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Here, we report the first comparative analysis of patient-reported outcomes (PROs) with chimeric antigen receptor T-cell therapy vs standard-of-care (SOC) therapy in second-line relapsed/refractory large B-cell lymphoma (R/R LBCL) from the pivotal randomized phase 3 ZUMA-7 study of axicabtagene ciloleucel (axi-cel) vs SOC. PRO instruments were administered at baseline, day 50, day 100, day 150, month 9, and every 3 months from randomization until 24 months or an event-free survival event. The quality of life (QoL) analysis set comprised patients with a baseline and ≥1 follow-up PRO completion. Prespecified hypotheses for Quality of Life Questionnaire-Core 30 (QLQ-C30) physical functioning, global health status/QoL, and EQ-5D-5L visual analog scale (VAS) were tested using mixed-effects models with repeated measures. Clinically meaningful changes were defined as 10 points for QLQ-C30 and 7 for EQ-5D-5L VAS. Among 359 patients, 296 (165 axi-cel, 131 SOC) met inclusion criteria for QoL analysis. At day 100, statistically significant and clinically meaningful differences in mean change of scores from baseline were observed favoring axi-cel over SOC for QLQ-C30 global health status/QoL (estimated difference 18.1 [95% confidence interval (CI), 12.3-23.9]), physical functioning (13.1 [95% CI, 8.0-18.2]), and EQ-5D-5L VAS (13.7 [95% CI, 8.5-18.8]; P < .0001 for all). At day 150, scores significantly favored axi-cel vs SOC for global health status/QoL (9.8 [95% CI, 2.6-17.0]; P = .0124) and EQ-5D-5L VAS (11.3 [95% CI, 5.4-17.1]; P = .0004). Axi-cel showed clinically meaningful improvements in QoL over SOC. Superior clinical outcomes and favorable patient experience with axi-cel should help inform treatment choices in second-line R/R LBCL. This trial was registered at www.clinicaltrials.gov as #NCT03391466.

The phase 2 CAVALLI (NCT02055820) study assessed efficacy and safety of venetoclax, a selective B-cell lymphoma-2 (Bcl-2) inhibitor, with rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) in first-line (1L) diffuse large B-cell lymphoma (DLBCL), including patients demonstrating Bcl-2 protein overexpression by immunohistochemistry (Bcl-2 IHC+). Eligible patients were ≥18 years of age and had previously untreated DLBCL, Eastern Cooperative Oncology Group performance status ≤2, and International Prognostic Index 2 to 5. Venetoclax 800 mg (days 4-10, cycle 1; days 1-10, cycles 2-8) was administered with rituximab (8 cycles) and cyclophosphamide, doxorubicin, vincristine, and prednisone (6-8 cycles) in 21-day cycles. Primary end points were safety, tolerability, and research_plete response (CR) at end of treatment (EOT). Secondary end points were progression-free survival (PFS) and overall survival. Comparative analyses used covariate-adjusted R-CHOP controls from the GOYA/BO21005 study, an appropriate contemporary benchmark for safety and efficacy. Safety and efficacy analyses included 206 patients. CR rate at EOT was 69% in the overall population and was maintained across Bcl-2 IHC+ subgroups. With a median follow-up of 32.2 months, trends were observed for improved investigator-assessed PFS for venetoclax plus R-CHOP in the overall population (hazard ratio [HR], 0.61; 95% confidence interval [CI], 0.43-0.87) and Bcl-2 IHC+ subgroups (HR, 0.55; 95% CI, 0.34-0.89) vs R-CHOP. Despite a higher incidence of grade 3/4 hematologic adverse events (86%), related mortality was not increased (2%). Chemotherapy dose intensity was similar in CAVALLI vs GOYA. The addition of venetoclax to R-CHOP in 1L DLBCL demonstrates increased, but manageable, myelosuppression and the potential of improved efficacy, particularly in high-risk Bcl-2 IHC+ patient subgroups. Key Points: • The phase 2 CAVALLI study assessed efficacy and safety of venetoclax + R-CHOP in patients with DLBCL, including Bcl-2+ subpopulations. • Venetoclax + R-CHOP showed potential for improved efficacy vs R-CHOP alone, supporting further investigation of venetoclax in Bcl-2+ DLBCL.

While no widely accepted standard treatment regimen exists for primary central nervous system lymphoma (PCNSL), growing evidence supports an approach that incorporates autologous stem cell transplantation (ASCT) as consolidative therapy when feasible. In November 2011, the Alberta Hematology Tumor Team established a new clinical practice guideline (CPG) for PCNSL involving high-dose methotrexate (HDMTX)/cytarabine-based induction followed by ASCT for eligible patients using a thiotepa and busulfan (TBu) conditioning regimen that omitted cyclophosphamide from the regimen that was used before 2011. This retrospective study analyzed all 64 patients with PCNSL diagnosed consecutively in 3 Canadian centers between November 2011 and December 2017 to evaluate adherence to the 2011 CPG and associated outcomes. Of the 64 patients with PCNSL, 38 were initiated on the transplantation-eligible protocol, of whom 30 underwent successful ASCT, and 26 were deemed transplantation-ineligible, of whom only 7 completed the transplantation-ineligible HDMTX-based protocol. For the transplantation-eligible and -ineligible cohorts, the projected 3-year overall survival (OS) rates were 83.8% and 14.3% and progression-free survival (PFS) rates were 78.1% and 0%, respectively. For the 30 patients who underwent TBu/ASCT, the 3-year OS and PFS rates were 92.7% and 88.9%, respectively, with no treatment-related mortality or significant neurotoxicity. These real-world results highlight the efficacy and tolerability of TBu/ASCT consolidation for PCNSL in patients young and fit enough for an intensive treatment program, along with the significant need for improved therapies for older or less fit patients with PCNSL.

Background Patients with diffuse large B-cell lymphoma (DLBCL) with an International Prognostic Index (IPI) ≥3 are at higher risk for relapse after a complete response (CR) to first-line rituximab-based chemotherapy (R-chemo). Everolimus has single-agent activity in lymphoma. PILLAR-2 aimed to improve disease-free survival (DFS) with 1 year of adjuvant everolimus. Patients and methods Patients with high-risk (IPI ≥3) DLBCL and a positron emission tomography/computed tomography-confirmed CR to first-line R-chemo were randomized to 1 year of everolimus 10 mg/day or placebo. The primary end point was DFS; secondary end points were overall survival, lymphoma-specific survival, and safety. Results Between August 2009 and December 2013, 742 patients were randomized to everolimus (n = 372) or placebo (n = 370). Median follow-up was 50.4 months (range 24.0–76.9). Overall, 47% of patients were ≥65 years, 50% were male, and 42% had an IPI of 4 or 5. 48% and 67% completed everolimus and placebo, respectively. Primary reasons for everolimus discontinuation versus placebo were adverse events (AEs; 30% versus 12%) and relapsed disease (6% versus 13%). Everolimus did not significantly improve DFS compared with placebo (hazard ratio 0.92; 95% CI 0.69–1.22; P = 0.276). Two-year DFS rate was 77.8% (95% CI 72.7–82.1) with everolimus and 77.0% (95% CI 72.1–81.1) with placebo. Common grade 3/4 AEs with everolimus were neutropenia, stomatitis, and decreased CD4 lymphocytes. Conclusions Adjuvant everolimus did not improve DFS in patients already in PET/CT-confirmed CR. Future approaches should incorporate targeted agents such as everolimus with R-CHOP rather than as adjuvant therapy after CR has been obtained. ClinicalTrials.gov NCT00790036

Background: Outcomes are poor for patients with large B-cell lymphoma (LBCL) who relapse early or are refractory to first-line therapy. Furthermore, patients receiving second-line standard-of-care (SOC) therapy often report poor health-related quality of life (QoL; Lin V, et al. J Clin Oncol. 2020;38:e20070). In the ZUMA-7 (NCT03391466) pivotal Phase 3, randomized, open-label, multicenter study of axi-cel (an autologous anti-CD19 chimeric antigen receptor [CAR] T-cell therapy) versus SOC, we conducted the first comparative analysis of patient-reported outcomes (PROs) with CAR T-cell therapy versus SOC as second-line treatment in relapsed/refractory (R/R) LBCL. Methods: PRO instruments, including the EORTC QLQ-C30 (cancer-specific 30-item questionnaire including global health status, functional, and symptom scales) and the EQ-5D-5L (a general questionnaire with 5 QoL domains plus a global assessment), were administered at baseline (prior to treatment), Day 50, Day 100, Day 150, Month 9, and every 3 months from randomization up to 24 months or time of event-free survival event (disease progression, death from any cause, or new lymphoma therapy), whichever occurred first. The QoL analysis set was defined as all patients who had a baseline PRO and ≥1 measure completed at Day 50, Day 100, or Day 150. Prespecified hypotheses for 3 PRO domains (EORTC QLQ-C30 Physical Functioning, EORTC QLQ-C30 Global Health Status/QoL, and EQ-5D-5L visual analog scale [VAS]) were tested using a mixed-effect model with repeated measures at Day 100 and subsequent time points if previous time points were statistically significant. False Discovery Rate was used to adjust P values across key endpoints; sensitivity analyses were conducted to control for covariates and patterns of missingness. A clinically meaningful change was defined as 10 points for each EORTC QLQ-C30 score and 7 points for EQ-5D-5L VAS score. Exploratory analyses on other domains of EORTC QLQ-C30 and EQ-5D-5L were also performed. Results: Of 359 patients enrolled in the ZUMA-7 study, 296 patients (165 axi-cel, 131 SOC) had baseline PROs and ≥1 follow-up measure and were included for analysis. Overall, 70% of patients had primary refractory disease, 42% had high second-line age-adjusted International Prognostic Index (2-3), and 30% were ≥65 years old. For patients in the QoL analysis set treated with axi-cel versus SOC, there was a statistically significant (P Additional exploratory analyses of PRO endpoints (eg, EORTC QLQ-C30 role functioning, social functioning, fatigue, nausea/vomiting, dyspnea, insomnia, appetite loss, diarrhea, and EQ-5D-5L index [US value set]) also showed improvements with axi-cel over SOC. Conclusion: ZUMA-7, the first randomized, global, multicenter Phase 3 study of axi-cel versus SOC in second-line R/R LBCL, showed that treatment with axi-cel results in clinically meaningful improvement in QoL over SOC at Day 100 as measured by multiple validated PRO instruments. Score comparisons at later timepoints warrant cautious interpretation, particularly in the SOC arm, as attrition due to disease progression, new lymphoma therapy, or death may select patients with the best outcomes. The data also suggest faster recovery to pretreatment QoL with axi-cel compared with SOC. The superior clinical outcomes and patient experience with axi-cel over SOC should help inform treatment choices in second-line R/R LBCL. These data are reported on behalf of all ZUMA-7 investigators and contributing Kite members. Figure 1 Figure 1. Disclosures Elsawy: Kite, a Gilead Company: Consultancy, Honoraria; Celgene/BMS: Honoraria; Novartis: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; BMS: Consultancy. Chavez: MorphoSys, AstraZeneca, BeiGene, Genentech, Kite, a Gilead Company, and Epizyme: Speakers Bureau; ADC Therapeutics: Consultancy, Research Funding; MorphoSys, Bayer, Karyopharm, Kite, a Gilead Company, Novartis, Janssen, AbbVie, TeneoBio, and Pfizer: Consultancy; AstraZeneca: Research Funding; BMS: Speakers Bureau; Merk: Research Funding. Avivi: Novartis: Speakers Bureau; Kite, a Gilead Company: Speakers Bureau. Larouche: Gilead: Consultancy. Wannesson: Novartis: Consultancy, Research Funding; MSD: Consultancy; BMS: Consultancy; AstraZeneca: Consultancy; Roche: Consultancy, Research Funding. Cwynarski: Kite, a Gilead Company: Consultancy, Other: travel to scientific conferences, Speakers Bureau; Takeda: Consultancy, Other: travel to scientific conferences, Speakers Bureau; Celgene: Consultancy; Atara: Consultancy; Gilead: Consultancy, Speakers Bureau; Incyte: Consultancy, Speakers Bureau; BMS/Celgene: Other: travel to scientific conferences; Janssen: Consultancy, Other: travel to scientific conferences; Roche: Consultancy, Other: travel to scientific conferences, Speakers Bureau. Osman: Kite, a Gilead Company: Consultancy. Davison: Merck: Consultancy; AstraZeneca: Consultancy; Janssen: Consultancy; Novartis: Consultancy; Gilead: Consultancy; Abbvie: Consultancy; Celegene: Consultancy. Rudzki: Kite, a Gilead Company: Consultancy, Research Funding, Speakers Bureau; Novartis: Consultancy, Research Funding, Speakers Bureau; Amgen: Consultancy; MSD: Consultancy; Roche: Consultancy, Speakers Bureau; BMS-Celgene: Consultancy. Dahiya: Jazz Pharmaceuticals: Research Funding; Miltenyi Biotech: Research Funding; Kite, a Gilead Company: Consultancy; Atara Biotherapeutics: Consultancy; BMS: Consultancy. Dorritie: OncLive/Institutional Perspectives on Cancer presentation: Honoraria; Janssen: Research Funding; University of Pittsburgh/UPMC Hillman Cancer Center: Current Employment; Juno/BMS: Research Funding; F. Hoffman-La Roche Ltd: Research Funding; Kite, a Gilead Company: Research Funding; Genmab: Research Funding; SITC presentation: Honoraria. Jaglowski: CRISPR Therapeutics: Consultancy; Takeda: Consultancy; Juno: Consultancy; Kite, a Gilead Company: Consultancy, Research Funding; Novartis: Consultancy, Research Funding. Radford: AstraZeneca: Current holder of individual stocks in a privately-held company; Takeda: Consultancy, Honoraria, Research Funding, Speakers Bureau; ADC Therapeutics: Consultancy, Current holder of individual stocks in a privately-held company, Honoraria, Speakers Bureau; BMS: Honoraria. Morschhauser: Servier: Consultancy; Roche: Consultancy, Speakers Bureau; Gilead: 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; Incyte: Membership on an entity's Board of Directors or advisory committees; BMS: Consultancy, Membership on an entity's Board of Directors or advisory committees; Epizyme: Consultancy, Membership on an entity's Board of Directors or advisory committees; Chugai: Honoraria; Genmab: Membership on an entity's Board of Directors or advisory committees; F. Hoffmann-La Roche Ltd: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Genentech, Inc.: Consultancy; Janssen: Honoraria; Celgene: Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees; AstraZenenca: Membership on an entity's Board of Directors or advisory committees. Cunningham: AstraZeneca: Research Funding; Clovis Oncology: Research Funding; MedImmune: Research Funding; Roche: Research Funding; Celgene: Research Funding; Bayer: Research Funding; 4SC: Research Funding; Eli Lilly: Research Funding; OVIBIO: Membership on an entity's Board of Directors or advisory committees. Martin Garcia-Sancho: Kern Pharma: Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company); Incyte: Consultancy; Takeda: Honoraria; Novartis: Consultancy; Eusa Pharma: Consultancy; Clinigen: Consultancy; Kyowa Kirin: Consultancy; Morphosys: Consultancy; Gilead: Consultancy, Honoraria; Servier: Consultancy, Honoraria, Other: Travel/Accommodations/Expenses; Janssen: Honoraria, Research Funding; Celgene/BMS: Consultancy; Celgene: Honoraria, Other: travel; Roche: Consultancy, Honoraria, Other: Travel/Accommodations/Expenses. Tzachanis: Partner: Consultancy; Takeda: Consultancy, Speakers Bureau; EUSA: Consultancy; Kite, a Gilead Company: Consultancy, Research Funding, Speakers Bureau; Kyowa Kirin: Consultancy; Magenta: Consultancy; Bristol Myers Squibb: Research Funding; Genentech: Research Funding; Incyte: Research Funding; Fate Therapeutics: Research Funding. Karmali: Roche: Consultancy; BMS/Celgene/Juno: Consultancy, Research Funding; EUSA: Consultancy; Kite, a Gilead Company: Consultancy, Research Funding, Speakers Bureau; Morphosys: Consultancy, Speakers Bureau; Epizyme: Consultancy; Janssen/Pharmacyclics: Consultancy; AstraZeneca: Speakers Bureau; Genentech: Consultancy; Karyopharm: Consultancy; BeiGene: Consultancy, Speakers Bureau; Takeda: Research Funding. Kekre: Gilead: Consultancy, Honoraria; Novartis: Consultancy, Honoraria; Celgene: Consultancy, Honoraria. Thieblemont: Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accommodations, Expenses ; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees; Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accommodations, Expenses , Research Funding; Bristol Myers Squibb/Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accommodations, Expenses ; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Gilead Sciences: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accommodations, Expenses ; Kyte: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accommodations, Expenses ; Incyte: Honoraria, Membership on an entity's Board of Directors or advisory committees; Abbvie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accommodations, Expenses ; Cellectis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accommodations, Expenses ; Hospira: Research Funding; Bayer: Honoraria; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accommodations, Expenses . Enblad: Kite, a Gilead Company: Consultancy; Gilead Sciences: Consultancy. Dreger: Riemser: Consultancy, Research Funding, Speakers Bureau; Novartis: Consultancy, Speakers Bureau; Bluebird Bio: Consultancy; Janssen: Consultancy; Gilead Sciences: Consultancy, Speakers Bureau; Roche: Consultancy, Speakers Bureau; BMS: Consultancy; AstraZeneca: Consultancy, Speakers Bureau; AbbVie: Consultancy, Speakers Bureau. Malladi: Gilead: Honoraria, Other: Travel support; Gilead Science: Consultancy. Joshi: Open Health: Current Employment; Kite, a Gilead Company: Consultancy, Research Funding; various clients via employment: Consultancy, Research Funding. Wang: Kite, a Gilead Company: Consultancy, Research Funding; additional companies through employment with Open Health: Consultancy, Current Employment, Research Funding. Solem: OPEN Health: Current Employment; Kite, a Gilead Company: Consultancy; multiple clients through employment at OPEN Health: Research Funding. Thornton Snider: Kite, a Gilead Company: Current Employment, Current holder of individual stocks in a privately-held company, Current holder of stock options in a privately-held company; Gilead: Current holder of individual stocks in a privately-held company, Current holder of stock options in a privately-held company. To: Kite, a Gilead Company: Current Employment, Other: stock or other ownership ; NantWorks: Ended employment in the past 24 months. Kersten: BMS/Celgene: Consultancy, Honoraria; Roche: Consultancy, Honoraria, Other: Travel support, Research Funding; Novartis: Consultancy, Honoraria, Other: Travel support; Miltenyi Biotec: Consultancy, Honoraria, Other: Travel support; Celgene: Research Funding; Takeda: Research Funding; Kite, a Gilead Company: Consultancy, Honoraria, Other: Travel support, Research Funding.

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

Circulating levels of angiopoietin-like 2 (ANGPTL2), a proinflammatory and proatherogenic protein, are elevated in patients with coronary artery disease (CAD). We hypothesized that high-intensity intermittent exercise (HIIE), known to be beneficial in patients with CAD, would reduce circulating ANGPTL2 levels.Plasma levels of ANGPTL2 were measured before and 20 minutes, 24 hours, and 72 hours after an acute exercise session in a crossover study comparing HIIE to moderate-intensity continuous exercise (MICE) in 14 patients with CAD and 20 age-matched and 20 young healthy controls.Pre-exercise ANGPTL2 levels were 3-fold higher in patients with CAD than in age-matched controls (P0.05) and correlated negatively with Vo2max/lean body mass (P0.0001). In healthy controls, ANGPTL2 levels were low and not affected by HIIE or MICE. In patients with CAD, ANGPTL2 levels decreased significantly by 41% after 20 minutes of HIIE, a reduction that was maintained after 24 and 72 hours (P0.05). In contrast, although ANGPTL2 levels decreased by 47% after 20 minutes of MICE, they increased by 104% after 24 hours and returned to baseline values after 72 hours (P0.05). A negative correlation was observed between this increase in ANGPTL2 levels and the mean rate-pressure product (heart rate × systolic blood pressure; index of myocardial O2 consumption) measured during MICE, suggesting that subclinical ischemia might promote ANGPTL2 expression.In patients with CAD, circulating ANGPTL2 levels are acutely reduced after HIIE and transiently increased after MICE. A sustained reduction in circulating ANGPTL2 levels could contribute to the chronic beneficial cardiometabolic effects of HIIE in patients with CAD.

Bendamustine is a bifunctional alkylating agent with unique properties that distinguish it from other agents in its class. Bendamustine is used as monotherapy or in combination with other agents to treat patients with non-Hodgkin lymphoma (nhl) and chronic lymphocytic leukemia (cll). The prospective interventional open-label bend-act trial evaluated bendamustine in patients with rituximab-refractory indolent nhl (inhl) and previously untreated cll. Study objectives were to assess the safety and tolerability of bendamustine monotherapy and to provide patients with access to bendamustine before Health Canada approval. The study aimed to enrol up to 100 patients. All patients with inhl received an intravenous dose of bendamustine 120 mg/m2 over 60 minutes on days 1 and 2 for up to eight 21- or 28-day treatment cycles. All patients with cll received an intravenous dose of bendamustine 100 mg/m2 over 30 minutes on days 1 and 2 for up to six 28-day treatment cycles. Of 90 patients treated on study (16 with cll and 74 with inhl), 35 completed the study (4 with cll and 31 with inhl). The most common treatment-emergent adverse events (teaes) were nausea (70%), fatigue (57%), vomiting (40%), and diarrhea (33%)&mdash, mostly grades 1 and 2. Ondansetron was the most common supportive medication used in the patients (63.5% of those with inhl and 68.8% of those with cll). Neutropenia (32%), anemia (23%), and thrombocytopenia (21%) were the most frequent hematologic teaes, with neutropenia being the most common grade 3 or 4 teae leading to dose modification. Dose delays occurred in 28 patients (31.3%) because of grade 3 or 4 teaes, with a higher incidence of dose delays being observed in inhl patients on the 21-day treatment cycle than in those on the 28-day treatment cycle (50.0% vs. 24.1%). During the study, 33 patients (36.7%) experienced at least 1 serious adverse event, and 4 deaths were reported (all in patients with inhl). The type and frequency of the teaes reported accorded with observations in earlier clinical trials and post-marketing experiences, thus confirming the acceptable and manageable safety profile of bendamustine.

Purpose This two-stage phase IB study investigated the pharmacokinetics and safety of subcutaneous (SC) versus intravenous (IV) administration of rituximab as maintenance therapy in follicular lymphoma. Patients and Methods In stage 1 (dose finding), 124 patients who responded to rituximab induction were randomly assigned to SC rituximab (375 mg/m2, 625 mg/m2, or an additional group at 800 mg/m2) or IV rituximab (375 mg/m2). The objective was to determine an SC dose that would yield a rituximab serum trough concentration (Ctrough) in the same range as that of IV rituximab. In stage 2, 154 additional patients were randomly assigned (1:1) to SC rituximab (1,400 mg) or IV rituximab (375 mg/m2) given at 2- or 3-month intervals. The objective was to demonstrate noninferior rituximab Ctrough of SC rituximab relative to IV rituximab 375 mg/m2. Results Stage 1 data predicted that a fixed dose of 1,400 mg SC rituximab would result in a serum Ctrough in the range of that of IV rituximab. Noninferiority (ie, meeting the prespecified 90% CI lower limit of 0.8) was then confirmed in stage 2, with geometric mean Ctrough SC:Ctrough IV ratios for the 2- and 3-month regimens of 1.24 (90% CI, 1.02 to 1.51) and 1.12 (90% CI, 0.86 to 1.45), respectively. Overall safety profiles were similar between formulations (in stage 2, 79% of patients experienced one or more adverse events in each group). Local administration-related reactions (mainly mild to moderate) occurred more frequently after SC administration. Conclusion The fixed dose of 1,400 mg SC rituximab predicted by using stage 1 results was confirmed to have noninferior Ctrough levels relative to IV rituximab 375 mg/m2 dosing during maintenance, with a comparable safety profile. Additional investigation will be required to determine whether the SC route of administration for rituximab provides equivalent efficacy compared with that of IV administration.

Background: Patients with follicular lymphoma (FL) have a heterogenous prognosis. Recently a simple score, the PRIMA-PI, was developed based on the PRIMA clinical trial (Bachy et al Blood. 2018). With only two factors (beta-2-microglobulin level > 3 mg/L and bone marrow involvement), this index was at least as discriminatory as FLIPI on the training and validation cohorts. The validity of the PRIMA-PI was confirmed on Czech and German FL cohorts and a patient group from the Nordic Lymphoma Group. However, further validation is needed to confirm the use of PRIMA-PI in place of FLIPI for prognostic assessment. Indeed, in the era of new chemo-free treatments, it seems important to challenge the potency of traditional prognostic factors and scores. Recently, rituximab combined with lenalidomide (R2) was compared to conventional immunochemotherapy (R-chemo) in the phase III RELEVANCE trial. The aim of our study was to validate PRIMA-PI in the RELEVANCE trial cohort and compare its performance with FLIPI (Solal-Celigny et al. Blood. 2004) and FLIPI2 (Federico et al. JCO. 2009). A secondary objective was to evaluate potential differences in terms of prognostic bio-clinical parameters between the R2 and R-chemo arms. Methods: All patients with available data for FLIPI, FLIPI2, and PRIMA-PI from the intention to treat population of the RELEVANCE study were included in the analysis. PFS according to each prognostic score were assessed in the total population and by treatment arms. Data were not mature enough to compare OS distributions. Performance metrics (log-rank p value and Net Reclassification Improvement [NRI]) were calculated for each group to assess concordance and discriminating ability of each score. Results: Median follow-up time for the study was 38 months. Overall, 846 RELEVANCE patients were included in the analysis. Data were available for 845 patients for FLIPI score assessment, 832 for FLIPI2 and 807 for PRIMA-PI. Group repartition according to the FLIPI and the FLIPI2 were largely imbalanced compared with PRIMA-PI. FLIPI classified very few patients in the low risk group (15% LR) while 49% of the patients were at high risk (HR), and 36% were at intermediate risk (IR). Similarly, FLIPI2 risk categories were as follow: 8% LR, 50% IR, and 42% HR. On the contrary, PRIMA-PI divided the study population into three equal groups (33%, 33% and 34%). In the total population, FLIPI and PRIMA-PI were predictive of PFS (p=0.029 and p=0.004, respectively); FLIPI2 showed poor performance (p=0.094). PFS curves based on each score are shown in Figure 1. NRI index indicated that the PRIMA-PI yielded analogous segregation for PFS with FLIPI (NRI 0.16; 95% CI: -0.008, 0.318; Table 1). In the R-chemo arm, both FLIPI and PRIMA-PI could isolate different prognostic groups for PFS, whereas FLIPI2 could not. Conversely, none of the indices were able to significantly discriminate outcomes for patients treated with R2. Interestingly, analysis showed that some usual prognostic factors, especially those likely to reflect tumor burden such as beta-2 microglobulin and LDH, were not predictive for PFS in the R2 arm. In contrast, low albumin ( Conclusion: For patients with FL treated upfront with immunochemotherapy, the PRIMA-PI is a valid scoring system that allows to segregate patients as efficiently as the FLIPI while using only two factors. These results confirm that the PRIMA-PI could substitute for the FLIPI for patients treated with upfront R-chemo. Athough our data have to be interpreted in light of the short median follow-up time, they also suggest that other clinical/biological parameters might be considered and new prognostic indexes established for patients treated with R2. Considering possible mechanisms of action of lenalidomide, prognostic factors related to the underlying patient's immunological status might be more predictive. Disclosures Fowler: Janssen: Membership on an entity's Board of Directors or advisory committees, Research Funding; TG Therapeutics: Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis Pharmaceuticals Corporation: Consultancy; ABBVIE: Membership on an entity's Board of Directors or advisory committees, Research Funding; Roche: Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding. Bachy:Roche: Consultancy; Janssen Cilag: Honoraria; Gilead Science: Honoraria; Amgen: Honoraria; Roche: Honoraria; Janssen Cilag: Other: Travel, accomodation, Expense. Feugier:abbvie: Honoraria, Research Funding, Speakers Bureau; roche: Honoraria, Research Funding, Speakers Bureau; janssen: Honoraria, Research Funding, Speakers Bureau; gilead: Honoraria, Research Funding, Speakers Bureau. Tilly:roche: Membership on an entity's Board of Directors or advisory committees; servier: Honoraria; merck: Honoraria; Gilead: Honoraria; Janssen: Honoraria; BMS: Honoraria; Karyopharm: Consultancy; Astra-Zeneca: Consultancy; Roche: Consultancy; Celgene: Consultancy, Research Funding. Palomba:Pharmacyclics: Membership on an entity's Board of Directors or advisory committees; Noble Insights: Consultancy; Evelo: Other: Immediate family member, Equity Ownership; MSK (IP for Juno and Seres): Other: Immediate Family Member, Patents & Royalties - describe: intellectual property rights ; Hemedicus: Other: Immediate Family Member, Speakers Bureau ; Merck & Co Inc.: Other: Immediate Family Member, Consultancy (includes expert testimony); Seres Therapeutics: Other: Immediate Family Member, Equity Ownership and Membership on an entity's Board of Directors or advisory committees; STRAXIMM: Other: Immediate Family Member, Membership on an entity's Board of Directors or advisory committees; Kite Pharmaceuticals: Other: Immediate Family Member, Membership on an entity's Board of Directors or advisory committees. Libby:Akcea: Consultancy; Alnylam: Consultancy; Abbvie: Consultancy; Pharmacyclics and Janssen: Consultancy. Casasnovas:Merck Sharp and Dohme: Membership on an entity's Board of Directors or advisory committees, Other: Travel support, Research Funding; Celgene: 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; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Gilead: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Gilead: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Bristol-Myers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel expenses. Flinn:TG Therapeutics, Trillum Therapeutics, Abbvie, ArQule, BeiGene, Curis, FORMA Therapeutics, Forty Seven, Merck, Pfizer, Takeda, Teva, Verastem, Gilead Sciences, Astra Zeneca (AZ), Juno Therapeutics, UnumTherapeutics, MorphoSys, AG: Research Funding; F. Hoffmann-La Roche Ltd: Research Funding; TG Therapeutics, Trillum Therapeutics, Abbvie, ArQule, BeiGene, Curis, FORMA Therapeutics, Forty Seven, Merck, Pfizer, Takeda, Teva, Verastem, Gilead Sciences, Astra Zeneca (AZ), Juno Therapeutics, UnumTherapeutics, MorphoSys, AG: Research Funding; AbbVie, Seattle Genetics, TG Therapeutics, Verastem: Consultancy; Acerta Pharma, Agios, Calithera Biosciences, Celgene, Constellation Pharmaceuticals, Genentech, Gilead Sciences, Incyte, Infinity Pharmaceuticals, Janssen, Karyopharm Therapeutics, Kite Pharma, Novartis, Pharmacyclics, Portola Pharmaceuticals: Research Funding. Haioun:Novartis: Honoraria; Janssen: Honoraria; F. Hoffmann-La Roche Ltd: Honoraria; Servier: Honoraria; Takeda: Honoraria; Miltenyi: Honoraria; Gilead: Honoraria; Celgene: Honoraria; Amgen: Honoraria. Bartlett:Pharmacyclics: Research Funding; Pfizer: Research Funding; Affimed: Research Funding; Celgene: Research Funding; Millenium: Research Funding; Merck: Research Funding; Seattle Genetics: Research Funding; Forty Seven: Research Funding; Bristol-Myers Squibb: Research Funding; ADC Therapeutics: Consultancy, Research Funding; Genenetech: Research Funding; Gilead: Research Funding; Immune Design: Research Funding; Janssen: Research Funding. Bouabdallah:Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees. Brice:BMS: Honoraria; Millennium Takeda: Research Funding; Takeda France: Consultancy, Honoraria. Ribrag:Nanostring: Membership on an entity's Board of Directors or advisory committees; Servier: Consultancy, Membership on an entity's Board of Directors or advisory committees; Epizyme: Consultancy, Research Funding; ArgenX: Research Funding; Roche: Other: Travel, accommodations, and expenses ; BMS: Membership on an entity's Board of Directors or advisory committees, Other: Travel, accommodations, and expenses ; MSD: Membership on an entity's Board of Directors or advisory committees; Incyte: Membership on an entity's Board of Directors or advisory committees; Gilead: Membership on an entity's Board of Directors or advisory committees; Infinity: Membership on an entity's Board of Directors or advisory committees; AZ: Membership on an entity's Board of Directors or advisory committees. Le Gouill:Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel support; Roche-Genentech: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel support. Martín:Teva: Research Funding; Gilead: Consultancy, Honoraria; Kiowa Kirin: Consultancy; Roche: Consultancy, Honoraria, Other: Travel Expenses; iQone: Consultancy; Servier: Honoraria, Other: Travel Expenses; Janssen: Honoraria, Other: Travel Expenses, Research Funding; Celgene: Consultancy, Honoraria, Other: Travel Expenses, Research Funding. Lopez-Guillermo:Roche: Consultancy, Research Funding; Gilead: Consultancy, Research Funding; Celgene: Consultancy, Research Funding; Janssen: Research Funding. Larouche:Bayer; Gilead Sciences; Merck; Roche: Research Funding. Ando:Eisai: Research Funding. Maria:Janssen Cilag: Consultancy, Other: Travel support; Gilead Sciences: Other: Travel support, Research Funding; Abbvie: Consultancy, Other: Travel support; Celgene: Consultancy; Roche: Consultancy, Other: Travel support. André:Takeda: 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; Karyopharm: Membership on an entity's Board of Directors or advisory committees; Gilead: Membership on an entity's Board of Directors or advisory committees, Other: Travel grants; Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding; Seattle Genetics: Membership on an entity's Board of Directors or advisory committees; Abbvie: Membership on an entity's Board of Directors or advisory committees; Roche: Other: Travel grants, Research Funding; Amgen: Other: Travel grants, Research Funding; Johnson & Johnson: Research Funding; Takeda Millenium: Research Funding; Chugai: Research Funding; Celgene: Other: Travel grants, Research Funding. Sehn:Merck: Consultancy, Honoraria; Acerta: Consultancy, Honoraria; TEVA Pharmaceuticals Industries: Consultancy, Honoraria; F. Hoffmann-La Roche/Genentech: Consultancy, Honoraria, Research Funding; TEVA Pharmaceuticals Industries: Consultancy, Honoraria; Seattle Genetics: Consultancy, Honoraria; Astra Zeneca: Consultancy, Honoraria; Lundbeck: Consultancy, Honoraria; Kite Pharma: Consultancy, Honoraria; Kite Pharma: Consultancy, Honoraria; Astra Zeneca: Consultancy, Honoraria; Acerta: Consultancy, Honoraria; Morphosys: Consultancy, Honoraria; Janssen-Ortho: Honoraria; Janssen-Ortho: Honoraria; F. Hoffmann-La Roche/Genentech: Consultancy, Honoraria, Research Funding; Merck: Consultancy, Honoraria; TG Therapeutics: Consultancy, Honoraria; TG Therapeutics: Consultancy, Honoraria; Lundbeck: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; Abbvie: Consultancy, Honoraria; Seattle Genetics: Consultancy, Honoraria; Abbvie: Consultancy, Honoraria; Morphosys: Consultancy, Honoraria. Tobinai:Daiichi Sankyo: Consultancy, Honoraria; Eisai: Honoraria, Research Funding; Verastem: Honoraria; Mundi Pharma: Consultancy, Honoraria, Research Funding; Zenyaku Kogyo: Consultancy, Honoraria; Yakult: Honoraria; Janssen Pharmaceutical: Honoraria, Research Funding; Celgene: Consultancy, Honoraria, Research Funding; HUYA Bioscience: Consultancy, Honoraria; Ono Pharmaceutical: Consultancy, Honoraria, Research Funding; Chugai Pharmaceutical: Honoraria, Research Funding; AbbVie: Research Funding; Solasia: Honoraria; Meiji Seika: Honoraria; Kyowa Kirin: Honoraria, Research Funding; Bristol-Myers Squibb: Honoraria; Takeda Pharmaceutical: Consultancy, Honoraria, Research Funding. Cartron:Roche, Celgene: Consultancy; Sanofi, Gilead, Janssen, Roche, Celgene: Honoraria. Delarue:Celgene Corporation: Employment, Equity Ownership. Czuczman:Celgene Corporation: Employment, Equity Ownership. Salles:BMS: Honoraria; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Educational events; Autolus: Consultancy, Membership on an entity's Board of Directors or advisory committees; Novartis, Servier, AbbVie, Karyopharm, Kite, MorphoSys: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Educational events; Amgen: Honoraria, Other: Educational events; Epizyme: Consultancy, Honoraria; Roche, Janssen, Gilead, Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Educational events; Merck: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees. Morschhauser:Bayer: Membership on an entity's Board of Directors or advisory committees; Gilead: Membership on an entity's Board of Directors or advisory committees; Epizyme: Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria; BMS: Membership on an entity's Board of Directors or advisory committees; F. Hoffmann-La Roche Ltd: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees.

Pro-inflammatory angiopoietin-like 2 (angptl2) promotes endothelial dysfunction in mice and circulating angptl2 is higher in patients with cardiovascular diseases. We previously reported that a single bout of physical exercise was able to reduce angptl2 levels in coronary patients. We hypothesized that chronic exercise would reduce angptl2 in patients with post-acute coronary syndrome (ACS) and endothelial dysfunction. Post-ACS patients (n = 40, 10 women) were enrolled in a 3-month exercise-based prevention program. Plasma angptl2, hs-CRP, and endothelial function assessed by scintigraphic forearm blood flow, were measured before and at the end of the study. Exercise increased VO2peak by 10% (p

Despite advances in the field, a clear treatment algorithm for most peripheral T-cell lymphoma (PTCL) subtypes remains to be defined. Generating reliable randomized data for this type of pathology remains a challenge because of the relative rarity of the disease and the heterogeneity of subtypes. Newer agents, such as the class-I selective histone deacetylase inhibitor romidepsin, have demonstrated efficacy and manageable toxicity in the relapsed and refractory setting. Whether novel agents should be used in conjunction with more conventional cytotoxic therapies or in sequence with a transplant strategy is unknown at this time. Here we report the successful use of romidepsin monotherapy as a bridge to allogeneic stem cell transplantation in a patient who had previously relapsed after several lines of conventional cytotoxic therapy for PTCL. Romidepsin provided the patient with sufficient disease control to proceed to transplantation while remaining in complete remission.

Introduction: BCL2 overexpression leading to evasion of apoptosis is common in hematologic malignancies. In DLBCL, 50% of patients (pts) overexpress BCL2 protein, 30% overexpress BCL2 and MYC (double-expressor [DE]) and 5-10% have translocations of BCL2 and MYC (double-hit [DH]), all of which are associated with a poor prognosis. We hypothesized that combination of the BCL2 inhibitor venetoclax (Ven) with chemotherapy would improve DLBCL outcomes based on pre-clinical and early clinical data. The Phase Ib part of the CAVALLI (NCT02055820) study assessed the maximum tolerated dose (MTD) of CHOP + rituximab (R) or obinutuzumab (G) with Ven (200-800mg) in non-Hodgkin lymphoma, recommending 800mg of Ven + R-CHOP for Phase II. The single-arm, multicenter Phase II part of CAVALLI investigated the efficacy of Ven + R-CHOP in all first-line (1L) DLBCL pts, by BCL2 immunohistochemistry (IHC) status within cell-of-origin (COO) subtypes, by BCL2 fluorescence in situ hybridization (FISH) and in DE and DH pts, with the intent to compare against a matched pt population in the R-CHOP arm of the GOYA Phase III study. Here we report the first safety, efficacy and biomarker analyses in all pts from this ongoing Phase II study. Methods: Eligible pts (age ≥18 yrs; Eastern Cooperative Oncology Group performance status ≤2; 1L DLBCL; International Prognostic Index score 2-5; ≥1 measurable lesion >1.5cm) were assigned to receive six 3-weekly cycles of R-CHOP + 800mg Ven daily for 10 days (Days 1-10, except Cycle 1: Days 4-10), followed by two 3-weekly cycles of 800mg Ven on Days 1-10 + R on Day 1. The primary endpoint was PET-CT response 6-8 weeks after the last R dose (EoT), according to a modified version of Lugano 2014 criteria. Secondary endpoints were progression-free survival (PFS) and safety. Biomarker analyses in CAVALLI and GOYA were performed in pre-treatment tumor samples including a BCL2 IHC assay (cutoff: 50% medium/high expression), MYC IHC assay (cutoff 40% signal), BCL2 and MYC FISH, and COO assay (Nanostring). Results: 211 pts were enrolled; 208 received any treatment and were included in efficacy and safety analyses. Overall, pt characteristics were similar for CAVALLI and GOYA, except CAVALLI enrolled more Ann Arbor Stage IV (65.4% vs 47.1%) and BCL2 IHC-positive pts (57.7% vs 50.0%). The EoT complete response rate in all pts did not differ significantly between CAVALLI and GOYA (69.2% vs 62.8%, respectively; Table 1), but was improved in BCL2-positive subgroups, specifically in BCL2 FISH-positive (70.0% vs 47.5%) and DH (71.4% vs 25.0%) pts. With 20 months' median follow-up in CAVALLI, disease progression and death had occurred in 29 and 6 pts, respectively. When compared with GOYA and adjusted for baseline covariates by Cox methodology, PFS improvement was observed in BCL2 IHC-positive pts (HR, 0.53; 95% CI: 0.30-0.93), including within both activated B-cell (ABC; HR, 0.43; 95% CI: 0.19-0.94) and germinal center B-cell (GCB; HR, 0.41; 95% CI: 0.17-0.95) COO subgroups. No PFS benefit was observed in BCL2 IHC-negative GCB pts; the BCL2 IHC-negative ABC subgroup was too small for evaluation (Figure 1). Grade 3-4 adverse events (AEs) occurred in 85% (176/208) of pts in CAVALLI versus 66% (373/574) in GOYA; the majority were cytopenias, infections and febrile neutropenia (Table 2). In CAVALLI, 1% (3/208) of AEs were fatal versus 5% (30/564) in GOYA but follow-up was longer in GOYA (57 vs 20 months). The higher rate of AEs in CAVALLI led to dose interruptions/discontinuations of both Ven and R-CHOP; 61% of pts had >90% relative dose intensity (RDI) of Ven; 73.2% of CAVALLI pts had >90% RDI of each of doxorubicin and cyclophosphamide versus 76.4% for doxorubicin and 77.6% for cyclophosphamide in GOYA. There were no major differences in grade 3-4 AEs or the RDI of R-CHOP across intention-to-treat and BCL2-positive subgroups. GCSF prophylaxis was recommended, but not uniformly delivered. Conclusions: The addition of Ven to R-CHOP in 1L DLBCL treatment resulted in improved efficacy in BCL2 IHC-positive pts compared with matched GOYA controls. Higher rates of cytopenia, infection and febrile neutropenia were observed in CAVALLI versus the R-CHOP arm in GOYA. These data further support exploration of Ven + R-CHOP in a high-risk population of BCL2-positive 1L DLBCL, including DH pts. Disclosures Morschhauser: Epizyme: Consultancy; Servier: Membership on an entity's Board of Directors or advisory committees; BMS: 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; Roche/Genentech: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Gilead: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees. Feugier: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; Abbvie: 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. Flinn:Agios: Research Funding; Verastem: Research Funding; Celgene: Research Funding; Pharmacyclics: Research Funding; Merck: Research Funding; ArQule: Research Funding; Constellation: Research Funding; Curis: Research Funding; Genentech: Research Funding; Forma: Research Funding; Novartis: Research Funding; BeiGene: Research Funding; Pfizer: Research Funding; Forty Seven: Research Funding; TG Therapeutics: Research Funding; Portola: Research Funding; Calithera: Research Funding; Seattle Genetics: Research Funding; Verastem: Consultancy, Research Funding; Trillium: Research Funding; Gilead: Research Funding; Incyte: Research Funding; Infinity: Research Funding; Janssen: Research Funding; Kite: Research Funding; Takeda: Research Funding. Gasiorowski:Novartis: Honoraria; MSD: Honoraria. Greil:Astra Zeneca: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; BMS: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Other: TRAVEL, ACCOMMODATIONS, EXPENSES; Abbvie: Consultancy, Membership on an entity's Board of Directors or advisory committees; MSD: Honoraria, Research Funding; Sandoz: Honoraria, Research Funding; Amgen: Honoraria, Other: TRAVEL, ACCOMMODATIONS, EXPENSES, Research Funding; Novartis: 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; Merck: Honoraria, Research Funding; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Illés:Janssen: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees; Roche: Membership on an entity's Board of Directors or advisory committees. Johnson:Merck: Consultancy, Honoraria; Roche: Consultancy, Honoraria, Other: travel, Research Funding; Bristol-Myers Squibb: Consultancy, Honoraria; Seattle Genetics: Honoraria; Lundbeck: Consultancy, Honoraria, Other: travel, Research Funding; AbbVie Inc.: Consultancy, Honoraria, Research Funding. Lugtenburg:Genmab: Consultancy; Squibb: Consultancy; Takeda: Consultancy, Research Funding; Celgene: Consultancy; Sandoz: Consultancy; Bristol-Meyers: Consultancy; Servier: Consultancy, Research Funding; Roche: Consultancy. Salles:BMS: Honoraria, Other: Advisory Board; Servier: Honoraria, Other: Advisory Board; Servier: Honoraria; Celgene: Honoraria, Other: Advisory Board, Research Funding; F. Hoffmann-La Roche Ltd: Consultancy, Honoraria, Research Funding; Epizyme: Honoraria; Morphosys: Honoraria; Abbvie: Honoraria; Acerta: Honoraria; Amgen: Honoraria; Novartis: Consultancy, Honoraria; Takeda: Honoraria; Merck: Honoraria; Pfizer: Honoraria; Janssen: Honoraria, Other: Advisory Board; Gilead: Honoraria, Other: Advisory Board. Trněný:Morphosys: Membership on an entity's Board of Directors or advisory committees, Other: Advisory board; F. Hoffman-La Roche Ltd: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Advisory board, Research Funding; Incyte: Membership on an entity's Board of Directors or advisory committees, Other: Advisory board; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Advisory board; Gilead: Honoraria; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Advisory board; Janssen: Membership on an entity's Board of Directors or advisory committees, Other: Advisory board; Sandoz: Honoraria; Abbvie: Honoraria, Research Funding. Mir:F. Hoffmann-La Roche: Employment. Kornacker:F. Hoffmann-La Roche Ltd: Employment. Punnoose:Roche: Equity Ownership; Genentech Inc: Employment. Samineni:Genentech Inc: Employment, Other: Ownership interests non-PLC. Szafer-Glusman:F. Hoffmann-La Roche Ltd: Employment, Other: Ownership interests PLC. Petrich:Abbvie: Employment, Other: Ownership interests PLC. Sinha:F. Hoffmann-La Roche Ltd: Employment. Mobasher:Genentech Inc: Employment; F. Hoffmann-La Roche Ltd: Other: Ownership interests non-PLC. Zelenetz:Celgene: Consultancy; Abbvie: Research Funding; Gilead: Consultancy, Research Funding; AstraZeneca: Consultancy; Genentech/Roche: Consultancy, Research Funding; Novartis/Sandoz: Consultancy; Amgen: Consultancy.

7500Background: Immunochemotherapy induction followed by rituximab maintenance is the standard of care in previously untreated symptomatic FL. Phase II studies of chemo-free combination immunotherapy with lenalidomide and rituximab (R2) show promising activity. Methods: RELEVANCE is a global, randomized, phase III trial (NCT01650701) of R2 vs R-chemo followed by rituximab in previously untreated grade 1-3a FL patients requiring therapy according to GELF criteria. Lenalidomide dose was 20 mg/d, d2-22/28 for 6-12 cycles (c), continued in responders at 10 mg/d for a total of 18 c. Rituximab dose was 375 mg/m2 weekly c1 and d1 c2-6 and continued in responders for 12 additional c (q8wk). R-chemo was given per investigator’s choice of standard R-CHOP, R-bendamustine (R-B), or R-CVP, followed by 12 c of rituximab (q8wk). Co-primary endpoints of CR/CRu at 120 wk and PFS (50% interim analysis by 1999 IWG) are reported here. Results: As of 31May2017, 1030 patients with high tumor burden were randomized to R2 (n = 5...

Purpose Patients with diffuse large B-cell lymphoma (DLBCL) usually relapse early following diagnosis but some relapses happen at 5 years or later. Few data exist regarding clinical characteristics and outcome of these patients. Patients and Methods We performed a retrospective analysis of all patients from two centers in Lyon, France, between 1985 and 2003 who had a biopsy-proven relapse 5 years or later following diagnosis of DLBCL. All available biopsies were reviewed and immunohistochemistry was completed. Results Among 1,492 patients with DLBCL, 54 were eligible. At diagnosis, 63% of patients had stage I-II, 82% had low/low-intermediate International Prognostic Index (IPI) score, 65% had extranodal involvement, 24% had an indolent component associated with DLBCL, 57% had germinal center phenotype, and 43% had non-germinal center phenotype. Median time from diagnosis to relapse was 7.4 years (range, 5 to 20.5 years). At time of relapse, 83% had DLBCL histology, and 17% had indolent histology. Having an indolent component at diagnosis was associated with indolent histology at relapse (P = .028). Five-year event free-survival (EFS) was 17% for patients with DLBCL relapse and 61% for patients with indolent relapse (P = .027). Five-year overall survival was 27% for patients with DLBCL and 75% for patients with indolent relapse (P = .029). For DLBCL relapse, 3-year EFS was 56% versus 18% with autologous stem-cell transplantation or not, respectively (P = .0661). Conclusion Patients with DLBCL who had a late relapse usually had localized stage, favorable IPI score, and extranodal involvement at diagnosis. The outcome of patients with DLBCL at time of relapse remains poor, and aggressive treatment such as autologous stem-cell transplantation should be pursued whenever possible. Biopsy at relapse is essential because some patients relapse with indolent histology.

Introduction: Exercise training in patients who have suffered an acute coronary syndrome is associated with a significant reduction in mortality and cardiovascular events. Moderate intensity continuous exercise training (MICET) is currently recommended. Recently, high-intensity interval training (HIIT), that utilizes short bursts of very intense efforts interspersed with periods of recovery, has been explored as an alternative to MICET. The safety aspects of HIIT in patients post acute coronary syndrome (ACS) have been poorly described. Methods: Thirty-seven low-risk patients post ACS (65% STEMI, fully revascularized, EF > 40%, age 61±9 years, 8 women) were randomized 4 weeks to 6 months post ACS; to 12 to 18 weeks of 2-3 sessions/week (total: 36 sessions) of isocaloric MICET or HIIT on cycle ergometer. VO2peak and maximal aerobic power (MAP) were determined using maximal cardiopulmonary exercise test (CPET) on cycle ergometer and continuous ECG and BP were monitored every 2 min. Cardiometabolic profile (body composition, blood lipids, BP), arrhythmias (24h-holter monitoring) and left ventricular ejection fraction (LVEF) were measured before and after the intervention. MICET consisted of: 5 min of warm-up period, 37 min at 60% maximal aerobic power (MAP) and 5 min of cool down. HIIT included: 5 min of warm-up, 3 sets of 10 minutes of repeated phases of 15 sec at 100% MAP alternating with 15 sec passive recovery and 5 min of cool down. Results: Significant improvement in VO2peak (normalized by lean body mass (LBM)) was observed in the MICET group only (MICET VO2peak: 29.26±4.87 vs. 34.26 mL/min/LBM, p0.05). No significant improvements in body composition, BP or blood parameters were observed in either group. No adverse events including no increase of ventricular arrhythmias or deterioration of LVEF were noted with HIIT (56±6 vs. 57±7%, p>0.05). Conclusion: In patients post-ACS, MICET appeared to have a greater impact on VO2peak compared to HIIT, while no improvement in cardiometabolic risk profile was observed in either group. HIIT was well tolerated and was not associated with increased ventricular arrhythmias or deterioration of cardiac function.

Purpose To determine whether autologous (auto) or allogeneic (allo) stem-cell transplantation (SCT) improves outcome in patients with transformed follicular lymphoma compared with rituximab-containing chemotherapy alone. Patients and Methods This was a multicenter cohort study of patients with follicular lymphoma and subsequent biopsy-proven aggressive histology transformation. Patient, treatment, and outcome data were collected from each transplantation center and combined for analysis. A separate control group was composed of patients with transformation treated with rituximab-containing chemotherapy but not SCT. The primary end point was overall survival (OS) after transformation. Results One hundred seventy-two patients were identified: 22 (13%) treated with alloSCT, 97 (56%) with autoSCT, and 53 (31%) with rituximab-containing chemotherapy. Five-year OS after transformation was 46% for patients treated with alloSCT, 65% with autoSCT, and 61% with rituximab-containing chemotherapy (P = .24). Five-year progression-free survival (PFS) after transformation was 46% for those treated with alloSCT, 55% with autoSCT, and 40% with rituximab-containing chemotherapy (P = .12). In multivariate analysis, patients treated with autoSCT had improved OS compared with those who received rituximab-containing chemotherapy (hazard ratio [HR], 0.13; 95% CI, 0.05 to 0.34; P < .001). On the other hand, there was no OS difference between those treated with alloSCT and rituximab-containing chemotherapy (HR, 0.44; 95% CI, 0.16 to 1.24; P = .12). OS and PFS after SCT were similar between those treated with autoSCT and alloSCT. Five-year transplantation-related mortality was 23% for those treated with alloSCT and 5% for autoSCT. Conclusion Patients undergoing autoSCT had better outcomes than those treated with rituximab-containing chemotherapy alone. AlloSCT did not improve outcome compared with rituximab-containing chemotherapy and was associated with clinically significant toxicity.

controlled trial of 39 low-risk patients 4 weeks to 6 months post ACS, EF > 40%, fully revascularized, were randomized to 12 to 18 weeks of 2-3 sessions/week (36 sessions total) of isocaloric MICET or HIIT on cycle ergometer. MICET protocol: 5 min warm-up at 30% maximal aerobic power (MAP) followed by 37 min at 60% MAP, followed by 5 min warm down at 30% MAP. HIIT included 3 sets of 10 minutes of repeated phases of 15 sec at 100 MAP alternating with 15 sec passive recovery. Warm up and cool down: 5 min at 30% MAP. MAP was determined using graded maximal cardiopulmonary exercise test (CPET) on cycle ergometer and continuous ECG and BP monitoring every 2 min. Metabolic and anthropometric profile, holter monitoring, as well as CPET was repeated before and after the intervention. RESULTS: 1 patient has yet to complete the intervention; complete data available for 35 patients (16 HIIT, 16 MICET). Baseline data is presented in Table 1. Significant improvement in VO2max was observed in both groups, with a greater increase seen in patients utilizing MICET (difference 102.4 46 vs 309.9 54 ml, p 1⁄4 0.011; 1.8 0.89 vs 3.5 0.84 ml/kg lean body mass difference, p1⁄40.018). No difference in respiratory exchange ratio at peak effort was observed (1.18 vs 1.16). No significant differences in systolic BP, weight, HRR, fasting lipids, glucose or insulin sensitivity were observed. No adverse events or ventricular arrhythmias were noted to be associated with exercise training. CONCLUSION: Both training modalities result in improvements in VO2max with greater effect in those using MICET. HIIT appears to be well tolerated in patients post ACS.

e19542 Background: Bendamustine (B) is widely used in the treatment of indolent non-Hodgkin’s lymphoma (iNHL) and chronic lymphocytic leukemia (CLL). Methods: An expanded access trial with the primary objective of safety was conducted at 16 centres across Canada and enrolled patients (pts) from March 2012 to June 2013. Eligible pts were at least 18 years old, able to provide informed consent with relapsed/refractory iNHL and were previously treated with a rituximab-containing regimen or previously untreated for CLL, and had an ECOG performance status 0-2 and good organ function. Pts with iNHL received up to 8 cycles of B (120mg/m2) on days 1 and 2 every 21 or 28 days; pts with CLL were given B 100 mg/m2on days 1 and 2 every 28 days for up to 6 cycles. Dose adjustment algorithms were followed for toxicities. Pts were followed for up to 6 weeks after completion of treatment. Results: Ninety pts started on treatment (74 iNHL;16 CLL). The mean age was 64(range 40–90), 44% of the CLL pts were at least 70 years...

8581 Background: Cisplatinum-based 2nd line therapy is poorly tolerated. We evaluated the activity and toxicity of an outpatient RGDOx regimen Methods: Patients (pts) with CD20+ NHL, without limita...

s S321 (HOMA-IR). R-R intervals (RRI) were collected during ten minutes of supine rest and the final five minutes of data were analysed for time and frequency domain and nonlinear HRV. Multiple linear regression models was used to determine which MetS risk factors were independent predictors of HRV. Models initially included all MetS risk factors and backwards elimination was used to serially remove the least important factors. RESULTS: High frequency power, width of the Poincare plot (SD1) and short-term scaling exponent alpha (a1) were independently predicted by WC (p1⁄40.02, 0.03 and 0.02, respectively) and SD1 was also predicted by FPG (p1⁄40.02). The standard deviation of normal-to-normal intervals was independently predicted by TG (p1⁄40.03), while low frequency power was predicted by TG (p1⁄40.047) and HDL (p1⁄40.04). When HOMA-IR was added to the model, it independently predicted HR (p1⁄40.003), along with both systolic (p1⁄40.007) and diastolic BP (p1⁄40.02). CONCLUSION: HRV parameters reflecting parasympathetic cardiac control and fractal characteristics of heart rate dynamics were independently predicted by WC and FPG, while parameters indicative of overall variability or under both parasympathetic and sympathetic influence were independently predicted by TG and HDL. HOMA-IR and BP only predicted HR, which may be an index of sympathetic activity in MetS. Therefore, treatment of different MetS risk factors could be targeted to HRV parameters with greatest prognostic significance. 587 COMPARISON OF HEMODYNAMIC RESPONSES AND SUBSTRATE UTILISATION DURING HIGH INTENSITY INTERMITTENT EXERCIE VS MODERATE CONTINOUS INTENSITY EXERCISE IN HEALHY ADULTS J Larouche, A Nigam, M Juneau, E Thorin, C Desrosiers, M Gayda

Abstract 1641 Rituximab has proven efficacy and tolerability for treating B-cell malignancies. IV rituximab administration can take several hours, consuming considerable healthcare resources. A SC rituximab formulation has been developed which may shorten administration time, increase patient (pt) convenience, and potentially reduce IV administration-associated costs. Rituximab efficacy depends on CD20 binding, and Ctrough rituximab levels reflect rituximab exposure throughout the therapy cycle; therefore, achieving a non-inferior Ctrough level with SC dosing is expected to provide comparable efficacy to IV dosing. BP22333 (NCT00930514) is a two-stage phase Ib study assessing PK and tolerability of SC vs IV maintenance rituximab in pts with first-line or relapsed FL. Stage 1 dose-finding results (Salar et al, ASH 2010, abstract 2858; Salar et al, EHA 2012, abstract 0794) identified a fixed dose of 1400 mg for formal Ctrough non-inferiority testing in Stage 2. We report Stage 2 data. The Stage 2 objective was to demonstrate non-inferiority of simulated Ctrough of rituximab SC and IV, using a non-inferiority test with a lower boundary of 0.8 for the 90% confidence interval (CI). Secondary endpoints include SC vs IV rituximab safety and area under the serum concentration-time curve. Eligible pts (N = 157) were aged ≥18 years with an ECOG performance status of ≤ 2, and histologically confirmed CD20-positive grade 1, 2, or 3a FL requiring treatment. Eligible pts must have achieved a complete or partial response following IV rituximab-based induction therapy for FL and have received ≥1 cycle of IV rituximab maintenance within 16 weeks of completing induction. Pts (N = 154) were randomized 1:1 to receive SC rituximab (1400 mg) or IV rituximab (375 mg/m2) for their remaining maintenance cycles, stratified by 2-monthly (q2m) vs 3-monthly (q3m) regimen. Study arms were balanced for age, sex, body surface area, FL grade at diagnosis, induction therapy and number of maintenance doses prior to study entry. As of May 11, 2012, 13 SC pts had withdrawn (7 for progressive disease [PD], 4 for AEs, 1 at investigator's decision, 1 for ineligibility) and 17 IV pts had withdrawn (10 for PD, 4 for AEs, 3 for ineligibility). Median treatment duration on-study was 14.8 months (range, 0–19) in the SC arm and 13.8 months (range, 0–19) in the IV arm. The primary endpoint of the study was met. Geometric mean Ctrough,SC:Ctrough,IV ratios were 1.24 and 1.12, respectively, for q2m and q3m, and lower limits of the two-sided 90% CI (1.02 and 0.86, respectively) exceeded the protocol-specified non-inferiority limit (Ctrough,SC:Ctrough,IV ratio of 0.8). Therefore, 1400 mg SC rituximab was concluded to be non-inferior to 375 mg/m2 IV rituximab administration. AE incidence and intensity were generally balanced; 79% of pts in each arm experienced AEs. Serious AEs were observed in 12% and 14% of pts in the SC and IV arms, respectively; none occurred in > 1 pt in either arm. Grade 3/4 AEs occurred in 18% and 17% of pts in the SC and IV arms, respectively; the only grade 3/4 AEs occurring in > 1 pt in either arm were neutropenia (2 pts in each arm) and arthralgia (2 pts in the IV arm). Administration-related reactions (ARRs) were the most frequent AE and had a higher incidence in the SC arm (reported in 31% of SC vs 4% of IV pts). ARRs were mostly local reactions; the most common in the SC arm were: erythema (13%), injection site erythema (5%), and myalgia (5%). Further safety data will be presented. PK data for SC and IV rituximab administration demonstrate non-inferiority of 1400 mg rituximab SC administration to that of the approved IV rituximab maintenance regimen for both q2m and q3m schedules. The overall AE profiles were similar for SC and IV rituximab administration, with the exception of local ARRs, which had a higher incidence in the SC arm compared with the IV arm, reflecting the expected change in the ARR profile with SC administration. Induction and maintenance therapy using the 1400 mg SC rituximab dose is being assessed in the phase III BO22334 study. Disclosures: Salar: Roche: Consultancy. Off Label Use: Subcutaneous (SC) administration of rituximab as maintenance therapy in patients with follicular lymphoma (FL). Larouche:Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees. Brewster:Roche: Employment, Equity Ownership. Catalani:Roche: Employment, Equity Ownership. McIntyre:Roche: Employment. Sayyed:Roche: Employment. Haynes:Roche: Consultancy, Honoraria.