publicly-traded company in the past 24 months. Paik: BeiGene USA, Inc.: Current Employment, Current equity holder in publicly-traded company. Cohen: BeiGene: Current Employment, Current equity holder in publicly-traded company, Other: Travel, Accommodations, Expenses. Huang: BeiGene: Current Employment, Current equity holder in publicly-traded company, Current holder of individual stocks in a privately-held company, Current holder of stock options in a privately-held company, Divested equity in a private or publicly-traded company in the past 24 months, Other: Travel, Accommodations, Expenses; Protara Therapeutics: Current holder of individual stocks in a privately-held company, Membership on an entity's Board of Directors or advisory committees, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company). Hillmen: BeiGene: Honoraria; Janssen: Honoraria, Other: Travel, Accommodations, Expenses, Research Funding; AbbVie: Honoraria, Other: Travel, Accommodations, Expenses, Research Funding; Pharmacyclics: Honoraria, Research Funding; Roche: Research Funding; Gilead: Research Funding; AstraZeneca: Honoraria; SOBI: Honoraria. OffLabel Disclosure: Zanubrutinib is an investigational agent and has not been approved for TN del(17p) CLL/SLL in the US

Introduction Ibrutinib, a once-daily oral Bruton's tyrosine kinase inhibitor, has shown progression-free survival (PFS) or overall-survival (OS) benefit over chemoimmunotherapy (CIT) in multiple phase 3 studies in previously untreated patients with CLL, and significantly longer time to next treatment compared with CIT in previously untreated high-risk patients in a RW setting. We conducted an adjusted comparison of ibrutinib versus RW treatment for previously untreated CLL using patient-level data from the phase 3 RESONATE-2™ (NCT01722487) trial and RW databases from 2 countries. Methods Previously untreated patients with CLL, fulfilling RESONATE-2™ eligibility criteria (age ≥ 65, no del17p) were selected from 2 RW data sources containing electronic medical records for patients with CLL: Centre Hospitalier Lyon-Sud, France; CLLEAR CLL registry from 7 academic centers in the Czech Republic. PFS and OS were compared between patients from the ibrutinib arm of RESONATE-2™ with a median follow-up of 60 months, and those receiving physicians' choice (PC) treatment other than ibrutinib from the RW database, adjusting for differences in baseline characteristics including age, gender, del11q, IGHV status, RAI/BINET disease stage, and Eastern Cooperative Oncology Group (ECOG) score. Hazard ratios (HRs) for ibrutinib versus RW PC treatment were estimated using a multivariable Cox proportional hazards model including available baseline characteristics as covariates, and using an inverse probability weighted (IPW) Cox model with average treatment effect for treatment (ATT) weights derived from propensity scores estimated from a logistic regression including the same covariates. Results The analysis included 136 patients from the RESONATE-2™ study receiving ibrutinib and 920 previously untreated RW patients receiving PC treatment (Lyon-Sud n = 162, CLLEAR n = 758). Baseline characteristics were generally balanced between treatment groups. The most common PC regimens contained CIT and were fludarabine + cyclophosphamide + rituximab (FCR) (n = 227), bendamustine + rituximab (BR) (n = 201), and rituximab + chlorambucil (R + Chlor) (n = 116). Older age, male gender, del11q and advanced disease stage were independent risk factors for PFS and OS. When comparing ibrutinib versus the overall PC cohort, the adjusted HR (95% confidence interval [CI]) was 0.24 (0.16-0.34) for PFS and 0.33 (0.21-0.52) for OS (both p < 0.0001). IPW-based comparative estimates were highly consistent for both PFS (HR = 0.27 [0.18-0.39]) and OS (HR = 0.39 [0.24-0.62]). ATT-weighted survival curves estimating PFS and OS for the RESONATE-2™ population as if treated with PC, showed a median value of 32.1 months and 72.5 months, respectively, while median values for Ibrutinib were not reached. When comparing ibrutinib versus FCR, BR, and R + Chlor, the adjusted HRs (95% CI) were 0.26 (0.17-0.38), 0.27 (0.18-0.41), and 0.27 (0.17-0.42), respectively, for PFS and 0.34 (0.20-0.56), 0.28 (0.16-0.49), and 0.61 (0.32-1.13), respectively, for OS (Figure). Concl usions Adjusted comparisons of the RESONATE-2™ trial and RW patient-level data demonstrates significantly improved PFS and OS for ibrutinib versus physician's choice treatment (predominantly CIT) in previously untreated patients with CLL. PFS and OS benefit for ibrutinib was consistent across a range of common regimens: FCR, BR, and R + Chlor. These results are consistent with data from phase 3 studies and support the use of ibrutinib for first-line CLL treatment. Funding Source: Sponsored by Janssen Pharmaceutica NV, and Pharmacyclics LLC, an AbbVie Company. The RW databases are independently owned. Writing assistance was provided by Emma Fulkes and Liqing Xiao of Parexel and funded by Janssen Pharmaceutica NV. Figure 1 Figure 1. Disclosures Doubek: Janssen-Cilag, AbbVie, AstraZeneca, Amgen, Gilead, Novartis: Honoraria, Research Funding. Smolej: AbbVie, AstraZeneca, Gilead, Janssen-Cilag, and Roche: Consultancy, Honoraria, Other: Travel Grants. Šimkovič: AbbVie, AstraZeneca, Janssen-Cilag, Gilead, Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel Grants. Lysak: Novartis, Janssen-Cilag, AbbVie; AstraZeneca: Honoraria, Research Funding. Bachy: Kite, a Gilead Company: Honoraria; Novartis: Honoraria; Daiishi: Research Funding; Roche: Consultancy; Takeda: Consultancy; Incyte: Consultancy. Ferrant: AbbVie: Honoraria, Other: Travel, Accommodations, Expenses; AstraZeneca: Honoraria; Janssen: Other: Travel, Accommodations, Expenses. Diels: Janssen: Current Employment. Cabrieto: Janssen: Current Employment. Nielsen: Janssen: Current Employment. Salles: Allogene: Consultancy; Regeneron: Consultancy, Honoraria; Velosbio: Consultancy; Takeda: Consultancy; Rapt: Consultancy; Genentech/Roche: Consultancy; Epizyme: Consultancy, Honoraria; Debiopharm: Consultancy; Genmab: Consultancy; Incyte: Consultancy; Ipsen: Consultancy; Janssen: Consultancy; Kite/Gilead: Consultancy; Loxo: Consultancy; Miltneiy: Consultancy; Morphosys: Consultancy, Honoraria; Novartis: Consultancy; BMS/Celgene: Consultancy; Beigene: Consultancy; Abbvie: Consultancy, Honoraria; Bayer: Honoraria.

With the emergence of targeted therapies, defining the best strategy for the treatment of previously untreated CLL patients remains challenging. The aim of this phase 2 study was to compare the efficacy of an association with ibrutinib and venetoclax (IV) to the standard FCR regimen in fit patients with intermediate risk CLL defined by either unmutated IGHV status, 11q deletion or complex karyotype in the absence of TP53 abnormality. Patients were randomized 1:1 between two treatment arms, ie FCR 6 cycles or IV. After a lead-in phase of ibrutinib as a single agent from month (M)1 to M3, the total duration of treatment with IV was based on the response achieved at M9; if bone marrow (BM) MRD was < 0.01% using flow cytometry, the treatment was continued for 6 additional months until M15 and then stopped; if BM MRD at M9 was ≥ 0.01%, the treatment with IV was continued for 18 additional months until M27. The primary endpoint was the percentage of patients with BM MRD < 0.01% at M27 in both arms. We present here the preliminary results on the first evaluation done at M9 including CT-scan, BM biopsy and MRD assessment in PB and BM after the inclusion of all the 120 patients as initially planned. One hundred and twenty patients were enrolled from September 2019 to February 2021. The median age was 59 [34-72] and 61 [34-74] years in the FCR and IV arms, respectively. The characteristics of the patients were well balanced between the 2 arms in terms of gender (male 72% FCR, 74% IV), PS ECOG 0-1 (59% FCR, 68% IV) and Binet stage (A, B and C 15%, 64%, 21% for FCR ; 8.5%, 59% and 32% for IV). No major difference in terms of cytogenetic features was noted, all patients but one had unmutated IGHV. At the time of data cut-off for this interim analysis, the median follow-up for the all cohort was 11 [2.9 - 19.8] months. The frequency of all grades adverse events (AE) observed so far was 53% (grade 3-4, 24%) in the FCR arm and 47% (grade 3-4, 17%) in the IV arm. The rate of infusion-related reactions (IRR) in the FCR arm was 35% on cycle 1-day 1 (14% grade 3-4) ; for the IV arm, 6% of patients experienced tumor lysis syndrome (TLS) (grade 4 for 4 patients). ibrutinib doses were reduced for 7 patients (4 permanently stopped and 3 resumed at a lower dose because of toxicities (digestive, hepatic or haematological)). Venetoclax was permanently discontinued before M9 in 4 patients (digestive toxicities and grade 4 neutropenia). Forty serious adverse events were reported of which 15 in the IV arm (1 sudden death, 1 ischemic stroke, 2 atrial fibrillations, 2 clinical TLS, 1 hepatitis, 1 neutropenia, 4 COVID pneumonitis and one osteoporotic fracture) and 25 in the FCR arm (2 neutropenias, 1 anemia, 1 thrombocytopenia, 1 autoimmune haemolytic anemia, 3 IRR, 4 TLS, 2 COVID pneumonitis, 4 fever episodes of undetermined origin, 1 community-acquired pneumonia, 1 gastrointestinal toxicity, 1 confusion, 2 chest pains, 1 acute myeloid leukemia, 1 myelodysplasic syndrome). The patients with COVID pneumonitis had a favorable evolution with the need for intensive care and convalescent plasma for 3 of them. The first 60 patients included in the study have reached M9 and among them, 6 prematurely discontinued the study, 3 in each arm (active hemolysis, ischemic stroke and sudden death in the IV arm; 2 grade 4 hematologic toxicities and 1 early progression in the FCR arm). In the evaluated patients (n=54), 71% of patients in the FCR arm and 48% of patients in the IV arm achieved bone BM MRD < 0.01%. The complete (CR, CRi) and partial response rates were 54% and 46% in the FCR arm and 76% and 24% in the IV arm respectively. In conclusion, the preliminary results show a lower BM MRD rate in the IV arm compared to the FCR arm at M9, with a toxicity that remains significant and relatively similar between the two arms. However, BM MRD rate should improve after longer exposure to the IV combination and the analysis of the primary endpoint at M27 will be decisive in determining the best therapeutic strategy. Disclosures Quinquenel: Abbvie: Honoraria; Janssen: Honoraria; AstraZeneca: Honoraria. Laribi: Le Mans Hospital: Research Funding; Novartis: Other: Personal Fees, Research Funding; Takeda: Other: Personal Fees, Research Funding; BeiGene: Other: Personal Fees; IQONE: Other: Personal Fees; AbbVie: Other: Personal Fees, Research Funding; Astellas Phama, Inc.: Other: Personal Fees; AstraZeneca: Other: Personal Fees; Jansen: Research Funding. Cymbalista: Lilly-LOXO: Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; ASTRA ZENECA: Honoraria, Membership on an entity's Board of Directors or advisory committees; Abbvie: Honoraria, Membership on an entity's Board of Directors or advisory committees; Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees. Leblond: AstraZeneca: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Lilly: Consultancy; AbbVie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel Support; Roche: Honoraria; Amgen: Honoraria; Beigene: Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees. Dartigeas: Astra-Zeneca: Membership on an entity's Board of Directors or advisory committees, Other: travel grants/Congress; Abbvie: Membership on an entity's Board of Directors or advisory committees, Other: travel grants/Congress; Janssen: Membership on an entity's Board of Directors or advisory committees, Other: travel grants/Congress. Ferrant: Janssen: Other: Travel, Accommodations, Expenses; AbbVie: Honoraria, Other: Travel, Accommodations, Expenses; AstraZeneca: Honoraria. de Guibert: Janssen: Consultancy, Honoraria; AbbVie: Consultancy, Honoraria; Gilead: Consultancy, Honoraria. Feugier: Astrazeneca: Consultancy, Honoraria; Gilead: Consultancy, Honoraria; Abbvie: Consultancy, Honoraria; Amgen: Honoraria; Janssen: Consultancy, Honoraria. Cartron: Roche, Celgene-BMS: Consultancy; Danofi, Gilead, Novartis, Jansen, Roche, Celgene-BMS, Abbvie, Takeda: Honoraria. Ysebaert: Abbvie, AstraZeneca, Janssen, Roche: Other: Advisory Board, Research Funding.

Background Richter syndrome (RS) refers to the onset of aggressive lymphoma, mostly diffuse large B cell lymphoma (DLBCL), in patients with chronic lymphocytic leukemia (CLL). The outcome of RS patients is usually very poor with both low response rates to chemoimmunotherapy and short survival. While BCR and BCL2 inhibitors have transformed the management of CLL patients, these drugs do not prevent the onset of RS. Modulating anti-tumor immunity has recently been suggested as a promising approach in RS (Ding, 2017). Blinatumomab is a bi-specific T-cell engaging antibody construct that transiently links CD3-positive T cells to CD19-positive B-cells, inducing T-cell activation and subsequent lysis of tumor cells. It has been approved for the treatment of patients with relapsed or refractory B-ALL and has also been evaluated in the setting of persisting minimal residual disease. Recently, blinatumomab (stepwise dosing 9-28-112 μg/d) has been evaluated in patients with relapsed or refractory DLBCL and demonstrated promising results (ORR 43%) with acceptable safety (Viardot, 2016). We hypothesized that blinatumomab would improve response in RS patients failing to achieve CR after initial debulking with R-CHOP. Methods We report here the first results of a phase 2 multicenter study investigating the efficacy and safety of blinatumomab after R-CHOP debulking therapy for patients with untreated RS of DLBCL histology (NCT03931642). The patients with persisting (PR, SD) or progressive disease (PD) after 2 cycles of R-CHOP were eligible to receive an 8-week course of blinatumomab induction. Blinatumomab was administered at a stepwise dose of 9 μg/d in the first week, 28 μg/d in the second week, and 112 μg/d thereafter. The primary endpoint was CR rate according to the revised Lugano criteria after the 8-week induction course of blinatumomab. An additional 4-week consolidation cycle was optional. Allo-HSCT was further allowed for eligible patients. Results A total of 34 patients out of 41 has already been enrolled in the trial to date. Median age was 66 years (range, 38-82) and sex ratio M/F was 23/12. CLL features at baseline were as follows: 57% had 17p deletion and 67% TP53 mutations. Sixty-five percent had complex karyotype and 79% unmutated IGHV status. Median number of prior therapeutic lines for CLL was 2 (range, 0-7): 19 (54%) patients previously received chemo-immunotherapy, 23 (66%) patients were exposed to ibrutinib and 11 (31%) to venetoclax. As of the data cut-off of June 1st, 2021, the blinatumomab induction course has been completed for 18 patients. Ten patients did not receive blinatumomab for the following reasons: 7 patients achieved CR after R-CHOP, 2 patients died because of febrile neutropenia after R-CHOP and 1 patient presented severe pneumonia after R-CHOP. Three patients are still on R-CHOP and 3 others on blinatumomab to date. Regarding toxicity during blinatumomab, data are available for the 18 patients having completed the blinatumomab induction to date. All patients had at least one grade 1 adverse event (AE), 10 had grade ≥3 AE. The most common AE (> 1 case), regardless of relationship to blinatumomab, were fever (4 patients), CRS (2 patients), sepsis (2 patients), vein thrombosis (2 patients), anemia (4 patients), neutropenia (3 patients), lymphopenia (5 patients), thrombocytopenia (3 patients) and hyperglycemia (5 patients). In terms of neurologic events, 5 (28%) experienced neurotoxicity (all recovered) including grade 3 encephalopathy, grade 4 confusion, grade 3 anxiety, grade 1 myoclonus, grade 2 ataxia, grade 1 sleep disorder and grade 1 ICANS (each in 1 pt). Blinatumomab was temporarly stopped in 3 patients and permanently in 2. In terms of efficacy, after R-CHOP debulking therapy (n=31 evaluable patients), 7 patients achieved CR, 6 patients were in PR, 7 patients were stable and 11 patients were progressive. At evaluation after the blinatumomab induction (n=18 evaluable patients), 4 (22.2%) patients achieved CR, 4 (22.2%) patients PR, 2 (11.1%) patients were stable and the remaining 8 (44.5%) were progressive. Considering the whole strategy (including R-CHOP debulking) (n=28), 15 (54%) patients achieved overall response including 11 (39%) CR. Conclusions Our preliminary data suggest that blinatumomab suggests encouraging anti-tumor activity and acceptable toxicity in patients with RS. Disclosures Ysebaert: Abbvie, AstraZeneca, Janssen, Roche: Other: Advisory Board, Research Funding. Ferrant: AstraZeneca: Honoraria; Janssen: Other: Travel, Accommodations, Expenses; AbbVie: Honoraria, Other: Travel, Accommodations, Expenses. de Guibert: Janssen: Consultancy, Honoraria; AbbVie: Consultancy, Honoraria; Gilead: Consultancy, Honoraria. Laribi: Astellas Phama, Inc.: Other: Personal Fees; AstraZeneca: Other: Personal Fees; Novartis: Other: Personal Fees, Research Funding; Le Mans Hospital: Research Funding; IQONE: Other: Personal Fees; Jansen: Research Funding; BeiGene: Other: Personal Fees; Takeda: Other: Personal Fees, Research Funding; AbbVie: Other: Personal Fees, Research Funding. Feugier: Abbvie: Consultancy, Honoraria; Gilead: Consultancy, Honoraria; Amgen: Honoraria; Astrazeneca: Consultancy, Honoraria; Janssen: Consultancy, Honoraria. OffLabel Disclosure: blinatumomab is approved for acute lymphoblastic leukemia. The aim of this phase 2 study is to evaluated it in patients with Richter's syndrome.

Median age at diagnosis of chronic lymphocytic leukemia is 72 years. However, only few patients over 80 years of age are included in clinical trials, even in those devoted to unfit patients. In order to evaluate both efficiency and safety of venetoclax in this category of patients, we conducted a multicentric retrospective study and collected data from 77 CLL patients from 19 FILO centers who started venetoclax after 80 years of age. Median age at venetoclax initiation was 86 years old (81-97). 63% of patients had a history of heart disease, 62% had renal failure (moderate 59% and severe 3%) and 29% had a history of severe infections. Despite their comorbidities and a CIRS greater than 6 in 70% of cases, their autonomy was preserved with a median performans status of 1 (0-4). In this comorbid geriatric population, pretherapeutic geriatric assessment was only performed in a single patient. The median number of prior therapies was 2 (0-6) with an exposure to a BCR inhibitor in 56% of cases. 11q and 17p deletion were found in 39% and 30% of cases respectively, 39% of patients had a complex karyotype and 30% harbored a TP53 mutation. However, in this real life population, these prognostic factors were only performed in half of patients. IGHV mutational status was only available in 11 patients, and 83% of them had unmutated IGHV. At the time of venetoclax initiation, the tumor lysis syndrome (TLS) risk was moderate in 57% of cases and high in 8% of cases. Venetoclax was administered as a single agent (42%) or in association with rituximab (58%). In total, half of the patients were hospitalized at each dose ramp-up, and only 3 patients were treated on outpatient basis. 82% of the cohort was able to reach the daily dose of 400mg. Half of the patients were included in a phone call monitoring program with oncology nurses to pre-emptively manage side effects and foster therapy adherence. The safety study reported 14% of TLS, with 2 discontinuations of treatment within the first month: one of which led to dialysis and the other to death. As in the previously published studies, 25% of patients had infectious complications, and grade 3 haematological and digestive toxicities were reported in 42% and 22% of cases, respectively. The reduction of the daily dose of venetoclax was necessary for 33%. Permanent discontinuation of venetoclax occurred in 40% of subjects, including 29% of early withdrawal (within the first 3 months). Main reasons for discontinuation were intolerance (21%), CLL progression (21%), death (21%) and scheduled treatment discontinuation (10%). The overall response rate was 86%, consisting of 49% of complete response (unconfirmed by bone marrow biopsy) and 37% of partial response. With a median follow-up of 21months, estimated progression free survival and overall survival were 29 and 38 months respectively. Prior exposure to a BCR inhibitor had no impact on progression free survival. To conclude, venetoclax has a manageable safety profile in elderly patients with comorbidities and can induce prolonged responses. Finally, if additional follow-up by oncology nurses seems to be more and more implemented, the pre-therapeutic onco-geriatric evaluation remains underexploited in this population. Disclosures Ferrant: AstraZeneca: Honoraria; AbbVie: Honoraria, Other: Travel, Accommodations, Expenses; Janssen: Other: Travel, Accommodations, Expenses. Feugier: Janssen: Consultancy, Honoraria; Gilead: Consultancy, Honoraria; Abbvie: Consultancy, Honoraria; Amgen: Honoraria; Astrazeneca: Consultancy, Honoraria. Laribi: AstraZeneca: Other: Personal Fees; Le Mans Hospital: Research Funding; AbbVie: Other: Personal Fees, Research Funding; Jansen: Research Funding; Novartis: Other: Personal Fees, Research Funding; IQONE: Other: Personal Fees; Astellas Phama, Inc.: Other: Personal Fees; BeiGene: Other: Personal Fees; Takeda: Other: Personal Fees, Research Funding. Tchernonog: JANSSEN: Consultancy; ABBVIE: Consultancy; ASTRAZENECA: Consultancy. Dartigeas: Astra-Zeneca: Membership on an entity's Board of Directors or advisory committees, Other: travel grants/Congress; Abbvie: Membership on an entity's Board of Directors or advisory committees, Other: travel grants/Congress; Janssen: Membership on an entity's Board of Directors or advisory committees, Other: travel grants/Congress. Quinquenel: Abbvie: Honoraria; Janssen: Honoraria; AstraZeneca: Honoraria.

Introduction Primary cerebral lymphoma (PCNSL) is an uncommon subtype of diffused large B-cell lymphoma (DLBCL) with a particular poor outcome as compared to systemic DLBCL, especially in elderly. For patients older than 60 years, standard treatment consists of high-dose methotrexate (HD-MTX) chemotherapy without consolidation brain radiotherapy to reduce the risk of leukoencephalopathy. Rituximab in combination with HD-MTX, procarbazine, vincristine followed by HD-cytarabine consolidation is one of standard of treatments for PCNSL patients with a 2-year PFS rate of 47% for patients aged of 60 or older in prospective trial (Morris JCO 2013). Etoposide and Ifosfamide are two drugs that can diffuse across blood-brain barrier and commonly used for relapsed/refractory PCNSL. To improve efficacy of R-MPVA protocol, we developed a new regimen which consisted in adding etoposide and ifosfamide for patients with a newly diagnosed PCNSL aged between 60 and 75 years old. Patients & Methods The protocol consisted of 3 cycles every 28 days of rituximab (375mg/m2, J1 and J15), MTX (3.5 g/m2, J1 and J15), vincristine (1.4 mg/m2, J1 and J15), vepeside (100mg/m2, J2) and procarbazine (100mg/m2, J1-7). Consolidation therapy consisted of 2 cycles every 21 days rituximab (375mg/m2, J1) in combination with cytarabine (3g/m2, J1-2) with ifosfamide (1.5 g/m2, J1-3). Response evaluations were planned after the 3 cycles of induction (R-MPV-VP16) and after consolidation (R-AraC-Ifo). We retrospectively reviewed treatment modalities, toxicities, response and outcome with this protocol and compared results with a matched group of patients with the same range age (60 - 75 years) treated with R-MPVA. Results Between 2013 and 2018, 28 PCNSL patients were treated with this protocol. The median age was 67.5 years old (range, 61-74). Poor performance status (PS 3-4) was presented in 9 patients (32%). As compared to 31 patients treated between 2007 and 2018 with R-MPVA, patients treated with intensive protocol were younger (66 vs. 69 years, P=0.01) and had less frequently a poor PS 3-4 (32% vs. 61%, P=0.04). In intent-to-treat analysis, 27 patients received 3 cycles of R-MPV-VP16 but one received only 2. Among them, five patients achieved PR and then received 1 to 2 additional cycles of R-MPV-VP16. Following this induction, 25 patients underwent 2 cycles R-AraC-ifo consolidation, 3 of them did not received ifosfamide for the second cycle because of hematological toxicity and poor PS. One patient in complete response (CR) after whole treatment received high-dose therapy followed by autologous stem cell transplantation. After R-MPV-VP16, 10 patients (36%) achieved CR and 14 partial responses (50%) (PR) as compared to 12 CR (39%) and 12 PR (39%) for patients treated with R-MPVA. After consolidation phase, 23 patients (82%) achieved CR after R-AraC-Ifo as compared to 21 CR (68%) after R-AraC in the historical arm. Differences were not statistically significant. R-MPV-VP16 regimen was associated with favorable toxicity profile with 13 (46%) grade 4 hematological toxicity, 8 (28%) grade 3 and one grade 4 (3%) renal toxicity, 3 (10%) grade 3 and one grade 4 (3%) hepatic toxicity, 6 (21%) grade 3 and 4 grade 4 (14%) and infectious toxicity. With a median follow-up of 46.5 months, patients treated with R-MPV-VP16 followed by R-AraC-ifo had a median event-free survival (EFS) of 33.2 months (95%CI, 17.6 - not reached [NR]) with a 2-year EFS rate of 52%; the median overall survival (OS) was not reached (95%CI, 58.6-NR) with a 2-year OS rate of 70%. With a median follow-up of 94.2 months, patients treated with R-MPVA had a median EFS of 18.3 months with a 2-year EFS rate of 39% (P=0.14, Fig 1); the median OS was 65.9 months with 2-year OS rate of 64% (P=0.33, Fig 1). Conclusions In this retrospective analysis of two HD-MTX and HD-AraC based regimens for PCNSL patients aged between 60 and 75 years performed in real-life setting, R-MPVA was more frequently proposed for older patients with a poorer PS. Combination of vepeside to R-MPV and ifosfamide to R-AraC was feasible with a favorable toxicity profile. Despite not statistically different, we observed a trend for an improvement of response rate at the end of treatment (82% vs. 68% of CR) and reduced rate of relapses (2-year EFS rates: 52% vs. 39%) with the intensified protocol. These first results deserve a confirmative larger prospective study of R-MPV-VP16 followed by R-AraC-ifosfamide for elderly PCNSL patients. Disclosures Ferrant: AbbVie: Honoraria, Membership on an entity's Board of Directors or advisory committees. Karlin:Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel support, personal fees; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel support, personal fees; Celgene: Other: Personal fees; Sanofi: Honoraria; GlaxoSmithKline: Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel support, personal fees; Celgene/Bristol-Myers Squibb: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel support; AbbVie: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel support. Bachy:Beigene: Membership on an entity's Board of Directors or advisory committees; Roche, Celgene, Amgen, Janssen, Gilead, Novartis, Sanofi: Honoraria; Amgen: Research Funding; Roche, Gilead: Consultancy.

Background: Zanubrutinib is a highly selective, next-generation Bruton tyrosine kinase (BTK) inhibitor designed to maximize BTK occupancy and minimize off-target effects. Zanubrutinib has been associated with improved specificity and durable clinical responses in patients with chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL; Tam, Blood 2019;134:851-9). Early clinical data from Arm C of the SEQUOIA trial suggested that zanubrutinib was active and well-tolerated in treatment-naïve (TN) CLL/SLL patients with the high-risk characteristic deletion of chromosome 17p13.1 [del(17p)] (Tam ASH 2019 #499). In that cohort, an overall response rate (ORR) of 92.7% was reported, and the most common adverse events (AEs; 20.1% contusion, 15.6% upper respiratory tract infection, 13.8% rash) and most common grade ≥3 AEs (10.1% neutropenia, 3.7% pneumonia, 2.8% hypertension) were consistent with those in previous reports of zanubrutinib treatment in patients with various B-cell malignancies. Venetoclax is a B-cell lymphoma 2 protein (BCL-2) inhibitor approved for the treatment of adult patients with CLL or SLL. Results of several phase 2 CLL trials of BCL-2 inhibitor and BTK inhibitor combinations have suggested that combination treatment is tolerable and may have synergistic activity (Hillmen JCO 2019;37:2722-9. Jain, NEJM 2019;380:2095-103. Siddiqi, EHA 2020 #S158.). Combination treatment given for a finite duration as determined by undetectable minimal residual disease (uMRD) is of significant interest and has the potential to alter the CLL/SLL treatment landscape if shown to induce deeper responses with a fixed duration of therapy. In the BOVen study, zanubrutinib was given in combination with venetoclax and obinutuzumab to TN CLL patients, and uMRD in the peripheral blood and bone marrow was used to determine treatment discontinuation (Soumerai, ASCO 2020 #8006.) Preliminary data showed that 62% of patients met the uMRD endpoint and successfully discontinued treatment after a median of 8 months (6 months of triplet therapy), and 100% of patients had a best response of partial response or higher (43% complete response/complete response with incomplete marrow recovery). The most common grade ≥3 AEs (15.4% neutropenia, 5.1% thrombocytopenia, 5.1% lung infection, 2.6% infusion-related reaction, 2.6% rash, 2.6% bleeding) were consistent with those previously reported in combination treatment studies, and no events of tumor lysis syndrome (TLS) were reported. Study Design and Methods : The SEQUOIA trial (NCT03336333) is an open-label, global, multicenter, phase 3 study that includes a nonrandomized cohort (Arm D) of up to 50 TN patients with del(17p) CLL/SLL. Arm D is designed to provide combination treatment of zanubrutinib and venetoclax and use serial monitoring of uMRD to determine treatment discontinuation. Patients are treated with zanubrutinib (160 mg twice daily) for 3 months followed by the combination of zanubrutinib (same dosing) and venetoclax (ramp-up cycle followed by 400 mg once daily). Combination treatment is given for 12-24 cycles until disease progression, unacceptable toxicity, or requirements for uMRD at 7% aberrant nuclei present. Initial safety and tolerability of zanubrutinib and venetoclax combination therapy will be assessed, including the risk of TLS at baseline and before initiation of venetoclax. Responses will be assessed by investigator for CLL per modified iwCLL criteria (Hallek, Blood 2008;111:5446-56. Cheson, JCO 2012;30:2820-2) and for SLL per Lugano criteria (Cheson, JCO 2014;32:3059-68). Secondary endpoints include ORR, progression-free survival, duration of response, rate of uMRD4 at various time points, safety, and pharmacokinetics of zanubrutinib and venetoclax. Exploratory endpoints include overall survival, patient-reported outcomes, and time to recurrence of detectable MRD after discontinuation of zanubrutinib and/or venetoclax. Recruitment began in November 2019 and is ongoing in 8 countries. Figure 1 Disclosures Tam: Janssen: Honoraria, Research Funding; AbbVie: Honoraria, Research Funding; BeiGene: Honoraria. Flinn:Novartis: Research Funding; Nurix Therapeutics: Consultancy; Portola Pharmaceuticals: Research Funding; Gilead Sciences: Consultancy, Research Funding; Forty Seven: Research Funding; Trillium Therapeutics: Research Funding; TG Therapeutics: Consultancy, Research Funding; F. Hoffmann-La Roche: Research Funding; Incyte: Research Funding; Curis: Research Funding; Calithera Biosciences: Research Funding; Karyopharm Therapeutics: Research Funding; Juno Therapeutics: Consultancy, Research Funding; Acerta Pharma: Research Funding; Great Point Partners: Consultancy; Genentech, Inc.: Research Funding; Loxo: Research Funding; Celgene: Research Funding; MorphoSys: Consultancy, Research Funding; Curio Science: Consultancy; Merck: Research Funding; Constellation Pharmaceuticals: Research Funding; Forma Therapeutics: Research Funding; Verastem: Consultancy, Research Funding; Yingli Pharmaceuticals ≠: Consultancy, Research Funding; Rhizen Pharmaceuticals: Research Funding; Johnson & Johnson: Other; Roche: Consultancy, Research Funding; Vincera Pharma: Consultancy; ArQule: Research Funding; Agios: Research Funding; AstraZeneca: Consultancy, Research Funding; BeiGene: Consultancy, Research Funding; Kite Pharma: Consultancy, Research Funding; IGM Biosciences: Research Funding; Takeda: Consultancy, Research Funding; Infinity Pharmaceuticals: Research Funding; Unum Therapeutics: Consultancy, Research Funding; Triphase Research & Development Corp.: Research Funding; Teva: Research Funding; Seattle Genetics: Consultancy, Research Funding; Iksuda Therapeutics: Consultancy; Janssen: Consultancy, Research Funding; AbbVie: Consultancy, Research Funding; Pfizer: Research Funding; Pharmacyclics LLC, an AbbVie Company: Consultancy, Research Funding. Tedeschi:Department of Hematology Niguarda Hospital Milano: Current Employment; Janssen spa: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; AstraZeneca: Consultancy, Membership on an entity's Board of Directors or advisory committees; BeiGene: Consultancy, Membership on an entity's Board of Directors or advisory committees; AbbVie: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Sunesis: Consultancy. Ferrant:AbbVie: Honoraria, Membership on an entity's Board of Directors or advisory committees. Brown:BeiGene: Consultancy; Genentech: Consultancy; Gilead: Consultancy, Research Funding; Acerta: Consultancy; Sun: Research Funding; Loxo: Consultancy, Research Funding; Verastem: Consultancy, Research Funding; TG Therapeutics: Consultancy; Sunesis: Consultancy; Rigel Pharmaceuticals: Consultancy; Pfizer: Consultancy; Octapharma: Consultancy; Novartis: Consultancy; Nextcea: Consultancy; MEI Pharma: Consultancy; Invectys: Membership on an entity's Board of Directors or advisory committees, Other: DSMC; Astra-Zeneca: Consultancy; Janssen: Honoraria; Morphosys: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other; Catapult: Consultancy; Dynamo Therapeutics: Consultancy; Eli Lilly and Company: Consultancy; Juno/Celgene: Consultancy; Kite: Consultancy; AbbVie: Consultancy; Pharmacyclics: Consultancy. Robak:GSK: Research Funding; Bristol Meyers Squibb: Research Funding; Roche: Consultancy, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company), Research Funding; AstraZeneca: Honoraria, Research Funding; Acerta: Research Funding; Janssen: Consultancy, Honoraria, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company), Research Funding; BioGene: Honoraria, Research Funding; Pharmacyclics LLC, an AbbVie Company: Honoraria, Research Funding; UCB: Honoraria, Research Funding; Medical University of Lodz: Current Employment; Momenta: Consultancy; Takeda: Consultancy; Octapharma: Honoraria; Morphosys: Research Funding; Novartis: Honoraria, Research Funding; Sandoz: Consultancy, Honoraria; AbbVie: Consultancy, Honoraria, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company), Research Funding; UTX-TGR: Research Funding; Pfizer: Research Funding. Ghia:Gilead: Consultancy, Honoraria, Research Funding; ArQule: Consultancy, Honoraria; Acerta/AstraZeneca: Consultancy, Honoraria; BeiGene: Consultancy, Honoraria; Janssen: Consultancy, Honoraria, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company), Research Funding; Celgene/Juno: Consultancy, Honoraria; Lilly: Consultancy, Honoraria; MEI: Consultancy, Honoraria; Sunesis: Consultancy, Honoraria, Research Funding; Adaptive, Dynamo: Consultancy, Honoraria; Novartis: Research Funding; AbbVie: Consultancy, Honoraria, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company), Research Funding. Kuwahara:BeiGene: Current Employment, Current equity holder in publicly-traded company, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company). Paik:BeiGene: Current Employment, Current equity holder in publicly-traded company. Hua:BeiGene USA Ltd.: Current Employment, Current equity holder in publicly-traded company, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company); Agios Pharmaceuticals Inc.: Current equity holder in publicly-traded company, Ended employment in the past 24 months; Vertex: Current equity holder in publicly-traded company. Cohen:BeiGene: Current Employment, Current equity holder in publicly-traded company, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company). Huang:BeiGene: Current Employment, Current equity holder in publicly-traded company, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company). Hillmen:Janssen: Honoraria, 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, Speakers Bureau; AbbVie: Honoraria, 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, Speakers Bureau; Astra Zeneca: Honoraria; F. Hoffmann-La Roche: Honoraria, Research Funding; Pharmacyclics: Research Funding; Gilead: Research Funding. OffLabel Disclosure: Zanubrutinib has not been approved for TN CLL/SLL with del(17p) in the US

Ibrutinib has revolutionized the management of RR CLL in the past 5 years, improving overall survival (OS) over standard chemo-immunotherapies (CIT) in the registration trials HELIOS and RESONATE. Recently, based on these two studies, a score has been validated able to predict 3 groups with different OS (acronym BALL, further validated in cohorts of patients treated with CIT or other targeted agents) (1). The BALL model consists of four factors with 1 point each (serum ß2-microglobulin>5mg/dL, lactate dehydrogenase >upper limit of normal, hemoglobin Methods We collected survival data and causes of death across 10 FiLO centers, in patients treated with ibrutinib monotherapy as per label for RR disease. We included patients across performans statuses, irrespective of previous line of therapies (LOT) or age, with 3 (n=329) or 4 (n=250) available BALL criteria at the time of initiation. Results Median FU was 29.3 months. Stratification of BALL scores in 250 patients (with 4 parameters known) was as follows: low risk (n=88, 35.2%), intermediate risk (n=122, 48.8%), and high risk (n=40, 16%), with estimated 2-years OS rates of 87.3%, 82.3% and 58.8%, respectively (Figure 1A, C-statistics index 0.64). These results are very similar (all 3 groups) to what Soumerai J et al.reported in their ibrutinib/CIT training dataset of 581 patients (1). Causes of 60/250 deaths were as follows: CLL 28.3%, Richter transformation 15%, infectious (33.3%) or cardiovascular (18.3%) toxicity, second cancer (5%). High risk score was significantly associated to deletion 17p/TP53 mutational status (69.4% vs47%, p We also calculated a "worse BALL score" by adding 1 point to 79 more patients with 3 known parameters (n=329 in total). Stratification was as follows: low risk (6.7%, 2y-OS 100%), intermediate risk (45.6%, 2y-OS 82.9%), and high risk (47.7%, 2y-OS 74.6%) (Figure 1B). The latter results were very comparable to the internal validation dataset of ibrutinib/CIT in 242 patients. Causes of 79/329 deaths were as follows: CLL 27.8%, Richter transformation 17.7%, infectious (35.4%) or cardiovascular (15.2%) toxicity, second cancer (3.8%). Altogether, the BALL score was useful to delineate 3 risk-groups with statistically different survivals in real-world ibrutinib patients, despite 50% of deaths were due to toxicity. By Cox univariate analysis for OS (n=227, events=57), variables with significant impact on prognosis were: age>79y (HR 2.09, p=0.003), male gender (HR 1.5, p=0.046), del17p/TP53 mutation (HR 1.45, p=0.049), previous lines of therapy (LOT1-2 vs 3+, HR 2.17, p These results further advocated for the use of BALL score in our practice, because we validated its use even in elderly RR patients. In the clinical trials used for model building, median age was 79y. On the other hand, LOT was excluded from the model, and so its impact left unanswered by the first publication. Our data suggested that OS of multi-relapsing patients (3 or more previous lines of therapy) was not adequately predicted by the BALL score. On the other hand, we confirmed that deletion 17p/TP53mutational status was not an independent factor for OS, because predicted by the BALL score parameters (1). Conclusions In our series, the BALL score also identified a well-defined cohort of real-world RR CLL patients with an unmet clinical need despite the use of ibrutinib (median OS 27 months). We suggest that patients in the high-risk group should be thoroughly monitored, or even proposed clinical trials with drug combinations, or even cellular therapies approaches (CAR-T cells, bispecific antibodies) due their shorter OS. (1) Soumerai J, et al. Risk Model for Overall Survival in Relapsed or Refractory Chronic Lymphocytic Leukaemia in the Era of Targeted Therapies. Lancet Haematol 2019. Disclosures No relevant conflicts of interest to declare.

Introduction: standard treatment for relapsed/refractory (R/R) diffuse large B-cell lymphoma (DLBCL) is high-dose chemotherapy followed by autologous stem-cell transplantation (ASCT) but this strategy is not appropriate for elderly DLBCL patients (pts) related to a high risk of toxicities. Multiple chemotherapy regimens had been developed for heavily pretreated elderly DLBCL patients such as R-bendamustine, R-gemcitabine-oxaliplatin (R-GEMOX) and pixantrone; the median progression free survival (PFS) of these regimens were 2, 4 and 3.5 months, respectively in prospective phase II studies for patients previously treated with R (Sehn 2017, Mounier 2013, Pettengel 2016). Adapted dose of ifosfamide and etoposide was firstly developed as sequential consolidation regimen after high-dose CHOP (ACVBP regimen) in first line therapy of young DLBCL patients (Tilly 2003). This regimen with a safe toxicity profile was then used in combination with R in Lyon University Hospital in elderly R/R DLBCL ineligible to intensive strategy. Methods: we retrospectively reviewed the efficacy and the safety profile of this regimen performed in two Lyon University Hospitals (Centre Hospitalier Lyon Sud and Leon Berard Cancer Center). Between June 2004 and March 2017, 75 pts with R/R DLBCL (63 de novo DLBCL, 12 transformed DLBCL) received R (375 mg/m2) in combination etoposide (300 mg/m2) and ifosfamide (1500 mg/m2) on day 1 (N=72, 96%) and on days 1-2 (N=3, 4%) at 2 (N=46, 61%) or 3-week (N=29, 39%) intervals. All medical records were reviewed for clinical and biological characteristics, modality of treatment and supportive care, toxicities, responses and outcome. Results: the median age was 79 years (range, 64-92) at the beginning of R-ifosfamide/VP16 treatment with 46% of the patients over 80 years. 13% of pts had a CIRS-G grade 3 or 4 >2 categories and 35% had a cumulative CIRS-G score more than 6. The performance status according to EORTC scale was 2-4 in 37% of the pts and 93% had III-IV Ann Arbor stages. Age-adjusted IPI were 0-1 in 20 pts (27%) and 2-3 in 55 pts (73%). All patients were previously treated in first-line therapy by R in combination with chemotherapy (CHOP, N=56, 75%, low-dose CHOP, N=14, 19%, other, N=5, 6%). The patients received a median number of 1 previous line (range, 1-8) and no patient was previously treated by ASCT. The median time between initial diagnosis and R-ifosfamide/VP16 was 20 months (range 4-187). The median time between the last treatment and R-ifosfamide/VP16 was 5 months (range 0-181). A refractory disease to first-line treatment was showed in 14 pts (19%). 31% of the patients had a refractory disease to the last regimen performed before R-ifosfamide/VP16. Patients received a median of 6 cycles (1-12). At the end of treatment, the overall response rate (ORR), defined by the rate of complete response (CR) and partial response (PR) was 37%, with 18% of CR. Evaluations were assessed for 29% of the pts by TEP scanner. For toxicity, among the 387 cycles, 10 patients developed febrile neutropenia (2.6%); 15 (20%) a grade 3-4 neutropenia; 7 (9%) a grade 3-4 thrombocytopenia; 5 patients needed platelet units and 16 patients received packed red blood cell units. No grade 3-4 non-hematological toxicity was observed and no toxic death occurred. With a median follow up of 31.3 months (range, 5.0-202.8), the median progression-free survival (PFS) was 4.3 months with a 1-year PFS rate of 26.0% (95%CI, 17.7-38.3) (Figure 1A). The median overall survival (OS) was 8.2 months with a 1-year OS rate of 40.8% (95%CI, 30.9-54.0) (Figure 1B). The median duration of response was 4 months (range 1-97). The median PFS was adversely affected by response (refractory versus CR/PR) to the last treatment (3.0 months versus 5.5 months, P=0.001) (Figure 1C). Conclusions: in this retrospective study, R-Ifosfamide/VP16 regimen provided effective results in R/R DLBCL transplant-ineligible pts with 37% of ORR and a median of PFS of 4.3 months with a safe toxicity profile. This regimen could also be considered as a platform for combinations with novel targeted agents in these categories of patients. Disclosures Karlin: Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: travel support; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: travel support; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees. Sarkozy:ROCHE: Consultancy. Bachy:Gilead Sciences: Honoraria; Takeda: Research Funding; Sandoz: Consultancy; Amgen: Honoraria; Roche: Research Funding; Celgene: Consultancy; Janssen: Honoraria. Salles:Abbvie: Honoraria; Epizyme: Honoraria; Amgen: Honoraria; F. Hoffmann-La Roche Ltd: Consultancy, Honoraria, Research Funding; Gilead: Honoraria, Other: Advisory Board; Acerta: Honoraria; Novartis: Consultancy, Honoraria; Servier: Honoraria; Servier: Honoraria, Other: Advisory Board; Takeda: Honoraria; BMS: Honoraria, Other: Advisory Board; Celgene: Honoraria, Other: Advisory Board, Research Funding; Janssen: Honoraria, Other: Advisory Board; Merck: Honoraria; Morphosys: Honoraria; Pfizer: Honoraria. Ghesquieres:Sanofi: Consultancy; Gilead: Consultancy; Celgene: Consultancy.

Purpose International Prognostic Index (IPS) is the most widely used risk stratification index for advanced stage Hodgkin's lymphoma (HL). The use of (18F)-fluorodeoxyglucose PET/CT at diagnosis allows a better characterization of extra-nodal involvement (ENI). We investigated if the type of ENI could affect the prognosis of stage IV HL patients diagnosed with PET/CT and if a specific prognostic index could be defined for these patients (pts). Patients and methods We retrospectively analyzed 220 stage IV HL patients treated from 2005 to 2015 in three LYSA centers. We considered the local investigator interpretation based on the nuclear medicine physician PET/CT report. Regarding ENI, six subgroups were identified: involvement of lung and/or pericard and/or pleural, liver, diffuse and/or focal bone involvement, digestive system, and other involvements; we also considered bone marrow involvement based on the results of bone marrow biopsy. The main outcome was event free survival (EFS) defined by relapse, progression, death from any cause and initiation of a new therapy. For prognostication, we first evaluated the six variables of IPS-6 (corresponding to IPS without "stage IV" item) in this population. ENI was tested adjusted on the retained IPS variables. Univariate and multivariate Cox models were used to assess their prognostic ability for EFS. Cross-validation (10-fold) was used to select the more robust variables avoiding optimism. The finally selected variables constituted a score that was tested on overall survival (OS). Results Among the 220 stage IV patients, 135 (61%) were male. Median age was 33 years (range, 16-86) and 72 pts (33%) were ≥45 years. 130 pts (59%) presented constitutional symptoms. Nodular sclerosis subtype was observed in 163 pts (74%), mixed cellularity subtype in 25 pts (11%) and 47/157 pts (30%) presented EBV-positive HL. For biological parameters of IPS, 158 pts (80%) had low albumin level 15G/L in 42pts (19%) and lymphocyte count Conclusions: For stage IV HL defined by PET/CT, we developed a simple prognostic score based on age (≥45y) and liver involvement that identify a subgroup of patients with a poor outcome. These findings need to be validated in independent cohorts. Based on these results, whether HL pathogenesis differs by ENI sites should be investigated. Disclosures Bachy: Celgene: Membership on an entity's Board of Directors or advisory committees; Takeda: Research Funding; Beigene: Membership on an entity's Board of Directors or advisory committees; Roche: Honoraria; Amgen: Honoraria. Karlin:Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: travel support; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: travel support. Sarkozy:ROCHE: Consultancy. Traverse-Glehen:Takeda: Research Funding; Astra Zeneca: Other: Travel. Salles:F. Hoffmann-La Roche Ltd: Consultancy, Honoraria, Research Funding; Servier: Honoraria, Other: Advisory Board; Novartis: Consultancy, Honoraria; BMS: Honoraria, Other: Advisory Board; Morphosys: Honoraria; Janssen: Honoraria, Other: Advisory Board; Abbvie: Honoraria; Pfizer: Honoraria; Amgen: Honoraria; Celgene: Honoraria, Other: Advisory Board, Research Funding; Epizyme: Honoraria; Gilead: Honoraria, Other: Advisory Board; Acerta: Honoraria; Merck: Honoraria; Servier: Honoraria; Takeda: Honoraria. Casasnovas:Takeda: Consultancy; Gilead: Consultancy, Research Funding; AbbVie: Consultancy; Roche: Consultancy, Research Funding; Bristol-Meyers Squibb: Consultancy; Merck: Consultancy. Ghesquieres:Celgene: Consultancy; Gilead: Consultancy; Sanofi: Consultancy.

Introduction: The 17p deletion (del(17p)) resulting in loss of the TP53 gene is associated with impaired response to genotoxic agents and has an impact on PFS following BTK inhibitor and possibly also venetoclax. The del(17p) usually coincides with TP53 mutation, leading to the impairment of the p53-associated pathway. Sole TP53 mutations appear also associated with poor outcome in prospective trials. The iwCLL guidelines recommend to look for del(17p) and TP53 mutation before each line of treatment. An original approach is the functional assay, which highlights the functional abnormalities of p53 whether it is a TP53 gene disruption (del(17p) and/or TP53 mutation) or a defect of another actor in the p53 pathway. We aim to validate this functional assay on a prospective trial and to study the impact of p53 status on the clinical response regardless of the biological method. Methods: Clinical and biological data were collected from 74 CLL patients (pts) enrolled in the BOMP phase II trial of the French Innovative Leukemia Organization (FILO) (NCT01612988) evaluating 6 monthly courses of BOMP including bendamustine, ofatumumab and high dose methylprednisolone in fit pts with relapsing CLL. In addition to conventional screening, we focused on p53 evaluation at time of inclusion. FISH analysis for del(17p) was done with a 5% cut-off for positive result. TP53 gene mutation screening was performed by Sanger sequencing of the coding region (exons 2-11). A targeted NGS screening (19 genes including TP53, Illumina MiSeq) was also performed. The p53 functional status was determined by a flow cytometry assay based on induction of p53 and p21 protein expression after etoposide and nutlin-3 exposition, as previously described (Le Garff-Tavernier M., 2011), which allows the detection of 3 types of p53 dysfunction (A, B and C), irrespective of an ATM default. Clinical response was evaluated by PFS, OS and TTNT Kaplan-Meier analyses (MedCalc stat). Results: Data from the whole cohort are available. Median age was 64 yrs. Pts had a median of 1 (1-3) lines of treatment previous to this trial, including FCR in >90%. Concerning p53 evaluation, a del(17p) was found in 30% of cases by FISH (22/73 pts with a median of 68% positive cells, range 10-98). The percentage of p53 abnormalities increased to 41% when TP53 mutations were screened (30/73 pts with 1 to 8 mutations, median VAF 10 %, range 1.6-90). Results from the p53 functional assay were available for 69 pts showing the highest level of p53 abnormalities. Indeed, p53 dysfunction was observed in 48% of pts (33/69) including type A (n=11), type B (n=17) and type C (n=5) dysfunction. Thus, the sensitivity and specificity of the p53 functional assay to detect pts with del(17p) and/or TP53 mutation were of 87% and 84% respectively (n=68 pts for which the 3 tests were available). Interestingly, discordant results were observed in 10 pts: 4 pts with a functional p53 despite a TP53 gene disruption (3 with TP53 mutation only and 1 with del(17p) only) and conversely 6 pts with a p53 dysfunction (all with type B dysfunction) but without any TP53 gene disruption, suggesting alternative alterations of the p53 pathway. The only similarity for those latter pts is the occurrence of at least one ATM abnormality (del(11q) and/or ATM mutation). The combination of the 3 assays defines 3 groups: (1) "intact p53" (no TP53 disruption and functional p53, n=32), (2) "altered p53" (TP53 disruption and p53 dysfunction, n=26) and (3) "discordant p53" (n=10). PFS and TTNT were higher in pts without (n=38) compared to those with TP53 gene disruption (n=30) (p=0.04 for both). The OS, even though not significant, presented a similar trend. When considering the functional status, a similar profile is observed but with a better discrimination between pts with normal p53 function (n=36) and pts with p53 dysfunction (n=32) (p=0.002 and 0.003, respectively). Combining the 3 assays, PFS and TTNT of the group 3 "discordant p53" profiles' appeared intermediate (Figure 1). Conclusion: This study shows that a p53 functional analysis can predict with an acceptable sensitivity the presence of a TP53 gene disruption. Interestingly, this functional assay coupled with cytogenetic and mutational screening could reveal a sub-group of pts with discordant results for which PFS and TTNT appeared intermediate. Evaluation of other discordant cases is mandatory to confirm these results and could lead to a wider use of this global functional approach. Figure 1. Figure 1. Disclosures Feugier: Abbvie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Gilead: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Sylvain:Gilead: Other: scientific advisor board. Schuh:Giles, Roche, Janssen, AbbVie: Honoraria. Guieze:abbvie: Honoraria; janssen: Honoraria; gilead: Honoraria. Leblond:Abbvie: Consultancy, Honoraria, Other: Travel, Accommodations, Expenses, Speakers Bureau; Roche: Consultancy, Honoraria, Other: Travel, Accommodations, Expenses, Speakers Bureau; Janssen: Consultancy, Honoraria, Speakers Bureau; Gilead: Honoraria, Speakers Bureau; Sandoz: Honoraria; Amgen: Honoraria.

Introduction: For relapsed or refractory (R/R) CLL patients (pts), combination of bendamustine and rituximab appears safe and effective (Fischer 2011). Ofatumumab monotherapy gives 58% ORR in heavily pre-treated (median 4 prior lines) R/R CLL pts (Wierda JCO 2010). High doses (HD) steroids are also active in poor prognosis pts with bulky nodal involvement or p53 impairment (Castro 2008, Xu 2010). We report a planned interim analysis of the ICLL01-BOMP phase II trial evaluating the association of Bendamustine, Ofatumumab and high-dose MethylPrednisolone for fit R/R CLL pts after 1-3 previous lines (NCT01612988). Patients and Methods: Primary endpoint was CR rate after 6 cycles (cy) of the BOMP regimen [i.e. bendamustine (70 mg/m2 d1, d2), ofatumumab (1000 mg d1;15 on cy#1-2 and d1 on cy#3-6) and HD methylprednisolone (1 g/m2 d1-3)]. The c#1 was preceded by an ofatumumab (300 mg) prephase. Response evaluation (IWCLL 2008) was done 3 months (m) after the last cy along with blood and bone marrow 10-color flow MRD analysis. Results: Among the 55 pts of this analysis, median age was 64 years (44-76). CIRS-G comorbidity score was 2-6 in 61% and pts had received 2-3 lines in 37% of the cases. Prior FCR-like regimens (50 (91%) patients) had been followed by relapse within 2y in 22/55 and 5/55 pts were fludarabine-refractory (FR). IGVH was unmutated (UM) in (47/52) 90.4%. Karyotypes were complex in 18/46 (39%) cases. Distribution according to FISH hierarchical model was: del(17p) in 15 (27%), del(11q) in 14 (26%), trisomy 12 in 4 (7%), del(13q) in 17 (31%) and normal in 5 (9%). Mutations on the TP53, SF3B1 and NOTCH1 genes occurred in 17 (31%), 14 (26%) and 5 (9%) pts, respectively. According to published risk stratification (Zenz, 2012), 34/55 pts (62%) belonged to the “highest-risk” group with either TP53 disruption (deletion and/or mutation) (n=19) and/or early relapse within 2 years post-FCR (n=22). The remaining patients belonged to either the “high-risk” group (UM-IGVH and/or Highb2mic and/or del11q) accounting for 17 pts (31%) or to the “low-risk” group (or non evaluable) accounting for 4 (7%) pts. Overall, 292 BOMP cy (mean 5.3 cy/pts) were delivered. Safety analysis recorded 158 grade 3-4 adverse events (G3-4/AE) with according to cy: neutropenia: 20.8%, thrombocytopenia: 11.3%, anemia: 2.4%, infection: 5,8%, hyperglycemia: 7,5%, liver enzyme elevation: 1,4%, cutaneous reaction: 1,4%, ofatumumab infusion related reaction: 0,3% and other AE: 3,4%. Overall 43 out of 55 pts (78.2%) had at least one G3-4/AE. Twenty-eight severe adverse events were reported in 20 pts. Treatment interruption before planned 6 cy occurred for pts' decision (n=3), excessive toxicity (n=5) or early progressive disease (PD) (n = 4). Response in the ITT population was 76.4% ORR with 20% CR (n=11), 56.4% PR (n=31 including 5 nPR and 1 CRi), 9.1% stable disease (n=5), 10.9% PD (n=6) and 3.6% (n=3) non evaluable. Blood MRD obtained in 45 pts was negative ( With median follow-up of 16.2 (5.1-23.6) months (m) we observed 9 deaths, related to PD (n=5), EBV-induced lymphoproliferation (n=1), PML encephalitis (n=1), sepsis/pancytopenia (n=1) or unknown origin (n=1). We recorded 22 relapses (including 4 Richter Syndromes) resulting in treatment in 17 cases, with a BTK inhibitor in 8 cases. The median OS has not been reached (estimation 84% at 18 m) (Fig 1B). The median PFS was 18.4 m (95%CI, 14.6-22.2) and the median time to next treatment 17.6 m (95%CI, 12.9-22.4). With 5 cases censored at time of RIC-Allo, the PFS (censored analysis) was 17.5 m (95%CI, 13.2-21.8). (Fig 1A) After univariate analysis, ORR was lower in the “highest-risk” (64,6%, p=0.01), del(17p) (40%, p=0.003), TP53 mutation (47.1%, p=0.01) and complex karyotype (61.2%, p=0.024) groups. PFS was shorter in the “highest-risk” (14 m, p=0.046), FR (4.96 m, p Conclusion: Relapse treatment of CLL is a challenge especially after prior FCR-like treatments, accounting for >90% of this trial population. These results in terms of response and survival appear noteworthy considering that >60% are “highest-risk” pts. This study provides important information for forthcoming comparison with next emerging CLL therapies. Figure 1 Figure 1. Disclosures de Guibert: Roche: Honoraria. Feugier:Roche: Honoraria. Schuh:Roche, Gilead, GSK, NAPP, Celgene: Honoraria. Leblond:Roche: Honoraria, Speakers Bureau. Tournilhac:mundipharma: Honoraria, Other, Research Funding; GSK: Honoraria, Other, Research Funding; Roche: Honoraria, Other, Research Funding.

Introduction: Rituximab dosing regimen is largely empirical in CLL patients and phase I study has suggested a dose response relationship in previously treated CLL patients. Pharmacokinetics data from REACH study, randomising FCR and FC for relapsed/refractory CLL, showed a correlation between rituximab exposure evaluated by AUC and Cthrough and clinical response. Pharmacokinetics analyses showed a faster clearance (CL2) of rituximab in CLL patients compared to non-Hodgkin’s lymphoma patients. We purposed to intensify rituximab regimen before the first course of FCR in order to improve rituximab exposure and increase response rate in untreated, medically fit CLL patients. Patients and Methods: Medically fit patients (cumulative illness rating scale (CIRS) score of up to 6), less than 65 years old, without 17p deletion, were enrolled between july 2012 and october 2013. Patients were stratified according to IGHV mutational status and 11q deletion. They were randomly assigned to receive either intensified pre-phase of rituximab: 500 mg total dose at day (D)0 (250 mg D-1, 250 mg D0 if leucocyte > 25 G/L), 2000 mg total dose at D1,D8 and D15 followed by 6 cycles of FCR (F 40mg/m2 PO D1-3 and C 250 mg/m2 PO D1–3; R: 500 mg/m2 D1 q 28 days: R-dense arm) or 6 cycles of FCR without prephase (F 40mg/m2 PO D1-3 and C 250 mg/m2 PO D1–3; R: 375 mg/m2 D1 cycle 1 and 500 mg/m2 D1 cycle 2-6 q 28 days, standard arm). Adverse events (AEs) were assessed using the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE, Version 3.0). The primary endpoint was the complete response (CR+CRi) rate according to iwCLL 2008 criteria associated with undetectable minimal residual disease (uMRD; < 10-4 by 8 colors FC assay) in peripheral blood and bone marrow 3 months after the last cycle. Results: 140 patients were included in this randomized phase II trial. Three patients were excluded of the analyse because of consent withdrawal: (n=1); haemolytic anemia (n=1) or detectable AgHbS (n=1). A total of 137 patients were analysed for response (ITT), 68 patients in R-dense arm, 69 in standard arm. Patients’ characteristics were well balanced between the two arms. The toxicity of rituximab intensified pre-phase was low with only one patient experiencing a grade ≥ 3 infusion related reaction, six and 12 patients experiencing neutropenia grade ≥ 3 at D8 and D15, respectively. Lymphocyte counts decreased rapidely and was lower than 5.0 G/L in 31%, 51% and 65% of patients at D8, D15 and D22. Six of 55 patients evaluable for MRD after rituximab-intensified pre-phase had less than 1% of clonal circulating cells. Toxicity of FCR was not statistically different between the two arms with 31% and 26.5% of neutropenia grade ≥ 3 for R-dense arm and standard arm, respectively. ORR were 96% (CR+CRi: 56%, PR+PRn: 40%) and 93% (CR+CRi: 55%, PR+PRn: 38%) in R-dense arm and standard-arm, respectively. The rate of CR+CRi with uMRD in marrow and peripheral blood was 26.5% and 24.6% for R-dense arm and standard arm, respectively. Conclusion: Intensified rituximab pre-phase is safe in untreated medically fit CLL patients and most of patients reached normal lymphocyte count at the end of this pre-phase. However, intensified rituximab pre-phase followed by FCR did not allow to significantly increase CR+CRi with uMRD rate compared to standard FCR. Longer follow-up of these patients is warranted. Disclosures Lepretre: Roche: Honoraria. Aurran:Roche: Honoraria. Feugier:Roche: Honoraria. de Guibert:Roche: Honoraria. Leblond:Roche: Honoraria, Speakers Bureau. Delmer:Roche: Honoraria. Cymbalista:Roche: Honoraria. Cartron:Roche: Consultancy, Honoraria.

Despite improvement in treatment strategies, virtually all chronic lymphocytic leukemia (CLL) patients will relapse and experience tumor resistance. The 17p deletion resulting in loss of the TP53 gene, found in up to 20-40% of relapsing patients, is strongly associated with impaired response to genotoxic agents, reduced progression free survival and poor overall survival. The 17p deletion usually coincides with TP53 mutation, leading to the impairment of the p53-associated pathway. In addition, sole TP53 mutations (without 17p deletion) appear also associated with poor outcome in prospective trials. However, TP53 mutation screening is time consuming, can be not exhaustive, and the respective impact of different patterns of TP53 gene impairment on p53 function and prognostic remains unclear. We previously developed a functional assay to detect p53 dysfunction (Le Garff-Tavernier, 2011) and we aim to validate this analysis on a large prospective trial. Clinical and laboratory data were collected from CLL patients (pts) enrolled in the ICLL001 – BOMP phase II trial of the French CLL intergroup (NCT01612988) evaluating a prephase of ofatumumab (300 mg) followed by 6 monthly courses of BOMP including bendamustine (70 mg/m2 d1-2), ofatumumab 1000 mg TD (d1 and d15 on 1st and 2nd courses) and high dose methylprednisolone (1 g/m2 d1-3) in fit patients with relapsing CLL and IWCLL treatment criteria. In addition to conventional screening, we focused on p53 evaluation. FISH analysis for 17p deletion was done with a 10% cut-off for positive result, TP53 gene mutation screening was performed using Sanger sequencing of the entire coding region (exons 2–11) and the p53 functional status in CLL cells was determined by a flow cytometry assay based on induction of p53 and p21 protein expression after etoposide and nutlin-3a exposition. Data from the first 55 enrolled pts are available. Sex ratio M/F was 3.3 and median age was 63.8 yrs (44.6-76.4). CLL diagnostic had been done 7,2 (1,9-16,8) years before inclusion. All patients had according to IWCLL criteria an active disease of Binet stage of A (11%), B (57%) and C (32%) respectively. Patients had been previously pretreated with a median of 1 (1-3) lines, including FCR (or FCR-like) in 51 (93%) pts and 22 (42%) pts had experienced high-risk relapses within 24 months post-FCR, with 7 (13%) pts being fludarabine refractory (less than PR after fludarabine regiment and/or response lasting less than 6 months). IGVH gene status was unmutated in 90%, elevated β2-microglobulin (>4) was found in 52%. Karyotypes were complex (≥ 3 abnormalities) in 18/46 (39%) successful cases. Using FISH, we found 15/55 (27%) del17p (median of positive cells 71%, range 10-98), 6/55 (11%) tri12, 18/55 (33%) del11q, 35/55 (64%) del13q. Results of p53 functional assay was available for 52 pts with the following results: normal in 31 pts and abnormal in 21 pts including type A (n=4), type B (n=13) and type C (n=4) dysfunction. Mutation screening was available in 55 pts. No mutation were detected in 38 pts, one significant mutation was detected in 14 pts within exon 5 (n=1), exon 6 (n=2), exon 7 (n=2), exon 8 (n=6), exon 10 (n=1) and intronic splice site (n=2) ; 3 pts had 2 mutations within exons 7 and 8 (n=1), exons 7 and 10 (n=1), exons 5 and 7 (n=1). Among the 52 pts with available functional results we found the 7 following groups (Table). In this study, the sensitivity and specificity of the p53 functional test to detect patient with 17p deletion and/or TP53 mutation was 89.5% (66.9 –99.7) and 87.9% (71.8 – 96.6) respectively. Response to p53/21 functional assay 17p deletion TP53 mutation n % Group 1 Normal No No 29 56 Group 2 Abnormal Yes Yes 13 25 Group 3 Abnormal Yes No 1 2 Group 4 Abnormal No Yes 3 5.5 Group 5 Abnormal No No 4 7.5 Group 6 Normal Yes No 1 2 Group 7 Normal No Yes 1 2 This study shows that an in vitro p53 functional analysis can predict with an acceptable sensitivity the presence of TP53 gene disruption and could be useful to identify pts with TP53 mutation without 17p deletion. Interestingly, this functional assay coupled with cytogenetic and mutational screening could reveal 3 sub-groups of pts with potential clinical consequences: i) normal p53 function despite a del17p deletion (group 6) ii) normal p53 function despite a TP53 mutation (group 7) and in contrast iii) abnormal p53 function without any TP53 gene disruption (group 5) allowing to describe alternative alterations of p53 pathway. Disclosures: Dilhuydy: Roche: Honoraria. Leblond:Roche: Consultancy, Honoraria, Membership on an entity’s Board of Directors or advisory committees, Speakers Bureau; Janssen: Honoraria, Membership on an entity’s Board of Directors or advisory committees; Mundipharma: Honoraria, Membership on an entity’s Board of Directors or advisory committees, Speakers Bureau. Feugier:Roche: Honoraria, Membership on an entity’s Board of Directors or advisory committees. Tournilhac:MUNDIPHARMA: Consultancy, travel funding Other; GSK: Consultancy, travel funding, travel funding Other; Celgene: Consultancy, teaching, teaching Other.

Abstract 2687 Classical Hodgkin lymphomas (cHL) are B lympho-proliferative disorders that can be cured in 80% of cases. The goal of current research is to identify, at diagnosis, the 20% patients, who are likely to relapse or be refractory to treatment. As cHL have an extensive micro-environment implicated in tumour growth, the prognostic value (disease-free survival) of 2 important subsets of lymphoid cells (CD45RO+ effector memory T cells and FOXP3+ regulatory T cells) of the micro-environment has been evaluated using Tissue Micro Array (TMA). Patients (n=96) treated and followed for cHL between 1998 and 2005 were included in this study. Six TMA with 3 spots per case, were built (3 formalin and 3 Bouin fixative). Immunostaining with anti-CD45RO (Dako, UCHL1, 1/400) and anti-FOXP3 (Abcam, 236A/E7 1/100) antibodies was performed on the Benchmark Ultra (Ventana). After scanning of the slides, the staining was quantified automatically using a function (pixel count) of Scanscope software (Aperio). ROC curves were used in order to calculate the best threshold for each marker, depending on the number and intensity of pixels. Survival curves were built according to these thresholds using the Kaplan Meier method and compared with the log-rank test. Then, a Cox model was used to estimate the risk of occurrence of an event in univariate and multivariate analyses. The demographic characteristics of patients and sub-types of HL were not different in the << formalin >> and << Bouin >> groups. Median follow-up of patients was 69 months (1-135). In univariate analysis, low quantities of CD45RO+ cells was associated to a 40% 5-years progression free survival (PFS) compared to a 87% 5-years PFS for patients with high number of CD45RO+ cells (p=0.003), and low number of FOXP3+ cells was related to a 56% 5-years PFS compared to a 86% 5-years PFS for patients with high number of FOXP3+ cells (p=0.026). In multivariate analysis, taking into account the International Prognostic Score (IPS) and the expression of CD15 by neoplastic cells, the association of CD45RO and FOXP3 was the only independent prognostic factor identified (p This preliminary study underlines the importance of certain subsets of cells from the microenvironment of HL in the control of tumour growth. These results are encouraging. When used in association with validated criteria, they could make it possible to identify patients at risk of relapse and/or drug resistance. Nevertheless, due to the small number of patients in our study, these findings need to be validated in a larger and/or independent cohort. Disclosures: No relevant conflicts of interest to declare.

Abstract 2931 Poster Board II-907 Introduction: PET assessment of early response allows to predict outcome of patients with DLBCL, but the more accurate criteria for early PET interpretation remain to be define. So we evaluated the prognostic value of PET after two cycles of immuno-chemotherapy and compared a semiquantitative approach using FDG uptake reduction, with two methods of visual analysis. Patients and methods: Forty five consecutive patients with newly diagnosed DLBCL treated in a single institution with rituximab and CHOP or CHOP-like regimen underwent 18F-FDG PET at baseline (PET0) and after 2 cycles of induction treatment (PET2). Images were interpreted visually according to two separate methods: - Juweid criteria (JCO 2007; 25: 571) (visual analysis-1) – A visual comparison of the FDG uptake between the residual mass and the normal hepatic tissue, a PET being considered as positive when the uptake of at least one residual mass was found greater than the liver (visual analysis-2). The quantitative approach was based on the lymphoma FDG uptake estimated by the maximal standardized uptake value (SUVmax) corrected to body weight. The SUV reduction between PET0 and PET2 (ΔSUVmax) was calculated for each patient. The ΔSUVmax cut-off was estimated to 65% by ROC analysis. Results: Patient median age was 50 years (range, 24 – 79) and 37 patients (73%) were younger than 61 years. The age-adjusted IPI score was, 2 or 3, 1 and 0 in 26 (49%), 16 (36%) and 7 (16%) patients respectively. With a median follow-up of 25 months, 6 (13%) out of 45 patients progressed or relapsed after treatment and 4 died from progressive disease. According to the visual analysis-1, PET2 was interpreted as negative in 16 (36%) patients and positive in the 29 remaining patients. Using the visual analysis-2, PET2 was negative in 25 cases (56%) and positive in 20 cases. The quantitative analysis showed a ΔSUVmax < 65% in 9 patients and a ΔSUVmax >= 65% in 36 patients (80%). The estimated efficiency of the three methods to predict patient outcome is detailed below: The probability of 2-years progression-free survival (PFS) for patients with a negative PET2 according to the visual analysis was slightly higher than those with a positive PET2 when using as well the Juweid criteria (93% vs 83%; p = 0.3), as the visual analysis-2 (95% vs 75%: p = 0.04). However, the quantitative aproach allows to better identify and split up the population of patients with a good outcome from those with a poor outcome, since the 2-years PFS was 56% in patients with a ΔSUVmax reduction less than 65% compared to a 94% 2-years PFS probability in patients with a ΔSUVmax higher than 65% (p=0.0009). A multivariate analysis was performed including the IPI score and the ΔSUVmax reduction as explanatory variables for PFS, showing that the PET2 result assessed by the ΔSUVmax reduction remains the only independant prognosis factor for PFS (p = 0.008; RR = 10). Conclusion: SUV-based assessment of PET after two courses of immuno-chemotherapy is more reliable to patient outcome than visual analysis. The SUVmax reduction is an early prognostic factor for DLBCL patients that may help to reduce false positive interpretations, and provides a useful tool to guide risk-adapted treatment. Disclosures: No relevant conflicts of interest to declare.