Kahl, Brad S.

Background: Standard first-line treatment for patients diagnosed with diffuse large B-cell lymphoma (DLBCL) is the R-CHOP regimen. Despite numerous efforts to improve on this regimen, in all comers and specifically in those with activated B-cell (ABC)-type DLBCL, results from large randomized studies have failed to show a significant clinical advantage above this standard. Recently, 2 large clinical trials in previously untreated DLBCL evaluated the combination of lenalidomide/R-CHOP (R2-CHOP) vs standard R-CHOP and demonstrated discordant results. We analyzed data from these trials to identify differences that may have impacted the disparate trial outcomes while identifying patient characteristics associated with benefit from the addition of lenalidomide across the trials. Methods: The 2 trials included in this evaluation are ROBUST, an international, randomized, double-blinded, placebo-controlled, phase III study of R2-CHOP vs placebo/R-CHOP, and the Intergroup ECOG-ACRIN 1412 (E1412) trial, a US-only, randomized, open-label, phase II study of R2-CHOP vs R-CHOP. Additional key study design differences included dosing, and subtype timing and inclusion (both studies used gene expression profiling [GEP] by NanoString). R-CHOP dosing differed only for prednisone, which was a flat 100 mg dose, d1-5 in ROBUST and 100 mg/m2, d1-5 in E1412. The lenalidomide dose and schedule varied between studies: 15 mg/d, d1-14/21 for ROBUST (210 mg/cycle) and 25 mg/d, d1-10/21 (250 mg/cycle) for E1412. ROBUST enrolled only patients prospectively identified with the ABC subtype, whereas E1412 enrolled all otherwise eligible patients and retrospectively evaluated for ABC-type with prespecified ABC-type accrual and power parameters. Both studies enrolled patients with IPI status ≥ 2, ECOG PS 0-2, and Ann Arbor stage II-IV (E1412 stage II with mass > 10 cm). The primary endpoint in both was progression-free survival (PFS; central review for ROBUST and investigator-assessed for E1412). Secondary endpoints included event-free survival (EFS; key for ROBUST), overall and complete response rates, overall survival (OS), and safety. Results: ROBUST enrolled 570 ABC patients and E1412 enrolled 280 GCB, ABC, and unclassified DLBCL patients. Patient profiles in both studies (ROBUST [ABC]/E1412 [all COO]) were similar in terms of median ages (65 y/66 y), male sex (58%/61%), and ECOG PS 1-2 (55%/63%). Patients in E1412 were more high risk: IPI 2 (42% ROBUST/34% E1412), IPI ≥ 3 (58%/66%), and Ann Arbor stage III/IV disease (87%/97%). Importantly, there was a notable difference in the time from patient diagnosis to treatment: median 31 days for ROBUST and 21 days (22% > 31 d) for E1412. Only 6% of patients in ROBUST were treated within 2 weeks of diagnosis vs 30% in E1412. At a median follow-up of ~2.5 y for both studies, E1412 met its primary endpoint of improvement in PFS with 34% reduction in the risk of PD/death (2-y PFS: 76% vs 70%) for all patients, but did not reach statistical significance in ABC-DLBCL patients for 2-y PFS (71% vs 61%) or 2-y OS (88% vs 76%). ROBUST showed no significant improvement in the primary PFS endpoint (2-y PFS: 67% vs 64%) or 2-y OS (79% vs 80%) in ABC patients. Subgroup analyses of PFS comparing R2-CHOP vs R-CHOP control within each study suggested that certain baseline factors favor the R2-CHOP arm, including: female sex, high IPI score (≥ 3), non-bulky disease (< 7 cm), and high Ann Arbor stage IV disease. Conclusion: While the ROBUST study design integrated state-of-the-art, real-time GEP to prospectively identify ABC-DLBCL patients with rapid lab turnaround time, cases of logistical delays in tissue submission for central analysis and staging procedures may have resulted in accrual of patients with lower-risk DLBCL and prolonged time from diagnosis to treatment. In contrast, E1412 retrospectively stratified patients by COO through GEP and was able to accrue higher-risk patients irrespective of COO within a shorter time from diagnosis to treatment, which among other differences (eg, smaller population size, study phase), could contribute to the improvement over R-CHOP control. Our comparative findings have significant implications for the design of future biomarker-driven trials and provide momentum for studies of novel combinations with R-CHOP in DLBCL. Further investigation into other factors, including dose intensity and their correlation with outcomes, will be presented. Disclosures Nowakowski: Celgene: Consultancy, Research Funding; NanoString: Research Funding; MorphoSys: Consultancy, Research Funding; Genentech, Inc.: Research Funding; F. Hoffmann-La Roche Ltd: Research Funding; Selvita: Membership on an entity's Board of Directors or advisory committees; Curis: Research Funding; Bayer: Consultancy, Research Funding. Chiappella:Servier: Other: advisory board, Speakers Bureau; Roche: Speakers Bureau; Teva: Speakers Bureau; Celgene: Other: advisory board, Speakers Bureau; Janssen: Other: advisory board, Speakers Bureau. Hong:Dana Farber Cancer Institute: Employment; Merck: Consultancy. Scott:Roche/Genentech: Research Funding; Celgene: Consultancy; Janssen: Consultancy, Research Funding; NanoString: Patents & Royalties: Named inventor on a patent licensed to NanoSting [Institution], Research Funding. Amengual:Appia Pharmaceuticals: Research Funding; Epizyme: Speakers Bureau. Leonard:BeiGene: Consultancy; Miltenyi: Consultancy; Sandoz: Consultancy; Gilead: Consultancy; Celgene: Consultancy; ADC Therapeutics: Consultancy; MorphoSys: Consultancy; ADC Therapeutics: Consultancy; Epizyme, Inc: Consultancy; Miltenyi: Consultancy; Genentech, Inc./F. Hoffmann-La Roche Ltd: Consultancy; Karyopharm Therapeutics: Consultancy; Akcea Therapeutics: Consultancy; Merck: Consultancy; Nordic Nanovector: Consultancy; Akcea Therapeutics: Consultancy; Bayer Corporation: Consultancy; Sandoz: Consultancy; MorphoSys: Consultancy; Gilead: Consultancy; BeiGene: Consultancy; AstraZeneca: Consultancy; Nordic Nanovector: Consultancy; Sutro Biopharma: Consultancy; Merck: Consultancy. Friedberg:Bayer: Honoraria, Other: Data & Safety Monitoring Committee; Acerta: Other: Data & Safety Monitoring Committee. Kostakoglu:F. Hoffman-La Roche: Consultancy; Genentech: Consultancy. Jurczak:Morphosys: Research Funding; Bayer: Research Funding; Roche: Research Funding; Incyte: Research Funding; Gilead: Research Funding; Celgene Corporation: Research Funding; Sandoz: Membership on an entity's Board of Directors or advisory committees, Research Funding; AstraZeneca: Membership on an entity's Board of Directors or advisory committees, Research Funding; Novo Nordisk: Research Funding; Servier: Research Funding; Takeda: Research Funding; TG Therapeutics: Research Funding; Celtrion: Research Funding; Janssen: Membership on an entity's Board of Directors or advisory committees, Research Funding; Loxo: Membership on an entity's Board of Directors or advisory committees, Research Funding. Yamamoto:Bristol-Myers Squibb: Consultancy, Honoraria; Bayer: Research Funding; Celgene Corporation: Consultancy, Honoraria, Research Funding; Mundipharma: Consultancy, Honoraria, Research Funding; Astra-Zeneca: Consultancy, Research Funding; Eisai: Consultancy, Honoraria, Research Funding; Meiji Seika Pharma: Consultancy, Honoraria; ARIAD: Research Funding; MSD: Consultancy, Honoraria; Gilead Sciences: Research Funding; Ono: Consultancy, Honoraria, Research Funding; SymBio: Research Funding; HUYA/IQVIA Services Japan: Consultancy, Honoraria; AbbVie: Consultancy, Research Funding; Chugai: Consultancy, Honoraria, Research Funding; Pfizer: Honoraria; Sumitomo Dainippon: Honoraria; Incyte: Research Funding; Janssen: Honoraria; Kyowa Kirin: Honoraria; Novartis: Honoraria, Research Funding; Otsuka: Honoraria; Sanofi: Honoraria; Solasia Pharma: Research Funding; Takeda: Consultancy, Honoraria, Research Funding. Czuczman:Celgene Corporation: Employment, Equity Ownership. Russo:Celgene Corporation: Employment, Equity Ownership. Hudak:Celgene Corporation: Employment, Equity Ownership; Novartis: Employment, Equity Ownership. Zhang:Celgene Corporation: Employment, Equity Ownership. Wade:Celgene: Employment, Equity Ownership. Kahl:ADC Therapeutics: Consultancy, Research Funding; BeiGene: Consultancy; TG Therapeutics: Consultancy; Seattle Genetics: Consultancy. Vitolo:Abbvie: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; F. Hoffmann-La Roche: Speakers Bureau; Juno Therapeutics: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Kite: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Gilead: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Janssen: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celgene: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. OffLabel Disclosure: Yes, these trials discuss off-label clinical trial investigation of lenalidomide plus R-CHOP in patients with newly diagnosed diffuse large B-cell lymphoma.

Background: Mantle Cell Lymphoma (MCL) is an aggressive form of Non Hodgkin Lymphoma (NHL) and typically presents in patients over the age of 60 years. Bendamustine and rituximab (BR) combination is one of the standard treatments for MCL and is given to patients for whom high dose chemotherapy with autologous stem cell rescue is planned in the first remission. Progression free survival (PFS) with BR is approximately 36 months (Rummel M Lancet 2013; Flinn IW Blood 2014) and the regimen is overall well tolerated. Venetoclax (VEN) is an orally available inhibitor of BCL2, an anti-apoptotic protein highly expressed in several NHL. Single agent activity has mostly been studied in a Phase I study (in various NHL histologies) where 28 MCL patients were enrolled. Overall response rate was 75% (21 of 28) but complete response (CR) rate was only 21% (6 of 28). Tumor lysis syndrome (TLS) has been associated with VEN and initial dosing requires a ramp up period (Davids MS JCO 2018). VEN has also been combined with other agents in MCL with promising activity (Tam CS NEJM 2018) VEN has been studied as a chemotherapy sensitizer and has shown pre-clinical synergy with chemotherapy. In Follicular lymphoma, BR+VEN was studied at 800mg PO continuous daily dosing and showed an excessive Grade 3-4 adverse event (AE) rate of 78% compared to historical studies of 46% (Zinzani ASH 2016). We hypothesize that, in MCL, VEN can be safely combined with BR at a lower dose and intermittent dosing with improvements to the response rate based on historical controls and maintain a better safety profile. Study Design: This Phase II single arm, multicenter study evaluates VEN at a max dose of 400mg with BR (Bendamustine 90mg/m2 IV day 1 and 2; rituximab 375mg/m2 IV or SQ equivalent day 1) for six 28-day cycles in untreated patients with MCL over the age of 60 years (NCT03834688). Cycle 1 will include a VEN dose titration over the 4 week course (20mg D1-7, 50mg D8-14, 100mg D15-21, and 200mg D22-28). For Cycles 2-6, VEN will be given at 400mg daily x 10 days starting with day 1. Participants are followed for 6 cycles, though will be followed for progression and survival afterward. Participants may receive maintenance rituximab at investigator's discretion. Eligible participants, age 60 years or older, must have biopsy proven untreated MCL with t(11;14) or cyclin D1 expression, though a short course of steroids is allowed for symptomatic MCL. They must have adequate organ function and not require any prohibited concomitant medications. Primary outcome is CR rate as assessed by the Lugano criteria. We estimate a historical CR rate of BR after induction of about 70%. A 15% increase in this rate, to 85% CR, is considered promising for the combination. To achieve this goal, the study will enroll 56 participants (53 eligible) to achieve a 90% power to detect the difference with a 10% Type I error rate. We will also evaluate PFS and overall survival. TLS is an AE of interest and will be evaluated after 19 participants have been enrolled and treated during cycle 1. Minimal residual disease (MRD) will be assessed throughout the study. MRD from peripheral blood will be compared to bone marrow aspirates in all participants undergoing bone marrow aspirate at the end of treatment. Tumor samples at screening and progression will be collected for future study. This study is conducted through PrECOG and is funded by Genentech, a member of the Roche Group. Venetoclax is co-developed by Genentech and AbbVie. The study is slated to open in Fall of 2019 at 10 US sites. Figure Disclosures Portell: AbbVie: Research Funding; Pharmacyclics: Consultancy; Janssen: Consultancy; Genentech: Consultancy, Research Funding; Amgen: Consultancy; Bayer: Consultancy; BeiGene: Consultancy, Research Funding; Kite: Consultancy, Research Funding; Acerta/AstraZeneca: Research Funding; TG Therapeutics: Research Funding; Xencor: Research Funding; Roche/Genentech: Research Funding; Infinity: Research Funding. Bennani:Seattle Genetics: Other: Advisory board; Adicet Bio: Other: Advisory board; Kite Pharma: Other: Advisory board; Seattle Genetics: Other: Advisory board; Adicet Bio: Other: Advisory board; Purdue Pharma: Other: Advisory board; Purdue Pharma: Other: Advisory board; Purdue Pharma: Other: Advisory board; Bristol-Myers Squibb: Research Funding; Bristol-Myers Squibb: Research Funding; Bristol-Myers Squibb: Research Funding; Adicet Bio: Other: Advisory board; Seattle Genetics: Other: Advisory board; Kite Pharma: Other: Advisory board; Kite Pharma: Other: Advisory board. Naik:Celgene: Other: Advisory board. Parsons:Celgene: Speakers Bureau; Amgen: Speakers Bureau. Kahl:BeiGene: Consultancy; ADC Therapeutics: Consultancy, Research Funding; Seattle Genetics: Consultancy; TG Therapeutics: Consultancy. OffLabel Disclosure: Venetoclax is not approved for use in MCL.

INTRODUCTION Complete staging via bone marrow assessment is standard of practice for most newly diagnosed non-Hodgkin lymphoma (NHL) patients, though the methods and patterns of bone marrow assessment vary in clinical practice. The 2014 Lugano Classification recommends that in diffuse large B cell lymphoma (DLBCL), positron emission tomography-computed tomography (PET/CT) alone can designated advanced-stage disease in many, but not all cases. For most other NHL subtypes, obtaining bone marrow biopsy (BMB) remains recommended. We aimed to assess clinical practice patterns of marrow assessment and the performance of PET/CT in the clinical setting. METHODS The Lymphoma Epidemiology of Outcomes (LEO) cohort is a prospective cohort from 8 academic medical centers. All patients were enrolled in the cohort within 6 months of diagnosis, and prospectively followed. Patients with lymphoma enrolled in the cohort between July 2015 and June 2017 were included for study. Baseline clinical characteristics at diagnosis, whether BMB and/or PET/CT were performed, and the result of these assessments were extracted from the database. Bone marrow involvement on PET/CT was abstracted via review of radiology reports. No central review of images was utilized. RESULTS In total, 3,251 patients were included, consisting of the following subtypes: DLBCL (n=1,098), follicular lymphoma (FL n=730), mantle cell lymphoma (MCL n=302), T-cell lymphoma (TCL n=278), marginal zone lymphoma (MZL n=269), other NHL (n=505) and composite lymphoma (n=69). Other clinical characteristics are shown in table 1. Staging BMB was obtained in 78% of patients, PET/CT was obtained in 56%, both BMB and PET/CT were obtained in 46% while neither were obtained in 9% (table 1). There were significant differences in lymphoma subtype between patients having any bone marrow assessment vs no bone marrow assessment (p<0.0001). MCL (96%) and DLBCL (94%) most frequently had any bone marrow assessment, while MZL was least frequently assessed (84%). Patients undergoing any bone marrow assessment had higher median lactate dehydrogenase (247 U/L vs 206 U/L, p=0.0002). Among the 8 enrolling medical centers, the frequency of bone marrow biopsy at diagnosis ranged from 53% to 86%, and the frequency of PET/CT at diagnosis ranged from 34% to 94% (p<0.0001, table 1). Among patients with DLBCL who had positive bone marrow by either PET/CT or BMB (N=107), 41% (44/107) were positive by BMB only, 19% (20/107) were positive by PET/CT only, and 40% (43/107) were positive by both. Figure 1 shows results of similar analyses for FL, MCL, MZL, and TCL. Using BMB as a gold standard for marrow involvement, the sensitivity, specificity, positive predictive value (PPV) and negative predictive value (NPV) of PET/CT for marrow assessment in DLBCL is 49%, 90%, 68% and 91%, respectively. Data for other subtypes are shown in table 2. Patients undergoing both PET/CT and BMB had lower median LDH (231 U/L vs 254 U/L, p=0.0032) than those undergoing one or neither assessments. CONCLUSION Overall, 91% of all patients with newly diagnosed NHL had bone marrow assessments via either PET/CT, BMB or both. The significant variation in the frequency of BMB and PET/CT use among the 8 centers reflects a lack of clear consensus on staging practices regarding bone marrow assessment. The sensitivity of PET/CT for detection of marrow involvement was less than 50% across all subtypes. It is possible the sensitivity of PET/CT could be improved via a centralized review process of the images, as is performed in some clinical trials, however practical approaches for implementing such reviews in clinical practice have not been developed. Between 92-100% of all positive bone marrows were detected by BMB, except in cases with DLBCL in which 19% of positive bone marrows were missed by BMB but detected by PET/CT. Thus, in our analysis, BMB more reliably captured marrow involvement that PET/CT in all subtypes in which both assessments were performed. However, neither PET/CT nor BMB alone were able to identify all cases of bone marrow involvement and use of both modalities may be necessary in cases where marrow involvement would have clinically important implications. Disclosures Rutherford: Juno Therapeutics Inc: Consultancy, Honoraria; Janssen Scientific Affairs: Consultancy, Honoraria; Seattle Genetics: Consultancy, Honoraria; Verastem: Consultancy, Honoraria; Karyopharm: Honoraria, Membership on an entity's Board of Directors or advisory committees; AstraZeneca: Consultancy, Honoraria; Celgene: Consultancy, Honoraria; Heron: Consultancy, Honoraria. Kahl:ADC Therapeutics: Consultancy, Research Funding; Seattle Genetics: Consultancy; TG Therapeutics: Consultancy; BeiGene: Consultancy. Lossos:Janssen Scientific: Membership on an entity's Board of Directors or advisory committees; NIH: Research Funding; Seattle Genetics: Membership on an entity's Board of Directors or advisory committees. Friedberg:Acerta: Other: Data & Safety Monitoring Committee; Bayer: Honoraria, Other: Data & Safety Monitoring Committee. Casulo:Celgene: Research Funding; Roche: Other: Travel, accommodation, expenses; Gilead: Honoraria, Other: Travel, accommodation, expenses. Cohen:Astra Zeneca: Research Funding; Takeda Pharmaceuticals North America, Inc.: Research Funding; Hutchison: Research Funding; Gilead/Kite: Consultancy; Bristol-Meyers Squibb Company: Research Funding; LAM Therapeutics: Research Funding; UNUM: Research Funding; Lymphoma Research Foundation: Research Funding; ASH: Research Funding; Seattle Genetics, Inc.: Consultancy, Research Funding; Janssen Pharmaceuticals: Consultancy; Genentech, Inc.: Consultancy, Research Funding. Nastoupil:TG Therapeutics: Honoraria, Research Funding; Novartis: Honoraria; Spectrum: Honoraria; Celgene: Honoraria, Research Funding; Janssen: Honoraria, Research Funding; Genentech, Inc.: Honoraria, Research Funding; Gilead: Honoraria; Bayer: Honoraria. Flowers:Denovo Biopharma: Consultancy; Spectrum: Consultancy; National Cancer Institute: Research Funding; Optimum Rx: Consultancy; Burroughs Wellcome Fund: Research Funding; Acerta: Research Funding; Bayer: Consultancy; BeiGene: Consultancy, Research Funding; Eastern Cooperative Oncology Group: Research Funding; TG Therapeutics: Research Funding; Genentech, Inc./F. Hoffmann-La Roche Ltd: Consultancy, Research Funding; Gilead: Consultancy, Research Funding; Karyopharm: Consultancy; AstraZeneca: Consultancy; Pharmacyclics/Janssen: Consultancy, Research Funding; AbbVie: Consultancy, Research Funding; V Foundation: Research Funding; Millenium/Takeda: Research Funding; Celgene: Consultancy, Research Funding. Cerhan:Janssen: Membership on an entity's Board of Directors or advisory committees; Celgene: Research Funding; NanoString: Research Funding. Martin:Sandoz: Consultancy; Karyopharm: Consultancy; Celgene: Consultancy; Teneobio: Consultancy; I-MAB: Consultancy; Janssen: Consultancy.

Key Points Five-year follow-up of S1106 demonstrates similar efficacy, MRD negativity, and 5-year survival with RH or RB, but RH was more toxic than RB. RB showed excellent efficacy and survival and less toxicity compared with a cytarabine-based regimen in transplant-eligible MCL patients.

Abstract Background: Bendamustine and rituximab (BR) is a commonly chosen frontline treatment for grade 1-2 (G 1-2) follicular lymphoma (FL). This regimen resulted in significantly longer progression-free survival (PFS) and less toxicity compared to R-CHOP in the STiL trial [Rummel et al., 2013] and similar results were observed when comparing BR vs. R-CHOP/R-CVP in the confirmatory BRIGHT trial [Flinn et al., 2014, updated ASCO 2017]. Importantly, patients (pts) with grade 3A (G 3A) FL were excluded from these studies, yet the conclusions are often extrapolated to the treatment of G 3A pts. Notably, G 3A pts were included in the GALLIUM trial which used both bendamustine as well as CHOP backbones. Several retrospective studies of FL pts treated with frontline R-CHOP have demonstrated equivalent or improved overall survival (OS) for G 3A relative to G 1-2 FL (Koch et al., 2016, Mustafa et al., 2017, Yuan et al., 2017, Maeshima et al., 2013). Early disease progression after diagnosis and treatment with frontline R-CHOP has been identified as a strong predictor of poor OS in FL pts [Casulo et al. 2015], but has not been assessed in pts treated with frontline BR. We retrospectively evaluated outcomes of a large cohort of FL pts treated with frontline BR and stratified the results based on histologic grade and early vs. late progression. Methods: We reviewed medical records of adult (age >18) pts with FL treated with frontline BR at 18 US cancer centers. There was no central pathology review; each academic institution confirmed the diagnosis and grade of FL. Pts with unknown grade, grade 3B, or cutaneous FL were excluded. Baseline characteristics between grades were evaluated with the Chi-Square test for categorical variables and the Mann-Whitney U for continuous variables. Outcomes were calculated from time of initiation of BR. Patients were grouped according to whether or not they had progression of disease within 24 months of BR initiation (POD24). OS and PFS were estimated using the Kaplan-Meier method and compared using the log-rank test. Results: 687 pts were included (616 G 1-2, 71 G 3A). Median age at diagnosis was 60 years (range 21-94) with 53% men. The median time from diagnosis to treatment with BR was 1 month (range 0-139). The median duration of follow up for the entire cohort was 39 months. Characteristics including age, gender, ethnicity, ECOG, stage, LDH, and FLIPI are shown in the Table, and did not significantly differ between G 1-2 and G 3A pts. Rates of complete response (CR) and partial response (PR) to BR were similar between G 1-2 and G 3A (72%/22% vs. 66%/21%, respectively, p=0.114) but progressive disease (PD) was higher in G 3A pts (11.9%) relative to G 1-2 (4.8%, p=0.025). As shown in the Figure (A and B), 3-year PFS and OS was significantly longer for G 1-2 vs. G 3A pts (75% vs. 65%, log rank p= 0.035 and 90% vs. 86%, log rank p=0.007, respectively). Seventy-six (12.3%) of the 616 G 1-2 pts and 13 (18.3%) of the 71 G 3A pts experienced POD24 (p=0.19). For pts with both G 1-2 and G 3A FL, POD24 was associated with inferior OS (3-year OS 95% vs. 57% for G 1-2 pts, log rank p<0.0001 and 3-year OS 93% vs. 37% for G 3A pts, log rank p<0.0001) compared to patients without POD24. Conclusions: G 3A FL pts have an inferior OS and are significantly more likely to have PD to frontline BR compared to G 1-2, which differs from the published experience with R-CHOP. Similar to outcomes after frontline treatment with R-CHOP, POD24 after frontline BR for FL is associated with very poor OS. Future studies are needed to address optimal frontline management of pts with G3A as well as for pts with any grade FL with POD24 after frontline BR. Disclosures Nastoupil: Novartis: Honoraria; Genentech: Honoraria, Research Funding; Gilead: Honoraria; Celgene: Honoraria, Research Funding; TG Therappeutics: Research Funding; Karus: Research Funding; Merck: Honoraria, Research Funding; Spectrum: Honoraria; Janssen: Research Funding; Juno: Honoraria. Cerhan:Jannsen: Other: Scientific Advisory Board; Celgene: Research Funding; Nanostring: Research Funding. Maurer:Celgene: Research Funding; Nanostring: Research Funding; Morphosys: Research Funding. Smith:Genentech: Research Funding; Incyte Corporation: Research Funding; Portola Pharmaceuticals: Research Funding; Pharmacyclics: Research Funding; Merck Sharp and Dohme Corp.: Consultancy, Research Funding; Acerta Pharma BV: Research Funding; Seattle Genetics: Research Funding. Lossos:Affimed: Research Funding. Portell:TG therapeutics: Research Funding; Amgen: Consultancy; Kite: Research Funding; AbbVie: Research Funding; BeiGene: Research Funding; Acerta: Research Funding; Genentech/Roche: Consultancy, Research Funding; Infinity: Research Funding. Calzada:Seattle Genetics: Research Funding. Cohen:Bristol-Myers Squibb: Research Funding; Infinity Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees; Infinity Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees; Millennium: Consultancy, Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees; Janssen: Research Funding; Seattle Genetics: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; AbbVie: Consultancy, Membership on an entity's Board of Directors or advisory committees; Janssen: Research Funding; Bristol-Myers Squibb: Research Funding; Celgene: 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; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Millennium: Consultancy, Membership on an entity's Board of Directors or advisory committees; Pharmacyclics: Consultancy, Membership on an entity's Board of Directors or advisory committees; Takeda: Research Funding; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; BioInvent: Consultancy; Pharmacyclics: Consultancy, Membership on an entity's Board of Directors or advisory committees; Seattle Genetics: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Takeda: Research Funding; BioInvent: Consultancy. Ghosh:Spectrum: Consultancy; SGN: Consultancy, Research Funding, Speakers Bureau; Pharmacyclics, an Abbvie Company: Consultancy, Research Funding, Speakers Bureau; TG Therapeutics: Honoraria, Research Funding; Celgene: Consultancy; Juno: Consultancy, Research Funding; Abbvie: Consultancy, Speakers Bureau; Genentech: Research Funding; F. Hoffman-La Roche Ltd: Research Funding; PCYC: Consultancy, Research Funding, Speakers Bureau; Gilead: Consultancy, Speakers Bureau; Forty seven Inc: Research Funding. Barta:Janssen: Membership on an entity's Board of Directors or advisory committees; Merck, Takeda, Celgene, Seattle Genetics, Bayer: Research Funding. Caimi:Kite Pharma: Other: Advisory Board Participation; Genentech: Other: Advisory Board PArticipation, Research Funding; Celgene: Speakers Bureau; Kite Pharma: Other: Advisory Board Participation. Danilov:Gilead Sciences: Consultancy, Research Funding; Aptose Biosciences: Research Funding; Bayer Oncology: Consultancy, Research Funding; Astra Zeneca: Consultancy; Genentech: Consultancy, Research Funding; Takeda Oncology: Research Funding; TG Therapeutics: Consultancy; Verastem: Consultancy, Research Funding. Martin:AstraZeneca: Consultancy; Seattle Genetics: Consultancy; Janssen: Consultancy; Kite: Consultancy; Gilead: Consultancy; Bayer: Consultancy. Kamdar:Seattle Genetics: Speakers Bureau; Genentech: Consultancy. Kahl:AstraZeneca: Consultancy; Acerta: Consultancy; Juno: Consultancy; CTI: Consultancy; Celgene: Consultancy; Gilead: Consultancy; Seattle Genetics: Consultancy; Abbvie: Consultancy; Genentech: Consultancy; ADC Therapeutics: Consultancy. Hill:Abbvie: Honoraria, Membership on an entity's Board of Directors or advisory committees; Seattle Genetics: Honoraria, Membership on an entity's Board of Directors or advisory committees; Pharmacyclics: Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees; Pharmacyclics: 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; Seattle Genetics: Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Research Funding; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees; Genentech: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees.

Abstract Introduction For patients with Stage III/IV Hodgkin lymphoma (HL), lack of response as assessed by PET scan following cycle 2 (PET2) of doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD) is predictive of poor clinical outcomes. SWOG Study S0816 utilized response-adapted therapy, where patients achieving a complete remission (CR) on PET2 (Deauville Score ≤ 3) continued 4 additional cycles of ABVD and those patients unable to achieve a complete remission (CR) on PET2 (Deauville Score > 3) were switched to therapy with escalated bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, and prednisone (eBEACOPP) for 6 cycles. This study demonstrated a 2-year PFS of 64% in the PET2+ patients after switching to eBEACOPP, which was much higher than expected (Press 2016). Herein, we report the 5-year follow-up of survival and toxicities of the patients treated on S0816. Methods Patients with Stage III/IV HL were enrolled to S0816 from 7/1/09-12/2/12 (n=358). Eligible patients were age 18-60 years, had measurable disease, no prior lymphoma therapy, a Zubrod performance status of 0-2, and no serious medical comorbidities. Patients were treated with response-adapted therapy as above. A subset of 336 eligible and HIV-negative patients were analyzed. Of 336, 331 had central review of PET2. PFS and OS estimates were calculated using the Kaplan-Meier method. The two-sided Fisher's exact test was used to compare the rate of second cancer between patients switched to treatment eBEACOPP and those treated with continued ABVD after 2 initial cycles of ABVD. Results The median age of patients was 32 years (range, 18-60). All were Stage III/IV and 51% had an International Prognostic Score of ≥ 3. PET2 was negative in 271 patients (82%) and positive in 60 patients (18%). Of PET2+ patients, 49 (82%) switched to eBEACOPP as planned and 11 (18%) declined. Median follow-up is now 5.9 years (range, 0.2-8.3 years). Eighty-five (25%) patients have either progressed or died, for an estimated 5-year PFS of 74% (95% CI: 69%-79%; Figure 1). There were 64 (24%) events in those patients who were PET2- for a 5-year PFS of 76% (95% CI: 71-81%; Figure 2). There were 20 (33%) events in those patients who were PET2+ for a 5-year PFS of 65% (95% CI: 51-76%; Figure 2). One event occurred in a patient without central review of PET2. Nineteen patients have died for an estimated 5-year overall survival of 94% (95% CI: 91%-96%; Figure 1). Eleven (3%) patients died of HL including 6 (2%) that had PET2- and 5 (8%) that had PET2+. Other causes of death included: treatment-related toxicity [sepsis (eBEACOPP n=1), bleomycin lung injury (eBEACOPP n=1; ABVD n=1), and graft versus host disease (ABVD n=1)]; second primary cancers [(eBEACOPP n=2; cervical cancer and non-Hodgkin lymphoma (NHL)]; and unknown causes (ABVD n=2). Post-therapy grade 3 adverse events were uncommon but included 1 case each of heart failure, peripheral neuropathy, prolonged neutropenia, diarrhea, DVT (catheter-related) in patients who received continued ABVD and osteonecrosis of hips/shoulders in patients who received eBEACOPP. There were 13 (4%) cases of reported second cancers, including 7 (14%) in patients treated with eBEACOPP [1 each of myelodysplastic syndrome, kidney, melanoma, NHL, cervical, medullary thyroid, and basal cell carcinoma] and 6 (2%) in patients treated with ABVD (1 each of kidney, melanoma, NHL, bladder, prostate, and squamous cell carcinoma; 2-sided Fisher's exact P value = 0.001). Conclusions The long-term overall survival of the patients treated on S0816 remains high (94%) at 5 years. Despite historical data suggesting favorable clinical outcomes in patients with a negative PET2, nearly 25% of these patients experienced relapse events, demonstrating limitations of a PET-adapted approach and of standard frontline therapy with ABVD. In patients who were PET2+, PFS was favorable relative to historical series, but was associated with a high rate of secondary malignancies. Our results emphasize the importance of long-term follow-up in this disease, and the need for better biomarkers at diagnosis of HL and less toxic approaches for patients with a positive PET2. Acknowledgment In memory of Oliver W. Press, principal investigator of this trial, who died in 2017. Disclosures Straus: DAVA Oncology: Consultancy, Honoraria; Medical Crossfire: Speakers Bureau; Millenium (Takeda): Consultancy, Research Funding; JUNO: Consultancy; Bayer: Consultancy; Onco Tracker: Consultancy; Seattle Genetics: Consultancy; Roch China: Speakers Bureau; InPractice Elselvier: Consultancy; Memorial Sloan Kettering Cancer Center: Employment. Rimsza:NanoString: Other: Inventor on the patent for the Lymph2Cx assay. Bartlett:ImaginAB: Research Funding; Genentech: Research Funding; Forty Seven: Research Funding; Bristol-Meyers Squibb: Research Funding; Merck & Co: Research Funding; Novartis: Research Funding; Celgene: Research Funding; Gilead: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Pfizer: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Pharmacyclics: Research Funding; Immune Design: Research Funding; Acerta: Membership on an entity's Board of Directors or advisory committees; Seattle Genetics: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; KITE: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Astra Zeneca: Research Funding; Millennium: Research Funding; Janssen: Research Funding; Affimed: Research Funding; Novartis: Research Funding; Pharmacyclics: Research Funding. Evens:Janssen: Consultancy; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees; Bayer: Consultancy; Seattle Genetics, Inc.: Membership on an entity's Board of Directors or advisory committees, Research Funding; Pharmacyclics International DMC: Membership on an entity's Board of Directors or advisory committees; Affimed: Consultancy; Abbvie: Consultancy; Novartis: Consultancy; Tesaro: Research Funding; Acerta: Consultancy. LaCasce:Seattle Genetics: Consultancy, Honoraria; Bristol-Myers Squibb: Other: Data safety and monitoring board; Research to Practice: Speakers Bureau; Humanigen: Consultancy, Honoraria. Barr:AbbVie, Gilead: Consultancy. Leonard:Gilead: Consultancy; Sutro: Consultancy; BMS: Consultancy; Juno: Consultancy; MEI Pharma: Consultancy; Celgene: Consultancy; Bayer: Consultancy; Pfizer: Consultancy; AstraZeneca: Consultancy; Biotest: Consultancy; Novartis: Consultancy; Karyopharm: Consultancy; Genentech/Roche: Consultancy; ADC Therapeutics: Consultancy; United Therapeutics: Consultancy. Kahl:Genentech: Consultancy; Celgene: Consultancy; Acerta: Consultancy; AstraZeneca: Consultancy; Juno: Consultancy; CTI: Consultancy; ADC Therapeutics: Consultancy; Abbvie: Consultancy; Gilead: Consultancy; Seattle Genetics: Consultancy. Smith:BMS: Consultancy; Portola: Honoraria. Friedberg:Bayer: Honoraria.

Abstract Introduction: The optimal initial management of mantle cell lymphoma (MCL) is unknown, but aggressive induction chemoimmunotherapy followed by autologous stem cell transplant confers long remission durations and is standard for younger patients. Cytarabine-based induction achieves higher rates of MRD-negativity compared to anthracycline-based induction regimens and correlates with improved outcomes. Whether a similar benefit exists after bendamustine-rituximab (RB) induction is unknown. S1106 compared induction R-HyperCVAD/MTX/ARAC (RH) or RB followed by autologous stem cell transplantation (ASCT). We previously reported similar 2-year (yr) progression-free survival (PFS) and overall survival (OS) with either regimen, and provocatively found that MRD negativity was similar with both regimens. RH was more toxic than RB and had higher stem cell mobilization failure rates. Methods: Inclusion criteria were untreated stage III, IV or bulky stage II MCL, Cyclin D1 +, age > 18-65, and adequate organ function. Randomization was stratified by MIPI. Patients (pts) received either 4 cycles of RH or 6 cycles of RB followed by ASCT. MRD was assessed at baseline and post induction. Extraction of genomic tumour DNA from paraffin embedded tissue or bone marrow aspirate and PCR amplification of IGH-VDJ, IGH-DJ, and IGK regions was performed followed by high-throughput sequencing to determine the tumor clonotype(s) (Adaptive Biotechnologies). DNA from peripheral blood mononuclear cells (PBMC) and plasma was amplified and sequenced to determine lymphoma molecules per million diploid genomes. Herein we report the results of the updated analysis at a median follow-up (mFU) of 5 yrs. Results: Fifty-two of 53 pts were evaluable. Baseline characteristics were similar between the two groups except for more female pts in the RH group. This study was closed based on prespecified criteria of stem cell mobilization failures in the RH arm. With mFU of 5 yrs (range, 29 days-6yrs), updated ORR (94.1% RH vs. 85.7% RB) and CR (41% RH vs. 43% RB) rates were similar. The 5-yr estimated PFS was 62% and 66% and the 5-yr estimated OS was 74% and 80% for RH and BR, respectively (Fig.1). Increased grade 3/4 toxicity and inadequate stem cell mobilization was seen in the RH arm thus challenging its use as an induction platform for future upfront MCL trials. 9/17 pts in RH and 23/35 pts in RB arm underwent ASCT. A landmark analysis was performed evaluating 5-yr PFS and 5-yr OS with and without ASCT in each arm. (Table 1) 27 patients consented to optional MRD assessment, with 12 paired serial samples (baseline and post induction). Overall, the estimated 5 yr PFS was 90% for all patients who achieved MRD negative status at the end of RB. Long-term toxicity included acute myeloid leukemia (N=1) in the RH arm at 5.4 yrs after diagnosis and lung cancer (n=1) in the RB arm at 2.9 yrs after diagnosis. Conclusion: The optimal induction regimen prior to ASCT in the initial management of MCL is a source of significant debate. Our initial findings supported RB as an effective platform with the ability to achieve MRD negativity. Long-term results of this study continue to demonstrate excellent response rates, 5-yr PFS and 5-yr OS with either RH or RB without any new toxicity signal. The 5-yr outcomes with RB compare favorably to more aggressive cytarabine-based induction regimens. Thus, R-Bendamustine could be an excellent backbone for induction therapy in transplant eligible patients and needs to be tested in larger phase III trials. Support: NIH/NCI grants CA180888, CA180819, CA180821, CA180820, and in part by Sequenta, Inc. (Adaptive Biotechnologies) Disclosures Kamdar: Seattle Genetics: Speakers Bureau; Genentech: Consultancy. Chen:Millennium Pharmaceuticals: Consultancy, Research Funding; Affimed: Research Funding; Seattle Genetics: Consultancy, Honoraria, Research Funding, Speakers Bureau; Bristol-Myers Squibb: Consultancy, Research Funding; Pharmacyclics: Consultancy, Research Funding; Merck & Co., Inc.: Consultancy, Research Funding, Speakers Bureau; Genentech Inc.: Consultancy. Rimsza:NanoString: Other: Inventor on the patent for the Lymph2Cx assay. Barr:AbbVie, Gilead: Consultancy. Phillips:Genentech: Consultancy; Seattle Genetics: Consultancy; Bayer: Consultancy; Gilead: Consultancy; Pharmacyclics: Consultancy, Research Funding; Abbvie: Research Funding. Leonard:ADC Therapeutics: Consultancy; Karyopharm: Consultancy; Bayer: Consultancy; Pfizer: Consultancy; Genentech/Roche: Consultancy; Gilead: Consultancy; Juno: Consultancy; Sutro: Consultancy; AstraZeneca: Consultancy; BMS: Consultancy; Novartis: Consultancy; Celgene: Consultancy; MEI Pharma: Consultancy; United Therapeutics: Consultancy; Biotest: Consultancy. Kahl:Seattle Genetics: Consultancy; AstraZeneca: Consultancy; Gilead: Consultancy; Abbvie: Consultancy; Celgene: Consultancy; Acerta: Consultancy; CTI: Consultancy; Juno: Consultancy; ADC Therapeutics: Consultancy; Genentech: Consultancy. Friedberg:Bayer: Honoraria. Smith:Portola: Honoraria; BMS: Consultancy.

Abstract Background: Checkpoint blockade therapies (CBT) have substantially improved outcomes for patients in a variety of cancers. However, they are associated with a unique spectrum of immune-related adverse events (AEs). Additionally, unlike standard chemotherapy, many patients (pts) remain on CBT for prolonged periods of time, thus immune-related symptomatic AEs may be chronic or low grade therefore important to capture long term tolerability when used as a single agent or in combination with chemotherapy. In this study, we applied the Toxicity over Time (ToxT) analytic approach (Thanarajasingam et al, Lancet Oncol 2016), which incorporates the dimension of time and includes chronic lower grade events, to the first 6 cohorts (A-F) of a Phase 1/2 ECOG-ACRIN sponsored study of the combinations of Brentuximab Vedotin (BV) and the CBT therapies ipilimumab (Ipi) and nivolumab (Nivo) in pts with relapsed or refractory Hodgkin lymphoma (R/R HL). Methods: Pts with confirmed R/R HL were treated with BV 1.8mg/kg + Ipi 1or 3 mg/kg (n=23); or Nivo 3mg/kg + BV: 1.2 or 1.8 mg/kg (n=19). BV was administered every 21 days for 16 cycles; Ipi every 21 days x 4 and then every 3 months for one year and Nivo every 21 days for up to 2 years. Seven symptomatic (subjective) AEs were selected: fatigue, peripheral sensory neuropathy (PSN), nausea/vomiting (NV), rash/skin (RS), diarrhea, ocular-all types, and hair loss. Treatment-related AEs of any grade were investigated by conventional maximum grade toxicity analysis (ToxC) and ToxT methods up to 12 cycles. Using ToxT, mean AE grades over cycles were analyzed for time trend with repeated measures models, time to grade 2 or higher AE (gr2+) was analyzed with time-to-event analysis; AE profile over the entire course of the study was summarized by area under the curve (AUC) analyses. Comparisons were performed between treatment groups: BV/Ipi(A-C arms) and BV/Nivo (D-F arms). Results: 9/23 (BV/Ipi) and 6/19 (BV/Nivo) pts completed 10 cycles. For BV/Ipi vs. BV/nivo, ToxC provides overall incidence rates (any grade): fatigue 52% vs 26% (p=0.09); PSN 61% vs 53%; NV 70% vs 53% ; RS 65% vs. 37% (p=0.07); diarrhea 57% vs. 21% (p=0.02); ocular 17% vs. 21% ; and hair loss 17% vs. 0% (p=0.06), respectively. Gr3 AE occurred in 1 pt (2.4%) each for PSN, NV, diarrhea, and 6 pts (14.3%) for RS, and were similar between BV/ipi and BV/nivo. AUC from ToxT which captures chronic lower grade AEs suggested for BV/Ipi: diarrhea (p=0.02) and NV (p=0.03) are significantly more substantial over time with a trend seen for fatigue (p=0.07), RS (p=0.07) and hair loss (p=0.07) . Additionally, ToxT captures the trajectory of AEs, demonstrated a rising incidence and worsening grade of PSN (BV-related) on BV/Ipi (c1: 9% gr1, c2: 21% gr1 5% gr2, c5: 11% gr1 and c10: 22% gr2 [p=0.005], Fig 1a). In contrast there was a slow but significant decreasing incidence of NV on both combinations; for BV/Nivo (c1:52% gr1, c5: 26% gr1 and c10: 22% gr1) and BV/Ipi (c1: 47% gr1 ,c5: 0% and c10 1% gr1) with p=0.006 (Fig 1b). RS and diarrhea appear early on treatment and are not cumulative (Fig1c and 1d). There is no significant difference in the time to gr 2+ toxicities in any of the 7 AE. Combining all 7 AEs and using the maximum grade as a pilot measure of overall AE burden , ToxC indicates no difference in any grade (100% vs 100%) but a significantly higher gr 3+ incidence (35% vs. 11%) for BV/Ipi. Additionally, ToxT further elucidates that BV/Ipi is associated with significantly higher overall AE over time (Fig 2a, p=0.02) and compared to BV/Nivo a significantly higher risk of developing gr 2+ toxicity ( 57% vs 16% gr2 + event by day 50) (HR=0.41, p=0.02, Fig 2b). Conclusions: The CBT therapies Ipi and Nivo, in combination with BV, are overall both well tolerated over time, although BV/Ipi has a higher overall AE burden. Neither regimen has significant cumulative immune toxicity. Results of this analysis should be interpreted in the context of limited number of pts in both cohorts. A larger scale examination of this analysis is planned to incorporate both phase 1 and the ongoing phase 2 components of E4412. Compared with conventional tox analysis, ToxT delineated important additional and clinically relevant depictions of AEs over time and adds a more comprehensive assessment of the tolerability of chronically administered immune therapies for lymphoma. Disclosures Hong: Merck: Consultancy. Ansell:Regeneron: Research Funding; Merck & Co: Research Funding; Takeda: Research Funding; Seattle Genetics: Research Funding; Bristol-Myers Squibb: Research Funding; Affimed: Research Funding; Pfizer: Research Funding; Celldex: Research Funding; Trillium: Research Funding; LAM Therapeutics: Research Funding. Cohen:Bristol-Myers Squibb: Research Funding; Millennium: Consultancy, Membership on an entity's Board of Directors or advisory committees; Janssen: Research Funding; Janssen: Research Funding; Bristol-Myers Squibb: Research Funding; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees; Celgene: 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; Infinity Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees; Infinity Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees; Seattle Genetics: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; BioInvent: Consultancy; AbbVie: Consultancy, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Millennium: Consultancy, Membership on an entity's Board of Directors or advisory committees; Pharmacyclics: Consultancy, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Takeda: Research Funding; BioInvent: Consultancy; Pharmacyclics: Consultancy, Membership on an entity's Board of Directors or advisory committees; Seattle Genetics: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Takeda: Research Funding. Advani:Kura: Research Funding; Janssen: Research Funding; Bayer: Membership on an entity's Board of Directors or advisory committees, Other: Participated in an advisory board; Autolus: Membership on an entity's Board of Directors or advisory committees, Other: Participated in an advisory board; Bristol Myers Squibb: Membership on an entity's Board of Directors or advisory committees, Other: Participated in an advisory board, Research Funding; Roche/Genentech: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Participated in an advisory board, Research Funding; Cell Medica: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Participated in an advisory board; Kyowa: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Participated in an advisory board; Astra Zeneca: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Participated in an advisory board; Millenium: Research Funding; Seattle Genetics: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Participated in an advisory board, Research Funding; Celgene: Research Funding; Agensys: Research Funding; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Infinity: Research Funding; Forty Seven Inc.: Research Funding; Celgene: Research Funding; Pharmacyclics: Membership on an entity's Board of Directors or advisory committees, Research Funding; Merck: Research Funding; Regeneron: Research Funding; Gilead/Kite: Membership on an entity's Board of Directors or advisory committees, Other: Participated in an advisory board. Barta:Janssen: Membership on an entity's Board of Directors or advisory committees; Merck, Takeda, Celgene, Seattle Genetics, Bayer: Research Funding. Svoboda:Pharmacyclics: Consultancy, Research Funding; Merck: Research Funding; KITE: Consultancy; TG Therapeutics: Research Funding; Bristol-Myers Squibb: Consultancy, Research Funding; Regeneron: Research Funding; Seattle Genetics: Consultancy, Research Funding; Kyowa: Consultancy. Karmali:AstraZeneca: Speakers Bureau; Gilead: Speakers Bureau. Witzig:Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding. Dueck:Bayer: Employment; Phytogine: Employment; Pfizer: Honoraria. Kahl:Genentech: Consultancy; Acerta: Consultancy; AstraZeneca: Consultancy; Abbvie: Consultancy; Juno: Consultancy; Celgene: Consultancy; Seattle Genetics: Consultancy; ADC Therapeutics: Consultancy; CTI: Consultancy; Gilead: Consultancy. Diefenbach:Merck: Consultancy, Research Funding; Bristol-Myers Squibb: Consultancy, Research Funding; Acerta: Research Funding; Millenium/Takeda: Research Funding; Genentech: Consultancy; Denovo: Research Funding; Incyte: Research Funding; Seattle Genetics: Consultancy, Research Funding; Trillium: Research Funding.

Abstract Background: Bortezomib has efficacy in follicular lymphoma (FL). Though generally well tolerated, it is associated with a few known toxicities, including neurotoxicity. As a chronically administered agent, it is important to investigate the tolerability of bortezomib over time as a single agent and in combination with chemotherapy. The current method of summarizing adverse events (AEs) -focusing on the maximum grade and reporting only grade 3 or higher incidences- fails to capture toxicity that evolves over time or chronic low grade AEs that may occur at significant expense to patients' quality of life. In this study, we applied the Toxicity over Time (ToxT) analytic approach (Thanarajasingam et al, Lancet Oncol 2016), which graphically and analytically depicts AEs longitudinally, to a randomized Phase 2 ECOG-ACRIN sponsored study, E2408, to characterize chronic toxicity of bortezomib (V) when added to standard bendamustine-rituximab (BR) induction in previously untreated high risk FL. Methods: In E2408, patients (pts) were randomized to one of 3 arms at a 1:2:2 ratio: A) BR x 6 followed by maintenance rituximab (MR) x 2 years (yrs) vs B) BVR x 6 (bortezomib 1.3 mg/m2 IV/SQ days 1, 4, 8, 11) then MR x 2 yrs vs C) BR x 6 then MR x 2 yrs + lenalidomide 20mg/day x 1 yr. Pts enrolled 1/2011-5/2015. This analysis focuses on the 6 cycles of induction only, with arms A and C combined. Six AEs of interests were selected, 4 symptomatic (subjective) AEs (peripheral sensory neuropathy (PSN), diarrhea, febrile neutropenia, fatigue); and 2 non-symptomatic (objective) AEs (neutropenia and thrombocytopenia). Treatment-related post baseline AEs of any grade were investigated by conventional maximum grade toxicity analysis (ToxC) and ToxT methods. The mean AE grades over cycles were analyzed by repeated measures models, time to grade 2 or higher (gr2+)AE were analyzed with time-to-event analysis; and AE profile over the entire course of the study was summarized by area under the curve (AUC) analyses. Comparisons were performed between treatment arms (BVR vs. BR). Results: All 280 randomized treated pts (187 on BR, 93 on BVR) were included in the analysis regardless of eligibility status; 87% (163/187 BR, 81/93 BVR) completed all 6 cycles. Analyzing the symptomatic AEs,ToxC indicates that the overall incidence of grade 3+ PSN was significantly higher in BVR (12%) than BR (1%) (p<.0001). Additional, ToxT captures the trajectory, demonstrating a rapid, rising incidence and worsening grade of PSN on BVR vs BR over 6 cycles in a steam plot of mean gr. by cycle (Fig 1a) and bar chart of incidence and grade per cycle (c1: 13% gr1 3% gr2, c6: 36% gr1 12% gr2 6% gr3 on BVR; c1: 3% gr1, c6: 10% gr1 1% gr2 on BR, Fig. 1b). Risk of developing gr2+ PSN was significantly higher in BVR than BR with 28% vs 0.5% by day 100 (HR=0.01, p<.0001, Fig. 1c). ToxC captures a higher incidence of grade 3+ diarrhea on BVR (7% vs. 1% , p=.01) while AUC from ToxT includes chronic lower grade diarrhea, that is substantial over time on BVR vs. BR (p<.0001), but is not cumulative. Furthermore, the risk of developing gr2+ diarrhea affecting drug tolerability is significantly higher on BVR than BR(13% vs 5% by day 100) (HR=0.3, p=.05). Febrile neutropenia appeared to be similar, and fatigue was marginally more severe under BVR (p=.06 by AUC). For objective AEs, ToxC reveals no significant difference in neutropenia or thrombocytopenia BVR vs BR (neutropenia gr 3+: 36% vs 31%, p=.4; thrombocytopenia gr3+: 10% vs. 5%, p=.12). However, ToxT illustrates that neutropenia is cumulative, worsening over repeated exposure to drug (c1: 2% gr1 5% gr2 5% gr 3+ , c6: 7% gr1 10% gr2 12% gr3+ both arms combined; p<.0001) on mean grade over time (Fig. 2a). In contrast, thrombocytopenia does not worsen with continued treatment (Fig 2b, p=.73). Conclusions: Compared with conventional toxicity analysis (ToxC), ToxT delineated important additional and clinically relevant depictions of both symptomatic and laboratory AEs over time for bortezomib added to BR in FL pts. In patients receiving BVR, close monitoring is suggested for PSN, diarrhea and neutropenia for reassessment of risks and benefits, symptom interventions and dose modification. Longitudinal toxicity analyses such as ToxT can guide AE interventions as well as patient and clinician education, and provide a more patient-centered toxicity assessment of chronically administered therapies for lymphoma. Disclosures Hong: Merck: Consultancy. Evens:Seattle Genetics, Inc.: Membership on an entity's Board of Directors or advisory committees, Research Funding; Acerta: Consultancy; Abbvie: Consultancy; Bayer: Consultancy; Janssen: Consultancy; Novartis: Consultancy; Tesaro: Research Funding; Affimed: Consultancy; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees; Pharmacyclics International DMC: Membership on an entity's Board of Directors or advisory committees. Advani:Kura: Research Funding; Roche/Genentech: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Participated in an advisory board, Research Funding; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Bristol Myers Squibb: Membership on an entity's Board of Directors or advisory committees, Other: Participated in an advisory board, Research Funding; Celgene: Research Funding; Pharmacyclics: Membership on an entity's Board of Directors or advisory committees, Research Funding; Kyowa: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Participated in an advisory board; Bayer: Membership on an entity's Board of Directors or advisory committees, Other: Participated in an advisory board; Cell Medica: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Participated in an advisory board; Infinity: Research Funding; Gilead/Kite: Membership on an entity's Board of Directors or advisory committees, Other: Participated in an advisory board; Janssen: Research Funding; Astra Zeneca: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Participated in an advisory board; Regeneron: Research Funding; Seattle Genetics: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Participated in an advisory board, Research Funding; Forty Seven Inc.: Research Funding; Merck: Research Funding; Millenium: Research Funding; Agensys: Research Funding; Celgene: Research Funding; Autolus: Membership on an entity's Board of Directors or advisory committees, Other: Participated in an advisory board. Gascoyne:NanoString: Patents & Royalties: Named Inventor on a patent licensed to NanoString Technologies. Witzig:Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding. Dueck:Bayer: Employment; Pfizer: Honoraria; Phytogine: Employment. Kahl:Genentech: Consultancy; Acerta: Consultancy; ADC Therapeutics: Consultancy; Seattle Genetics: Consultancy; Abbvie: Consultancy; Juno: Consultancy; Gilead: Consultancy; Celgene: Consultancy; CTI: Consultancy; AstraZeneca: Consultancy.

Abstract Background: There remains a critical need to identify untreated HR FL patients (pts) who are at increased risk of early progression and death with conventional treatment. Data examining baseline PET has been reported to be prognostic in FL, however, there remains a paucity of data analyzing this in the context of bendamustine/rituximab (BR) induction followed by maintenance rituximab (MR). We examined the prognostic impact of baseline PET metabolic imaging from the randomized BIONIC study for pts with untreated HR FL. Methods: The BIONIC study conducted by the ECOG-ACRIN Cancer Research Group enrolled untreated grade I/II or IIIa FL pts with HR disease defined as GELF high tumor burden and/or FLIPI score of 3-5. Pts were randomized to: a) standard BR induction x 6 followed by maintenance rituximab (MR) q 2 months x 2 years vs b) bortezomib + BR x 6 followed by MR q 2 months x 2 years vs c) BR x 6 followed by q 2 months MR x 2 years + lenalidomide given concurrently with the first year of MR. Survival analyses showed no significant differences in 4-year progression-free survival (PFS) or overall survival (OS) for any study arm (Evens AM et al, ASH 2017). All pts were thus pooled for the purpose of analyzing baseline PET imaging and other characteristics and for correlation with clinical outcomes. Kruskal-Wallis & Wilcoxon Rank Sum test were used to assess differences in distribution of: metabolic measurements (SUVmax and SUVmean of the dominant mass (i.e., the mass/lesion with the highest SUV uptake); metabolic tumor volume (MTV); and total lesion glycolysis (TLG) by categorical variables); induction treatment response; and end-of-induction (EOI) PET response vis-à-vis Deauville scoring (1-3 = negative). Cox proportional hazards regression was used to correlate these metabolic measurements with PFS & OS and multivariable analyses were conducted. An optimal cutoff threshold (grouping into 'High' or 'Low' categories) was used for the metabolic measurements that were significantly associated with PFS & OS. Results: Metabolic data were received and measurements were analyzed centrally on 182 (71%) of 257 eligible pts. The EOI overall response rate (ORR) for all pts on study was 92% with a complete remission (CR) rate of 73%. Additionally, 12% of pts experienced early progression of disease (POD) within 2 years. SUVmax was borderline for association with PFS (P=0.06) and MTV and TLG were not associated with PFS or OS. We demonstrated a statistically significant linear relationship between continuous SUVmean score with PFS and OS, and thereafter, used the minimum p-vlaue approach to determine the optimal cutoff threshold of 7.03 to group pts into 'High' and 'Low' risk groups; with this threshold, baseline SUVmean of the dominant mass was categorized as high risk in 27% pts. The 4-year PFS rates for SUVmean low vs high groups were 80% (95% CI 72, 90%) vs 55% (40, 74%), respectively, P<0.001; and the corresponding 4-year OS rates were 93% (89, 98)% vs 80% (95% CI 69, 93%), respectively, P=0.01 (see Fig. 1). Sensitivity analyses showed no differences in baseline SUVmean by study arm, GELF or FLIPI. The only clinical characteristic that varied among patients with low vs high baseline SUVmean was Black race (0.8 vs 8.0%, respectively, Chi-square P=0.08); there were no other differences based on age, sex, stage, FLIPI, GELF status, ECOG PS, LDH, or # of extranodal sites. In addition, baseline SUVmean correlated with EOI PET (negative EOI PET with baseline SUVmean Low vs High: 81% vs 62%, respectively, P=0.03). In multivariable analyses, both baseline SUVmean and EOI PET remained significant (SUVmean: PFS HR 2.62 (95% CI 1.40-4.92), P=0.001, OS HR 2.37 (95% CI 1.01-5.56), P=0.02; EOI PET PFS HR 4.70 (95% CI 2.74-9.54), P<0.001, OS HR 2.78 (95% CI 1.18-6.56), P=0.01). Finally, baseline SUVmean was also strongly predictive of FL pts who experienced early 2-year POD (Chi-square P<0.001). Conclusions: High baseline SUVmean of the dominant mass was a strong independent prognostic factor for survival for untreated HR FL pts treated with BR-based induction with rituximab maintenance and significance was independent of FLIP or GELF criteria. Collectively, this represents a novel and simple method to identify FL pts at increased risk of early POD and poor survival with standard therapy. Continued investigation of combined PET imaging analyses and other correlative studies to enrich prognostication are warranted. Disclosures Hong: Merck: Consultancy. Advani:Bristol Myers Squibb: Other: Consultancy/Advisory role and Institutional Research Support; Kyowa: Other: Consulting/Advisory Role; Infinity: Other: Institutional Research Support; Pharmacyclics: Other: Institutional Research Support; Seattle Genetics: Other: Consultancy/Advisory role, Institutional Research Support; Regeneron Pharmaceuticals, Inc.: Other: Institutional Research Support; Millenium: Other: Institutional Research Support; Bayer Healthcare Pharmaceuticals: Other: Consultancy/Advisory Role; Autolus: Other: Consultancy/Advisory Role; Takeda: Other: Consultancy/Advisory Role; Celgene: Other: Institutional Research Support; Roche/Genentech: Other: Consultancy/Advisory Role, Institutional Research Support; AstraZeneca: Other: Consultancy/Advisory Role; Cell Medica: Other: Consultancy/Advisory Role; Gilead/Kite: Other: Consultancy/Advisory Role; Agensys: Other: Institutional Research Support; Kura: Other: Institutional Research Support; Forty Seven, Inc: Other: Institutional Research Support; Merck: Other: Institutional Research Support; Janssen Pharmaceutical: Other: Institutional Research Support. Gascoyne:NanoString: Patents & Royalties: Named Inventor on a patent licensed to NanoString Technologies. Witzig:Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding. Kahl:Acerta: Consultancy; Celgene: Consultancy; Abbvie: Consultancy; Juno: Consultancy; CTI: Consultancy; Gilead: Consultancy; Seattle Genetics: Consultancy; Genentech: Consultancy; AstraZeneca: Consultancy; ADC Therapeutics: Consultancy. Evens:Affimed: Consultancy; Novartis: Consultancy; Acerta: Consultancy; Bayer: Consultancy; Tesaro: Research Funding; Pharmacyclics International DMC: Membership on an entity's Board of Directors or advisory committees; Janssen: Consultancy; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees; Seattle Genetics, Inc.: Membership on an entity's Board of Directors or advisory committees, Research Funding; Abbvie: Consultancy.