Pfreundschuh, Michael

Abstract Background We have previously reported and validated that the E-IPI, provided better discrimination of overall survival (OS) than the IPI for DLBCL patients > 60 years of age treated with R-CHOP (Advani et al., BJH 2010 and 12-ICML 2013 Abstract 222). Recent reports suggest that males > 60 years treated with R-CHOP have worse outcomes likely related to differences in rituximab clearance (Muller et al., Blood 2012). In this study, we explored if the addition of male sex to the E-IPI further improved risk stratification. Methods DLBCL patients > 60 years treated with R-CHOP on the E4494, RICOVER-60 and GELA 98-5 trials were included. A multivariate analysis was performed to assess whether male sex is an independent prognostic factor for OS in addition to the five E-IPI risk factors, E-IPI score, and E-IPI risk group. Male sex (S) was added as an additional risk factor to the E-IPI (S-EIPI, 0-6) and patients regrouped according to the number of risk factors: low (L)=0-1, low intermediate (LI)=2, high intermediate (HI)=3 and high (H)=4-6 based on the observed OS using Kaplan-Meier curves. C-statistic was used to compare the discrimination ability. The 5 year OS was estimated using the Kaplan-Meier method. Results 1079 patients (E4494, n=267; RICOVER-60, n=610; GELA 98-5, n=202) with a median follow-up of 8.9 years were included. In multivariate analyses, male sex was a significant independent predictor for OS adjusting for all five E-IPI factors, (HR 1.5, p < 0.0001), E-IPI score (HR 1.42, p < 0.001), and E-IPI risk group (HR 1.42, p < 0.001) (Table 1). C-statistic was 0.66 for S-EIPI and 0.64 for EIPI. Incorporation of sex into the E-IPI shifted 35% patients to higher risk groups, including 110 patients into the highest risk group (Table 2). The estimated 5 year OS for the S-EIPI L, LI, HI, and H risk groups was 87%, 70%, 58%, and 40%, respectively (Table 3). Compared to E-IPI, the 95% C.I. did not overlap among S-EIPI risk groups. Conclusion For DLBCL patients >60 years treated with R-CHOP, our results suggest the addition of male sex to the E-IPI may improve categorization of patients into well-defined clinically relevant risk groups. Patients with low risk S-EIPI have an excellent outcome (5 year OS 87%). Patients with high risk S-EIPI have a 5 year OS of only 40% and therapies beyond standard R-CHOP need to be explored. Disclosures: Horning: Genentech: Employment; Roche: Equity Ownership.

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.

Abstract Diffuse large B-cell lymphoma (DLBCL) is a genetically heterogeneous disease characterized by multiple low-frequency alterations including somatic mutations, copy number alterations (CNAs) and chromosomal rearrangements. We sought to identify previously unrecognized low-frequency genetic events, integrate recurrent alterations into comprehensive signatures and associate these signatures with clinical parameters. For these reasons, our multi-institutional international group assembled a cohort of 304 primary DLBCLs from newly diagnosed patients, 87% of whom were uniformly treated with state-of-the-art therapy (rituximab-containing CHOP regimen) and had long term followup. Tumors were subjected to whole exome sequencing with an extended bait set that included custom probes designed to capture recurrent chromosomal rearrangements. In this cohort, 47% of samples had available transcriptional profiling and assignment to associated disease subtypes. Analytical pipelines developed at the Broad Institute were used to detect mutations (MuTect), CNAs (Recapseq+Allelic Capseq) and chromosomal rearrangements (dRanger+Breakpointer) and assess clonality (Absolute). To analyze formalin-fixed paraffin-embedded tumors without paired normals we developed a method which utilized 8334 unrelated normal samples to stringently filter recurrent germline events and artifacts. Significant mutational drivers were identified using the MutSig2CV algorithm and recurrent CNAs were assessed with GISTIC2.0. In addition, we utilized a recently developed algorithm, CLUMPS2, to prioritize somatic mutations which cluster in 3-dimensional protein structure. With this approach, we identified > 90 recurrently mutated genes, 34 focal amplifications and 41 focal deletions, 20 arm-level events and > 200 chromosomal rearrangements in the DLBCL series. Of note, 33% of the mutational drivers were also perturbed by chromosomal rearrangements or CNAs, underscoring the importance of a comprehensive genetic analysis. In the large DLBCL series, we identified several previously unrecognized but potentially targetable alterations including mutations in NOTCH2 (8%) and TET2 (5%). The majority of identified chromosomal rearrangements involved translocations of potent regulatory regions to intact gene coding sequences. The most frequently rearrangements involved Ig regulatory elements which were translocated to BCL2, MYC, BCL6 and several additional genes with known roles in germinal center B-cell biology. After identifying recurrent somatic mutations, CNAs and chromosomal rearrangements, we performed hierarchical clustering and identified subsets of DLBCLs with comprehensive signatures comprised of specific alterations. A large subset of tumors shared recurrent alterations previously associated with follicular lymphoma including mutations of chromatin modifiers such as CREBBP, MLL2, and EZH2 in association with alterations of TNFRSF14 and GNA13 and translocations of BCL2. This cluster was enriched in GCB-type DLBCLs and contained a subset with select genetic alterations associated with an unfavorable outcome. An additional cohort of tumors was characterized by alterations perturbing B-cell differentiation including recurrent BCL6 translocations or alterations of PRDM1. A subset of these DLBCLs had alterations of NOTCH2 and additional pathway components or mutations of MYD88 in association with TNFAIP3, CD70 and EBF1, a master regulator of B-cell differentiation. An additional group of DLBCLs exhibited frequent MYD88 mutations in association with alterations of CD79B, PIM1, TBL1XR1 and ETV6 and BCL2 copy gain; these tumors were highly enriched for ABC-type DLBCLs. This coordinate signature and additional alterations of p53 pathway components were associated with outcome. We explored bases for the identified genetic alterations in DLBCL by performing an in silico mutational signature analysis. The most frequent mutational signatures were those of spontaneous deamination (aging) and AID with rare cases of microsatellite instability. We also assessed the clonality of identified genetic features to define cancer cell fraction and establish the timing of specific genetic events. The comprehensive genetic signatures of clinically annotated DLBCLs provide new insights regarding approaches to targeted therapy. Disclosures Link: Kite Pharma: Research Funding; Genentech: Consultancy, Research Funding. Rodig:Perkin Elmer: Membership on an entity's Board of Directors or advisory committees; BMS: Research Funding. Pfreundschuh:Boehringer Ingelheim, Celegene, Roche, Spectrum: Other: Advisory board; Roche: Honoraria; Amgen, Roche, Spectrum: Research Funding. Shipp:Gilead: Consultancy; Sanofi: Research Funding; BMS: Membership on an entity's Board of Directors or advisory committees, Research Funding; Merck: Membership on an entity's Board of Directors or advisory committees; Bayer: Membership on an entity's Board of Directors or advisory committees, 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.

Key Points HGBL-DH/TH makes up 8% of de novo DLBCL, with HGBL-DH/TH with BCL2 rearrangement being a GCB phenomenon. Restricting FISH testing to tumors with dual protein expression and GCB subtype results in testing <15% of tumors, but missing ∼35% of HGBL-DH/TH.