Schmitz, Norbert

Abstract Mature T-cell lymphomas constitute the most common indication for allogeneic hematopoietic cell transplantation (allo-HCT) of all lymphomas. Large studies evaluating contemporary outcomes of allo-HCT in mature T-cell lymphomas relative to commonly used donor sources are not available. Included in this registry study were adult patients who had undergone allo-HCT for anaplastic large cell lymphoma, angioimmunoblastic T-cell lymphoma (AITL), or peripheral T-cell lymphoma not otherwise specified (PTCL-NOS) between 2008 and 2018. Hematopoietic cell transplantation (HCT) platforms compared were posttransplant cyclophosphamide-based haploidentical (haplo-)HCT, matched sibling donor (MSD) HCT, matched unrelated donor HCT with in vivo T-cell depletion (MUD TCD+), and matched unrelated donor HCT without in vivo T-cell depletion (MUD TCD−). Coprimary end points were overall survival (OS) and progression-free survival (PFS); secondary end points included nonrelapse mortality (NRM), and relapse/progression incidence (RI). A total of 1942 patients were eligible (237 haplo-HCT; 911 MSD; 468 MUD TCD+; 326 MUD TCD−). Cohorts were comparable for baseline characteristics with the exception of higher proportions of patients with decreased performance status (PS) and marrow graft recipients in the haplo-HCT group. Using univariate and multivariate comparisons, OS, PFS, RI, and NRM were not significantly different among the haplo-HCT, MSD, MUD TCD+, and MUD TCD− cohorts, with 3-year OS and PFS of 60%, 63%, 59%, and 64%, respectively, and 50%, 50%, 48%, and 52%, respectively. Significant predictors of inferior OS and PFS on multivariate analysis were active disease status at HCT and decreased PS. AITL was associated with significantly reduced relapse risk and better PFS compared with PTCL-NOS. Allo-HCT can provide durable PFS in patients with mature T-cell lymphoma (TCL). Outcomes of haplo-HCT were comparable to those of matched donor allo-HCT.

Abstract Disease progression after frontline therapy for Diffuse large B‐cell lymphoma (DLBCL) is a clinically significant event. Patients who experience early progression or have refractory disease have especially poor outcomes. Simple, clinically applicable prognostic tools are needed for selecting patients for consideration for novel therapies and prognostication in the relapsed/refractory (R/R) setting. Model building was performed in patients from the Surrogate endpoints in aggressive lymphoma (SEAL) consortium with disease progression after frontline immunochemotherapy. The primary endpoint was overall survival (OS) measured from date of progression. Validation was performed in the University of Iowa/Mayo Clinic SPORE Molecular Epidemiology Resource (MER) and Danish National Lymphoma Register (LYFO) cohorts. Model performance was assessed using time‐dependent concordance indices (c‐statistic) and calibration with metrics evaluated at 2 years from progression. Note, 1234 of 5112 patients treated with frontline immunochemotherapy in the SEAL consortium developed progressive disease. Time to progression on immunochemotherapy and age at progression were strongly associated with post‐progression OS (both p < 0.001). A prognostic model was developed incorporating spline fit for both variables. The model had good concordance in the discovery (0.67) and validation sets (LYFO c = 0.64, MER c = 0.68) with generally good calibration. Time to progression on frontline therapy is strongly associated with post‐progression OS in DLBCL. We developed and validated a simple to apply clinical prognostic tool in the R/R setting. The useful prediction of expected outcomes in R/R DLBCL and can inform treatment decisions such as considerations for CAR‐T therapy as well as trial designs. The model is available in smartphone‐based point of care applications.

Abstract Great heterogeneity in survival exists for patients newly diagnosed with diffuse large B-cell lymphoma (DLBCL). Three scoring systems incorporating simple clinical parameters (age, lactate dehydrogenase, number/sites of involvement, stage, performance status) are widely used: the International Prognostic Index (IPI), revised IPI (R-IPI), and National Comprehensive Cancer Network IPI (NCCN-IPI). We evaluated 2124 DLBCL patients treated from 1998 to 2009 with frontline rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP; or variant) across 7 multicenter randomized clinical trials to determine which scoring system best discriminates overall survival (OS). Median age was 63 years, and 56% of patients were male. Five-year OS estimates ranged from 54% to 88%, from 61% to 93%, and from 49% to 92% using the IPI, R-IPI, and NCCN-IPI, respectively. The NCCN-IPI had the greatest absolute difference in OS estimates between the highest- and lowest-risk groups and best discriminated OS (concordance index = 0.632 vs 0.626 [IPI] vs 0.590 [R-IPI]). For each given IPI risk category, NCCN-IPI risk categories were significantly associated with OS (P ≤ .01); the reverse was not true, and the IPI did not provide additional significant prognostic information within all NCCN-IPI risk categories. Collectively, the NCCN-IPI outperformed the IPI and R-IPI. Patients with low-risk NCCN-IPI had favorable survival outcomes with little room for further improvement. In the rituximab era, none of the clinical risk scores identified a patient subgroup with long-term survival clearly &lt;50%. Integrating molecular features of the tumor and microenvironment into the NCCN-IPI or IPI might better characterize a high-risk group for which novel treatment approaches are most needed.

Background: Disease progression (PD) after frontline IC therapy for DLBCL is a clinically significant event and only 20-40% of patients achieve durable remissions with salvage chemotherapy. Patients who experience early PD or have disease refractory to IC have especially poor outcomes. Chimeric antigen receptor T-cell therapy has emerged as a novel effective therapy for selected cases of relapsed or refractory (r/r) DLBCL, although its availability is limited by cost and logistic challenges. Simple, clinically applicable prognostic tools would be useful for selecting patients for consideration for novel therapies vs those who are more likely to be successfully managed by conventional therapies, but few have been developed for r/r DLBCL. Methods: Model building was performed in patients with PD after IC from 13 frontline, multicenter, randomized DLBCL clinical trials from the SEAL Consortium. All patients received rituximab and an anthracycline-based combination IC and were followed systematically; however therapy received, clinical, and laboratory data at progression were not available. OS was defined as time from first progression until death from any cause. Associations between variables and OS were evaluated using Cox models; splines were used to model functional forms. Validation was performed in the University of Iowa/Mayo Clinic SPORE Molecular Epidemiology Resource (MER) and Danish LYFO cohorts. Model performance was assessed using time-dependent concordance indices (c-stat), Brier scores, and calibration with metrics evaluated at two years from progression. Results: Model Development (SEAL): 1125 of 5112 patients had PD after IC. Median time to PD (TTP) was 11.8 months (IQR 6.6-23.5); median age at PD was 68 years (IQR 60-73). At a median follow-up of 21 months from PD (IQR 7-43), 732 patients (65%) had died and 24 month overall survival after PD (OS24) was 35% (95% CI: 32-38). TTP was strongly associated with post PD OS (spline p-value&lt;0.0001) with OS24 ranging from 18% in patients with TTP &lt;6 months compared to 69% in patients with TTP &gt; 36 months (Figure A). Additionally, age at PD (spline p-value&lt;0.0001) was associated with post PD OS. A model consisting of age at PD including patients 40-80 years and TTP ranging 0-60 months was created (n=1011, Figure B) due to sparse data outside these intervals. C-stat was 0.67, and the model was well calibrated (predicted OS24 = 34% vs. actual OS24 = 34%). External Validation (MER): The model was validated in 290 patients with DLBCL who initiated 2nd line therapy after PD to IC. Median age at PD was younger than the SEAL cohort at 62 years (IQR 57-70). Patients with biopsy proven indolent histology at relapse were excluded. Median TTP was 8.2 months (IQR 5.1-17.0). At a median follow-up of 87 months from PD, 201 patients (69%) had died. OS24 was 47% (95% CI: 41-53). The model showed similar concordance (c-stat=0.65), but underestimated OS24 (predicted =33% vs. 47% actual, Figure C). External Validation (LYFO): The model was validated in 599 patients with DLBCL and PD after frontline IC. Median age at PD was 67 years (IQR 60-73). Median TTP was 10.1 months (IQR 6.0-19.4). At a median follow-up of 82 months from PD, 435 patients (73%) had died. OS24 was 38% (95% CI: 34-42). The model showed similar concordance (c-stat=0.67) when applied to the LYFO cohort, but again underestimated OS24 (predicted =32% vs. 38% actual, Figure D). Case vignettes: A 74 year old patient who progressed 9 months after diagnosis would have a predicted OS24 of 20%. A 58 year old patient who progressed 32 months after diagnosis would have a predicted OS24 of 65% Conclusions: TTP to following IC is strongly associated with post-progression survival in DLBCL. We developed a model from the largest frontline clinical trial dataset in DLBCL and validated a simple to apply clinical prognostic tool in the r/r setting. The model allows better understanding of expected outcomes in r/r DLBCL and can aid design and interpretation of trial results in this setting. The model underestimated the actual survival probability when applied to non-trial validation cohorts. Recalibration of the model for transplant eligible patients and development of smartphone based point-of-care application of the model is ongoing. Figure Disclosures Maurer: Celgene: Research Funding; Nanostring: Research Funding; Morphosys: Membership on an entity's Board of Directors or advisory committees. Schmitz:Riemser: Consultancy, Honoraria; Celgene: Equity Ownership; Gilead: Honoraria; Novartis: Honoraria. Farooq:Kite Pharma: Research Funding; Celgene: Honoraria. Flowers:Optimum Rx: Consultancy; Burroughs Wellcome Fund: Research Funding; BeiGene: Consultancy, Research Funding; Karyopharm: Consultancy; AstraZeneca: Consultancy; Gilead: Consultancy, Research Funding; Eastern Cooperative Oncology Group: Research Funding; Genentech, Inc./F. Hoffmann-La Roche Ltd: Consultancy, Research Funding; Bayer: Consultancy; TG Therapeutics: Research Funding; Acerta: Research Funding; Celgene: Consultancy, Research Funding; National Cancer Institute: Research Funding; Denovo Biopharma: Consultancy; Pharmacyclics/Janssen: Consultancy, Research Funding; Spectrum: Consultancy; Millenium/Takeda: Research Funding; AbbVie: Consultancy, Research Funding; V Foundation: Research Funding. Frederiksen:Alexion: Research Funding; Gilead: Research Funding; Abbvie: Research Funding; Janssen Pharmaceuticals: Research Funding; Novartis: Research Funding. Cunningham:Eli Lilly: Research Funding; 4SC: Research Funding; Bayer: Research Funding; MedImmune: Research Funding; Celgene: Research Funding; AstraZeneca: Research Funding; Merrimack: Research Funding; Sanofi: Research Funding; Amgen: Research Funding; Janssen: Research Funding; Merck: Research Funding; Clovis: Research Funding. Jørgensen:Gilead: Membership on an entity's Board of Directors or advisory committees; Roche: Membership on an entity's Board of Directors or advisory committees. Poeschel:Amgen: Other: Travel, accommodations, expenses; Abbvie: Other: Travel, accomodations, expenses; Hexal: Speakers Bureau; Roche: Other: Travel, accomodations, expenses. Nowakowski:F. Hoffmann-La Roche Ltd: Research Funding; Curis: Research Funding; Selvita: Membership on an entity's Board of Directors or advisory committees; NanoString: Research Funding; MorphoSys: Consultancy, Research Funding; Genentech, Inc.: Research Funding; Bayer: Consultancy, Research Funding; Celgene: Consultancy, Research Funding. Seymour:Takeda: Consultancy; Celgene: Consultancy, Research Funding, Speakers Bureau; AbbVie: Consultancy, Honoraria, Research Funding, Speakers Bureau; Acerta: Consultancy; Janssen: Consultancy, Research Funding; Roche: Consultancy, Research Funding, Speakers Bureau. Merli:Takeda: Honoraria, Other: Travel Expenses; Gilead: Honoraria; Mundipharma: Honoraria; Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel expenses, Research Funding; Sandoz: Membership on an entity's Board of Directors or advisory committees; Teva: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees, Other: Travel Expenses; Janssen: Honoraria. Haioun:novartis: Honoraria; celgene: Honoraria; roche: Consultancy; celgene: Consultancy; gilead: Consultancy; takeda: Consultancy; janssen cilag: Consultancy; amgen: Honoraria; servier: Honoraria. 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; Celgene: Consultancy, Research Funding; Roche: Consultancy. Salles:Amgen: Honoraria, Other: Educational events; BMS: Honoraria; Merck: Consultancy, Honoraria, 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; Autolus: Consultancy, Membership on an entity's Board of Directors or advisory committees; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, 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. El-Galaly:Roche: Employment, Other: Travel support; Takeda: Other: Travel support.

Abstract Background Despite improvements in outcome following the addition of rituximab (R) to CHOP (cyclophosphamide, doxorubicin, vincristine, prednisone) (R-CHOP), patients with newly diagnosed diffuse large B-cell lymphoma (DLBCL) and International Prognostic Index (IPI) scores of 3-5 at diagnosis have a poor outcome. Enzastaurin is a potent inhibitor of PKCβ, a component of the B-cell receptor signaling complex, with preclinical activity and clinical activity in a phase II trial in patients with relapsed DLBCL, providing the rationale for this study in the primary therapy setting. Methods PRELUDE was a multi-national, randomized, double-blinded, placebo-controlled study. Patients were required to have a histologic diagnosis of DLBCL, pre-treatment IPI score ≥3, and a complete response (CR) or CRu by International Working Group Criteria, or a negative FDG-PET scan after 6–8 cycles of R-CHOP. Patients were randomly assigned in a 2:1 ratio to receive either enzastaurin 500 mg daily or an identical placebo as maintenance therapy, for a planned treatment duration of 3 years. The primary endpoint was DFS, defined as lack of disease progression or death. Assuming a 2-year DFS rate in the control group of 70%, the primary analysis had 80% power to detect a HR of 0.67, eg, a 2-year DFS rate of 79% in the enzastaurin group. Secondary endpoints included overall survival (OS) and event-free survival (EFS). Data were analyzed 3 years after the last enrolled patient initiated treatment. Results From May 2006–April 2010, 758 patients were enrolled (enzastaurin, n=504; placebo, n=254). Median age at enrollment was 64 years (range 21-89); at diagnosis, 65% of patients had stage IV disease, 48% had B symptoms, and 25% had a mass >10 cm; baseline disease and patient characteristics were well balanced between treatment arms. Fifty-seven percent had a negative PET scan following completion of R-CHOP. Median follow-up time for all patients was 48 months (range 0.03–80). At the time of analysis, 209 events had occurred. The DFS HR for enzastaurin vs. placebo was 0.92 (95% CI: 0.69, 1.22; 2-sided log-rank p=0.54). DFS at 24 and 48 months were 79% and 70% for the enzastaurin arm, and 75% and 71% for placebo, respectively. OS at 24 and 48 months was 87% and 81% for enzastaurin, and 89% and 82% for placebo; HR for enzastaurin vs. placebo was 1.04 (95% CI: 0.74, 1.47; 2-sided log-rank p=0.81). Percent of ITT population patients on therapy at 12, 24, and 36 months was 70.6%, 60.6%, and 20.1% for enzastaurin; 72.3%, 60.6%, and 22.1% for placebo. Biomarker subgroup analysis was performed and will be available at time of presentation. Treatment emergent AEs (all grades) that were possibly study drug-related and significantly different between enzastaurin and placebo included chromaturia (18.5% vs. 0.4%), QTc prolongation (10.8% vs. 3.6%), and diarrhea (10.3% vs. 2.8%). There were no significant differences in number of patients with at least 1 grade 3 or higher AE between treatment arms. No significant differences were observed in the frequency of deaths while on therapy. Conclusion Enzastaurin did not improve DFS, EFS, or OS in patients with high-risk DLBCL and CR following R-CHOP treatment. Disclosures: Crump: Roche: Honoraria; Jansen-Ortho: Honoraria; Celgene: Honoraria; Lundbeck: Honoraria; Novartis: Research Funding; Seattle Genetics: Honoraria. Off Label Use: rituximab for maintenance therapy post autolgous transplant for lymphoma. Leppä:Eli Lilly: Research Funding. Ogura:Eli Lilly: Research Funding. Rifkin:Millenium, Celgene, ONYX: Membership on an entity’s Board of Directors or advisory committees. Mackensen:Eli Lilly: Consultancy. Offner:Eli Lilly: Membership on an entity’s Board of Directors or advisory committees. Smith:Genentech, Celgene, Spectrum, Seattle Genetics, Gilead, Amgen/Micronet: Consultancy. Tobinai:Eli Lilly: Research Funding. Hahka-Kemppinen:Eli Lilly: Employment. Thornton:Eli Lilly: Employment. Shi:Eli Lilly: Employment. Lin:Eli Lilly: Employment. Kahl:Genentech: Consultancy. Savage:Eli Lilly: Consultancy.

Abstract Background: Patients (pts) with DLBCL who receive first-line anthracycline based immunochemotherapy and remain in remission at 2 years have excellent outcomes with overall survival (OS) in one study that was comparable to the age and sex matched general population in cohorts from the US and France (Maurer et al, JCO 2014). To evaluate whether these findings are robust and generalizable, we assessed OS stratified by progression-free survival at 24 months (PFS24) using individual patient data from pts with DLBCL enrolled in 14 multi-center, international randomized clinical trials as part of the SEAL consortium. Methods: Central data alignment was performed by the SEAL statistics and data center. All enrolled patients treated with rituximab-containing anthracycline-based immunochemotherapy as part of initial induction therapy were included in this analysis using an intent-to-treat approach. PFS was defined as time from initiation of first-line therapy to progression or death. PFS24 was defined as being alive and progression-free 24 months (731 days) after initiation of therapy. Overall survival from PFS24 was defined as time from achieving PFS24 until death due to any cause. OS was compared to each patient's age-, sex-, and country- matched general population using expected survival and standardized mortality ratios (SMR). Country-level population rate tables were obtained from www.mortality.org where available. A per-study average rate table was used when country information was unavailable. OS beyond 9 years from treatment initiation was only available the time of analysis from two trials (13% of cohort) and thus follow-up from PFS24 was restricted to the first 7 years after PFS24 for this analysis. Results: Fourteen studies with 7975 patients were included in the SEAL database. 5853 (73%) received rituximab as part of induction therapy and used in this analysis. Median age was 62 years (range 18-92) with 56% >60 years, 54% were male, 57% had elevated LDH, 63% had stage III/IV disease, 13% had ECOG PS 2-4, and IPI was 0-1 in 36%, 2 in 25%, 3 in 23%, and 4-5 in 16%. At a median follow-up of 4.4 years, 1337 (23%) had disease progression, 1489 patients (25%) had died, and 5101 patients were evaluable for PFS24. 1423 (28%) of evaluable patients failed to achieve PFS24. These patients had poor outcomes after progression with median OS of 7.2 months (95% CI 6.8-8.1), 5-year OS of 19%, and SMR of 32.1 (95% CI: 30.0-34.4). Outcome was excellent (median unreached) in the 3678 patients who were progression-free at 24 months, with subsequent OS after achieving PFS24 approaching the age and sex matched general population (Figure). The observed vs. expected OS at 3, 5, and 7 years after achieving PFS24 was 93.1% vs. 94.4%, 87.6% vs. 89.5%, and 80.0% vs. 83.7%, respectively, the SMR was 1.22 (95% CI: 1.09-1.37). In subset analyses examining pts achieving PFS24, adverse prognostic characteristics at baseline (elevated LDH, advanced stage, ECOG PS 2-4, high IPI) were associated with greater decrement in OS from the general population based expected survival (Table). Conclusions: PFS24 from the start of initial therapy stratifies DLBCL pts into populations with distinct outcomes. DLBCL pts treated with rituximab containing anthracycline-based immunotherapy on large randomized clinical trials who are alive without progression at 24 months from start of initial therapy have excellent outcomes with survival that is marginally lower but clinically indistinguishable from the age-, sex-, and country-matched background population for at least 7 years after achieving PFS24. Further follow-up time will be needed to assess any long-term impact of late relapse and survivorship issues in this population. Table Table. Figure Figure. Disclosures Shi: Mayo Clinic: Employment. Cunningham:Amgen: Research Funding; Astra-Zeneca: Research Funding; Bayer: Research Funding; Celgene: Research Funding; Merrimack: Research Funding; Medimmune: Research Funding. Seymour:AbbVie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel support, Research Funding, Speakers Bureau; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel support, Speakers Bureau; Genentech: 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, Speakers Bureau; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees. Jaeger:Roche: Honoraria, Research Funding; Celgene: Honoraria, Research Funding. Haioun:Sandoz: Honoraria, Membership on an entity's Board of Directors or advisory committees; Gilead: 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; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees; Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees. Ghesquieres:Mundipharma: Consultancy; Roche France: Research Funding; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees. Merli: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; Teva Pharmaceuticals Industries: Membership on an entity's Board of Directors or advisory committees. Herbrecht:Servier: Membership on an entity's Board of Directors or advisory committees; Gilead: Membership on an entity's Board of Directors or advisory committees; Cell Therapeutics, Inc: Membership on an entity's Board of Directors or advisory committees. Flament:Celgene: Employment, Equity Ownership. Fu:Celgene: Employment, Equity Ownership. Flowers:Gilead: Consultancy, Research Funding; Roche: Consultancy, Research Funding; Acerta: Research Funding; ECOG: Research Funding; Mayo Clinic: Research Funding; Pharmacyclics, LLC, an AbbVie Company: Research Funding; Millenium/Takeda: Research Funding; Infinity: Research Funding; TG Therapeutics: Research Funding; Genentech: Consultancy, Research Funding; NIH: Research Funding; AbbVie: Research Funding. Ou:Mayo Clinic: Employment. Sargent:Celgene: Research Funding. Coiffier:MorphoSys: Consultancy; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees; Gilead: Consultancy, Membership on an entity's Board of Directors or advisory committees; Roche: Consultancy; Celltrion: 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, Research Funding; Pfizer: Consultancy, Membership on an entity's Board of Directors or advisory committees.

Abstract Background OSis the gold standard primary efficacy endpoint for evaluating treatment strategies for DLBCL. Because current standard of care first-line regimens with rituximab plus chemotherapy produce median OS > 8 years, an endpoint assessed earlier would accelerate the evaluation of new therapies and potentially allow patients (pts) to more rapidly benefit from study results. The SEAL group formally evaluated PFS as a surrogate endpoint for OS in first-line therapy for DLBCL. Methods Through a systematic literature search and input from lymphoma experts on the SEAL committee, we identified multicenter, randomized controlled clinical trials that evaluated active treatment and enrolled at least 100 pts with previously untreated DLBCL or aggressive non Hodgkin lymphoma by WHO/REAL classification, published after January 1, 1995. Studies which enrolled only early stage (I or II) pts and studies that could not provide individual pt data (IPD) were excluded from surrogacy analysis. Potential surrogate candidates for OS included: 1) PFS, defined as the time from initiation of induction treatment to progressive disease, relapse or death due to any cause, and 2) PFS rate at 24 months after initiation of induction treatment (PFS24). These endpoints were derived consistently for all studies based on IPD. Surrogacy was evaluated by the correlation between surrogate candidates and OS. Pt-level correlation was measured by the rank correlation coefficient (ρ) and global odds ratio for PFS and PFS24, respectively, estimated by the Copula model. Trial-level correlation was evaluated by the correlation between trial-specific treatment effects on surrogate candidates and OS with two commonly used trial-level R2s: R2WLS (Sargent et al JCO 2005) and R2Copula (Burzykowski et al J R Stat Soc C 2001 and Burzykowski et al J R Stat Soc A 2004). For the R2 measures, a value closer to 1 indicates a stronger correlation. We pre-specified that if either trial-level R2 was >=0.80 and its 95% confidence interval (CI) excluded 0.60, the candidate would meet criteria for surrogacy. Results Thirteen of 14 studies collected to date in the SEAL database met all inclusion criteria. IPD for 7507 pts (median age 63 years, 54% male, 46% ECOG performance status 0, 8% IPI 0, 50% IPI 1-2, 64% stage III/IV, median follow-up time of 52 months) were analyzed. Among 13 studies, one tested maintenance treatment only and two tested both induction and maintenance regimens. One study included four treatment arms. Thus at the trial level, 17 two-arm comparisons were formed: 14 comparisons comparing induction regimens and 3 comparing maintenance; 15 comparisons involved rituximab. Longer PFS was highly correlated with longer OS at the pt level (ρ= 0.85, 95% CI 0.84-0.86), as was PFS24 (Global odds ratio = 61.1, 95% CI 52.6-69.6). The Table shows trial-level correlations, and the Figure shows trial-level association between estimated treatment effects (log(HR) [hazard ratio]) on PFS and OS. The trial-level correlation between PFS and OS was strong and met the pre-specified surrogacy criteria, with R2WLS of 0.83 (95% CI 0.58-0.94) and R2Copula of 0.85 (95% CI 0.72-0.99). Sensitivity analyses including only comparisons including rituximab or only induction regimens showed consistent results. The overall trial-level correlation between PFS24 and OS was reduced slightly, with R2WLS of 0.77 (95% CI 0.49-0.92) and R2Copula of 0.78 (95% CI 0.59-0.96). Performance of PFS24 was improved when restricting analysis to only including induction studies (see table). Conclusion This large IPD pooled-analysis demonstrates that PFS duration met the pre-specified criteria as a robust surrogate endpoint for OS, and can be considered as a surrogate endpoint for OS for frontline DLBCL trials evaluating immunochemotherapy. The earlier endpoint of PFS24 showed promise as a potential surrogate and further validation is warranted. Figure Figure. Disclosures Shi: Mayo Clinic: Employment. Flowers:Millenium/Takeda: Research Funding; TG Therapeutics: Research Funding; Pharmacyclics, LLC, an AbbVie Company: Research Funding; Gilead: Consultancy, Research Funding; NIH: Research Funding; Mayo Clinic: Research Funding; ECOG: Research Funding; Acerta: Research Funding; Infinity: Research Funding; AbbVie: Research Funding; Roche: Consultancy, Research Funding; Genentech: Consultancy, Research Funding. Ou:Mayo Clinic: Employment. Cunningham:Merrimack: Research Funding; Celgene: Research Funding; Bayer: Research Funding; Astra-Zeneca: Research Funding; Amgen: Research Funding; Medimmune: Research Funding. Pfreundschuh:Amgen: Consultancy, 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; Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Spectrum: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding. Seymour:AbbVie Inc.: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Genentech: 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, Speakers Bureau; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Gilead: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees. Jaeger:Roche: Honoraria, Research Funding; Celgene: Honoraria, Research Funding. Haioun:Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Gilead: Honoraria, Membership on an entity's Board of Directors or advisory committees; Sandoz: Honoraria, Membership on an entity's Board of Directors or advisory committees; Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees. Ghesquieres:Mundipharma: Consultancy; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees; Roche France: Research Funding. Merli:Teva Pharmaceuticals Industries: Membership on an entity's Board of Directors or advisory committees; 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. Herbrecht:Cell Therapeutics, Inc: Membership on an entity's Board of Directors or advisory committees; Gilead: Membership on an entity's Board of Directors or advisory committees; Servier: Membership on an entity's Board of Directors or advisory committees. Flament:Celgene: Employment, Equity Ownership. Fu:Celgene: Employment, Equity Ownership. Coiffier:MorphoSys: Consultancy, Membership on an entity's Board of Directors or advisory committees; Gilead: Consultancy, Membership on an entity's Board of Directors or advisory committees; Pfizer: Consultancy, Membership on an entity's Board of Directors or advisory committees; Celltrion: 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, Research Funding; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees. Sargent:Celgene: Research Funding.

Purpose Overall survival (OS) is the definitive and best-established primary efficacy end point to evaluate diffuse large B-cell lymphoma (DLBCL) therapies, but it requires prolonged follow-up. An earlier end point assessed post-treatment would expedite clinical trial conduct and accelerate patient access to effective new therapies. Our objective was to formally evaluate progression-free survival (PFS) and PFS at 24 months (PFS24) as surrogate end points for OS in first-line DLBCL. Patients and Methods Individual patient data were analyzed from 7,507 patients from 13 multicenter randomized controlled trials of active treatment in previously untreated DLBCL, published after 2002, with sufficient PFS data to predict treatment effects on OS. Trial-level surrogacy examining the correlation of treatment effect estimates of PFS/PFS24 and OS was evaluated using both linear regression ( R2WLS) and Copula bivariable ( R2Copula) models. Prespecified criteria for surrogacy required either R2WLS or R2Copula ≥ 0.80 and neither < 0.7, with lower-bound 95% CI > 0.60. Results Trial-level surrogacy for PFS was strong ( R2WLS = 0.83; R2Copula = 0.85) and met the predefined criteria for surrogacy. At the patient level, PFS strongly correlated with OS. The surrogate threshold effect had a hazard ratio of 0.89. Surrogacy was consistent across comparisons with or without rituximab and with rituximab maintenance trials. Trial-level surrogacy for PFS24 was relatively strong ( R2WLS = 0.77; R2Copula = 0.78) but did not meet prespecified criteria. At the patient level, PFS24 significantly correlated with OS. The surrogate threshold effect had an odds ratio of 1.51. Conclusion This large pooled analysis of individual patient data supports PFS as a surrogate end point for OS in future randomized controlled trials evaluating chemoimmunotherapy in DLBCL. Use of this end point may expedite therapeutic development with the intent of bringing novel therapies to this patient population years before OS results are mature.