Nicolas‐Virelizier, Emmanuelle

Abstract We have recently reported that event-free survival at 24 months from diagnosis (EFS24) is a robust endpoint for assessment of disease related outcome for newly diagnosed patients with diffuse large B-cell lymphoma (DLBCL) treated with anthracycline-based immunochemotherapy (IC). Patients who achieve EFS24 following IC have a subsequent overall survival that is equivalent to the age and sex matched general population. The IPI was developed in the pre-rituximab era using OS/EFS endpoints. While the IPI is associated with outcome in the IC era, the original survival estimates for the IPI risk groups are outdated. The IPI is also a discrete risk classifier, with only 6 possible groups. Here we remodel the IPI using EFS24 as the endpoint in a large international cohort of patients treated with IC. This model provides an individual level 0-100% risk of failing to achieve EFS24 for each patient and can be used for patient prognosis, treatment stratification, and risk assessment. Methods Newly diagnosed DLBCL patients treated with immunochemotherapy from the University of Iowa/Mayo Clinic SPORE Molecular Epidemiology Resource, NCCTG N0489 clinical trial, GELA LNH2003B program, and a Lyon, France based hospital registry were included in the original EFS24 study. Patients with a relapse, progression, unplanned re-treatment, or death due to any cause within 730 days of diagnosis were considered a failure for the EFS24 endpoint. Patients alive and progression/relapse free at 730 days from diagnosis with no subsequent treatment following initial IC were considered a success for the EFS24 endpoint. Variables selected for potential model inclusion were the IPI components (age, stage, ECOG PS, number of extranodal sites, and LDH), as well as standard clinical variables typically reported in studies of DLBCL: presence of B-symptoms, bone marrow involvement, bulky disease (>10 cm), and sex. The IPI24, a prognostic model for EFS24, was developed using logistic regression models. Model building began by fitting the classic IPI score (0-5), then allowing individual IPI variables to carry different model weights and number of categories, followed by dropping insignificant variables, finally adding any additional significant variables. Model performance was assessed using bias corrected c-statistics, AIC, and R2 values. Model selection was done using the complete case set with multiple imputation on the full dataset used to refine parameter estimates for the final model. Results 1596 total patients were available for modeling. The median age was 62 (range 18-93) and 53% were male; 33% were IPI 0-1, 25% were IPI 2, 25% were IPI 3, and 17% were IPI of 4-5. The failure rate for achieving EFS24 was 29%. All variables but sex (p=0.33) were univariately associated with EFS24 (p<6.4x10-5). The original IPI had good prognostic ability for EFS24 (c=0.696, p=2.2x10-32). Allowing multiple categories for ECOG PS, stage, and age (continuous) improved model fit and prognostic ability (c=0.727). The number of extranodal sites was not significant when IPI variables were modeled separately and was removed from the model. Sex and bulky disease were additional significant variables when added to the model. Thus, the final IPI24 model contained the following risk predictors: male sex, ECOG PS (0 vs. 1 vs 2 vs 3-4), stage (I vs. II, vs. III vs. IV), LDH (elevated vs. normal range), bulky disease > 10cm, and age (continuous). This model resulted in improved fit and prognostic ability (c=0.749) over the standard IPI (c=0.696, bootstrap p<0.001). Model validation was performed on an additional 158 patients from the SPORE MER and showed good concordance (c=0.697). Additional validation is planned in a larger set of independent patients. Conclusion The IPI24, generated using standard clinical variables, yields an individual risk prediction for failing to achieve EFS24 following IC for treatment of DLBCL. The IPI24 has superior prognostic ability to the standard IPI and can be implemented in the clinic using a nomogram or as a simple electronic application. Disclosures: No relevant conflicts of interest to declare.

Abstract Abstract 1540 Background: Diffuse Large B-cell Lymphoma (DLBCL) is the most common lymphoma in the western world. Outcomes have improved with the standard initial therapy of rituximab and anthracyline based chemotherapy (immunochemotherapy). However, 20–40% of patients will either fail to achieve remission or relapse following initial immunochemotherapy. Most relapses occur early, and long-term outcome of relapsed/refractory patients is generally poor despite salvage regimens and stem cell transplant. Traditionally, studies for DLBCL have been evaluated using progression-free and/or overall survival. However, the event rate in DLBCL slows significantly approximately 12–18 months after diagnosis, and late events are often due to competing (non-DLBCL related) risks, especially in older patients. Here we examine outcome of DLBCL patients based on their event status at 12 months. Methods: Newly diagnosed DLBCL patients were prospectively enrolled in the University of Iowa/Mayo Clinic Lymphoma SPORE Molecular Epidemiology Resource (MER). Clinical data were abstracted from medical records using a standard protocol. Patients were actively followed for events (progression, re-treatment, or death due to any cause) and overall survival (OS). Event-free status at 12 months after diagnosis (EFS12) was assessed as a dichotomous variable. Cause of death was determined by medical record and death certificate review using prospectively determined definitions. Expected survival was based on age and sex matched survival using the Minnesota population death rates. Confirmation cohorts were from a Lyon, France hospital based registry and NCCTG clinical trial N0489. Results: 680 patients with newly diagnosed DLBCL and treated with rituximab + anthracycline based chemotherapy were enrolled in the MER from 2002 to 2009. The median age was 62 years (range 18–92). 53% were male. At a median follow-up of 59 months (range 8–116), 266 patients (39%) had an event and 188 patients (28%) died. 162 patients (24%) had an event in the first 12 months after diagnosis, comprising 60% of all events. Patients with an event in the first 12 months had poor survival with death almost exclusively due to disease (Figures 1a, 2a). In contrast, patients who were event-free at 12 months had comparable survival to the age and sex matched general population (Figure 2b) and were more likely to die of other causes than DLBCL (Figure 1b). Overall survival rates by EFS12 status were validated in patients from a French hospital-based registry (N=265) and the NCCTG N0489 clinical trial (N=87) with additional replication studies underway. Conclusions: DLBCL patients who are event-free at 12 months after diagnosis have an excellent prognosis with an overall survival similar to that of an age- and sex- matched general population and are more likely to die of other causes than DLBCL. This finding has implications for clinical management, new clinical trials, and follow-up testing in this patient population. In contrast, patients with an event within the first 12 months after diagnosis have a poor prognosis with almost all deaths secondary to DLBCL. EFS status at 12 months identifies patients with poor outcomes due to disease. This can be utilized as an endpoint in biologic studies and clinical trials to address early treatment failures. EFS status at 12 months should be incorporated into prognostic models to identify high risk patients in newly diagnosed DLBCL. Disclosures: No relevant conflicts of interest to declare.

Abstract Background: Follicular lymphoma (FL) is an indolent lymphoma generally considered incurable with current standard therapies. Recent advances have resulted in prolongation of overall survival (OS) for patients with FL such that death from competing causes may now limit the mortality impact of FL in some patient groups. Identification of patients for whom FL related mortality is expected to be minimal, or conversely those at high risk of disease related mortality, is highly clinically relevant. We recently reported (Maurer et al, JCO 2014;32:1066-73) that event-free survival (EFS) at 24 months from diagnosis is a robust endpoint for disease related outcome in patients with diffuse large B cell lymphoma (DLBCL). Here we use the same approach to assess if landmark timepoints of EFS can stratify subsequent OS in FL. Methods: All newly diagnosed grade 1-3a FL patients enrolled on the University of Iowa/Mayo Clinic Lymphoma SPORE Molecular Epidemiology Resource (MER) from 2002-2011 were eligible. Patients with grade 3b FL, transformation, or presence of DLBCL at diagnosis were excluded. EFS was defined as time from diagnosis to progression, relapse, re-treatment, or death due to any cause. EFS12 was defined based on EFS status 12 months after date of diagnosis; we also assessed EFS at 24 months. OS was defined as time from a specific timepoint (diagnosis, event, or EFS12) until death due to any cause. OS was compared to age and sex matched survival in the general US population using an expected survival approach and standardized mortality ratios (SMR) and 95% confidence intervals (CI). Outcomes were examined in all patients as well as selected subsets defined by initial treatment. Replication was performed using a Lyon, France hospital registry of newly diagnosed grade 1-3a FL patients enrolled from 2002-2010 with survival compared to French population data. Results: 936 patients with grade 1-3a FL were eligible from the MER. The median age at diagnosis was 60 years (range 19-91) and 53% were male. 86% had grade 1-2 disease and 14% grade 3a disease. 23% had high-risk disease (FLIPI score ≥3). 347 (37%) were initially treated with alkylator or anthracyline based immunochemotherapy (IC), 113 (12%) rituximab monotherapy (RM), and 318 (34%) were initially observed; the remaining patients received radiation for limited stage disease (8%), chemotherapy without rituximab (4%), or other therapy (5%). At a median follow-up of 59 months (range 1-131), 403 patients (43%) had an event and 120 patients (13%) had died; 155 patients (17%) failed to achieve EFS12. From diagnosis, patients with FL had inferior OS compared to the general population (SMR=1.24, 95% CI: 1.03-1.48, p=0.018); results were similar for patients with grade 1-2 (SMR=1.23) and grade 3a (SMR=1.29) disease. The survival deficit was eliminated in patients who achieved EFS12 (SMR=0.85, 95% CI: 0.66-1.09, p=0.20, Fig 1a), and so we did not pursue modeling EFS24. In contrast, patients with a non-death event (relapse, retreatment, or progression) within 12 months of diagnosis had inferior subsequent OS (SMR=3.90, 95% CI: 2.89-5.25, p=4.8x10-19, Fig 1b). These results were replicated in 153 FL patients from the Lyon registry: patients who achieved EFS12 had equivalent subsequent OS to the general French population (SMR=0.82, 95% CI: 0.39-1.72, p=0.60, Fig 1c), while patients who failed to achieve EFS12 had poor subsequent OS (SMR=4.16, 95% CI: 1.34-12.91, p=0.013, Fig 1d). In subset analysis of the MER, patients achieving EFS12 initially treated with IC (SMR=0.98, 95% CI: 0.63-1.54, p=0.93), RM (SMR=0.66, 95% CI: 0.31-1.38, p=0.27), or observation (SMR=0.73, 95% CI: 0.47-1.15, p=0.18) had equivalent OS to the population. In contrast, for patients not achieving EFS12, OS after event was inferior for those treated with IC (SMR=15.0, 95% CI: 10.22-22.05, p=2.0x10-43) or RM (SMR=4.96, 95% CI: 1.24-19.84, p=0.023), while trending towards inferior for those initially observed (SMR=1.55, 95% CI: 0.81-2.99, p=0.19). Summary: Events within the first 12 months of diagnosis are associated with poor OS in FL, especially in patients treated with IC, while patients achieving EFS12 have excellent subsequent survival, overall and in the main treatment subsets. Prognosis for FL patients should be recalibrated at 12 months from diagnosis. EFS12 will be useful in counseling and should be considered as an endpoint in studies of newly diagnosed FL. Figure 1 Figure 1. Disclosures No relevant conflicts of interest to declare.

Recent advances in follicular lymphoma (FL) have resulted in prolongation of overall survival (OS). Here we assessed if early events as defined by event‐free survival (EFS) at 12 and 24 months from diagnosis (EFS12/EFS24) can inform subsequent OS in FL. 920 newly diagnosed grade 1‐3A FL patients enrolled on the University of Iowa/Mayo Clinic Lymphoma SPORE Molecular Epidemiology Resource (MER) from 2002‐2012 were initially evaluated. EFS was defined as time from diagnosis to progression, relapse, re‐treatment, or death due to any cause. OS was compared to age‐and‐sex‐matched survival in the general US population using standardized mortality ratios (SMR) and 95% confidence intervals (CI). We used a cohort of 412 FL patients from two Lyon, France hospital registries for independent replication. Patients who failed to achieve EFS12 had poor subsequent OS (MER SMR = 3.72, 95%CI: 2.78‐4.88; Lyon SMR = 8.74, 95%CI: 5.41‐13.36). Conversely, patients achieving EFS12 had no added mortality beyond the background population (MER SMR = 0.73, 95%CI: 0.56‐0.94, Lyon SMR = 1.02, 95%CI: 0.58‐1.65). Patients with early events after immunochemotherapy had especially poor outcomes (EFS12 failure: MER SMR = 17.63, 95%CI:11.97‐25.02, Lyon SMR = 19.10, 95%CI:9.86‐33.36; EFS24 failure: MER SMR = 13.02, 95%CI:9.31‐17.74, Lyon SMR = 7.22, 95%CI:4.13‐11.74). In a combined dataset of all patients from both cohorts, baseline FLIPI was no longer informative in EFS12 achievers. Reassessment of patient status at 12 months from diagnosis in follicular lymphoma patients, or at 24 months in patients treated with immunochemotherapy, is a strong predictor of subsequent overall survival in FL. Early event status provides a simple, clinically relevant endpoint for studies assessing outcome in FL. Am. J. Hematol. 91:1096–1101, 2016. © 2016 Wiley Periodicals, Inc.

Purpose We examined the utility of post-therapy surveillance imaging in a large, prospectively enrolled cohort of patients with diffuse large B-cell lymphoma (DLBCL) from the United States and confirmed our results in an independent cohort of patients from France. Methods Patients with newly diagnosed DLBCL and treated with anthracycline-based immunochemotherapy were identified from the Molecular Epidemiology Resource (MER) of the University of Iowa/Mayo Clinic Lymphoma Specialized Program of Research Excellence and the Léon Bérard Cancer Center, Lyon, France. In those with relapse, details at relapse and outcomes were abstracted from records. Results 680 individuals with DLBCL were identified from the MER, 552 (81%) of whom achieved remission after induction. 112 of the 552 patients (20%) suffered a relapse. The majority (64%) of relapses were identified before a scheduled follow-up visit. Surveillance imaging detected DLBCL relapse before clinical manifestations in nine out of 552 patients (1.6%) observed after therapy. In the Lyon cohort, imaging identified asymptomatic DLBCL relapse in four out of 222 patients (1.8%). There was no difference in survival after DLBCL relapse in patients detected at scheduled follow-up versus before scheduled follow-up in both the MER (P = .56) and Lyon cohorts (P = .25). Conclusion The majority of DLBCL relapses are detected outside of planned follow-up, with no difference in outcome in patients with DLBCL detected at a scheduled visit compared with patients with relapse detected outside of planned follow-up. These data do not support the use of routine surveillance imaging for follow-up of DLBCL.

Purpose Studies of diffuse large B-cell lymphoma (DLBCL) are typically evaluated by using a time-to-event approach with relapse, re-treatment, and death commonly used as the events. We evaluated the timing and type of events in newly diagnosed DLBCL and compared patient outcome with reference population data. Patients and Methods Patients with newly diagnosed DLBCL treated with immunochemotherapy were prospectively enrolled onto the University of Iowa/Mayo Clinic Specialized Program of Research Excellence Molecular Epidemiology Resource (MER) and the North Central Cancer Treatment Group NCCTG-N0489 clinical trial from 2002 to 2009. Patient outcomes were evaluated at diagnosis and in the subsets of patients achieving event-free status at 12 months (EFS12) and 24 months (EFS24) from diagnosis. Overall survival was compared with age- and sex-matched population data. Results were replicated in an external validation cohort from the Groupe d'Etude des Lymphomes de l'Adulte (GELA) Lymphome Non Hodgkinien 2003 (LNH2003) program and a registry based in Lyon, France. Results In all, 767 patients with newly diagnosed DLBCL who had a median age of 63 years were enrolled onto the MER and NCCTG studies. At a median follow-up of 60 months (range, 8 to 116 months), 299 patients had an event and 210 patients had died. Patients achieving EFS24 had an overall survival equivalent to that of the age- and sex-matched general population (standardized mortality ratio [SMR], 1.18; P = .25). This result was confirmed in 820 patients from the GELA study and registry in Lyon (SMR, 1.09; P = .71). Simulation studies showed that EFS24 has comparable power to continuous EFS when evaluating clinical trials in DLBCL. Conclusion Patients with DLBCL who achieve EFS24 have a subsequent overall survival equivalent to that of the age- and sex-matched general population. EFS24 will be useful in patient counseling and should be considered as an end point for future studies of newly diagnosed DLBCL.