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Background Brentuximab vedotin (BV) has been investigated in several single arm phase II trials as a new therapeutic option for patients with a first relapse or primary refractory classical Hodgkin lymphoma (R/R cHL), but no randomized controlled trials have been done that compare the addition of BV to salvage chemotherapy in the R/R setting. The aim of this study was to investigate the effect of BV addition to salvage chemotherapy compared to chemotherapy alone on progression free survival (PFS), overall survival (OS) and complete metabolic response (CMR) rate prior to autologous stem-cell transplant (ASCT), and to identify prognostic factors for response and survival. Methods We collected individual patient data of 718 transplant eligible R/R cHL patients treated in prospective clinical trials, of which 391 patients were treated with BV and salvage chemotherapy (BV-cohort), and 327 with salvage chemotherapy alone (Chemo-cohort), followed by ASCT [Table 1]. For PFS and OS analysis, the BV- and Chemo-cohorts were matched by propensity scores on baseline characteristics (i.e. relapsed/refractory, bulky disease, extranodal disease, stage I-II/III-IV, B-symptoms and first-line treatment with BEACOPP). Primary refractory disease was defined as not having achieved a CMR on first-line treatment. A CMR was defined as Deauville score (DS)1-3. PET-scans in the Chemo-cohort were assessed using IWG criteria (Cheson 2007) at the time of the original study. Therefore, we re-evaluated PET-positive scans using DS. Results After matching by propensity scores, there were no statistically significant differences in baseline characteristics between the BV- and Chemo-cohorts [Table 2]. The 3-year PFS was 74% (95%CI: 68-80%) in the BV-cohort compared to 67% (61-74%) in the Chemo-cohort (p=0.13) [Fig1A]. The 3-year OS was 94% (90-97%) versus 80% (74-86%); p When corrected for baseline characteristics, there were no significant differences in PFS between studies within the BV-cohort that used a sequential approach, multiple chemotherapeutic agents (e.g. DHAP/ICE/ESHAP vs bendamustine/gemcitabine) or different cumulative BV doses. Patients treated with a sequential approach with BV-ICE or ICE-GVD who achieved a CMR pre-ASCT on BV or ICE alone showed no difference in PFS compared to patients who achieved a CMR after BV-ICE or ICE-GVD (p=0.97). Pre-ASCT PET response data were available for all patients in the BV-cohort and n=93 patients in the Chemo-cohort from the sequential ICE-GVD study. Patients with a CMR (n=349) had significant better PFS compared to patients with a partial response (n=67), with a 3-year PFS of 79% (75-84%) versus 58% (47-71%); p Conclusions The addition of BV to salvage chemotherapy followed by ASCT seems to increase PFS in relapsed, but not in primary refractory cHL patients. This suggests that in patients who are chemotherapy resistant other treatment modalities such as checkpoint inhibitors (CPI) should be considered. The observed increase in OS for the BV-cohort could be due to advances in treatment over time since novel therapies for patients who fail ASCT, such as CPI and BV, were not yet available at time of studies in the Chemo-cohort. Our study confirms the strong prognostic value of pre-ASCT CMR for PFS. B-symptoms, stage and primary refractory disease are prognostic factors for PFS and for achieving a pre-ASCT CMR. Figure 1 Figure 1. Disclosures Driessen: Takeda: Other: Travel support for ASH 2019. Herrera: Gilead Sciences: Research Funding; Merck: Consultancy, Research Funding; AstraZeneca: Consultancy, Research Funding; Seagen: Consultancy, Research Funding; Bristol Myers Squibb: Consultancy, Research Funding; ADC Therapeutics: Consultancy, Research Funding; Tubulis: Consultancy; Kite, a Gilead Company: Research Funding; Karyopharm: Consultancy; Genentech: Consultancy, Research Funding; Takeda: Consultancy. Zinzani: ImmuneDesign: Consultancy, 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, Speakers Bureau; Bristol Myers Squibb: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Portola: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Gilead: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Janssen-Cilag: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Sandoz: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Incyte: 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, Speakers Bureau; TG Therapeutics Inc: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Servier: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Kyowa Kirin: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Verastem: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; BeiGene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Merck Sharp & Dohme: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; EUSA Pharma: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celltrion: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Abbvie: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; ADC Therapeutics: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Sanofi: Consultancy, Membership on an entity's Board of Directors or advisory committees. LaCasce: Bristol-Myers Squibb Company.: Other: Data Safetly and Monitoring. Moskowitz: Merck & Co., Inc.: Research Funding. Fuchs: MSD: Honoraria; Takeda: Consultancy, Honoraria; Lukon: Honoraria; BMS: Honoraria; Celgene: Honoraria. Borchmann: Gilead Sciences: Honoraria; BMS/Celgene: Honoraria; Janssen: Honoraria; Miltenyi Biotech: Honoraria; Novartis: Honoraria. Zijlstra: Takeda: Research Funding. Moskowitz: Incyte: Research Funding; Miragen: Research Funding; Takeda: Consultancy; Seattle Genetics: Consultancy, Research Funding; Janpix Ltd.: Consultancy; Imbrium Therapeutics L.P./Purdue: Consultancy; Bristol-Myers Squibb: Research Funding; Merck: Consultancy, Research Funding; Beigene: Research Funding; ADC Therapeutics: Research Funding. Kersten: BMS/Celgene: Consultancy; Kite/Gilead: Consultancy, Honoraria, Research Funding; Miltenyi Biotech: Consultancy; Takeda: Consultancy; Novartis: Consultancy, Honoraria; Roche: Honoraria.

Introduction Patients with high grade B cell lymphoma that harbor a MYC rearrangement with concomitant BCL2 and/or BCL6 rearrangements (double hit and triple hit (HGBL-DH/TH)) face a poor prognosis upon standard treatment with R-CHOP [Rosenwald, JCO 2019]. DA-EPOCH-R might yield higher complete metabolic remission (CMR) rates and longer disease free survival (DFS) as compared to R-CHOP, but improvement of overall survival (OS) has not been demonstrated [Dunleavy, Lancet Haematol 2018]. Tumors with MYC overexpression may be susceptible for immune checkpoint inhibition (CI) [Casey, Science 2016], providing a rationale for CI after reaching CMR to improve tumor immune surveillance for minimal residual disease (MRD) positive disease. Here, we present data of the planned interim analysis of 33/97 patients included in the HOVON-152 trial (NCT03620578). Methods HOVON-152 is a prospective, multi-center, single arm phase II trial. Inclusion criteria are newly diagnosed HGBL-DH/TH; age ≥ 18 year; WHO performance status 0-3; Ann Arbor stage II-IV. During the screening period for rearrangements patients receive 1 cycle of R-CHOP followed by 5 cycles of DA-EPOCH-R induction treatment. All patients receive intrathecal prophylaxis. All diagnostic lymphoma samples are centrally reviewed. PET-CT scans are performed at diagnosis, midterm and end-of-induction. Patients in CMR after induction treatment (Deauville 1-3 or a negative lymphoma biopsy in case of Deauville 4) proceed with Nivolumab consolidation (480 mg iv every 4 weeks) for one year. The primary objective is to improve 12 months DFS with Nivolumab consolidation from 70% to 85% in patients in CMR after induction treatment. Secondary objectives include evaluation of CMR rates, OS and safety. Exploratory side studies investigate blood-based biomarkers for response prediction by immune profiling using multicolor flow cytometry after 1 cycle of R-CHOP and molecular circulating tumor DNA (ctDNA) analyses using ClonoSEQ (Adaptive Biotechnologies, Seattle) after 1 cycle of R-CHOP and at midterm. Results From August 2018 to June 2021, 69 of planned 97 patients have been enrolled. Baseline characteristics of the first 33 patients included in the interim analysis are shown in Table 1. Dose adjustments of EPOCH (according to protocol) resulted in 48% of patients receiving dose level ≤1 and 52% dose level ≥ 2 at the last cycle. After induction, 20/33 patients (61%; 95% CI 42%-77%) reached CMR. 11/33 patients (33%) did not reach CMR and 2/33 (6%) patients went off protocol (due to progression). During DA-EPOCH-R, one patient (3%) experienced grade 5 AE (sepsis), 9 patients (27%) experienced a grade 4 AE, and 9 (27%) patients grade 3. Neurotoxicity led to dose adjustments or discontinuation of vincristine in 52% of the patients. In an amendment the vincristine dose was capped at 2 mg/cycle. Twenty patients received 6 cycles of Nivolumab consolidation. One patient had a grade 4 AE (neutropenia); 2 patients had a grade 3 AE (one lung infection and one colitis (reason for going off protocol)). The Data Safety Monitoring Board recommended to continue the trial. Exploratory biomarker analyses show that patients achieving CMR after DA-EPOCH-R (data available for 19/20 patients) have higher percentages of T cells (p=0.04) after 1 cycle of R-CHOP than patients that do not achieve CMR (data available for 12/13 patients). ctDNA analysis was possible in 16/28 patients (in 12/28 patients no clone could be detected for monitoring). 10/16 patients achieved CMR, of which 9/10 were negative for minimal residual disease (MRD) at midterm. The patient that was MRD positive at midterm relapsed shortly after CMR. 4/5 patients that did not achieve CMR were MRD positive at midterm. Conclusions Interim analysis of the HOVON-152 trial demonstrates that 61% (95% CI 42%-77%) of the patients with HGBL-DH/TH achieve CMR after induction with DA-EPOCH-R. Toxicity of DA-EPOCH-R consists mainly of neurotoxicity leading to a protocol amendment (dose cap of vincristine). Nivolumab consolidation is safe with only one patient going off protocol due to colitis. Biomarkers for CMR after induction with DA-EPOCH-R point out to ctDNA-based MRD negativity at midterm and to higher T percentages after 1 cycle of R-CHOP, supporting the hypothesis of contributive immune surveillance for response in patients with HGBL-DH/TH. The trial is ongoing. Figure 1 Figure 1. Disclosures Nijland: Roche: Research Funding; Nordic Nanovector: Research Funding; Takeda: Research Funding. Van Der Poel: Roche, Janssen, Abbvie: Honoraria. Klerk: Van Lanschot Kempen: Other: I have an investment porfolio which is managed by Van Lanschot Kempen as a portfolio manager (vermogensbeheerder). Van Lanschot Kempen invests on my behalf, and takes investment decisions on a discretionary basis. I am not involved in the investment decis. Pegtel: Exbiome BV: Current holder of individual stocks in a privately-held company; Takeda: Other: Travel compensation. Mutis: Novartis: Research Funding; ONK Therapeutics: Research Funding; Janssen: Honoraria; Takeda: Research Funding; Genmab: Research Funding. Zijlstra: Takeda: Research Funding. Kersten: BMS/Celgene: Consultancy; Kite/Gilead: Consultancy, Honoraria, Research Funding; Milteny Biotech: Consultancy; Novartis: Consultancy, Honoraria; Roche: Honoraria; Takeda: Consultancy. Chamuleau: Gilead: Research Funding; Genmab: Research Funding; Celgene: Research Funding. OffLabel Disclosure: Nivolumab as immune checkpoint inhibitor (inhibiting PD-1) in consolidation phase for the treatment of DH/TH-HGBL patients.

Background The primary analysis of the HD16 trial initiated in 2018 found that, in the treatment of early-stage favorable Hodgkin lymphoma (HL), involved-field radiotherapy (IF-RT) cannot be omitted from standard combined-modality treatment (CMT) without a clinically significant loss of tumor control. We thus complement the published analysis with prolonged follow-up and data on long-term toxicity. Methods Between 11/2009 and 12/2015, we enrolled 1150 patients aged 18-75 years with newly diagnosed HL in stages I or II without risk factors. Patients were randomized between standard CMT, with 2 cycles of ABVD followed by a centrally reviewed PET/CT-based restaging (PET-2) and 20 Gy IF-RT regardless of PET-2 result, and PET-2-guided treatment, with 2 cycles ABVD followed by 20 Gy IF-RT only in case of a positive PET-2 in terms of a Deauville score (DS) ≥3. Primary endpoint was PFS, analyzed according to Kaplan-Meier using Cox regression and log-rank test as applicable. We aimed at excluding inferiority of the PET-2-guided regimen in terms of a Hazard ratio (HR) of 3.01 or above in the PET-2-negative per-protocol cohort. Another aim was to assess the prognostic impact of PET-2 among those patients assigned to receive CMT. This follow-up analysis aims at repeating the main analyses with prolonged follow-up and complement efficacy results with long-term safety data. Findings With a median follow-up of 64 months, PET-2-negative patients had five-year PFS of 94.2% (95% CI 91.6-96.9) after CMT (n=328) and 86.7% (82.5-90.9) after ABVD alone in the PET-2-guided treatment group (n=300; HR 2.05 [1.20-3.51] including the non-inferiority margin; log-rank p=0.0072). The difference primarily resulted from recurrences that were at least in part located within the potential radiation field, with 5-year cumulative incidences of 2.0% (0.4-3.7) after CMT vs. 10.4% (6.7-14.1) after ABVD alone (p=0.0002). There was no difference regarding second primary malignancies, with 5-year cumulative incidences of 4.6% (2.1-7.1) after CMT vs. 4.2% (1.6-6.8) after ABVD (p=0.57). Five-year overall survival was 98.3% (96.9-99.8) and 98.8% (97.4-100), respectively (p=0.14), with 4 of the 12 documented deaths caused by second primary malignancies and only 1 by HL. Among patients assigned to receive CMT, PFS was superior in the PET-2-negative subgroup (DS 1-2) (n=353; 5-year PFS 94.0% [91.4-96.6]) compared with those having DS ≥3 (n=340; 90.3% [86.9-93.6]; p=0.012). The difference was more pronounced when the more commonly used cutoff of DS 4 was used for positivity (DS 1-3: n=571; 94.0% [91.9-96.0] vs. DS ≥4: n=122; 83.6% [76.6-90.6]; p After 5 years of follow-up, cardiac parameters showed normal outcomes in both randomized treatment groups and no relevant decrease compared with baseline values. Among 293 female patients aged 18-40 years at enrollment, the 5-year incidence of childbirth after therapy was 24.0% (15.9-32.2) after standard CMT vs. 17.9% (10.4-25.5) after PET-guided treatment. Conclusion We conclude that radiotherapy cannot be omitted from the treatment of early-stage favorable HL after a negative PET-2 without a clinically relevant and statistically significant loss of efficacy. We could not observe any disadvantage of standard CMT over PET-guided therapy in terms of acute or late toxicities. Overall survival is on a high level and not impaired by the omission of radiotherapy due to effective second-line therapies. Noteworthy the results of the HD16 trial became more pronounced with longer follow-up. This holds true for the per-protocol as well as for the intention-to-treat group. A positive PET after 2 cycles of ABVD in terms of DS ≥4 is associated with significantly inferior efficacy compared with a negative PET, indicating the need for further improvement in this group of patients. Taken together, we recommend that CMT is to be regarded as standard treatment for early-stage favorable HL. Disclosures Fuchs: BMS: Honoraria; Takeda: Consultancy, Honoraria; MSD: Honoraria; Celgene: Honoraria; Lukon: Honoraria. Greil: Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accommodations, Expenses, Research Funding; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accommodations, Expenses, Research Funding; Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accommodations, Expenses, Research Funding; BMS: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accommodations, Expenses, Research Funding; Takeda: 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, Other: Travel, Accommodations, Expenses, Research Funding; AstraZeneca: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accommodations, Expenses, Research Funding; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accommodations, Expenses; MSD: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accommodations, Expenses, Research Funding; Gilead: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accommodations, Expenses, Research Funding; Daiichi: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accommodations, Expenses, Research Funding; Sankyo: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accommodations, Expenses, Research Funding; Sanofi: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Merck: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Amgen: Honoraria, Other: Travel, Accommodations, Expenses, Research Funding; Sandoz: Honoraria, Research Funding. Topp: Amgen: Consultancy, Research Funding; Macrogeniecs: Research Funding; Regeneron: Consultancy, Research Funding; Gilead: Research Funding; Roche: Consultancy, Research Funding; Novartis: Consultancy; Kite, a Gilead Company: Consultancy, Research Funding; Universitatklinikum Wurzburg: Current Employment; Janssen: Consultancy; Celgene: Consultancy, Research Funding. Hertenstein: BMS: Honoraria; Celgene: Honoraria; Novartis: Honoraria; Sanofi: Honoraria. Zijlstra: Takeda: Research Funding. Engert: Astra Zeneca: Consultancy, Honoraria; ADC Therapeutics: Consultancy; Tessa Therapeutics: Consultancy; Hexal: Honoraria; MSD: Honoraria; Amgen: Honoraria; BMS: Honoraria, Research Funding; Takeda: Consultancy, Honoraria, Research Funding.

Introduction Genetic abnormalities, such as MYC oncogene rearrangements, contribute to the outcome heterogeneity in diffuse large B-cell lymphoma (DLBCL) patients. These rearrangements occur in 10-15% of DLBCL patients and have been associated with a poor prognosis. Recently, radiomics features extracted from PET/CT scans have shown to be predictive of outcome. The aim of this study was to investigate if the ability to predict outcome in DLBCL can be improved by combining different clinical, radiomics and genetic features. Methods 323 DLBCL patients from the HOVON-84, HOVON-130, and PETAL trials with a baseline PET/CT scan and a minimum follow-up of two years were included. MYC status was assessed using Fluorescence in situ hybridization (FISH). 245 patients were MYC negative, whereas 25 patients had a MYC rearrangement and 57 patients had MYC and BCL2 and/or BCL6 rearrangements. Lesions were delineated using a semi-automated preselection of 18F-FDG avid structures defined by a SUV4.0 threshold using the ACCURATE tool. Next, 5 conventional PET features (maximum standardized uptake value (SUV max), SUV peak, SUV mean, metabolic tumor volume (MTV) and total lesion glycolysis and 18 dissemination features were extracted. Dissemination features were pertaining to distance between lesions, differences in uptake between lesions and differences in volume between lesions. Logistic regression with backward feature selection was used to predict 2-year time to progression, defined as time from baseline PET/CT to progression. We tested the predictive value of 4 models. 1) a clinical model using individual components of the international prognostic index (IPI): Ann Arbor stage (categorical), WHO performance status (categorical), lactate dehydrogenase (LDH) levels (dichotomous) and age (continuous), 2) a model that included clinical and genetic predictors: MYC status (categorical) and IPI components, 3) a model that included radiomics features: 5 conventional PET and 18 dissemination features and 4) a model that combined clinical and genetic predictors with radiomics features. Model performance was assessed using repeated cross-validation (5-fold, 1000 repeats) yielding the cross-validated area under the curve of the receiver-operator-characteristics curve (CV-AUC). To match prevalence of MYC-positive patients with real-world prevalence (Rosenwald et al, JCO 2019) all 245 MYC-negative patients were used for each repeat, and 10 MYC-FISH_positive DLBCL patients and 20 patients with MYC and BCL2 and/or BCL6 rearrangements were selected using random stratified sampling. Regression coefficients were averaged over all folds to calculate the probability of progression for all patients. High- and low-risk groups were defined based on prevalence of events and the diagnostic performance was assessed using positive- and negative predictive values. Results The highest model performance for the clinical model was observed when combining Ann Arbor stage, LDH and extranodal involvement and yielded in a CV-AUC of 0.69 (95% confidence interval (CI): 0.52-0.83). MYC status combined with WHO performance status, LDH and extranodal involvement yielded an improved CV-AUC of 0.71 (95% CI: 0.52-0.86). The highest model performance for the radiomics model was observed for MTV combined with the maximum distance between the largest lesion and any other lesions (Dmax bulk), the maximum difference in SUV peak between two lesions (DSUVpeak patient) and the maximum difference in volume between two lesions (DVol patient) yielding a CV-AUC of 0.77 (95% CI: 0.62-0.90). The optimal combined model included MYC status, WHO performance status, LDH, MTV, Dmax patient, DSUVpeak patient and DVol patient after backward feature selection and yielded a CV-AUC of 0.77 (95% CI: 0.60 - 0.90). The positive predictive value was highest for the combined model (53.0%) and increased by 20% compared to the optimal clinical model (33.1%). Negative predictive values were comparable between models and ranged between 85.8-88.1%. Conclusions Prediction models using 18F-FDG PET/CT radiomics features at baseline aids in identifying DLBCL patients at high risk for relapse. The positive predictive value increased when radiomics features were added to the clinical and genetic parameters. Therefore, radiomics features can increase the efficiency of clinical trials by only selecting poor prognosis patients. Figure 1 Figure 1. Disclosures Chamuleau: Gilead: Research Funding; Genmab: Research Funding; Celgene: Research Funding. Lugtenburg: Incyte: Honoraria; Regeneron: Honoraria; Genmab: Honoraria; Servier: Honoraria, Research Funding; Takeda: Honoraria, Research Funding; Celgene: Honoraria, Other: Non-financial support; Travel support; Roche: Honoraria, Research Funding. Dührsen: CPT Cellex Patient Treatment: Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees. Hüttmann: Celgene: Honoraria; Gilead: Honoraria; Lead Discovery Center GmbH: Consultancy; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees. Richter: HTG Molecular Diagnostics, Inc.: Current Employment, Research Funding. Klapper: Regeneron: Consultancy, Research Funding; Amgen: Research Funding; Roche: Consultancy, Research Funding; Takeda: Consultancy, Research Funding. Zijlstra: Takeda: Research Funding.

Introduction: Selinexor is a first-in-class Selective Inhibitor of Nuclear Export (SINE) that blocks XPO1, forcing the nuclear retention and re-activation of tumor suppressor proteins including p53, p73, FOXO, I□B and Rb. The phase 2b SADAL study included 134 patients with relapsed or refractory DLBCL with single agent oral selinexor twice weekly. The overall response rate (ORR) was 29.1%, median duration of response (DOR) was 9.3 months and the median overall survival (OS) was 9 months. Based on these data, selinexor was recently approved by the US FDA for the treatment of relapsed or refractory DLBCL, de novo or transformed from follicular lymphoma. Patients with DLBCL tend to be older (over the age of 65) and have a number of comorbidities, which limits the use of aggressive and multi-agent combination therapies. We performed post-hoc analyses of the SADAL study to determine the effects of age on the efficacy and safety of selinexor in this population. Methods: The SADAL study is multi-center, open-label Phase 2b study that enrolled patients with DLBCL previously treated with 2-5 lines of therapy. Patients may have progressed post-stem cell therapy (SCT) or were not candidates for SCT. In this study, 60 mg of selinexor was administered twice weekly until disease progression. The primary endpoint was ORR, and other endpoints included DOR, OS, and safety assessments. For the current analysis, outcomes were assessed in patients Results: Of the 134 patients enrolled in the study, 52 (39%) were 65 (3.8% vs. 11.0%). Conclusions: Patients with relapsed/refractory DLBCL who were ≥65 years had a similar clinical benefit to those Disclosures Schuster: Amgen, Abbvie, Gilead, Takeda, Celgene, Pharmacyclics, Astellas, Verastem, Merck, Novartis, Takeda, Genentech,, Seattle Genetics: Other: Personal Fees; Karyopharm: Membership on an entity's Board of Directors or advisory committees. Canales:Janssen: Honoraria; Roche: Speakers Bureau; Gilead: Honoraria; Sandoz: Honoraria; Janssen: Speakers Bureau; Sandoz: Speakers Bureau; Roche: Speakers Bureau; Novartis: Honoraria; Karyopharm: Honoraria; Janssen: Honoraria; Celgene: Honoraria; Sandoz: Honoraria; Roche: Honoraria; Takeda: Speakers Bureau; Novartis: Honoraria; Sandoz: Speakers Bureau; iQone: Honoraria; Karyopharm: Honoraria; Takeda: Speakers Bureau; Roche: Honoraria; Janssen: Speakers Bureau. Westin:Genentech: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; Curis: Consultancy, Research Funding; BMS: Consultancy, Research Funding; Kite: Consultancy, Research Funding; Astra Zeneca: Consultancy, Research Funding; Morphosys: Consultancy, Research Funding; 47: Research Funding; Amgen: Consultancy; Janssen: Consultancy, Research Funding. Zijlstra:Roche: Research Funding. Follows:Karyopharm, Roche, Abbvie, Astrazeneca, Janssen, BMS: Membership on an entity's Board of Directors or advisory committees. Karmali:Takeda: Research Funding; Karyopharm: Honoraria; AstraZeneca: Speakers Bureau; BeiGene: Speakers Bureau; BMS/Celgene/Juno: Honoraria, Other, Research Funding, Speakers Bureau; Gilead/Kite: Honoraria, Other, Research Funding, Speakers Bureau. Kalakonda:Verastem, Gilead, Celgene, Roche: Research Funding; Gilead, Janssen, Karyopharm: Honoraria. Goy:Constellation: Research Funding; Regional Cancer Care Associates/OMI: Current Employment; COTA: Consultancy, Current equity holder in publicly-traded company, Other: leadership role; Infinity: Research Funding; Karyopharm: Research Funding; PracticeUpdate Oncology: Consultancy; MD Anderson: Research Funding; AbbVie: Research Funding; Acerta: Consultancy, Honoraria, Other: leadership role, Research Funding; AstraZeneca: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: leadership role, Research Funding; Xcenda: Consultancy; Infinity Verastem: Research Funding; RCCA/OMI: Current Employment; Morphosys: Research Funding; Genentech/Roche: Research Funding; Hackensack UMC and University of Nebraska: Research Funding; Bayer: Research Funding; Celgene: Honoraria, Research Funding; Janssen: Consultancy, Honoraria, Other: leadership role, Research Funding; Kite, a Gilead Company: Consultancy, Current equity holder in publicly-traded company, Honoraria, Other: leadership role, Research Funding; CALBG: Research Funding. Casasnovas:Roche: Consultancy, Honoraria, Other: travel, accomodations, expenses, Research Funding; Gilead: Consultancy, Honoraria, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company), Research Funding; Takeda: Consultancy, Honoraria, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company), Research Funding; Abbvie: Consultancy, Honoraria; MSD: Consultancy, Honoraria; Amgen: Consultancy, Honoraria. Thieblemont:Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company); AbbVie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company); Cellectis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company), Speakers Bureau; Bristol-Myers Squibb: Consultancy, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company); Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company); Hospira: Research Funding; Kite, a Gilead Company: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company); Incyte: Honoraria; Bayer: Honoraria; Roche: Consultancy, Honoraria, 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; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: travel support. Cavallo:Gilead: Other: Speaker Fee; Takeda, Janssen: Membership on an entity's Board of Directors or advisory committees. Hill:Pharmacyclics: Consultancy, Honoraria, Research Funding; Beigene: Consultancy, Honoraria, Research Funding; AstraZenica: Consultancy, Honoraria, Research Funding; Kite, a Gilead Company: Consultancy, Honoraria, Research Funding; Novartis: Consultancy, Honoraria; BMS: Consultancy, Honoraria, Research Funding; Celgene: Consultancy, Honoraria, Research Funding; Takeda: Research Funding; Karyopharm: Consultancy, Honoraria, Research Funding; Abbvie: Consultancy, Honoraria, Research Funding; Genentech: Consultancy, Honoraria, Research Funding. Tilly:BMS: Honoraria. Jaeger:Novartis: Consultancy, Honoraria, Research Funding; Gilead: Honoraria, Research Funding; Karyopharm: Honoraria; CDR Life AG: Consultancy, Research Funding; Miltenyi: Consultancy, Honoraria; F. Hoffmann-La Roche: Honoraria, Research Funding; BMS/Celgene: Consultancy, Honoraria, Research Funding; AbbVie: Honoraria. Gurion:JC Health CARE: Consultancy, Honoraria; Medison: Consultancy, Honoraria; Gilead Sciences: Consultancy, Honoraria; Takeda Pharmaceuticals: Consultancy, Honoraria; Roche: Consultancy, Honoraria. Caimi:Celgene Corp: Other: Incyte Corporation - Ownership - Pharmacyclics, Inc. - Ownership - Celgene Corp. - Other, Speakers Bureau; ADC Therapeutics: Research Funding; Genentech: Research Funding. Martin:Janssen: Consultancy; Regeneron: Consultancy; Teneobio: Consultancy; Celgene: Consultancy; Sandoz: Consultancy; I-MAB: Consultancy; Bayer: Consultancy; Beigene: Consultancy; Cellectar: Consultancy; Incyte: Consultancy; Kite: Consultancy; Morphosys: Consultancy; Karyopharm: Consultancy, Research Funding. Davies:Roche: Other: TRAVEL, ACCOMMODATIONS, EXPENSES; Roche, Celgene, Kite Pharma, Acerta, Karyopharma, Regeneron, Incyte: Consultancy; Roche, Acerta Pharma, AstraZeneca, Celgene, Gilead, ADC Therapeutics, Gilead: Research Funding; Celegene, Roche, Kite Pharma, Celegene: Honoraria. Smith:TG Therapeutics: Consultancy, Research Funding; Genentech/Roche: Consultancy, Other: Support of parent study and funding of editorial support, Research Funding; FortySeven: Research Funding; Karyopharm: Consultancy, Research Funding; Pharmacyclics: Research Funding; Acerta: Research Funding; Celgene: Consultancy, Research Funding; BMS: Consultancy; Janssen: Consultancy. Collins:Amgen: Research Funding; Pfizer: Honoraria; Celgene: Research Funding; Celleron: Consultancy, Honoraria, Research Funding; Novartis: Consultancy, Honoraria, Speakers Bureau; ADC Therapeutics: Consultancy, Honoraria; Roche: Consultancy, Honoraria, Other: travel, accommodations, expenses , Speakers Bureau; Taekda: Consultancy, Honoraria, Other: travel, accommodations, expenses, Speakers Bureau; Gilead: Consultancy, Honoraria, Speakers Bureau; MSD: Consultancy, Honoraria, Research Funding; BeiGene: Consultancy; BMS: Consultancy, Honoraria, Research Funding, Speakers Bureau. Salles:Abbvie: Consultancy, Honoraria, Other: Participation in educational events; Novartis: Consultancy, Honoraria, Other; MorphoSys: Consultancy, Honoraria, Other; Debiopharm: Consultancy; Genmab: Consultancy; Karyopharm: Consultancy; Amgen: Honoraria, Other: Participation in educational events; Kite: Consultancy, Honoraria, Other; Epizyme: Consultancy; F. Hoffman-La Roche Ltd: Consultancy, Honoraria, Other; Takeda: Consultancy, Honoraria, Other; Bristol Myers Squibb: Consultancy, Other; Autolus: Consultancy; Gilead: Consultancy, Honoraria, Other: Participation in educational events; Janssen: Consultancy, Honoraria, Other: Participation in educational events; Celgene: Consultancy, Honoraria, Other: Participation in educational events. Ma:Karyopharm: Current Employment, Current equity holder in private company. Corona:Karyopharm: Current Employment. Saint-Martin:Karyopharm: Current Employment. Joshi:Karyopharm Therapeutics Inc: Consultancy. Chamoun:Karyopharm: Current Employment. Wang:Curis: Ended employment in the past 24 months; Karyopharm: Current Employment. Shah:Karyopharm: Current Employment, Current equity holder in publicly-traded company. Shacham:Karyopharm: Current Employment, Current equity holder in publicly-traded company, Patents & Royalties: (8999996, 9079865, 9714226, PCT/US12/048319, and I574957) on hydrazide containing nuclear transport modulators and uses, and pending patents PCT/US12/048319, 499/2012, PI20102724, and 2012000928) . Kauffman:Karyopharm Therapeutics Inc: Current Employment, Current equity holder in publicly-traded company, Membership on an entity's Board of Directors or advisory committees.

Introduction: Selinexor is a first-in-class Selective Inhibitor of Nuclear Export (SINE) that blocks XPO1, forcing the nuclear retention and re-activation of tumor suppressor proteins including p53, p73, FOXO, IkB and Rb. The phase 2b SADAL study included 134 patients with relapsed or refractory DLBCL with single agent oral selinexor twice weekly. The overall response rate (ORR) was 29.1%, median duration of response (DOR) was 9.3 months and the median overall survival (OS) was 9 months. Based on these data, selinexor was recently approved by the US FDA for the treatment of relapsed or refractory DLBCL, de novo or transformed from follicular lymphoma. Patients with DLBCL tend to have a number of comorbidities, including poor renal function, which can require a reduction in the dose of intensive chemotherapy as well as lenalidomide, leading to inferior outcomes. Selinexor is not metabolized nor cleared by the kidneys and has been demonstrated to be safe and active in patients with myeloma and renal dysfunction. We performed post-hoc analyses of the SADAL study to determine the efficacy and safety among patients stratified by renal function at baseline. Methods: The SADAL study is multi-center, open-label Phase 2b study that enrolled patients with DLBCL previously treated with 2-5 lines of therapy. Patients may have progressed post-stem cell therapy (SCT) or were not candidates for SCT. In this study, 60 mg of selinexor was administered twice weekly until disease progression. The primary endpoint was ORR, and other endpoints included DOR, OS, and safety assessments. For the current analysis, outcomes were assessed according to baseline renal function as estimated by the Cockroft-Gault formula for creatinine clearance (CrCl). Groups included those with reduced (CrCl ≤60 mL/min) and normal (CrCl >60 mL/min) renal function. Results: Of 134 patients, 37 (28%) had a reduced baseline CrCl (≤60 mL/min) while 97 (72%) had CrCl >60 mL/min. The median age of patients with reduced CrCl was 74 years with 70% ≥70 years, while the median for those with normal CrCl was 65 years, with 35% ≥70 years. De novo and transformed DLBCL showed similar renal function levels: 78% and 22% with reduced CrCl and 76% and 24% with normal CrCl. Of patients with reduced CrCl, the DLBCL subtype was 41% GCB and 57% non-GCB compared to 50% and 46% in patients with normal CrCl. The group of patients with reduced CrCl had baseline ECOG performance status of 2 in 16% vs 11% in those with normal CrCl. Treatment with selinexor demonstrated a similar ORR in patients with a baseline reduced CrCl (29.7%) versus normal CrCl (28.9%). A complete response (CR) was observed in 8 (21.6%) patients with reduced and 10 (10.3%) patients with normal CrCl. The median duration of response (DOR) in patients who had reduced CrCl was 23.0 months compared to 9.2 months in patients with normal CrCl. The median progression-free survival (PFS) was 3.5 months (95% CI 1.7, 24.8) and 2.3 months (95% CI 1.9, 3.7) and overall survival was 7.8 months and 9.1 months in patients with reduced CrCl and those with normal CrCl. The most common grade ≥3 treatment-related AEs for patients with reduced versus normal CrCl were thrombocytopenia (45.9% vs. 38.1%), nausea (5.4% vs. 6.2%), and fatigue (8.1% vs. 11.3%). There was no clinically significant increase in treatment-related serious adverse events (21.6% vs. 20.6%) and adverse events leading to discontinuation (10.8% vs. 7.2%) in patients with reduced or normal CrCl, respectively. Conclusions: Selinexor showed similar anti-DLBCL activity and tolerability in patients with relapsed/refractory DLBCL with a reduced renal function (CrCl Disclosures Schuster: Amgen, Abbvie, Gilead, Takeda, Celgene, Pharmacyclics, Astellas, Verastem, Merck, Novartis, Takeda, Genentech,, Seattle Genetics: Other: Personal Fees; Karyopharm: Membership on an entity's Board of Directors or advisory committees. Canales:Novartis: Honoraria; Janssen: Honoraria; Novartis: Honoraria; iQone: Honoraria; Sandoz: Speakers Bureau; Karyopharm: Honoraria; Janssen: Speakers Bureau; Janssen: Honoraria; Roche: Speakers Bureau; Takeda: Speakers Bureau; Janssen: Speakers Bureau; Roche: Speakers Bureau; Sandoz: Speakers Bureau; Takeda: Speakers Bureau; Celgene: Honoraria; Roche: Honoraria; Sandoz: Honoraria; Sandoz: Honoraria; Gilead: Honoraria; Roche: Honoraria; Karyopharm: Honoraria. Westin:Novartis: Consultancy, Research Funding; Kite: Consultancy, Research Funding; Curis: Consultancy, Research Funding; Genentech: Consultancy, Research Funding; Janssen: Consultancy, Research Funding; Astra Zeneca: Consultancy, Research Funding; BMS: Consultancy, Research Funding; Morphosys: Consultancy, Research Funding; Amgen: Consultancy; 47: Research Funding. Zijlstra:Roche: Research Funding. Follows:Karyopharm, Roche, Abbvie, Astrazeneca, Janssen, BMS: Membership on an entity's Board of Directors or advisory committees. Karmali:Takeda: Research Funding; AstraZeneca: Speakers Bureau; Karyopharm: Honoraria; BeiGene: Speakers Bureau; BMS/Celgene/Juno: Honoraria, Other, Research Funding, Speakers Bureau; Gilead/Kite: Honoraria, Other, Research Funding, Speakers Bureau. Kalakonda:Gilead, Janssen, Karyopharm: Honoraria; Verastem, Gilead, Celgene, Roche: Research Funding. Goy:AbbVie: Research Funding; Celgene: Honoraria, Research Funding; Janssen: Consultancy, Honoraria, Other: leadership role, Research Funding; Acerta: Consultancy, Honoraria, Other: leadership role, Research Funding; MD Anderson: Research Funding; Xcenda: Consultancy; Kite, a Gilead Company: Consultancy, Current equity holder in publicly-traded company, Honoraria, Other: leadership role, Research Funding; Regional Cancer Care Associates/OMI: Current Employment; Bayer: Research Funding; PracticeUpdate Oncology: Consultancy; RCCA/OMI: Current Employment; Morphosys: Research Funding; Karyopharm: Research Funding; Genentech/Roche: Research Funding; Constellation: Research Funding; CALBG: Research Funding; Infinity Verastem: Research Funding; AstraZeneca: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: leadership role, Research Funding; COTA: Consultancy, Current equity holder in publicly-traded company, Other: leadership role; Hackensack UMC and University of Nebraska: Research Funding; Infinity: Research Funding. Casasnovas:Takeda: Consultancy, Honoraria, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company), Research Funding; Gilead: Consultancy, Honoraria, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company), Research Funding; Roche: Consultancy, Honoraria, Other: travel, accomodations, expenses, Research Funding; Abbvie: Consultancy, Honoraria; MSD: Consultancy, Honoraria; Amgen: Consultancy, Honoraria. Thieblemont:Cellectis: Speakers Bureau; Roche, Amgen, Kyte Gilead, Celgene, Abbvie, Novartis, Cellectis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel support; Roche, Hospita: Research Funding. Cavallo:Takeda, Janssen: Membership on an entity's Board of Directors or advisory committees; Gilead: Other: Speaker Fee. Hill:Celgene: Consultancy, Honoraria, Research Funding; Genentech: Consultancy, Honoraria, Research Funding; Novartis: Consultancy, Honoraria; Kite, a Gilead Company: Consultancy, Honoraria, Research Funding; AstraZenica: Consultancy, Honoraria, Research Funding; Beigene: Consultancy, Honoraria, Research Funding; Pharmacyclics: Consultancy, Honoraria, Research Funding; Abbvie: Consultancy, Honoraria, Research Funding; Karyopharm: Consultancy, Honoraria, Research Funding; BMS: Consultancy, Honoraria, Research Funding; Takeda: Research Funding. Tilly:BMS: Honoraria. Jaeger:Novartis: Consultancy, Honoraria, Research Funding; Gilead: Honoraria, Research Funding; BMS/Celgene: Consultancy, Honoraria, Research Funding; Karyopharm: Honoraria; AbbVie: Honoraria; F. Hoffmann-La Roche: Honoraria, Research Funding; Miltenyi: Consultancy, Honoraria; CDR Life AG: Consultancy, Research Funding. Gurion:JC Health CARE: Consultancy, Honoraria; Roche: Consultancy, Honoraria; Takeda Pharmaceuticals: Consultancy, Honoraria; Gilead Sciences: Consultancy, Honoraria; Medison: Consultancy, Honoraria. Caimi:Celgene Corp: Other: Incyte Corporation - Ownership - Pharmacyclics, Inc. - Ownership - Celgene Corp. - Other, Speakers Bureau; ADC Therapeutics: Research Funding; Genentech: Research Funding. Martin:Kite: Consultancy; Morphosys: Consultancy; I-MAB: Consultancy; Janssen: Consultancy; Sandoz: Consultancy; Regeneron: Consultancy; Incyte: Consultancy; Karyopharm: Consultancy, Research Funding; Teneobio: Consultancy; Celgene: Consultancy; Bayer: Consultancy; Cellectar: Consultancy; Beigene: Consultancy. Davies:Roche, Acerta Pharma, AstraZeneca, Celgene, Gilead, ADC Therapeutics, Gilead: Research Funding; Roche, Celgene, Kite Pharma, Acerta, Karyopharma, Regeneron, Incyte: Consultancy; Roche: Other: TRAVEL, ACCOMMODATIONS, EXPENSES; Celegene, Roche, Kite Pharma, Celegene: Honoraria. Smith:TG Therapeutics: Consultancy, Research Funding; Janssen: Consultancy; Celgene: Consultancy, Research Funding; BMS: Consultancy; Karyopharm: Consultancy, Research Funding; FortySeven: Research Funding; Pharmacyclics: Research Funding; Acerta: Research Funding; Genentech/Roche: Consultancy, Other: Support of parent study and funding of editorial support, Research Funding. Collins:BeiGene: Consultancy; MSD: Consultancy, Honoraria, Research Funding; Novartis: Consultancy, Honoraria, Speakers Bureau; Taekda: Consultancy, Honoraria, Other: travel, accommodations, expenses, Speakers Bureau; BMS: Consultancy, Honoraria, Research Funding, Speakers Bureau; Pfizer: Honoraria; ADC Therapeutics: Consultancy, Honoraria; Celleron: Consultancy, Honoraria, Research Funding; Gilead: Consultancy, Honoraria, Speakers Bureau; Celgene: Research Funding; Roche: Consultancy, Honoraria, Other: travel, accommodations, expenses , Speakers Bureau; Amgen: Research Funding. Salles:Epizyme: Consultancy; Gilead: Consultancy, Honoraria, Other: Participation in educational events; Abbvie: Consultancy, Honoraria, Other: Participation in educational events; Janssen: Consultancy, Honoraria, Other: Participation in educational events; Kite: Consultancy, Honoraria, Other; Debiopharm: Consultancy; Celgene: Consultancy, Honoraria, Other: Participation in educational events; Karyopharm: Consultancy; Genmab: Consultancy; Amgen: Honoraria, Other: Participation in educational events; Autolus: Consultancy; MorphoSys: Consultancy, Honoraria, Other; Novartis: Consultancy, Honoraria, Other; F. Hoffman-La Roche Ltd: Consultancy, Honoraria, Other; Bristol Myers Squibb: Consultancy, Other; Takeda: Consultancy, Honoraria, Other. Ma:Karyopharm: Current Employment, Current equity holder in private company. Corona:Karyopharm: Current Employment. Saint-Martin:Karyopharm: Current Employment. Joshi:Karyopharm Therapeutics Inc: Consultancy. Chamoun:Karyopharm: Current Employment. Wang:Curis: Ended employment in the past 24 months; Karyopharm: Current Employment. Shah:Karyopharm: Current Employment, Current equity holder in publicly-traded company. Shacham:Karyopharm: Current Employment, Current equity holder in publicly-traded company, Patents & Royalties: (8999996, 9079865, 9714226, PCT/US12/048319, and I574957) on hydrazide containing nuclear transport modulators and uses, and pending patents PCT/US12/048319, 499/2012, PI20102724, and 2012000928) . Kauffman:Karyopharm Therapeutics Inc: Current Employment, Current equity holder in publicly-traded company, Membership on an entity's Board of Directors or advisory committees.

Background: In early unfavorable Hodgkin Lymphoma (HL), long-term tumor control with 4xABVD and 30Gy involved field radiotherapy (IFRT) is approximately 80%. To improve these results, the GHSG HD14 trial compared an intensified chemotherapy regimen consisting of 2xBEACOPPescalated plus 2xABVD (2+2) to 4xABVD. All patients received 30Gy IFRT. Due to a progression-free survival (PFS) difference of 6.2% at five years in favor of the intensified treatment, 2+2 plus 30Gy RT is the current GHSG standard and is a treatment option in the NCCN guidelines for early unfavorable HL. However, there was no overall survival (OS) difference between 2+2 and 4xABVD at the final analysis of HD14 and the potential long-term toxicity of 2+2 is debated. We therefore performed a long-term follow up analysis of HD14. Patients and Methods: Between January 2003 and July 2008, 1,550 patients with early unfavorable HL ≤60 years were randomized and treated with 4xABVD or 2+2, followed by 30Gy IFRT in all patients. Randomization was discontinued after the third planned interim analysis showed a significant advantage of 2+2 in terms of the primary endpoint freedom from treatment failure (FFTF, difference 7.2% at 5 years). Accrual to the 2+2 arm continued from July 2008 to December 2009 and 339 additional qualified patients were treated with 2+2 plus 30Gy IFRT. These patients were not reported in the initial report and are added to all analyses of this long-term follow-up. Time-to-event end points were compared between groups using the Kaplan-Meier method as well as univariate and multivariate Cox regression models. Results: After a median observation time of 97 months, 10.2% (79 of 777) and 3.4% (38 of 1112) of patients treated with 4xABVD and 2+2, respectively, had progression or relapse. The 10-year PFS was 85.6% for 4xABVD (95%-CI 82.9% to 88.4%) and 91.2% for 2+2 (95%-CI 89.0% to 93.4%) accounting for a significant PFS difference of 5.6% (95%-CI 2.1% to 9.1%) in favor of 2+2 (Figure 1). Two or more relapses were experienced by 21 of 777 (2.7%) and 10 of 1112 (0.9%) patients who had received 4xABVD or 2+2 as first-line treatment, respectively. However, there was still no OS difference between the two groups (OS 94.1% [95%-CI 92.3% to 96%] and 94% [95%-CI 92.3% to 95.8%] for 4xABVD and 2+2, respectively; difference at 10 years -0.1% [95%-CI -2.6% to 2.4%], median observation time for OS 104 months). In a multivariate regression analysis adjusting for age, B-symptoms, infra-diaphragmatic disease, and the 4 GHSG risk factors (elevated ESR, involvement of ≥3 lymph node areas, extranodal disease, and large mediastinal tumor) as predictive factors for PFS, age ≥50 (HR 2.260, 95%-CI 1.543 to 3.309), presence of infra-diaphragmatic disease (HR 1.766, 95%-CI 1.055 to 2.955), or of a large mediastinal tumor (HR 1.811, 95%-CI 1.226 to 2.675) and treatment with 4xABVD (HR 1.929, 95%-CI 1.423 to 2.614) were significant predictors of PFS. Slightly more patients in the 4xABVD group died from toxicity of salvage therapy as compared to 2+2 patients (1% [8 of 777] versus 0.6% [7 of 1112]) whereas there were relatively more deaths due to study therapy in the 2+2 group as compared to 4xABVD patients (0.6% [7 of 1112] versus 0.1% [1 of 777]), leading to a similar OS in both groups. There were no apparent differences in other causes of death including HL (5 of 777 [0.6%] versus 9 of 1112 [0.8%]) and second neoplasms (12 of 777 [1.5%] versus 16 of 1112 [1.4%]) between 4xABVD and 2+2, respectively. A total of 95 second malignancies corresponding to 10-year cumulative second malignancy incidences of 4.7% and 6.4% were reported for 4xABVD and 2+2, respectively, without a difference between the two groups (p=0.86). Standardized incidence ratios (SIR) showed elevation compared to the general German population and no significant difference between 4xABVD (2.3 [95%-CI 1.6 to 3.2]) and 2+2 (2.6 [95%-CI 2.0 to 3.4]). Conclusions: This long-term analysis confirms the superior tumor control of 2+2 as compared to 4xABVD in patients ≤60 with early unfavorable HL. However, this does not translate into an OS difference. At longer follow-up, there is no difference regarding second primary malignancies between the groups. In comparison to 4xABVD, the 2+2 regimen spares a significant number of patients from the burden of cancer recurrence and additional treatment without increased long-term toxicity. Therefore, 2+2 remains the GHSG standard for patients with early unfavorable HL ≤60. Disclosures Greil: Novartis: Consultancy, Honoraria, Other: Travel/accomodation expenses, Research Funding; GSK: Research Funding; Takeda: Consultancy, Honoraria, Research Funding; Ratiopharm: Research Funding; Roche: Consultancy, Honoraria, Other: Travel/accomodation expenses, Research Funding; Eisai: Honoraria; Boehringer Ingelheim: Honoraria; Pfizer: Honoraria, Research Funding; Mundipharma: Honoraria, Research Funding; MSD: Consultancy, Honoraria, Other: Travel/accomodation expenses, Research Funding; Amgen: Consultancy, Honoraria, Other: Travel/accomodation expenses, Research Funding; AbbVie: Consultancy, Honoraria, Research Funding; Gilead: Consultancy, Honoraria, Other: Travel/accomodation expenses, Research Funding; Daiichi Sankyo: Consultancy, Honoraria; Sandoz: Honoraria; Janssen-Cilag: Honoraria; Genentech: Honoraria, Research Funding; Sanofi Aventis: Honoraria; Celgene: Consultancy, Honoraria, Other: Travel/accomodation expenses, Research Funding; Merck: Consultancy, Honoraria, Research Funding; AstraZeneca: Consultancy, Honoraria, Other: Travel/accomodation expenses, Research Funding. Topp:Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Boehringer Ingelheim: Membership on an entity's Board of Directors or advisory committees, Research Funding; KITE: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Roche: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Regeneron Pharmaceuticals, Inc.: 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; Novartis: Membership on an entity's Board of Directors or advisory committees. Zijlstra:Gilead: Consultancy, 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; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria. Borchmann:Novartis: Honoraria, Research Funding. von Tresckow:Takeda: Consultancy, Honoraria, Other: Travel and congress funding, Research Funding; Novartis: Consultancy, Honoraria, Other: Travel and congress funding, Research Funding; Pfizer: Honoraria; Amgen: Honoraria; Roche: Honoraria; MSD: Consultancy, Honoraria, Other: Travel and congress funding, Research Funding.

Introduction Baseline metabolic tumor volume (bMTV) is increasingly studied as a prognostic factor for classical Hodgkin lymphoma (cHL). Before implementation as a clinical prognostic marker, it is important to investigate different methods for deriving bMTV since not all methods are suitable for each type of malignancy. Semi-automatic segmentation is influenced less by observer bias and variability compared to manual segmentation and might therefore be more reliable for assessing bMTV. However, not much is known about the use of different semi-automatic segmentation methods and how this influences the prognostic value of bMTV in cHL. Here we present a comparison of bMTV derived with 6 semi-automatic segmentation methods. In addition, a visual quality scoring of all segmentations is performed to gain insight into which segmentation methods could be used to determine bMTV in cHL. Methods We selected 61 baseline 18FDG-PET-CT scans that met specific quality criteria (http://EARL.EANM.org) from patients treated in the Transplant BRaVE study for relapsed/refractory cHL [Blood 2018 132:2923]. Six semi-automatic segmentation methods were applied using the Accurate tool, an in-house developed software application which has already been validated in other types of cancer, including diffuse large B-cell lymphoma [Eur Radiol 2019 06178:9, J Nucl Med. 2018;59(suppl 1):1753]. We compared two fixed thresholds (SUV4.0 and SUV2.5), two relative thresholds (A50P: a contrast corrected 50% of standard uptake value (SUV) peak, and 41max: 41% of SUVmax), and 2 majority vote methods, MV2 and MV3 selecting delineations of ≥2 and ≥3 of previously mentioned methods, respectively. Quality of the segmentation was scored using visual quality scores (QS) by two reviewers (JD, GZ): QS-1 for complete selections containing all visible tumor localizations; QS-2 when segmentations 'flood' into regions with physiological FDG uptake; QS-3 when segmentations do not select all visible lesions; or QS-4: a combination of QS-2 and QS-3. In addition, the quality of the delineation was rated: QS-A for good visual delineation of lesions; QS-B for too small delineation; and QS-C for too large delineation. All segmentations that had score QS-2 or QS-4 were manually adapted by erasing regions that flooded into areas with high physiological uptake. Figure 1 shows examples of the quality scores. We used Spearman's correlations to compare the bMTV of all semi-automatic methods. Comparison of quality scores was performed using chi-square tests. Results The median bMTV differed substantially among the segmentation methods, ranging from 24 mL for SUV4.0 to 88 mL for 41max (Table 1). However, there was a high significant correlation (p The quality of the segmentation was best using the SUV2.5 threshold with QS-1 in 64% of scans and delineation was best for MV3 with QS-A in 56% (Table 3). The segmentation quality was significantly better when less than 5 lesions were present on a scan. A large difference was observed for SUV2.5 with score QS-1 in 91% of cases for scans with Conclusions We found a good correlation between all methods, suggesting that the segmentation method used will probably not influence the predictive value of bMTV. Ease of use was highest with a semi-automatic segmentation of bMTV using the SUV2.5 segmentation method. SUV2.5 had the best visual quality and needed least manual adaptation. To investigate possible implementation of bMTV in clinical practice, we will validate the quality of the segmentation methods and the predictive value of bMTV in a larger cohort of patients with other prognostic parameters including quantitative radiomics analysis of baseline PET-scans. Disclosures Kersten: Bristol-Myers Squibb: Honoraria, Research Funding; Gilead: Honoraria; Roche: Honoraria, Research Funding; Celgene: Honoraria, Research Funding; Novartis: Honoraria; Mundipharma: Honoraria, Research Funding; Amgen: Honoraria, Research Funding; Miltenyi: Honoraria; Takeda Oncology: Research Funding; Kite Pharma: Honoraria, Research Funding. Zijlstra:Janssen: Honoraria; Gilead: Consultancy, Honoraria, 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; Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees.

Introduction: R/R DLBCL patients who have received ≥2 lines of therapy, including those progressed post stem cell transplantation (SCT) or who are not candidates for SCT, have limited treatment options. Selinexor, a selective oral XPO1 inhibitor leads to nuclear accumulation and activation of tumor suppressor proteins and reductions in c-Myc and Bcl-2 oncogenes. Selinexor plus low dose dexamethasone (Sel-dex) was recently approved in relapsed/refractory myeloma in the United States based on data from the STORM study, wherein Sel-dex induced an overall response rate (ORR) of 26.2% in patients with penta-exposed, triple-class refractory multiple myeloma. We conducted the SADAL study to evaluate the efficacy and safety of single agent selinexor in patients with R/R DLBCL. In this patient population, selinexor demonstrated deep and durable responses with an overall response rate (ORR) of 28.3% including a 11.0% complete response (CR) rate. The median duration of response (DOR) was 9.2 months. In patients with CR, the DOR was 13.4 months. Here we evaluate the effect of prior therapy on the efficacy and safety of selinexor. Methods: SADAL is a multicenter, open-label study in R/R DLBCL patients with 2-5 prior lines of therapy, who may have progressed post SCT or are not candidates for SCT. Patients were stratified by subtype (germinal center B-cell or non-GCB) and treated with 60 mg selinexor BIW per 28-day cycle. The primary endpoint was ORR. Secondary endpoints included duration of response (DOR) and safety. We performed post-hoc analyses to compare outcomes based on the number (2 vs. >2) and type (SCT vs. no SCT) of prior lines of therapy received. Results: Of 127 patients, 83 (65%) received 2 prior lines of therapy and 43 (34%) received >2 prior lines of therapy. Thirty-six patients (28%) received prior SCT and 91 (72%) had no prior SCT. In general, patient demographic and baseline characteristics were well balanced in both subgroups. ORR was 30.1% vs. 25.6% (P=0.74) in patients with 2 vs >2 prior lines of therapy respectively. The CR rate was 10.8% in patients with 2 prior lines of therapy compared with 11.6% in patients with >2 prior lines of therapy (P=1.00). The median DOR was 9.2 months in patients with 2 prior lines of therapy compared with 8.4 months in those with >2 prior lines of therapy (P=0.64). Median progression free survival was 3.7 months and 1.9 months (P=0.37) and median overall survival was 11.0 months and 9.8 months (P=0.69) in patients with 2 and >2 prior lines of therapy respectively. In patients with prior SCT, the ORR was 44.4% compared with 22.0 % (P=0.02) in patients with no prior SCT. The CR rate was 16.7% in patients with prior SCT compared with 8.8% in patients with no prior SCT (P=0.34). The DOR was 8.4 months in patients with prior SCT and 9.2 months with no prior SCT (P=0.80). Median progression free survival was 5.9 months and 2.3 months (P=0.07) and median overall survival was 9.1 and 9.8 months (P=0.36) in patients with prior SCT and no prior SCT respectively. The most common related adverse events (AEs) [grade ≥3] included thrombocytopenia (2 prior lines: 36%, >2 prior lines: 42%; prior SCT: 58%, no prior SCT: 31%), neutropenia (2 prior lines: 19%, >2 lines: 23%; prior SCT: 25%, no prior SCT: 20%), and anemia (2 prior lines: 15%, >2 prior lines: 14%, prior SCT: 17%, no prior SCT: 14%). Treatment-related serious AEs were reported in 23%, 14%, 25%, and 19% of patients with 2 prior lines, >2 prior lines, prior SCT, and no prior SCT respectively. Conclusions: Single agent oral selinexor with its novel mechanism of action demonstrated deep and durable responses with no new safety signals regardless of prior therapy. Patients with 2 prior lines of therapy had a higher response rate (30.1% vs. 25.6%) compared with those with >2 prior lines of therapy. The greatest benefit, with an ORR of 44.4% was observed in patients with prior SCT. Collectively, these data support the clinical benefit of single agent selinexor and importantly in earlier lines of therapy. Further evaluation of selinexor in combination with other agents to improve outcomes in R/R DLBCL is ongoing. Disclosures Cavallo: Takeda: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees. Follows:Roche: Consultancy, Honoraria, Speakers Bureau; Abbvie: Consultancy, Honoraria, Speakers Bureau; Janssen: Consultancy, Honoraria, Speakers Bureau; AstraZeneca: Consultancy, Honoraria, Speakers Bureau; Gilead: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Goy:Astrazenca: 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; Hackensack University Medical Center, RCCA: Employment; Pharmacyclics/Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Grants outside of the submitted work, Research Funding; Kite, a Gilead Company: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Grants outside of the submitted work; Takeda: Other: Grants outside of the submitted work; Acerta: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Grants outside of the submitted work, Research Funding; Genentech: Other: Grants outside of the submitted work, Research Funding; University of Nebraska: Research Funding; Hakensackumc: Research Funding; COTA: Equity Ownership, Membership on an entity's Board of Directors or advisory committees, Other: leadership role for profit healthcare company. Casasnovas: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; 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. Zijlstra:Gilead: Consultancy, 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; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria. Choquet:Keocyt: Honoraria. Gurion:Roche: Consultancy. Hill:TG therapeutics: Research Funding; Abbvie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Genentech: Consultancy, Research Funding; Kite: Consultancy, Honoraria; Gilead: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Pharmacyclics: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; AstraZeneca: Consultancy, Honoraria; Celegene: Consultancy, Honoraria, Research Funding; Seattle Genetics: Consultancy, Honoraria; Takeda: Research Funding; Amgen: Research Funding. Jaeger:Novartis, Roche, Sandoz: Consultancy; AbbVie, Celgene, Gilead, Novartis, Roche, Takeda Millennium: Research Funding; Celgene, Roche, Janssen, Gilead, Novartis, MSD, AbbVie, Sanofi: Membership on an entity's Board of Directors or advisory committees; Amgen, AbbVie, Celgene, Eisai, Gilead, Janssen, Novartis, Roche, Takeda Millennium, MSD, BMS, Sanofi: Honoraria. Sancho:Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Sandoz: Consultancy; F. Hoffmann-La Roche Ltd: 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: Consultancy, Honoraria, Other: Advisory board; Novartis: Honoraria; Kern Pharma: Honoraria, Membership on an entity's Board of Directors or advisory committees; Sanofi: Honoraria; Celltrion: Membership on an entity's Board of Directors or advisory committees; Bristol-Myers Squib: Membership on an entity's Board of Directors or advisory committees. Schuster:Celgene: Speakers Bureau; Genentech: Speakers Bureau; Janssen: Speakers Bureau; Novartis: Speakers Bureau; Seattle Genetics: Speakers Bureau; Takeda: Speakers Bureau; Verastem: Speakers Bureau; Astellas: Speakers Bureau; Actinium: Research Funding; Incyte: Research Funding; Karyopharm Therapeutics: Research Funding; Morphosys: Research Funding; Nordic Nanovector: Research Funding; Pharmacyclics: Research Funding, Speakers Bureau; Rafael: Research Funding; F2G Ltd.: Research Funding; AbbVie: Speakers Bureau; Amgen: Speakers Bureau. Thieblemont:Roche: Honoraria, Research Funding; Gilead: Honoraria; Novartis: Honoraria; Kyte: Honoraria; Janssen: Honoraria; Celgene: Honoraria; Cellectis: Membership on an entity's Board of Directors or advisory committees. Vassilakopoulos:Abbvie: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene / GenesisPharma: Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: 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; WinMedica: 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. McCarthy:Karyopharm Therapeutics: Employment, Equity Ownership. Ma:Karyopharm: Employment, Equity Ownership. Corona:Karyopharm Therapeutics: Employment, Equity Ownership. Saint-Martin:Karyopharm Therapeutics: Employment, Equity Ownership. Joshi:Karyopharm Therapeutics: Employment, Equity Ownership. Shah:Karyopharm Therapeutics: Employment, Equity Ownership. Van Den Neste:Gilead: Other: travel support. Canales:Sandoz: Honoraria; F. Hoffmann-La Roche Ltd: Honoraria, Speakers Bureau; Celgene: Honoraria; Novartis: Honoraria; Takeda: Speakers Bureau; SOBI: Research Funding; iQone: Honoraria; Karyopharm: Honoraria; Gilead: Honoraria; Janssen: Honoraria, Speakers Bureau.

Background The anti-PD1 antibodies nivolumab and pembrolizumab are approved for relapsed or refractory classical Hodgkin lymphoma (r/r cHL) due to high overall response rates (ORR) with a favorable safety profile. However, complete responses (CR) are rare, and patients eventually develop progressive disease. Treatment options in this situation are very limited and usually regarded palliative. Innovative therapies for patients with progressive r/r cHL or insufficient response to anti-PD1 antibodies are hence an unmet clinical need. Radiotherapy (RT) is highly effective and potentially curative in cHL. Local RT results in immunogeneic cell-death at times leading to immune-mediated systemic effects termed abscopal response (AR). Case reports in different cancers including cHL highlight this effect of local therapies potentially enhanced by systemic immunotherapies. Combining the approved systemic anti-PD1 treatment with local RT to a single cHL lesion might hence work synergistically and result in improved tumor control with limited additional toxicity. It thereby would constitute a viable therapeutic option for patients with r/r cHL and could in the future also be incorporated in earlier lines of therapy. However, prospective data regarding this treatment strategy is lacking and will be generated with the recently activated herein presented GHSG AERN trial. Study Design & Methods AERN is an investigator-sponsored, prospective, international, multicenter, single-arm, two-stage phase II trial (NCT03480334) conducted at 10 European trial sites in Austria, Germany, United Kingdom, Netherlands and Norway. Patients with r/r cHL on active anti-PD1 therapy >18 years of age without serious concomitant diseases or organ dysfunction are eligible for enrollment. Patients either have to present with progressive disease (PD) or stable disease (SD) >6 months as best response to the ongoing anti-PD1 antibody. After registration for the screening phase, eligibility will be verified by a centralized GHSG review facility who will also define a single target lesion for RT to ensure at least one cHL lesion outside the 10% RT isodose for evaluation of the primary endpoint (abscopal response rate after 6x nivolumab, ARR-6). All patients will receive 240mg nivolumab at 2-weekly intervals and 20 Gy RT to the target lesion at 2 Gy fractions on ten consecutive working days starting day 6 of nivolumab treatment. Nivolumab will be discontinued in case of inacceptable toxicity or further disease progression and continued for a maximum of 18 months within the AERN trial. During the first stage of the trial, 9 qualified patients will be treated and their response to treatment will be centrally evaluated after the first 6 nivolumab doses. If no AR is observed in stage I, the trial will be terminated for futility. Otherwise 20 additional patients will be enrolled into the second stage for a total trial population of 29 r/r cHL patients. The null hypothesis H0: ARR-6 < 5% will be tested against a one-sided alternative at a confidence level of α = 5%, and at least 4 AR need to be observed for the rejection of H0. Secondary endpoints include e.g. ORR, overall ARR, CR rate, PFS and OS but also feasibility aspects, (S)AEs and quality of life (QoL) measures. To understand the underlying mechanisms of efficacy but also resistance or toxicity a comprehensive set of correlative studies will be conducted. Baseline and sequential blood samples as well as tumor biopsies and rectal swabs for microbiome analyses will be taken during AERN in patients with separate informed consent. This allows detailed evaluation of serological, cellular, functional, histological and genetic parameters to elucidate synergies between anti-PD1 and RT. Ultimately the correlative studies should help to further refine anti-PD1 based combination therapies, ideally beyond the setting of r/r cHL. In summary AERN, to our knowledge, is the first prospective trial formally evaluating the postulated abscopal effect in r/r cHL. The trial addresses an unmet clinical need in r/r cHL patients with insufficient or lost response to anti-PD1 antibodies. AERN additionally will provide proof-of-concept for a synergy of local RT with checkpoint inhibition substantiated by comprehensive correlative studies in blood, tumor tissue and microbiome. Recruitment has started but preliminary data regarding safety or efficacy are not yet available. Figure Disclosures Bröckelmann: MSD Sharpe & Dohme: Research Funding; Takeda: Consultancy, Honoraria, Other: Travel Support, Research Funding; Bristol-Myers Squibb: Honoraria, Other: Travel Support, Research Funding. Greil:Amgen: Consultancy, Honoraria, Other: Travel/accomodation expenses, Research Funding; Celgene: Consultancy, Honoraria, Other: Travel/accomodation expenses, Research Funding; Eisai: Honoraria; Mundipharma: Honoraria, Research Funding; Merck: Consultancy, Honoraria, Research Funding; Ratiopharm: Research Funding; Gilead: Consultancy, Honoraria, Other: Travel/accomodation expenses, Research Funding; Takeda: Consultancy, Honoraria, Research Funding; Novartis: Consultancy, Honoraria, Other: Travel/accomodation expenses, Research Funding; Janssen-Cilag: Honoraria; Sanofi Aventis: Honoraria; MSD: Consultancy, Honoraria, Other: Travel/accomodation expenses, Research Funding; Sandoz: Honoraria; AbbVie: Consultancy, Honoraria, Research Funding; Pfizer: Honoraria, Research Funding; Roche: Consultancy, Honoraria, Other: Travel/accomodation expenses, Research Funding; Genentech: Honoraria, Research Funding; GSK: Research Funding; Daiichi Sankyo: Consultancy, Honoraria; AstraZeneca: Consultancy, Honoraria, Other: Travel/accomodation expenses, Research Funding; Boehringer Ingelheim: Honoraria. Zijlstra:Janssen: Honoraria; Takeda: 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; Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees. Illidge:Div of Cancer Sciences, Faculty of Biology, Medicine and Health, Univ of Manchester, National Institutes of Health and Research Biomedical Research Center, Manchester Academic Health Sciences, Christie Hospital National Health Service Foundation Trust: Employment; Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Seattle Genetics, Inc.: Research Funding. Zimmermann:Takeda: Honoraria, Other: Travel Expenses; Novartis: Other: Travel Expenses; MSD: Other: Travel Expenses; BMS: Other: Travel Expenses.

Contains fulltext : 137565.pdf (Publisher’s version ) (Closed access) We assessed risk, localization, and timing of third malignancies in Hodgkin lymphoma (HL) survivors. In a cohort of 3122 5-year HL survivors diagnosed before the age of 51 years and treated between 1965 and 1995, we examined whether risk factors for second and third malignancies differ and whether the occurrence of a second malignancy affects the risk of subsequent malignancies, using recurrent event analyses. After a median follow-up of 22.6 years, 832 patients developed a second malignancy and 126 patients a third one. The risk of a second malignancy was 4.7-fold increased (95% confidence interval [CI], 4.4-5.1) compared with risk in the general population; the risk for a third malignancy after a second malignancy was 5.4-fold (95% CI, 4.4-6.5) increased. The 10-year cumulative incidence of any third malignancy was 13.3%. Compared with patients still free of a second malignancy, patients with a second malignancy had a higher risk of developing subsequent malignancies. This risk depended on age, with hazard ratios of 2.2, 1.6, and 1.1 for patients aged

[§ share last authorship] Background: In 2000-2010, the first large prospective trials in peripheral T-cell lymphoma (PTCL) showed outcomes burdened by high failure rates during induction. Concurrently, trials with the anti-CD52 monoclonal antibody alemtuzumab (ALZ) yielded promising responses in PTCL while demonstrating the feasibility of combining ALZ with CHOP. Hence, the Nordic Lymphoma Group initiated the randomized ACT-1 trial to test, in younger patients (pts) (18-65yrs), the addition of ALZ to CHOP + autologous stem cell transplant (ASCT). Primary endpoint was the 3 years event-free survival (EFS). Here, we present the final analysis of the ACT-1 trial (ClinicalTrials.gov: NCT00646854). Patients and Methods: Overall, 136 pts were randomized (43% of planned sample size due to slow accrual), five did not receive study treatment, and 131 were analyzed (ALZ-CHOP: 65; CHOP: 66). Due to lack of tumoral CD52 expression, anaplastic large cell lymphomas (ALCL) were not included in the ACT-1 trial. An amendment tapering ALZ dose from 360 mg (30 mg on days 1+2 of each CHOP course) to 120 mg (30 mg on day 1 of CHOP courses 1-4) was introduced early on due to systemic fungal infections in 2 pts. Of the 65 pts treated with ALZ-CHOP, 4 received the pre- and 61 (94%) the post-amendment dose. Monitoring for CMV- and EBV-DNA and antimicrobial prophylaxis were mandatory. Results: The median observation time for the Full Analysis Set was 66 months and the median age 51 yrs. The ALZ-CHOP and CHOP cohorts were well balanced with regard to classical prognostic factors and histological subtypes (PTCL-NOS 58% vs 54%, AILT 21% vs 25%, other 21% vs 21%). Feasibility: Neither CHOP nor ALZ-CHOP pts experienced substantial treatment delay. ALZ exposure did not affect stem cell harvest nor hematopoietic recovery. Grade 4 leucopenia was more frequent in ALZ-CHOP pts (73% vs 35%; p=0.001), whereas the occurrence of grade 3-4 anemia and thrombocytopenia did not differ significantly. After ALZ dose amendment, the frequency of bacterial and fungal infections of grade ≥3 was similar in both treatment arms. ALZ treated pts had more viral events (22/57=42% vs 4/23=17%), mainly due to asymptomatic CMV reactivations. The ratio of serious adverse events per ALZ-CHOP treated patient dropped markedly (from 3.25 to 0.86, comparable with 0.46 for CHOP) after dose amendment. Additional toxicity was mild and similar in both arms. Treatment related mortality was 4% (5% vs 3%). Efficacy: Complete remission (CR) was 52% in ALZ-CHOP vs 42% in CHOP. Primary refractory disease occurred for ALZ-CHOP and CHOP in 23% and 38% of pts, respectively. Overall, females had a significantly better outcome than males (p=0.004), also after adjustment for classical prognostic factors. Analyzing time-related endpoints without knowledge of CD52 expression, 3-years EFS, progression-free, and overall survival (PFS, OS) did not differ significantly between ALZ-CHOP and CHOP (EFS 35% vs 26%, PFS 37% vs 26%, OS 52% vs 50%). Fig.1A shows EFS by treatment arm, by gender, and by gender and treatment arm. Although not significantly different, EFS, PFS and OS values of ALZ-CHOP treated females in the ACT-1 trial were consistently higher than those of non-ALZ treated females or of males regardless of treatment group. RNA sequencing from evaluable pre-therapeutic tumor biopsies defined a signature of differentially expressed genes to be predictive of clinical outcome in ALZ-CHOP but not CHOP treated pts (n=33). Tumor microenvironment genes were prominent in determining response to ALZ. Tumors rich in B-cell milieu showed good responses, while the opposite was observed in tumors with signatures enriched with high endothelial cell genes (p Disclosures Leppä: Roche: Consultancy, Honoraria, Research Funding; Takeda: Consultancy, Research Funding; Bayer: Research Funding; Janssen: Consultancy, Research Funding; Celgene: Consultancy. Silva:Gilead Sciences: Research Funding; Abbvie, Gilead Sciences, Janssen, BMS: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Roche, Janssen, Celgene: Other: Travel Support; Roche, Janssen: Other: Institution's payment for consultancy. Hagberg:Roche: Honoraria. Lugtenburg:takeda: Consultancy, Research Funding; servier: Consultancy, Research Funding; roche: Consultancy; BMS: Consultancy; Celgene: Consultancy; Sandoz: Consultancy; GenMab: Research Funding. Walewski:Roche, GSK/Novartis, Takeda, and Janssen-Cilag: Research Funding; Roche, Celgene, Takeda, Janssen-Cilag, and Servier: Honoraria; Roche, Celegene, Takeda, Janssen-Cilag, and Servier: Membership on an entity's Board of Directors or advisory committees. Hopfinger:Janssen: Honoraria; Gilead: Honoraria, Research Funding; GlaxoSmithKline: Honoraria; Celgene: Honoraria; Novartis: Consultancy, Honoraria; Takeda: Consultancy, Honoraria; Roche: Consultancy, Honoraria. Jantunen:Amgen: Honoraria; Genzyme/Sanofi: Honoraria; Takeda: Honoraria. Steidl:Seattle Genetics: Consultancy; Juno Therapeutics: Consultancy; Tioma: Research Funding; Bristol-Myers Squibb: Research Funding; Nanostring: Patents & Royalties: patent holding; Roche: Consultancy. Gascoyne:NanoString: Patents & Royalties: Named Inventor on a patent licensed to NanoString Technologies. Scott:Celgene: Consultancy, Honoraria; Janssen: Research Funding; Roche: Research Funding; NanoString: Patents & Royalties: Named Inventor on a patent licensed to NanoString Technologies, Research Funding.

Introduction Achieving a PET-negative metabolic (m)CR with salvage chemotherapy prior to autologous stem cell transplantation (ASCT) in relapsed/refractory Hodgkin lymphoma (R/R HL) is a strong predictive factor for long-term progression-free survival (PFS). In a phase I dose-escalation trial we have shown a favorable toxicity profile of 3 cycles of DHAP in combination with brentuximab vedotin (BV) with a high mCR rate (12/12 patients). A subsequent phase II study in 55 patients has been performed; the 6 patients treated at full dose of BV-DHAP in the phase I part were added to the current analysis. Methods BV was given at a fixed dose of 1.8 mg/kg on day (d) 1 of 3 cycles of DHAP q 3 weeks (dexamethasone 40 mg iv d 1-4, cisplatin 100 mg/m² iv d1 and cytarabine 2x2 g/m² iv d2). Cycle 2 was used for stem cell mobilization; after the 1st and 3rd cycle patients received pegylated G-CSF to prevent prolonged neutropenia and dose delays. The primary endpoint of the study was the mCR rate after 3 cycles of BV-DHAP based on central PET-review. Patients with a partial or complete response proceeded to high dose chemotherapy (BEAM) and ASCT. Results Twenty-three of the 61 patients (29 males; median age 29 yrs, range 19-71) had not achieved a CR to 1st line treatment (37%), which consisted of ABVD (n=45), (escalated) BEACOPP (n=11) or other regimens (n=5). The median time from response to 1st line treatment to relapse was 6 months (range 0-160 months); 38 patients (62%) had either primary refractory disease or early relapse ( All patients received the 1st cycle of BV-DHAP, 90% completed all 3 cycles and 87% underwent ASCT. G-CSF mobilized stem cells were harvested successfully after the 2nd cycle with 1 apheresis in all patients (median yield: 6x106 CD34+/kg; range: 2-23). Based on intention to treat analysis 48 patients achieved a metabolic CR after 3x BV-DHAP (mCR rate 79% (n=48/61)), 5 patients had a metabolic PR (8%) and 4 had PD (6.5%). Four patients went off study before the first evaluation (1 PD after cycle 1, 1 liver function abnormalities after cycle 2, 2 withdrew because of emotional problems). After ASCT 4 out of 5 patients with mPR converted to an mCR. At a median follow-up of 20.9 months the 2-year PFS is 76% (95% CI 65-89), and the OS projected at 2 years is 92% (95% CI 84-100). Hematologic toxicity after BV-DHAP consisted of neutropenia grade 3/4 in up to 63% of patients and thrombocytopenia grade 3/4 in up to 81% of patients. Only 3 patients had a bleeding event (epistaxis (n=2) and menorrhagia (n=1), all recovered without sequelae after platelet transfusion). Febrile neutropenia or infections after BV-DHAP occurred in 18 patients (15 grade 3 and 3 grade 4). A total of 21 SAE's other than fever/infections were reported, with kidney dysfunction (n=4; most likely related to cisplatin), malaise (n=3), nausea/vomiting (n=3) and liver function abnormalities (n=3) occurring in 3 or more patients. 11 patients had peripheral neuropathy (PN) already at baseline (10 grade 1, 1 grade 2); worsening of PN was not observed in those patients. New onset PN was seen in 19 patients (15 grade 1, 4 grade 2); no grade 3/4 PN was observed. Three deaths occurred during the study period, 1 encephalitis (exact cause unknown), 1 veno-occlusive disease, both after BEAM/ASCT and 1 trauma capitis (unrelated). One patient who refused further treatment after cycle 1 and went off study died of progressive disease. Conclusions Salvage immunochemotherapy with 3 cycles of BV-DHAP induces a high mCR rate of 79% in patients with R/R HL, which is an optimal starting point for consolidation with BEAM and ASCT and may contribute to a higher cure rate. The toxicity of combining BV and DHAP is acceptable and mainly consists of manageable hematologic toxicity and fever/infections. Figure. Figure. Disclosures Hagenbeek: Millennium/Takeda: Consultancy, Honoraria, Research Funding. Morschhauser:Janssen: Other: Scientific Lectures; BMS: Membership on an entity's Board of Directors or advisory committees; Epizyme: Consultancy; Gilead: Consultancy, Membership on an entity's Board of Directors or advisory committees; Roche: Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees. Lugtenburg:Millennium/Takeda: Consultancy, Research Funding; Servier: Consultancy, Research Funding; Roche: Consultancy; BMS: Consultancy; Sandoz: Consultancy; Genmab: Consultancy. Gastinne:Millennium/Takeda: Honoraria. Tonino:Takeda: Consultancy, Honoraria. Kersten:Millennium/Takeda: Honoraria, Research Funding; Celgene: Honoraria, Research Funding; Roche: Honoraria, Research Funding; Gilead: Honoraria; Kite Pharma: Honoraria; Novartis: Honoraria.

Introduction: Patients (pts) with relapsed/refractory (R/R) DLBCL after two or more lines of therapy and who are not candidates for stem cell transplantation have limited effective treatment options and a poor prognosis. Selinexor, an oral XPO1 inhibitor, causes nuclear accumulation and activation of tumor suppressor proteins including p53, p21, and IκBα, along with reductions in c-Myc and Bcl-2 oncogenes. In a phase 1 clinical study (NCT01607892), pts with R/R DLBCL treated with selinexor had an overall response rate (ORR) of 32%, with 4 complete responses (CRs, 6%). Based on these findings, a phase 2b open-label study (SADAL) of selinexor in pts with R/R DLBCL not candidates for transplantation was initiated. Methods: Pts with R/R DLBCL were stratified by subtype (GCB or non-GCB). Pts achieving a best response of PR/CR on prior therapy required a 8 week washout before enrolling on trial. The primary objectives included efficacy (ORR and associated DOR) and safety.Pts were initially randomized to 60 or 100 mg of selinexor twice weekly (8 doses) per 28-day cycle. Disease response was assessed by an Independent Central Radiological Review (ICRR), using the Lugano Classification (Cheson, 2014). Results: Preliminary results from the planned interim analysis showed similar ORRs on the 60 and 100 mg doses, but reduced DOR and tolerability at the higher dose; the 100 mg arm was therefore discontinued. 110 pts were enrolled on the 60 mg arm (66 M/ 44 F, median age 67 yrs) with a median of 3 (range 2-5) prior treatment regimens. The most frequently reported treatment related adverse events (AEs) included(all grades, grades 3, 4): nausea (51%, 6%, 0%), fatigue (50%, 10%, 0%), thrombocytopenia (47%, 22%, 15%), anorexia (35%, 2%, 0%), neutropenia (27%, 20%, 0%), and anemia (27%, 12%, 1%). These AEs were managed with dose modifications and/or standard supportive care. At the planned interim analysis (N=32, 60 mg) the ICRR determined ORR was 34.4% (5 CRs and 6 partial responses (PRs)). The median duration of response (DOR) was 8.4 months. ORR was 33.3% in GCB and 35.3% in non-GCB subtypes. The median overall survival (OS) was 9.0 months. Median OS (Figure 1) in pts ≥PR was not reached and was significantly longer vs median OS for pts ≤ stable disease (SD) of 4.1 months (p= Conclusion: Single agent oral selinexor is active in pts with R/R DLBCL across both GCB and non-GCB subtypes. Responses were deep with CRs noted on therapy and durable, with some responses >24 months, consistent with significant clinical benefit. Importantly, response to therapy (≥PR) was associated with significant improvement in OS of 9.0 months vs 4.1 months for those with ≤SD. Enrollment completion is expected by September 2018. Full study results (N=130) will be presented, including longer follow up (DOR and OS) of pts from the original interim analysis. Pts enrolled in SADAL represent an unmet medical need population, and selinexor may help address this need. Disclosures Casasnovas: Roche: Consultancy, Research Funding; Merck: Consultancy; Bristol-Meyers Squibb: Consultancy; AbbVie: Consultancy; Takeda: Consultancy; Gilead: Consultancy, Research Funding. Goy:Acerta: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Takeda: 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, Research Funding, Speakers Bureau; Pharmacyclics/J&J: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Hackensack University Medical Center: Employment; Kite/Gilead: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Genentech: Research Funding; Seattle Genetics: Research Funding; COTA: Membership on an entity's Board of Directors or advisory committees. Hill:Abbvie: Honoraria, Membership on an entity's Board of Directors or advisory committees; Genentech: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Amgen: Research Funding; Seattle Genetics: Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees; Pharmacyclics: Honoraria, Membership on an entity's Board of Directors or advisory committees; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees; Pharmacyclics: Honoraria, Membership on an entity's Board of Directors or advisory committees; Abbvie: Honoraria, Membership on an entity's Board of Directors or advisory committees; Seattle Genetics: Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees. Follows:Gilead, Janssen, Roche, Abbvie, Takeda, BMS: Membership on an entity's Board of Directors or advisory committees. Jaeger:Gilead: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; AbbVie: Consultancy, Honoraria; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding; AOP Orphan: Membership on an entity's Board of Directors or advisory committees; Amgen: Membership on an entity's Board of Directors or advisory committees; GSK: 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; Mundipharma: Membership on an entity's Board of Directors or advisory committees; Takeda-Millenium: Membership on an entity's Board of Directors or advisory committees; Takeda-Millenium: Membership on an entity's Board of Directors or advisory committees; Infinity: Membership on an entity's Board of Directors or advisory committees; Bioverativ: Membership on an entity's Board of Directors or advisory committees; MSD: Research Funding. Kuruvilla:Gilead: Consultancy, Honoraria; Seattle Genetics: Consultancy, Honoraria; Karyopharm: Honoraria; Roche: Consultancy, Honoraria, Research Funding; BMS: Consultancy, Honoraria; Princess Margaret Cancer Foundation: Research Funding; Janssen: Consultancy, Honoraria, Research Funding; Abbvie: Consultancy; Merck: Consultancy, Honoraria; Celgene: Honoraria; Amgen: Honoraria; Lundbeck: Honoraria; Leukemia and Lymphoma Society Canada: Research Funding. Caimi:Kite Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees; ADC Therapeutics: Research Funding; Genentech: Membership on an entity's Board of Directors or advisory committees; Celgene: Speakers Bureau. Matczak:Karyopharm Therpeutics: Employment. Ma:Karyopharm Therapeutics: Employment. Saint-Martin:Karyopharm Therapeutics: Employment. Shah:Karyopharm Therapeutics: Employment. Kauffman:Karyopharm Therapeutics: Employment, Equity Ownership, Membership on an entity's Board of Directors or advisory committees. Shacham:Karyopharm Therapeutics: Employment, Equity Ownership, Membership on an entity's Board of Directors or advisory committees.

Background. Combined modality treatment (CMT) consisting of two cycles of ABVD (doxorubicin, bleomycin, vinblastine, dacarbazine) and 20 Gy of involved-field radiotherapy (IFRT) is widely accepted standard of care for early-stage favorable Hodgkin lymphoma (HL). Recent clinical research suggests that metabolic response assessment after two cycles of chemotherapy using FDG-PET (PET-2) can predict the individual outcome and PET-2 negativity might allow reducing the overall treatment intensity. Aims. We assessed whether omitting consolidating radiotherapy in patients with negative PET-2 is feasible without loss of efficacy as determined by progression-free survival (PFS). Furthermore, we analyzed the prognostic impact of PET-2 among patients receiving CMT. Methods. Between November 2009 and December 2015, we recruited patients with newly diagnosed, early-stage favorable HL aged 18-75 years from Germany, Switzerland, Austria, and the Netherlands for this double-blind, randomized, parallel-group phase 3 trial. Patients were randomly assigned to receive standard CMT with 2x ABVD and 20 Gy IFRT or PET-guided treatment, whereby IFRT was restricted to those patients with a positive PET after 2xABVD. PET-2 was centrally assessed by a panel blinded towards the randomization result, with FDG uptake not higher than the mediastinal blood pool (i.e., Deauville score 1-2) defined as negative. The trial was designed to exclude inferiority of 10% or more in 5-year PFS of ABVD only compared with CMT in a per-protocol analysis among PET-negative patients, corresponding to a non-inferiority margin of 3.01 for the hazard ratio, and to detect a 5-year PFS difference of 5% or more between PET-2-positive and -negative patients receiving CMT, each with 80% power. Results. A total of 1150 patients were enrolled; 628 patients with negative PET-2 were eligible for the per-protocol non-inferiority analysis and were treated with CMT (n=328) or ABVD alone (n=300). With a median follow-up of 47 months, the estimated 5-year PFS was 93.4% (90.4-96.5) with CMT and 86.1% (81.4-90.9) with chemotherapy only (difference 7.3%, 95% CI 1.6%-13.0%). The hazard ratio was 1.78 with a 95% CI ranging from 1.02 to 3.12, including the non-inferiority margin of 3.01. The PFS difference primarily resulted from a significant increase in disease recurrences with in-field recurrence rates of 2.1% vs. 8.7% (p=0.0003); there was no relevant difference regarding out-field recurrences (3.7% vs. 4.7%, p=0.55). Estimated 5-year overall survival in the per-protocol population was 98.1% (96.5-99.8) with CMT and 98.4% (96.5-100.0) with ABVD. 693 patients assigned to receive CMT were eligible for the analysis of the PET objective and had a negative (n=353) or positive (n=340) PET-2. With a median follow-up of 46 months, estimated 5-year PFS was 93.2% (90.2-96.2) among PET-2-negative and 88.1% (83.8-92.3) among PET-2-positive patients (p=0.035). When using the more common liver cutoff (Deauville score 4) for the definition of PET-2 positivity, the difference was more pronounced (5-year PFS 93.1% [90.7%-95.5%] vs. 80.1% [71.2%-88.9%], p=0.0004). Conclusion. In early-stage favorable HL, radiotherapy cannot be safely omitted from standard CMT without a clinically relevant loss of tumor control in patients with negative PET-2. PET positivity after 2xABVD represents a risk factor for PFS in HL patients treated with standard CMT, particularly when a Deauville score of 4 is considered as cutoff for positivity. Disclosures Greil: Takeda: 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; Astra Zeneca: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Merck: Honoraria, Research Funding; Abbvie: Consultancy, Membership on an entity's Board of Directors or advisory committees; Janssen: Other: TRAVEL, ACCOMMODATIONS, EXPENSES; Amgen: Honoraria, Other: TRAVEL, ACCOMMODATIONS, EXPENSES, Research Funding; Sandoz: Honoraria, Research Funding; MSD: Honoraria, 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; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. von Tresckow:MSD: Honoraria, Other: Travel support, Research Funding; Novartis: Honoraria, Other: Travel support, Research Funding; Takeda: Honoraria, Other: Travel support, Research Funding. Borchmann:Novartis: Consultancy, Honoraria.

We evaluated the role of rituximab during remission induction chemotherapy in relapsed aggressive CD20+ non-Hodgkin lymphoma. Of 239 patients, 225 were evaluable for analysis. Randomized to DHAP (cisplatin-cytarabine-dexamethasone)-VIM (etoposide-ifosfamide-methotrexate)-DHAP (cisplatin-cytarabine-dexamethasone) chemotherapy with rituximab (R; R-DHAP arm) were 119 patients (113 evaluable) and to chemotherapy without rituximab (DHAP arm) 120 patients (112 evaluable). Patients in complete remission (CR) and partial remission (PR) after 2 chemotherapy courses were eligible for autologous stem-cell transplantation. After the second chemotherapy cycle, 75% of the patients in the R-DHAP arm had responsive disease (CR or PR) versus 54% in the DHAP arm (P = .01). With a median follow-up of 24 months, there was a significant difference in failure-free survival (FFS24; 50% vs 24% vs, P < .001), and progression free survival (PFS24; 52% vs 31% P < .002) in favor of the R-DHAP arm. Cox-regression analysis demonstrated a significant effect of rituximab treatment on FFS24 (HR 0.41, 95% confidence interval [CI] 0.29-0.57 versus 0.51, 95% CI 0.37-0.70) and overall-survival (OS24: HR 0.60 [0.41-0.89] vs 0.76 [0.52-1.10]) when adjusted for time since upfront treatment, age, World Health Organization performance status, and secondary age-adjusted international prognostic index. These results demonstrate improved FFS and PFS for relapsed aggressive B-cell NHL if rituximab is added to the re-induction chemotherapy regimen.

In this issue of Blood, Barrington et al present the analyses of centrally reviewed positron emission tomography-computed tomography (PET-CT) used for staging and response monitoring after 2 cycles of doxorubicin, bleomycin, vinblastine, dacarbazine (ABVD) to guide treatment modification in a large prospective clinical trial in Hodgkin lymphoma (HL) (Response-Adapted Therapy in Advanced Hodgkin Lymphoma [RATHL]).

Background: In our GHSG HD18 study for patients with newly diagnosed advanced-stage Hodgkin's lymphoma (HL), we used early interim positron emission tomography after 2 cycles of eBEACOPP (PET-2) to guide further treatment. In contrast to other groups, we defined a Deauville score at interim staging (iDS) ≥ 3 as positive. The prognostic impact of PET-2 in the context of eBEACOPP was and still is unclear, however. We thus investigated its association with baseline characteristics and treatment outcome in patients treated with eBEACOPP in our international phase 3 HD18 trial (NCT00515554). Methods: We recruited 2101 patients aged 18-60 years between 05/2008 and 07/2014. All patients received 2xeBEACOPP followed by centrally assessed PET-2, determining the iDS ranging from 1 (no FDG uptake) to 4 (FDG uptake above liver). Before 06/2011, patients were randomized 1:1 between 8xeBEACOPP and experimental treatment depending on iDS. After 06/2011, patients with iDS 1-2 were randomized 1:1 between 6xeBEACOPP and 4xeBEACOPP treatment, while all patients with iDS 3-4 received 6xeBEACOPP. Radiotherapy was recommended in case of residual lesions with DS ≥ 3 (until 04/2014)/ DS 4 (after 04/2014) after chemotherapy. We explored the association of iDS with baseline characteristics, and assessed treatment outcomes according to iDS among patients treated with 6xeBEACOPP within our trial after 06/2011, considering different cutoffs for positivity. We applied means of descriptive statistics, Fisher's exact test and multivariate logistic regression, and analyzed survival outcomes according to Kaplan-Meier, using Cox regression for comparisons. Findings: Among 1945 randomized patients, 1005 (52%), 471 (24%) and 469 (24%) had iDS 1-2, 3 and 4, respectively, according to central review of PET-2. Many clinical risk factors were associated with an unfavorable iDS, including adverse performance status, high international prognostic score (IPS) and the presence of large mediastinal mass (LMM), extranodal disease, 3 or more nodal areas and elevated ESR. Since patients with clinical stage (CS) IIB were only qualified for the trial when presenting with a large mediastinal mass, they had a high iDS more often than patients with CS III or IV or without B symptoms. Accordingly, in a multivariate analysis including all factors with univariate p After 06/2011, 216 patients with iDS 1-2 and all 506 patients with iDS 3-4 were assigned to receive 6xeBEACOPP. Among those 722 patients, PET after chemotherapy due to the presence of residual lesions was done in 83 (38%), 204 (76%) and 188 (80%) of patients with iDS of 1-2, 3, and 4, respectively, and FDG uptake above the liver (DS4) was observed in 3 (1%), 19 (7%) and 73 (31%), respectively (p Conclusion: The Deauville score after 2xeBEACOPP is associated with many clinical risk factors at baseline. For patients treated with 6xeBEACOPP followed by irradiation of PET-positive residuals, iDS 3 does not indicate an increased risk of treatment failure and is associated with long-term outcomes identical to those after clearly negative PET-2 (iDS 1-2). DS 4 at PET-2 adds some prognostic information to the baseline risk factors, but 3-year outcomes do not suggest a need for treatment intensification beyond standard therapy. Based on these results, the GHSG has decided to adopt the more widely used cutoff of iDS 4 for PET positivity. Thereby, about 75% of patients could take advantage of the abbreviated treatment with only 4 cycles of eBEACOPP in a PET-2-guided approach as defined in the HD18 study. Figure 1 Figure 1. Disclosures Borchmann: Novartis Pharmaceuticals Corporation: Honoraria. Greil: Takeda: Honoraria, Research Funding; Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: travel support, Research Funding; Novartis, Celgene: Research Funding; BMS, Amgen: Honoraria. Meissner: Takeda: Other: Non-Financial Support; BMS: Other: Non-Financial Support; Celgene: Other: Non-Financial Support; Amgen: Other: Non-Financial Support. Krause: Novartis: Honoraria. Engert: Affimed: Consultancy, Research Funding; Amgen: Consultancy, Research Funding; Bristol-Meyers Squibb: Consultancy, Research Funding; Takeda Oncology: Consultancy, Research Funding.

Introduction. The standard first-line treatment of young and fit mantle cell lymphoma (MCL) patients consists of a rituximab containing induction of CHOP and high dose ARA-C, followed by high dose consolidation and autologous stem cell transplant (ASCT). Thus far, almost all patients relapse after ASCT. Bortezomib is a proteasome inhibitor with activity in MCL. We investigated in a randomized phase II study whether there was any indication that maintenance therapy with bortezomib after ASCT could improve the outcome of treatment, measured as event free survival (EFS). Methods. Patients 18-65 years with newly diagnosed MCL were treated with 3 cycles of R-CHOP and 2 cycles of ARA-C (2 x 2 g/m2 iv d1-4) and rituximab (375 mg/m2, iv d11). Patients in PR or CR continued with ASCT after BEAM conditioning. Patients with a PR or CR after ASCT, with a neutrophil count > 0.5 x 109/l and platelets > 80 x 109/l were randomized between bortezomib and no further treatment. Bortezomib 1.3 mg/m2 iv was given once every two weeks, for 2 years, starting between 6 - 12 weeks after transplantation. Results . Between October 2007 and February 2012, 140 patients aged 34-66 years (median 57) were registered. Five patients were not eligible. The MIPI score was low, intermediate, high or unknown in 57%, 32%, 10% and 1% respectively. All eligible patients started induction treatment with R-CHOP. Two patients did not receive the first ARA-C cycle, because of progressive disease and physician decision. Hundred-fifteen patients (85%) received the BEAM and ASCT. Reasons to stop protocol treatment before ASCT were: progressive disease (PD) (n=6), inadequate stem cell harvest (n=3), excessive toxicity (n=3), other reasons (n=8). The response after ASCT was CR/CRu in 99 patients (86%), PR in 15 (13%), unknown in 1 (1%). Only 62 patients (45%), aged 34-65 years (median 56) were randomized between bortezomib maintenance and no further treatment. Two patients were randomized, but not eligible. Reasons for no randomization were: not eligible (n=30), patient refusal (n=14), excessive toxicity (n=2, and other reasons (n=7). In each treatment arm 30 patients were included. The patient characteristics were well balanced, except the MIPI score. In the no maintenance arm 21 patients (70%) had a low MIPI, compared to 15 patients (50%) in the bortezomib arm, and 6 (20%) versus 11 (37%) patients had an intermediate MIPI score. In both arms 3 patients (10%) had a high MIPI. Fifteen patients (50%) in the maintenance group continued bortezomib for 2 years. Reasons to stop earlier were excessive toxicity (n=6), PD/relapse (n=4), patients refusal (n=3) and other (n=2). The main adverse events during maintenance therapy were neurologic (CTC grade 2: 14%, grade 3: 4%), and infectious (grade 2: 11%, grade 3: 7%). Three patients developed a secondary malignancy: a basal cell carcinoma in the no maintenance group, a melanoma and a prostate carcinoma in the bortezomib group. With a median follow-up of the patients still alive of 50.9 months EFS at 4 years for all patients is 61%, and the overall survival (OS) 78%. The median follow-up of the randomized patients still alive is 42.9 months. The EFS at 4 years is 72% without maintenance versus 71% in the patients randomized for bortezomib maintenance. The OS at 4 years also shows no significant difference between the groups, 90% versus 93% respectively. Conclusion. There is no indication that bortezomib iv maintenance in a frequency of once every 2 weeks does improve the EFS of newly diagnosed MCL patients after intensive induction treatment with R-CHOP, double ARA-C and BEAM followed by ASCT. Figure 1. Figure 1. Figure 2. Figure 2. Disclosures Doorduijn: Celgene: Consultancy; Janssen: Consultancy; Roche: Consultancy. Off Label Use: bortezomib maintenance in MCL. Minnema:Celgene: Consultancy; Jansen Cilag: Consultancy; Amgen: Consultancy. Kersten:janssen: Honoraria, Research Funding; takeda millennium: Research Funding; roche: Honoraria, Research Funding. Lugtenburg:Mundipharma: Consultancy; Servier: Consultancy; Janssen-Cilag: Consultancy; Celgene: Consultancy; Roche: Consultancy. Schipperus:Novartis: Consultancy. Zijlstra:Celgene: Consultancy; Roche: Consultancy.

Background: Primary progressive disease still remains an unmet medical need in Hodgkin Lymphoma (HL). Due to missing data on treatment effects and survival there is no established standard of care. We thus performed a retrospective analysis using the German Hodgkin Study Group (GHSG) database to improve the knowledge on the course of primary progressive HL patients. Methods: Patients aged between 18 and 60 years treated within the GHSG first-line trials HD13-HD15 were screened for primary progressive HL. Primary progression was defined as progressive disease during ongoing therapy, within 3 months after the end of treatment, or up to 6 months after the end of treatment in patients with partial response or stable disease in the final restaging. We investigated types and outcome of second-line treatment approaches and overall survival, which was calculated from first diagnosis of HL (OS) and from diagnosis of first progression or relapse (OSp). Results: We analyzed 5,126 patients, of whom 112 (2.2%) were identified with primary progressive disease. Of those, 62 (55%) patients had initially been treated for advanced-stage HL with BEACOPP (bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, and prednisone) variants, 30 (27%) for early-stage unfavorable HL with ABVD (doxorubicin, bleomycin, vinblastine, and dacarbazine)- or BEACOPP-like regimens (24 and 6 patients, respectively) and 20 (18%) for early-stage favorable HL with ABVD variants. The median age at the time of progression was 33 years. 3 patients (3%) died before a salvage therapy was started. Second-line treatment strategies included reinduction with intensified salvage regimens (77%), conventional chemotherapy (14%), and radiotherapy (8%). Autologous stem cell transplantation (ASCT) was performed in 76% of the patients who had received intensified reinduction chemotherapy, and allogeneic stem cell transplantation in ten (9%) patients. After the first salvage therapy, 42% of all patients achieved a complete remission (CR) and did not require further treatment. In total, 66% of the patient cohort achieved a CR after one or more second-line approaches. Median duration of the first CR was 61 months. After a median observation time of 7 years, 55 of the patients with primary progressive disease (49%) had died, mostly from progressive or relapsed HL (n=36) or toxicity of salvage treatment (n=10). The majority of the 57 survivors was in CR at the time of analysis; 2 were under treatment for HL and there was no information available for one patient. Median OSp for the entire cohort was 83 months, 5-year OSp was 55.4% (95%-CI, 46% to 65%). Since OSp differed among patients of different initial stages and types of pre-treatment (early-stage favorable and unfavorable patients treated with ABVD variants, OSp 74.2% [61%-87%] vs. higher-stage patients treated with BEACOPP variants, OSp 42.9% [31% - 55%]), treatment groups were analyzed for survival separately. In both groups, patients responding to the first salvage therapy had a significantly better OSp compared to those not responding (each p Conclusion: Overall, the 5-year OSp in this unselected patient cohort of primary progressive HL patients is encouraging and supports the use of aggressive salvage regimens and consolidating high-dose chemotherapy in general. However, this approach is known to induce severe long-term toxicities and has limited efficacy in patients failing first-line treatment for advanced stage disease. We conclude that there is a need to develop different treatment approaches in primary progressive HL patients. Disclosures von Tresckow: Novartis: Consultancy, Other: Travel and accomodation, Research Funding; Amgen: Other: honoraria for preparation of scientific educational events; Celgene: Other: honoraria for preparation of scientific educational events; Takeda: Consultancy. Zijlstra:Celgene: Consultancy; Roche: Consultancy. Topp:Astra: Consultancy; Regeneron: Consultancy; Affimed: Consultancy, Research Funding; Roche: Consultancy, Other: Travel Support; Jazz: Consultancy; Pfizer: Consultancy; Amgen: Consultancy, Honoraria, Other: Travel Support. Engert:Takeda: Consultancy, Research Funding. Borchmann:Millennium: Research Funding.

Background: Patients with relapsed/ refractory diffuse large B-cell lymphoma (DLBCL) after- or not eligible for autologous stem cell transplantation (ASCT) have a poor prognosis. Treatment with salvage chemotherapy has generally been disappointing. In many centers in the Netherlands the oral PECC regimen is used for such patients. 90Y-ibritumomab tiuxetan (Zevalin®, Spectrum Pharmaceuticals) radioimmunotherapy (RIT) is clinically active as a single agent in relapsed DLBCL. We conducted a prospective multi-center phase II study evaluating salvage therapy with Rituximab (R)-PECC, in responsive patients followed by 90Y-ibritumomab tiuxetan consolidation. Methods: Adult patients with refractory/relapsed DLBCL, more than one year after or not eligible for ASCT, were treated with R-PECC (Prednisone 40 mg/m2 po D1-5; Etoposide 100 mg/m2 po D1-5; Chlorambucil 8 mg/m2 po D1-5; Lomustine 80 mg/m2 po D1 and Rituximab 375 mg/m2 iv D1) q 28 days for 4 cycles. Complete (CR) or partial responders (PR) received consolidation with a single dose 90Y-ibritumomab tiuxetan (15 MBq/kg, 0.4 mCi/kg). Response was evaluated according to the revised Cheson criteria (2007). Results: Between November 2008 and February 2012 62 patients were enrolled. Median age was 70 years (range, 45-82). Secondary IPI score was high-intermediate or high in 42% patients. All patients had received CHOP at first-line, 12 without rituximab. Prior therapies consisted of (R)-CHOP (65%), R-CHOP and R-DHAP/VIM (24%) or R-CHOP and R-DHAP/VIM plus ASCT (11%). Fourteen patients (23%) were refractory to the last prior therapy. After 4 cycles of R-PECC the overall response rate (ORR) was 31/62 (50%), with 14 of 62 (23%) patients achieving a CR and 17 of 62 (27%) achieving a PR, 13 of 62 (21%) patients had progressive disease. ORR of relapsed patients was significantly higher than that of patients refractory to their last prior treatment (63% vs 7%, p=0.0001). 29 of 31 responsive patients received consolidation with RIT. The remaining two patients with PR did not proceed to RIT because of one toxic death and one misinterpretation of the response. The ORR after the end of the entire treatment was 29% (23% CR, 6% PR), RIT consolidation improved the overall best response (from PR to CR) in 5 of the 17 PR pts after the R-PECC only regimen. The median follow-up time of patients still alive is 48 months (range, 0-67 months). The median response duration in the patients that received R-PECC only was 9 months (range 3-63 months). The median response duration in the patients that received RIT consolidation was 20 months (range 0-59 months). The failure free survival at 1 yr from start of RIT consolidation was 52% (95% CI=[33%,68%]) and the overall survival 62% (95% CI=[42%,77%]). There was one treatment related death, due to sepsis and pneumonia after the first R-PECC cycle. The R-PECC regimen was well tolerated by most patients. The most common grade 3 or 4 adverse events during R-PECC treatment were hematological toxicity (27%), infection (19%) and malaise (11%). Adverse events after RIT were primarily hematologic. Grade 3 to 4 trombocytopenia and neutropenia occurred in 8 patients (28%) and 5 patients (17%), respectively. Eight patients received platelet transfusions and 6 patients red blood cell transfusions. Conclusions: The R-PECC regimen shows good clinical activity in relapsed DLBCL patients. Its activity in refractory patients is low. This largely oral regimen provides patients not eligible for high-dose salvage treatment with a convenient treatment schedule with an acceptable safety profile. Consolidation with RIT was well tolerated and resulted in long response durations in half of the patients. Disclosures Lugtenburg: Mundipharma: Consultancy; Servier: Consultancy; Janssen-Cilag: Consultancy; Roche: Consultancy; Celgene: Consultancy. Off Label Use: 90Ytrium-ibritumomab tiuxetan for diffuse large B-cell lymphoma. Zijlstra:Celgene: Consultancy; Roche: Consultancy. Doorduijn:Celgene: Consultancy; Janssen: Consultancy; Roche: Consultancy. Hoogendoorn:Gilead: Consultancy; Novartis: Consultancy.

Introduction Autologous stem cell transplantation (AuSCT) is widely used in patients with histologic transformation of indolent lymphoma. Although probably superior to standard chemotherapy, there is still room for improvement. We are currently studying the effect of the addition of 90Yttrium ibritumomab tiuxetan (Zevalin) to BEAM conditioning followed by an AuSCT on survival in a prospective phase 2 trial. It is known that, after rituximab-BEAM-AuSCT, recovery of T cells occurs after 4 months and of B cells after 9 months, with normal levels only being reached after 1 and 2 years, respectively. (1,2) It is however unclear if, in patients uniformly pre-treated with rituximab-chemotherapy, followed by BEAM and AuSCT, the addition of Zevalin further hampers immune reconstitution. Materials and methods Patients (n=14) with histologically proven transformed lymphoma were included in this prospective phase 2 trial when conditioning for AuSCT was started. AuSCT was planned when CR or PR was reached after (re)induction containing a minimum of 6 courses of rituximab (375 mg/m2) and chemotherapy. Patients subsequently received pre-doses of rituximab on day -15 and -8 (250 mg/m2), Zevalin on day -8 (0.4 mCi/kg) and BEAM conditioning on day -7 to -1, followed by AuSCT at day 0. Blood samples were taken before the first predose of rituximab (day -15,t=0) and 3-6, 12-18 and 24-30 months after AuSCT. Absolute neutrophils were counted and samples were analyzed for NK-, B- and T-cell subsets using multicolor flowcytometry. T cells were defined using CD3 combined with either CD4 or CD8. NK cells were defined as CD45+, CD3-, CD56+ and/or CD16+, B cells as CD45+, CD3-, CD19+, memory B cells CD19+,CD27+. Recovery was defined as: Neutrophils > 0.5 x 109/l, CD19+ B cells >0,07 x 109/l (CD27+ B cells >0,03 x 109/l) CD4>0,4 x 109/l,CD8>0,13 x 109/l, NK cell > 0,08 x 109/l. (1,2) All infections after neutrophil recovery following AuSCT were registered. IgG levels were measured at baseline and after 2 years. Results A median of 3 (range 1-4) measurements were obtained depending on length of follow up. The median follow up was 26 months (range 3-30 months). Median time to neutrophil recovery was 22 days after AuSCT (range 17-29 days). As expected, patients were already severely B-cell depleted at start of consolidation (t=0, figure 1).B cells started to appear after nine months and reached (low) normal values after 12-18 months. T cell and NK cell recovery started after 3 months and took one year to normalize. (figure 1) All patients had IgG levels >5 g/l after AuSCT, without support. Only three infectious episodes were reported in 14 patients. In one patient an episode of herpes simplex virus infection with diarrhea was reported two months after AuSCT. In another patient a pneumonia was diagnosed two months after recovery from AuSCT (cultures stayed negative). Both had enough neutrophils but B cells and CD4 cells were not yet recovered. Both patients recovered completely after antiviral and empirical antibiotic and antimycotic therapy, respectively. One patient developed a herpes zoster virus infection at 2 years after AuSCT, recovering completely after antiviral therapy. Conclusion Compared to figures reported in literature (1,2), the addition of Zevalin to consolidation with BEAM and AuSCT after (re)induction with R-chemotherapy does not seem to lead to an increase of infectious complications or delayed immune-reconstitution as analyzed by T cell, B cell and NK cell recovery. References Kasamon YL, Jones RJ, Brodsky RA, Fuchs EJ, Matsui W, Luznik L, Powell D, Blackford AL, Goodrich A, Gocke CD, Abrams RA, Amvinder RF, Flinn IW. Immunologic recovery following autologous stem-cell transplantation with pre-and posttransplantation rituximab for low-grade or mantle cell lymphoma. Ann Oncol 2009: 1-8 van der Velden AMT, Claessen AME, van Velzen-Blad H, de Groot MR, Kramer MHH, Biesma DH, Rijkers GT. Vaccination responses and lymphocyte subsets after autologous stem cell transplantation.Vaccine 2007:8512-8517 Figure 1 Figure 1. Disclosures Wondergem: spectrum pharmaceuticals: Research Funding. Visser:spectrum pharmaceuticals: Research Funding.

Abstract 2729 Background. Patients with relapsed or refractory diffuse large B-cell lymphoma (DLBCL) after- or not eligible for autologous stem cell transplantation (ASCT) have a poor prognosis. The optimum salvage therapy for these patients is not known. Treatment results with second-line chemotherapy have generally been disappointing. In some centers in the Netherlands PECC (Prednisone, Etoposide, Chlorambucil and Lomustine) combination chemotherapy is used as salvage treatment for such patients. PECC is a completely oral schedule. The efficacy and toxicity of PECC in this patient category has not been evaluated systematically before. 90Y-ibritumomab tiuxetan (Zevalin®) showed clinical activity as a single agent in relapsed DLBCL. We conducted a prospective multi-center phase II study evaluating induction therapy with Rituximab (R)-PECC followed in responsive patients by 90Y-ibritumomab tiuxetan consolidation. Methods. Patients aged ≥ 18 years with refractory CD20 positive DLBCL or first or second relapse, more than one year after or not eligible for ASCT, were enrolled. Treatment consisted of R-PECC (Prednisone 40 mg/m2 po D1–5; Etoposide 100 mg/m2 po D1–5; Chlorambucil 8 mg/m2 po D1–5; Lomustine 80 mg/m2 po D1 and Rituximab 375 mg/m2 iv D1), every 28 days for 4 cycles. Patients with progressive disease after 2 cycles went off protocol. Patients in complete or partial remission after 4 cycles received consolidation treatment with 90Y-ibritumomab tiuxetan at the standard single dose of 15 MBq/kg (0.4 mCi/kg) 6 to 12 weeks after start of the last R-PECC cycle. Response to treatment was evaluated according to the revised 2007 Cheson criteria. Results. Between November 2008 and February 2012 64 patients were enrolled. We report preliminary data for the first 50 patients evaluable for response and toxicity after the induction treatment with R-PECC. The median age was 70 years (range, 45–82) and median time since first diagnosis was 17 months (range 3–172). All patients had been treated with CHOP as first-line treatment and 8 patients (16%) had not been exposed to rituximab at first-line. Prior therapies consisted of (R)-CHOP (72%), R-CHOP and R-DHAP/VIM (16%) or R-CHOP and R-DHAP/VIM plus ASCT (12%). Eleven patients (22%) were refractory to their last prior systemic therapy. According to the secondary IPI, 26%, 28%, 34% and 8% of the patients belonged to the low-, low-intermediate-, high-intermediate-, and high risk group, respectively. Median relative dose intensities for the myelosuppressive agents of the PECC regimen were 93.7% (90% CI = 62.8–106.9%), 94.3% (90% CI = 71.6–104.7%) and 97.4% (90% CI 76.0–104.7%) for Lomustin, Etoposide and Chlorambucil, respectively. Progressive disease occurred in 14 patients (28%). Overall response rate (ORR) after induction treatment was 52%, including 34% complete response and 18% partial response. ORR of relapsed patients was significantly higher than that of patients refractory to their last prior treatment (64% vs. 9%, p=0.099). Patients more than one year from start of upfront treatment had a significant higher ORR than that of patients less than one year from start of upfront treatment (81% vs 21%, p=0.005). Median response duration was 13 months. One patient died because of treatment related toxicity due to sepsis and pneumonia after the first R-PECC cycle. The most common grade 3 or 4 adverse event was haematological toxicity (42%), followed by infection (14%), malaise (13%) and gastro-intestinal toxicity (6%). Eighteen serious adverse events (SAEs) occurred in 14 patients, 14 of the SAEs were possibly related to treatment (mainly hospitalisations because of infections). Approximately half of the patients (46%) have entered the 90Y-ibritumomab tiuxetan consolidation phase of the study. Conclusions. The R-PECC regimen shows good clinical activity in relapsed DLBCL patients. Its activity in refractory patients is low. This largely oral regimen provides patients not eligible for high-dose salvage treatment with a convenient treatment schedule with an acceptable safety profile. Disclosures: Off Label Use: 90Y-ibritumomab tiuxetan is not registered for DLBCL.

Abstract 3658 Introduction Patients (pts) with transformed NHL have an extremely poor prognosis. However when diagnosed at an early stage outcome may be better, making early diagnosis crucial. Nowadays, transformation is diagnosed using biopsy of a lymph node when it starts growing rapidly or when the patient develops B symptoms or hypercalcemia. These pts often have advanced disease and diagnosis may be delayed because the lymph node biopsied is not representative. Positron emission tomography (PET) might be of value here: the commonly used tracer 18F-fluorodeoxyclucose (FDG)-PET can distinguish between indolent and aggressive lymphoma, but with considerable overlap in Standard Uptake Values (SUV). However, 18F-fluorothymidine (FLT) is thought to more directly reflect proliferation. We performed a head-to-head comparison of FDG and FLT PET in pts with indolent and transformed lymphoma to explore which tracer qualifies best for future research in timely diagnosis of transformation. Materials and methods Pts were selected based on histology: either follicular lymphoma or transformed lymphoma (defined as diffuse large B cell lymphoma diagnosed in a patient with former or simultaneous diagnosis of follicular lymphoma in a lymph node).In each patient two PET scans were made, one with FDG and one with FLT, maximum one week apart, before any treatment.Scans were made on the Philips Gemini TF PET-CT camera, 1 hour after injection of 185 MBq of FDG or FLT.Uptake (we present data as SUVmax normalized to body weight) was measured in all lymph nodes ≥ 2 cm (minimizing partial volume effects). Results 17 pts with indolent lymphoma and 10 with transformed lymphoma were included. Median age was 59 years (range 35–81) and a median of 9 lymph nodes were measured per patient (range 2–23). Between patients, SUVmax in the lymph node with the highest uptake for both FDG (p=0.01) as well as FLT (p=0.04) uptake was significantly higher in transformed lymphoma. For FDG values ranged from 4,9 to 19,6 in indolent and from 9,6 to 29,9 in transformed lymphoma, for FLT values were respectively 3,6 to 16,6 and 5,45 to 16,3. Accordingly, between patients, we found considerable overlap between highest values for indolent and transformed lymphoma with either tracer, making the determination of a cut off level for transformation difficult. The data suggest that, at least for FDG, the range between the lymph node with the highest and the lowest uptake within one patient was the best criterium to identify the transformed lymphomas, with significantly higher ranges for transformed lymphoma (p Conclusion Uptake of both FDG and FLT are significantly higher in transformed lymphoma than in indolent lymphoma. However, FDG-PET may better distinguish between indolent and transformed lymphoma. For further research, intrapatient heterogeneity of FDG uptake qualifies as a potential marker of transformation, ultimately to facilitate timely diagnosis of transformation and improved patient outcome. Disclosures: No relevant conflicts of interest to declare.

Abstract 589FN2 Purpose: Intensified chemotherapy with eight cycles of BEACOPPescalated in advanced stage Hodgkin lymphoma (HL) is highly effective but also associated with relevant treatment related toxicity. In addition, the need for radiotherapy in this setting is unclear. To reduce toxicity without losing efficacy the German Hodgkin Study Group thus conducted the prospective randomized clinical HD15 trial investigating two less intensive chemotherapy variants, followed by positron emission tomography (PET) guided radiotherapy. Methods: Between January 2003 and April 2008, 2182 patients with newly diagnosed, histology-proven HL aged 18–60 years were included. Patients in Ann-Arbor stage IIB with large mediastinal mass or extranodal lesions, or those in stage III or IV were randomly assigned to receive either eight cycles of BEACOPPescalated (8Besc), six cycles of BEACOPPescalated (6Besc), or eight cycles of BEACOPP14 (8B14). After completion of chemotherapy, patients in partial response (PR) with a persistent mass measuring 2.5 cm or more were assessed by PET. Only patients who were positive on centrally-reviewed PET scan received additional radiotherapy (RT) with 30Gy. The study was designed to show non-inferiority for the primary endpoint, freedom from treatment failure (FFTF). Other endpoints included overall survival, tumor response, side effects of treatment and progression-free survival (PFS) after PET. Results: The full analysis set comprised 2126 patients, 705 with 8Besc, 711 with 6Besc and 710 with 8B14. Baseline characteristics were balanced between groups with a median age of 33 years and 334 patients (15.7%) in stage II disease. 682 patients (32.1%) had an International Prognostic Score (IPS) of 0–1, 1115 (52.4%) of 2–3, and 329 (15.5%) of 4–7. Hematological toxicities occurred in 92.4% (8Besc), 91.7% (6Besc), and 79.7% (8B14) of cases. After a median follow-up of 48 months, there were 53 deaths (7.5%) in the 8Besc group, 33 (4.6%) in the 6Besc group and 37 (5.2%) in the 8B14 group. The higher number of deaths in the 8Besc group mainly resulted from acute toxicity of chemotherapy (15 vs. 6 vs. 6) and secondary neoplasms (13 vs. 5 vs. 8). There were 72 secondary cancers including 29 secondary acute myeloid leukemias and myelodysplastic syndroms, 19 (2.7%) after 8Besc, 2 (0.3%) after 6Besc and 8 (1.1%) after 8B14. Complete response (CR) was achieved in 90.1% of patients after 8Besc, in 94.2% after 6Besc and in 92.4% after 8B14 (p=0.01). FFTF at 5 years was 84.4% in the 8Besc group, 89.3% in the 6Besc group (97.5% confidence interval (CI) for difference 0.5% to 9.3%), and 85.4% in the 8B14 group (97.5 CI −3.7% to 5.8%), respectively (see figure). Accounting for planned interim analyses, both 97.5 repeated CIs for the hazard ratio excluded the non-inferiority margin of 1.51 (8Besc vs. 6Besc, 0.44 to 1.02; 8Besc vs. 8B14, 0.62 to 1.36). Overall survival at five years was 91.9%, 95.3%, and 94.5%, and was also better with 6Besc compared to 8Besc (97.5% CI 0.2% to 6.5%). PFS results were similar to FFTF. Per-protocol and subgroup analyses supported the primary analysis. PET scans performed after chemotherapy were centrally reviewed in 822 patients of whom 739 were in PR with residual mass ≥ 2.5 cm having no other exclusion criteria. 548 patients were PET-negative (74.2%) and 191 were PET-positive (25.8%). Importantly, PFS was comparable between patients in CR or those in PET-negative PR after chemotherapy with 4-year PFS rates of 92.6% and 92.1%, respectively. Only 11% of all patients in HD15 received additional RT as compared to 71% in the prior HD9 study. Conclusion: Six cycles of BEACOPPescalated followed by PET-guided RT are more effective and less toxic compared to 8 cycles in patients with advanced stage HL. In particular, critical toxicities observed with 8 cycles where reduced with 6 cycles of BEACOPPescalated. PET performed after chemotherapy can guide the need of additional RT in this setting and reduces the number of patients requiring RT. Disclosures: No relevant conflicts of interest to declare.

Abstract 765 Purpose: Combined modality treatment consisting of 4 cycles of chemotherapy and IF-RT is the standard treatment for early unfavorable HL. Overall survival (OS) and freedom from treatment failure (FFTF) at 5 years in this group of patients was 91% and 83%, respectively, in our prior HD8 study. Thus, the rationale for HD14 was to improve on these results by increasing dose intensity using BEACOPP escalated. Methods: Between January 2003 and July 2008, 1655 patients with histologically confirmed diagnosis of Hodgkin lymphoma in early unfavorable stages were randomized. Patients had to be 16–60 years old and have CS I, IIA with one of the following risk factors: large mediastinal mass (a), extranodal disease (b), elevated ESR (c), or ≥ 3 nodal areas (d), IIB with risk factors c or d). Patients were randomized to either 4 cycles of ABVD (arm A) or 2 cycles BEACOPP escalated followed by 2 cycles ABVD (arm B). All patients received 30Gy IF-RT after chemotherapy. Primary objective was the improvement of FFTF. Results: The full analysis set comprised 1623 patients (98.1%) who were documented and followed for treatment effects; 818 were in arm A and 805 in arm B. Patient characteristics were well balanced between the two arms with a median age of 33.6 years and most patients in stage IIA (67%). The overall response rate to treatment was 95% in each arm. With a median follow-up of 42.4 months, 20 patients had died in each arm; 19 patients in arm A had secondary neoplasia compared to 16 patients in arm B. Progressive disease was observed in 2.9% versus 0.9% of patients in arms A and B, respectively; early relapse rates were 2.8% versus 0.9%, and late relapse rates were 2.3% versus 0.9%. The estimated 4-year FFTF rate was 89.3% in arm A and 94.7% in arm B (p=0,0001, hazard ratio HR=2.04, 95%-CI: 1.39–2.94). There was no significant difference in overall survival yet (p=0.95). Acute grade III-IV toxicity rates of chemotherapy were higher in arm B (87.1%) than in arm A (50.7%) with leucopenia rates of 79% versus 24%, hair loss 48% versus 24%, thrombocytopenia 22% versus 0.1% and anemia 9% versus 1% in arms B and A respectively. 7.3% of patients had grade III/IV infections in arm B as compared to 3.4% in arm A. However, we observed no differences in treatment-related death or secondary neoplasia rates between treatment arms. Conclusion: Intensifying treatment for patients with early unfavorable HL using 2 cycles of BEACOPP escalated followed by 2 × ABVD and IFRT results in a significant improvement in tumor control as compared to our prior standard of 4 × ABVD plus IFRT. As defined in the study protocol, this more aggressive treatment was implemented as new standard of care for early unfavorable HL in our follow-up study (GHSG HD17). Disclosures: Greil: Cephalon: Research Funding.

Abstract 764 Introduction The role of additional radiotherapy after chemotherapy for advanced-stage Hodgkin lymphoma is unclear. The German Hodgkin Study Group (GHSG) thus performed the HD15 trial in which advanced-stage Hodgkin lymphoma patients having residual disease after 6–8 cycles of BEACOPP were evaluated by 18F-fluorodesoxyglucose positron emission tomography (PET) following chemotherapy. Methods Entry criteria for the PET question in HD15 were partial remission (PR) after the end of chemotherapy with at least one involved nodal site measuring more than 2.5 cm in diameter by computed tomography (CT). Exclusion criteria included diabetes, elevated blood sugar levels and skeletal involvement with risk of instability. Calculations were restricted to those cases with either progressive disease (PD) or relapse within 12 months after PET or at least 12 months of follow-up. A total of 2,137 patients with de novo HL were included in HD15 of whom 728 had a tumor bulk ≥ 2.5 cm after BEACOPP chemotherapy and were qualified for the PET question. An expert panel performed the assessment of response and PET. Only PET-positive patients were scheduled for radiotherapy of residual disease. The negative prognostic value (NPV) of PET was defined as the proportion of PET-negative patients without progression, relapse or radiotherapy despite being PET-negative within 12 months. Results The full analysis set included 728 patients of whom 699 had at least 12 months of follow-up. Median age was 30 years, 57% were males and 66% had NS histology. Of the 728 qualified patients with residual disease ≥ 2.5 cm after BEACOPP, 74.2% were PET-negative and 25.8% PET-positive. In the PET-negative group, a total of 28 patients relapsed or had radiotherapy despite being PET-negative (8 patients including 1 relapsing patient) resulting in a negative prognostic value of 94.6% (95% CI 92.7% to 96.6%). With a median follow-up of 38 months, the time-to-progression after PET at 3 years was 92.1% for PET-negative patients counting radiotherapy as failure and 86.1% for PET-positive patients (95%-CI for difference -11.9% to -0.1%). Overall, only 11% of patients had additional radiotherapy as compared to 71% after BEACOPPescalated in our prior HD9 trial. In addition, there was no difference in PFS or overall survival as compared to our earlier trials in advanced-stage HL. Discussion The NPV of PET of 0.95 suggests that indeed only patients with residual disease after chemotherapy who are PET-positive need additional radiotherapy. PET-negative patients at least after BEACOPP can be spared from additional radiotherapy. Disclosures: No relevant conflicts of interest to declare.

Despite the increasing number of publications concerning 18F-Fluorodeoxyglucose Positron Emission Tomography (FDG-PET) for post-treatment evaluation of lymphoma and the increasing availability of this novel diagnostic modality, its exact role in response assessment after therapy is still unknown. The aim of this study was to systematically review the literature regarding the diagnostic performance of dedicated FDG-PET in evaluation of first line therapy of Hodgkin’s disease and (aggressive) non-Hodgkin’s lymphoma, and to calculate summary estimates of its sensitivity and specificity. The databases of PubMed and Embase were searched for relevant studies, up to January 2004. Criteria for inclusion of studies were 1) histologically proven Hodgkin’s disease (HD) or aggressive non-Hodgkin’s lymphoma (NHL), 2) evaluation of post-treatment patients following first line therapy, 3) the use of dedicated (ring) PET using 18FDG, and 4) study population of at least ten patients. Two reviewers independently assessed the methodological quality of each study. As a valid reference test, histology or follow-up of at least 12 months were accepted. A meta-analysis of the reported sensitivity, specificity, and positive Likelihood Ratio (LR+) and negative Likelihood Ratio (LR−) of each study were performed. Fifteen studies, involving 705 patients, met the inclusion criteria. The studies had several design deficiencies. The majority of studies did not describe whether the reference test was interpreted without knowledge of the FDG-PET findings. Furthermore, in only two studies, patients entered the study consecutively. In all studies, there was a description of the spectrum of patients included, i.e. all patients for post-treatment evaluation or only patients with substantial residual masses post-treatment. Pooled sensitivity, specificity, LR+ and LR- for detection of residual disease in Hodgkin’s lymphoma were 84% (95% CI 71–92%), 90% (95% CI 84–94%), 5.5 (95% CI 3.4–8.7) and 0.25 (95% CI 0.1–0.55), respectively. For non-Hodgkin’s lymphoma, pooled sensitivity, specificity, LR+ and LR− were 72% (95% CI 61–82%), 100% (95% CI 97–100%), 36 (95% CI 11–125) and 0.30 (95% CI 0.21–0.42), respectively. In conclusion, FDG-PET showed reasonable sensitivity and high specificity for evaluation of first line therapy in Hodgkin’s and in non-Hodgkin’s lymphoma.