Leonard, John P.

Abstract Background: The histone deacetylase (HDAC) inhibitors are a class of epigenetic agents undergoing clinical testing. HDAC inhibitors modulate expression of genes involved in cell cycle regulation, leading to induction of differentiation or apoptosis. Romidepsin, a novel, HDAC inhibitor, has previously demonstrated activity as a single agent in patients (pts) with T-cell lymphoma in a phase 1 NCI study. Aims: To evaluate the efficacy and tolerability of romidepsin in the treatment of advanced PTCL and as an exploratory endpoint, to examine the molecular effects of romidepsin in both PTCL and cutaneous T-cell lymphoma (CTCL). Methods: This Phase 2, open-label, multi-arm, multicenter study enrolled 43 PTCL pts from the NCI and 9 extramural sites. CTCL pts were also enrolled in this study. The clinical results for pts with PTCL are presented here; the clinical results for the pts with CTCL and the biomarker analyses for both PTCL and CTCL are presented elsewhere. This study is now closed to accrual. Pts with relapsed or refractory PTCL or primary cutaneous anaplastic large cell lymphoma were eligible. Pts received romidepsin 14 mg/m2 as a 4-hr infusion on days 1, 8 and 15 every 28 days. Responses were assessed using elements of the IWG criteria and RECIST, as appropriate, for pts with lymph node involvement and extranodal disease. Results: 43 pts (23[53%] men and 20 [47%] women) with a mean age of 58.1 (range: 27 to 84) years were treated with romidepsin. 31 pts received ≥ 2 cycles of therapy. Mean number of prior therapies was 3.9 (range 1 to 12). Objective disease response rates (ORR) are summarized in the table. The mean number of cycles of treatment was 6.8 (range 1–37) and the overall median duration of response was 8.3 months (range 1.6 months to 4.8+ yrs) for all pts. The median duration of response for the 7 pts who achieved CR was 8.5 months (range 4.6 months to 4.8+yrs). The most frequent drug-related AEs (all grades, all cycles) were generally mild and included: nausea (86%; 0% ≥grade 3), fatigue (79%; 0% ≥grade 3), decreased platelets (70%; 7% ≥grade 3), and decreased AGC (63%; 5% ≥grade 3). One death, in a pt with significant cardiovascular disease who had achieved a CR, was considered possibly related to treatment. Conclusions: This study demonstrates tolerability and durable clinical benefit (ORR of 39% and median duration of response of 8.3 months) of romidepsin in pts with recurrent or refractory PTCL. Based on these promising results, a Phase 2B protocol investigating romidepsin in pts with progressive or relapsed PTCL is ongoing at multiple international centers. All Pts N=43 Pts ≥ 2 cycles N=31 ORR (CR+PR), n (%) 17 (39%) 17 (55%) PR, n (%) 10 (23%) 10 (32%) CR, n (%) 7 (16%) 7 (23%)

Abstract As part of a randomized, prospective clinical trial in large cell lymphoma, we conducted serial fluorodeoxyglucose positron emission tomography (FDG-PET) at baseline, after 2 cycles of chemotherapy (interim PET [i-PET]), and at end of treatment (EoT) to identify biomarkers of response that are predictive of remission and survival. Scans were interpreted in a core laboratory by 2 imaging experts, using the visual Deauville 5-point scale (5-PS), and by calculating percent change in FDG uptake (change in standardized uptake value [ΔSUV]). Visual scores of 1 through 3 and ΔSUV ≥66% were prospectively defined as negative. Of 524 patients enrolled in the parent trial, 169 agreed to enroll in the PET substudy and 158 were eligible for final analysis. In this selected population, all had FDG-avid disease at baseline; by 5-PS, 55 (35%) remained positive on i-PET and 28 (18%) on EoT PET. Median ΔSUV on i-PET was 86.2%. With a median follow-up of 5 years, ΔSUV, as continuous variable, was associated with progression-free survival (PFS) (hazard ratio [HR] = 0.99; 95% confidence interval [CI], 0.97-1.00; P = .02) and overall survival (OS) (HR, 0.98; 95% CI, 0.97-0.99; P = .03). ΔSUV ≥66% was predictive of OS (HR, 0.31; 95% CI, 0.11-0.85; P = .02) but not PFS (HR, 0.47; 95% CI, 0.19-1.13; P = .09). Visual 5-PS on i-PET did not predict outcome. ΔSUV, but not visual analysis, on i-PET predicted OS in DLBCL, although the low number of events limited the statistical analysis. These data may help guide future clinical trials using PET response-adapted therapy. This trial was registered at www.clinicaltrials.gov as #NCT00118209.

AbstractImmunochemotherapy followed by autologous transplant (ASCT) in CALGB/Alliance 59909 achieved a median progression‐free survival (PFS) in mantle cell lymphoma (MCL) of 5 years, but late recurrences occurred. We evaluated tolerability and efficacy of adding post‐transplant bortezomib consolidation (BC) or maintenance (BM) to this regimen in CALGB/Alliance 50403, a randomized phase II trial. Following augmented‐dose R‐CHOP/ methotrexate, high‐dose cytarabine‐based stem cell mobilization, cyclophosphamide/carmustine/etoposide (CBV) autotransplant, and rituximab, patients were randomized to BC (1.3 mg/m2 IV days 1, 4, 8, 11 of a 3‐week cycle for four cycles) or BM (1.6 mg/m2 IV once weekly × 4 every 8 weeks for 18 months) beginning day 90. The primary endpoint was PFS, measured from randomization for each arm. Proliferation signature, Ki67, and postinduction minimal residual disease (MRD) in bone marrow were assessed. Of 151 patients enrolled; 118 (80%) underwent ASCT, and 102 (68%) were randomized. Both arms met the primary endpoint, with median PFS significantly greater than 4 years (P < .001). The 8‐year PFS estimates in the BC and BM arms were 54.1% (95% CI 40.9%‐71.5%) and 64.4% (95% 51.8%‐79.0%), respectively. Progression‐free survival was significantly longer for transplanted patients on 50403 compared with those on 59909. Both the PFS and OS were significantly better for those who were MRD‐negative post‐induction. The high risk proliferation signature was associated with adverse outcome. Both BM and BC were efficacious and tolerable, although toxicity was significant. The comparison between studies 50403 and 59909 with long‐term follow up suggests a PFS benefit from the addition of BC or BM post‐ transplant.

7514 Background: Relapse is expected in treated indolent lymphoma patients, and an unmet need exists to prolong remission with effective therapies. Lenalidomide + rituximab (R2) may improve the efficacy of next treatment by their unique mechanisms. Methods: The AUGMENT phase III study evaluated patients with R/R FL gr 1-3a (82%) and MZL (18%) after ≥ 1 prior systemic therapy (not rituximab refractory). Randomization was 1:1 to R2 (lenalidomide PO 20 mg/d, d1-21/28 X12 cycles [c] + rituximab [R] IV 375 mg/m2/wk, c1, d1, 8, 15, 22 and c2-5, d1) and R/placebo (same dosing schedule). The primary endpoint was PFS by 2007 IWG; secondary/exploratory analyses were time to next antilymphoma/chemotherapy treatment (TTNLT/TTNCT) and response to next treatment. Per regulatory guidance, PFS2 was defined as time from randomization to first PD or death from any cause after next antilymphoma treatment, or initiation of a third antilymphoma treatment. Results: Median PFS was superior for R2 over R/placebo (39.4 vs 14.1 mo; HR = 0.46; P < 0.0001). As of 22June2018, median TTNLT, TTNCT, and PFS2 were not reached for R2, and were significantly longer than R/placebo (HR = 0.54, 0.50, and 0.52, respectively). For 49/178 (28%) R2 and 80/180 (44%) R/placebo patients receiving next antilymphoma therapy, response was generally higher with R2 (57% ORR; 31% CR) than R/placebo (36% ORR; 16% CR; Table). Conclusions: These analyses suggest that R2 (vs R/placebo) prolonged time to subsequent treatment and is associated with longer PFS2, enabling greater response to next therapy. Although patient numbers were modest, it is hypothesized that patients who received R2 were generally more sensitive to subsequent therapy than those treated with R/placebo. Clinical trial information: NCT01938001. [Table: see text]

Initial therapy for MCL is effective, but most patients eventually relapse. Validated intermediate biomarkers for MCL are important to provide early assessment of treatment efficacy, prognostic information and potentially guide consolidation. The US-Canadian Intergroup trial E1411 randomly assigned patients (pts) to receive induction with BR ± bortezomib (V), followed by consolidation with R ± L. As a planned correlative, MRD was assessed after cycle 3 (I3), end of induction (EOI) and after 4 cycles of consolidation (C4) by two methods: a research version of clonoSEQ® a next generation sequencing (NGS) MRD assay, (Adaptive Biotechnologies, Seattle, WA) that leverages multiplex PCR followed by NGS to identify and track rearrangements of IgH, V-J, D-J and IgK/L loci as well as translocations in Bcl1/2-IgH, and flow cytometry (FC) (I3 and EOI only) at a central laboratory (Mayo Clinic). While outcomes by treatment arm remain blinded, we report here the results of the MRD assessments by each method and the associated progression free survival (PFS). In E1411, 373 pts, accrued between May 2012 - Sept. 2016, were randomly assigned (stratified by MIPI and age (&lt;/≥60)) to receive BR induction x 6 followed by R for 2 years, BVR followed by R, BR followed by LR or BVR followed by LR. Eligible pts were ≥ age 18 and had untreated MCL, ECOG PS 0-2, and adequate hematologic and organ function. Of the 373 pts, 296 (79%) consented to correlatives. Of these, 255 (86%) had baseline NGS samples, and 214 were analyzable. Excluded were 6 patients that were protocol ineligible, 20 without clinical follow-up; only 7 (2.7%) patients were ineligible due to inability to identify a dominant clone necessary to follow MRD by the NGS method. At baseline pre-treatment, NGS detected a dominant clone in bone marrow (BM) or peripheral blood (PB) in 92%, with only 17 (8%) requiring study of biopsy tissue. Of the 296, 240 had baseline FC data, 9 were protocol exclusions, leaving 231 analyzable. FC detected a non-MCL monoclonal B cell lymphocytosis clone in a small number of cases. While NGS may have higher sensitivity, as FC sensitivity is 10-4, for this analysis we used that cutoff for both NGS and FC. Cohen's Kappa statistic compares concordance between MRD pairs, and p-value is from exact McNemar's test. BR-based initial MCL therapy achieved early MRD negativity (&lt; 10-4) in a high proportion of patients. Analyzing PB at mid-induction (I3): by NGS 89% MRD-, 9% MRD+ and 2% indeterminate, whereas by FC 87% MRD-, 12% MRD+ and 1% indeterminate. Concordance was high with 127 MRD- by both methods, 13 MRD+ by both, and 6 NGS-/FC+ (Kappa Statistic = 0.79, p-value = 0.031). By NGS, of 12 pts MRD+ at I3, 7 became MRD- at EOI, and 4 remained MRD+ (1 indeterminate). Analyzing at EOI: MRD- rates were 91% by NGS analysis of PB (147/161) and 90% in BM (96/107), vs 95% (174/183) by FC in PB. As some were indeterminate, only 7% were MRD+ by NGS in BM, 3% by NGS in PB and 5% by FC. In 88 informative samples with EOI NGS in both BM and PB, concordance was high, with 81 negative in both, 1 positive in both and 6 BM+/PB- (Kappa Statistic = 0.23, p-value = 0.031). Of 101 pts with data at all 3 timepoints, I3, EOI, and C4: 7 were MRD+ at I3, 5 of these were MRD- at EOI, but 2 of these 5 were again MRD+ at C4. Of 2 MRD+ EOI, 1 became MRD- at C4. By FC, of 17 patients MRD+ at I3, 11 (65%) became MRD- at EOI. MRD status correlated with progression-free survival (PFS). Due to the low MRD+ rate at EOI and C4, we focus here on MRD status at I3 (10-4 cutoff for both NGS and FC), using a landmark analysis of 4 months on study. Median PFS (Figure) for pts MRD- at I3 mid-induction was 58.9 months by either NGS or FC, while for those MRD+ by NGS it was 26.9 months, vs 29.9 months MRD+ by FC. Conclusions: Both NGS and FC were feasible to assess MRD status in this multi-center trial. Results of NGS and FC are concordant at the 10-4 cutoff. NGS can be more sensitive when adequate material is available, and analysis of this subgroup is ongoing. The high MRD- rate (≥ 90%) at EOI in this BR-based trial and MRD correlation with PFS supports its use as a platform for MCL trials, although consolidation may confound PFS. Early interim MRD testing at cycle 3 identifies a high-risk population who may benefit from alternative treatment strategies. Analysis by treatment arm with longer follow-up, as well as comparison with centrally reviewed PET/CTs included in this study, will help define the most informative method(s), cutoff values, and timing for assessing degree of response in MCL. Figure. Disclosures Smith: Astra-Zeneca: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; EUSA: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Parekh:Foundation Medicine Inc.: Consultancy; Celgene Corporation: Research Funding; Karyopharm Inc.: Research Funding. Martin:Sandoz: Consultancy; Karyopharm: Consultancy; Teneobio: Consultancy; Celgene: Consultancy; Janssen: Consultancy; I-MAB: Consultancy. Till:Mustang Bio: Patents & Royalties, Research Funding. Leonard:Gilead: Consultancy; Akcea Therapeutics: Consultancy; Bayer Corporation: Consultancy; Genentech, Inc./F. Hoffmann-La Roche Ltd: Consultancy; BeiGene: Consultancy; Celgene: Consultancy; Akcea Therapeutics: Consultancy; Nordic Nanovector: Consultancy; ADC Therapeutics: Consultancy; Sandoz: Consultancy; MorphoSys: Consultancy; Sutro Biopharma: Consultancy; Karyopharm Therapeutics: Consultancy; Karyopharm Therapeutics: Consultancy; Merck: Consultancy; Genentech, Inc./F. Hoffmann-La Roche Ltd: Consultancy; Epizyme, Inc: Consultancy; Gilead: Consultancy; AstraZeneca: Consultancy; Epizyme, Inc: Consultancy; Bayer Corporation: Consultancy; Miltenyi: Consultancy; Celgene: Consultancy; ADC Therapeutics: Consultancy; MorphoSys: Consultancy; Sandoz: Consultancy; Miltenyi: Consultancy; AstraZeneca: Consultancy; Nordic Nanovector: Consultancy; Merck: Consultancy; BeiGene: Consultancy; Sutro Biopharma: Consultancy. Friedberg:Bayer: Honoraria, Other: Data & Safety Monitoring Committee; Acerta: Other: Data & Safety Monitoring Committee. Kahl:TG Therapeutics: Consultancy; ADC Therapeutics: Consultancy, Research Funding; Seattle Genetics: Consultancy; BeiGene: Consultancy.

Introduction MCL is a rare cancer, and current clinical practice guidelines list multiple reasonable treatment options for MCL. It can be challenging to select treatment (Tx) that optimizes outcomes for patients with a mixture of presenting features. In 2014, we developed an online MCL decision support tool designed to provide expert guidance on optimal treatment for defined patient scenarios. An analysis of the 2014 tool showed that Tx recommendations of community healthcare providers (HCPs) did not consistently align with experts for many patients with MCL (Gopalsamy, et al. Leuk Lymphoma. 2019 Mar 8:1-9). Here we report data from an updated version (2018) of this tool that captures evolving practice patterns among experts and community HCPs and the differences between these 2 groups. Methods In September 2018, a panel of 5 experts provided Tx recommendations for 240 patient scenarios in newly diagnosed or relapsed/refractory MCL. These distinct scenarios were defined by patient and disease characteristics that the experts considered important when making treatment choices, including disease setting, patient age and fitness, cytogenetic information, LDH and Ki67 levels, and information on any previous lines of therapy. To use the tool, HCPs entered specific patient/disease characteristics using expert-defined options along with the Tx planned for each case. The users were then shown the 5 MCL expert recommendations and were asked to indicate the impact of the expert recommendations on their planned Tx approach. Results A total of 387 HCPs entered 654 patient scenarios in the 2018 online tool. For HCPs who answered an optional question on how many patients with MCL they treat per year (n = 145), 81% indicated that they treated 10 or fewer patients with MCL per year, highlighting the rarity of this disease and lack of experience among many HCPs. Furthermore, 74% of these HCPs indicated that they refer &lt; 50% of their patients with MCL for clinical trials or to academic institutions for treatment. Among experts, the primary consensus for initial Tx recommendations for younger, fit patients with MCL were bendamustine/rituximab (BR) and R-HyperCVAD in both 2014 and 2018. In comparison, HCPs chose these 2 regimens for a minority of these patients with newly diagnosed MCL in both editions of the tool. For older or unfit patients, experts predominantly recommended BR (85% in 2014 and 75% in 2018), whereas only 35% to 40% of HCPs would choose this regimen in this setting (Table). Of note, nearly 20% of the HCPs indicated that they would recommend a very aggressive chemotherapy regimen for older or unfit patients. For patients with disease progression after chemoimmunotherapy, the recommendation of ibrutinib-based therapy increased among experts from 2014 to 2018 from 66% to 100%. By contrast, the percentage of HCPs using ibrutinib-based therapy remained low at 29% or 37% in the 2014 and 2018 tools, respectively. Another 14% of HCPs selected acalabrutinib, another approved BTK inhibitor, in 2018. In addition, approximately 20% of HCPs in both 2014 and 2018 were unsure of the optimal use of additional therapy (eg, ASCT or maintenance therapy) for their patients. Among users who answered an optional question on the tool's clinical impact, 47% indicated the expert recommendations changed their planned Tx and 38% indicated that expert recommendations confirmed their approach. Conclusions The analysis of data from this online tool found several areas of expert consensus regarding Tx for patients with MCL, particularly for patients who are progressing after initial chemoimmunotherapy. However, practice patterns of community HCPs did not align with expert recommendations for the majority of cases entered into the tool. The consistent Tx gap between practice patterns of community HCPs and expert recommendations over this time period suggests a continued need for online decision tools like this and other innovative approaches to involve experts in the care of patients with MCL. A detailed comparison of expert and user data from the online tool will be presented. Disclosures Ansell: LAM Therapeutics: Research Funding; LAM Therapeutics: Research Funding; Affimed: Research Funding; LAM Therapeutics: Research Funding; Regeneron: Research Funding; Affimed: Research Funding; Bristol-Myers Squibb: Research Funding; LAM Therapeutics: Research Funding; Affimed: Research Funding; LAM Therapeutics: Research Funding; Affimed: Research Funding; Bristol-Myers Squibb: Research Funding; Bristol-Myers Squibb: Research Funding; Trillium: Research Funding; Bristol-Myers Squibb: Research Funding; LAM Therapeutics: Research Funding; Trillium: Research Funding; Regeneron: Research Funding; Trillium: Research Funding; Mayo Clinic Rochester: Employment; Trillium: Research Funding; Bristol-Myers Squibb: Research Funding; Mayo Clinic Rochester: Employment; Bristol-Myers Squibb: Research Funding; Mayo Clinic Rochester: Employment; LAM Therapeutics: Research Funding; Regeneron: Research Funding; Seattle Genetics: Research Funding; Regeneron: Research Funding; Bristol-Myers Squibb: Research Funding; Seattle Genetics: Research Funding; LAM Therapeutics: Research Funding; Mayo Clinic Rochester: Employment; Affimed: Research Funding; Regeneron: Research Funding; Trillium: Research Funding; Trillium: Research Funding; Seattle Genetics: Research Funding; Mayo Clinic Rochester: Employment; Trillium: Research Funding; Seattle Genetics: Research Funding; Mayo Clinic Rochester: Employment; Mayo Clinic Rochester: Employment; Regeneron: Research Funding; Seattle Genetics: Research Funding; Regeneron: Research Funding; Regeneron: Research Funding; Mayo Clinic Rochester: Employment; Bristol-Myers Squibb: Research Funding; Regeneron: Research Funding; Trillium: Research Funding; Mayo Clinic Rochester: Employment; LAM Therapeutics: Research Funding; Trillium: Research Funding; Seattle Genetics: Research Funding; Seattle Genetics: Research Funding; Affimed: Research Funding; Bristol-Myers Squibb: Research Funding; Affimed: Research Funding; Affimed: Research Funding; Seattle Genetics: Research Funding; Seattle Genetics: Research Funding; Affimed: Research Funding. Leonard:Nordic Nanovector: Consultancy; Karyopharm Therapeutics: Consultancy; BeiGene: Consultancy; Sutro Biopharma: Consultancy; Gilead: Consultancy; MorphoSys: Consultancy; Merck: Consultancy; Nordic Nanovector: Consultancy; Akcea Therapeutics: Consultancy; MorphoSys: Consultancy; Miltenyi: Consultancy; Epizyme, Inc: Consultancy; AstraZeneca: Consultancy; Bayer Corporation: Consultancy; Celgene: Consultancy; AstraZeneca: Consultancy; ADC Therapeutics: Consultancy; Genentech, Inc./F. Hoffmann-La Roche Ltd: Consultancy; Gilead: Consultancy; Bayer Corporation: Consultancy; Genentech, Inc./F. Hoffmann-La Roche Ltd: Consultancy; Celgene: Consultancy; Karyopharm Therapeutics: Consultancy; Sutro Biopharma: Consultancy; Epizyme, Inc: Consultancy; Merck: Consultancy; Sandoz: Consultancy; Akcea Therapeutics: Consultancy; Miltenyi: Consultancy; Sandoz: Consultancy; ADC Therapeutics: Consultancy; BeiGene: Consultancy. Vose:Acerta Pharma: Honoraria, Other: Grants, Research Funding; Bristol-Meyers Squibb Company: Research Funding; Celgene Corporation: Research Funding; Incyte Corporation: Research Funding; Kite Pharma: Honoraria, Other: Grants, Research Funding; Novartis: Research Funding; Seattle Genetics: Research Funding; AbbVie: Consultancy, Honoraria; Epizyme: Consultancy, Honoraria; Legend Pharmaceuticals: Honoraria. Wang:BioInvent: Consultancy, Research Funding; Dava Oncology: Honoraria; Aviara: Research Funding; Juno Therapeutics: Research Funding; Celgene: Honoraria, Research Funding; AstraZeneca: Consultancy, Honoraria, Research Funding, Speakers Bureau; Pharmacyclics: Honoraria, Research Funding; Janssen: Consultancy, Honoraria, Research Funding, Speakers Bureau; VelosBio: Research Funding; Acerta Pharma: Consultancy, Research Funding; Kite Pharma: Consultancy, Research Funding; Guidepoint Global: Consultancy; MoreHealth: Consultancy, Equity Ownership; Loxo Oncology: Research Funding. Flowers:BeiGene: Consultancy, Research Funding; Celgene: Consultancy, Research Funding; Denovo Biopharma: Consultancy; Millenium/Takeda: Research Funding; V Foundation: Research Funding; Bayer: Consultancy; Acerta: Research Funding; Genentech, Inc./F. Hoffmann-La Roche Ltd: Consultancy, Research Funding; TG Therapeutics: Research Funding; Burroughs Wellcome Fund: Research Funding; Eastern Cooperative Oncology Group: Research Funding; National Cancer Institute: Research Funding; Optimum Rx: Consultancy; Spectrum: Consultancy; Pharmacyclics/Janssen: Consultancy, Research Funding; AstraZeneca: Consultancy; Gilead: Consultancy, Research Funding; AbbVie: Consultancy, Research Funding; Karyopharm: Consultancy.

Introduction Limited stage disease accounts for 30-40% of Diffuse Large B-cell Lymphoma (DLBCL), with better overall survival than advanced stage disease, but with increased late relapses regardless of treatment strategy (Stephens 2016). Preferred treatment for these patients (pts) per NCCN guidelines is abbreviated R-CHOP followed by radiotherapy. Based on promising results of radioimmunotherapy consolidation in SWOG S0313 (Persky 2015), and of PET-directed experience by the BC Cancer Agency (Sehn 2011), we designed a National Clinical Trials Network (NCTN) PET-directed study to tailor therapy after 3 cycles of R-CHOP, to improve outcomes and decrease toxicities. Methods Pts had non-bulky (&lt; 10 cm) stage I/II untreated DLBCL. Mediastinal, HIV-associated, testicular, central nervous system, and indolent lymphoma were excluded. Pts received standard R-CHOP therapy and had an interim PET scan on day 15-18 of cycle 3, which was centrally reviewed in real time. Pts with negative PET scan (Deauville 1-3, iPET-neg) proceeded with 1 additional cycle of R-CHOP. Pts with positive PET scan (Deauville 4-5, iPET-pos) initiated 36 Gy of involved field radiation therapy (IFRT), plus additional boost to FDG-avid area up to 9 Gy, within 5 weeks of 3rd cycle of R-CHOP. This was followed by ibritumomab tiuxetan (IFRT-Zevalin) 3-6 weeks after completing IFRT. Final PET scan was performed 12 weeks after treatment completion. Results The study completed accrual in June 2016. Safety, response, interim PET, and immunohistochemistry-based cell of origin (COO) and MYC/BCL2 analyses were presented previously (Persky 2017, Stephens 2017). Of 159 pts enrolled, 1 was upstaged by PET, and 26 pts were ineligible - due to incorrect histology (mostly concurrent indolent or follicular lymphoma grade 3B) (21), lack of diagnostic tissue submission for central pathology review (3), and bulky disease (2). In 132 eligible pts, median age was 62 years, 62% had stage I, 17% had B symptoms, 14% had elevated LDH, 43% had extranodal involvement, and 66% had exclusive involvement of the head and neck region. Stage modified IPI (smIPI, Miller 1998) was 0 in 27%, 1 in 42%, 2 in 28%, and 3 in 4% of the pts. COO by Lymph2Cx was assessable in 87 pts - 68% were GCB, 23% were ABC, and 9% were unclassifiable. Double protein expressers (MYC and BCL2, DPE) were 16%, while 4 (3%) pts had "double hit" lymphoma (DHL) - 2 with MYC/BCL2 and 2 with MYC/BCL6 rearrangements - none of which were DPE. Of 132 eligible pts, 128 had an interim PET scan centrally reviewed, of which 110 were iPET-neg. Only 18 were iPET-pos, 4 of them due to infection (Deauville X) which were treated as iPET-neg. Of 14 truly iPET-pos pts (11%), 2 refused radiation, and 12 pts received IFRT-Zevalin. Eight pts (67%) converted from PR to CR after IFRT-Zevalin and 4 (33%) had PR, for an overall CR of 92% and PR of 4% (with 4% unevaluable). With median follow up of 4.5 yrs (range 1.1 - 7.5 yrs), only 5 pts progressed and 2 died from lymphoma. Of 5 progressors, 3 received R-CHOP x 4, 1 was iPET-pos but declined radiation, and 1 went off treatment after 1 cycle of R-CHOP. Eleven pts died from non-lymphoma causes, including 1 pt from secondary AML (iPET-neg arm), and 1 of lung adenocarcinoma diagnosed upon iPET. S1001 5-yr PFS estimate is 87% and OS estimate is 90% (figure 1), with iPET-pos and iPET-neg pts having similar outcomes - PFS 86% vs. 88%, OS 93% vs. 91%, respectively. Five-yr PFS by smIPI was 97% for smIPI of 0, 86% for 1-2, and 30% for 3. GCB had 5-yr PFS of 95%, vs. 70% for ABC and 47% for unclassifiable. DPE pts had 5-yr PFS of 70, vs. 89% for non-DPE pts. All 4 DHL pts maintain remission. Conclusions S1001 is the largest US study of limited stage DLBCL in the rituximab era, with best NCTN results in this disease subset. Only 5 patients progressed and 2 died from lymphoma. Our study confirms the distinct biology of limited stage DLBCL, with predominance of GCB origin (68%), and head and neck location (66%). Due to small number of lymphoma events, no strong conclusions about prognostic ability of smIPI, COO, DPE, or DHL, could be made. S1001 demonstrated that 89% of pts maintained excellent outcomes after R-CHOP x 4 with PET-directed therapy. Only 11% of pts were iPET-pos and required radiation, but they also had excellent outcomes. Together with the FLYER trial in younger pts (Poeschel 2018), this NCTN trial establishes R-CHOP x 4 alone as the new standard approach to limited stage disease for majority of the pts. Disclosures Persky: Sandoz: Consultancy; Morphosys: Other: Member, Independent Data Monitoring Committee; Debiopharm: Other: Member, Independent Data Monitoring Committee; Bayer: Consultancy. Stephens:Acerta: Research Funding; Karyopharm: Research Funding; Gilead: Research Funding. Park:BMS: Consultancy, Research Funding; Rafael Pharma: Membership on an entity's Board of Directors or advisory committees; G1 Therapeutics: Consultancy; Teva: Consultancy, Research Funding; Gilead: Speakers Bureau; Seattle Genetics: Research Funding, Speakers Bureau. Bartlett:Seattle Genetics: Research Funding; ADC Therapeutics: Consultancy, Research Funding; Pfizer: Research Funding; Millenium: Research Funding; Bristol-Myers Squibb: Research Funding; Celgene: Research Funding; Genenetech: Research Funding; Immune Design: Research Funding; Gilead: Research Funding; Forty Seven: Research Funding; Janssen: Research Funding; Affimed: Research Funding; Merck: Research Funding; Pharmacyclics: Research Funding. Swinnen:Pharmacyclics: Consultancy; AbbVie: Consultancy. Barr:Celgene: Consultancy; Merck: Consultancy; Seattle Genetics: Consultancy; Genentech: Consultancy; Verastem: Consultancy; Gilead: Consultancy; Astra Zeneca: Consultancy, Research Funding; Janssen: Consultancy; AbbVie: Consultancy; Pharmacyclics LLC, an AbbVie company: Consultancy, Research Funding; TG Therapeutics: Consultancy, Research Funding. Leonard:Nordic Nanovector: Consultancy; Akcea Therapeutics: Consultancy; BeiGene: Consultancy; Gilead: Consultancy; Miltenyi: Consultancy; ADC Therapeutics: Consultancy; Nordic Nanovector: Consultancy; Akcea Therapeutics: Consultancy; Sandoz: Consultancy; ADC Therapeutics: Consultancy; Miltenyi: Consultancy; Genentech, Inc./F. Hoffmann-La Roche Ltd: Consultancy; Karyopharm Therapeutics: Consultancy; Epizyme, Inc: Consultancy; Sutro Biopharma: Consultancy; AstraZeneca: Consultancy; AstraZeneca: Consultancy; Bayer Corporation: Consultancy; Bayer Corporation: Consultancy; Celgene: Consultancy; Epizyme, Inc: Consultancy; Celgene: Consultancy; Genentech, Inc./F. Hoffmann-La Roche Ltd: Consultancy; Merck: Consultancy; MorphoSys: Consultancy; Karyopharm Therapeutics: Consultancy; Gilead: Consultancy; Sutro Biopharma: Consultancy; BeiGene: Consultancy; Merck: Consultancy; MorphoSys: Consultancy; Sandoz: Consultancy. Kahl:TG Therapeutics: Consultancy; ADC Therapeutics: Consultancy, Research Funding; Seattle Genetics: Consultancy; BeiGene: Consultancy. Fisher:Celgene: Consultancy; AstraZeneca: Consultancy; Barclays: Honoraria; prIME: Honoraria. Rimsza:NanoSting: Patents & Royalties: Named inventor on a patent licensed to NanoSting [Institution]. Smith:Portola Pharmaceuticals: Research Funding. Friedberg:Bayer: Honoraria, Other: Data & Safety Monitoring Committee; Acerta: Other: Data & Safety Monitoring Committee. OffLabel Disclosure: Ibritumomab tiuxetan in diffuse large B-cell lymphoma

Background: The combination of lenalidomide+rituximab (R2) recently showed superior efficacy vs R-placebo in patients (pts) with R/R iNHL (Leonard et al. J Clin Oncol 2019). Based on these AUGMENT study results, R2 was approved by the US FDA for treatment of adult pts with previously treated follicular lymphoma (FL) or marginal zone lymphoma (MZL). Advanced age at diagnosis is a risk factor in pts with iNHL. We performed post-hoc subgroup analyses by age from AUGMENT and data here focus on pts age ≥ 70 y. Methods: AUGMENT (NCT01938001) is a multicenter, double-blind, randomized phase III study of R2 vs R-placebo in pts with FL grade 1-3a or MZL previously treated with ≥ 1 systemic therapy with R/R disease but not refractory to rituximab. Pts were randomized 1:1 to R2 or R-placebo. R2 was oral lenalidomide 20 mg/d, d1-21/28 for 12c plus rituximab IV 375 mg/m2 weekly in c1 and d1 of c2-5. R-placebo was rituximab+placebo on the same schedule. The primary endpoint was progression-free survival (PFS) per 2007 IWG response criteria (without PET) as assessed by IRC (central review). Secondary endpoints included overall response rate (ORR), complete response (CR), time to next anti-lymphoma treatment (TTNLT) and safety. Post-hoc analyses were performed by dividing pts into age &lt; 70 y and ≥ 70 y subgroups, the latter group considered unfit for chemotherapy. Results: Of 358 pts randomized (R2, n = 178; R-placebo, n = 180), 267 pts were age &lt; 70 y (R2, n = 131; R-placebo, n = 136), and 91 pts were age ≥ 70 y (R2, n = 47; R-placebo, n = 44). Baseline characteristics including histology, disease status, and prior treatments are shown in the table and were similar across treatment arms in pts ≥ 70 y. At a median follow-up of 28.3 mo, the study met its primary endpoint of PFS, with a hazard ratio (HR) of 0.46 (95% CI, 0.34-0.62; P &lt; 0.0001) in the overall population. R2 had superior PFS vs R-placebo in both &lt; 70 and ≥ 70 y subgroups, with HR of 0.41 (95% CI, 0.29-0.59) and HR of 0.66 (95% CI, 0.37-1.18), respectively. In pts ≥ 70 y, median PFS with R2 vs R-placebo was 24.9 vs 14.3 mo; ORR/CR was 81%/26% vs 59%/16%; and TTNLT was not reached in either arm. Efficacy results for all pts and those &lt; 70 y are reported in the table; notably in pts receiving R2, mPFS was longer in pts &lt; 70 y vs ≥ 70 y (39.4 mo [95% CI, 22.9-NE] vs 24.9 mo [95% CI, 16.4-NE]). In pts ≥ 70 y, any-grade adverse events (AEs) with a ≥ 10 % difference between R2 vs R-placebo included neutropenia (63% vs 11%), constipation (33% vs 16%), cough (33% vs 16%), leukopenia (26% vs 2%), anemia (24% vs 9%), pyrexia (24% vs 9%), pruritus/pruritus generalized (24% vs 2%), muscle spasms (22% vs 11%), rash/rash maculopapular (22% vs 5%), headache (20% vs 9%), thrombocytopenia (17% vs 2%), dyspepsia (13% vs 2%), influenza (13% vs 2%), back pain (7% vs 18%), and nasopharyngitis (4% vs 16%). Also, tumor flare was reported in 9% vs 0% of pts, respectively. In pts ≥ 70 y, 75% of R2 pts vs 36% of R-placebo pts had ≥ 1 grade 3/4 AE, mainly due to neutropenia (50% vs 7%). All other grade 3/4 AEs occurred in &lt; 10% of pts ≥ 70 y in both treatment arms. One grade 5 AE occurred in pts ≥ 70 y (R-placebo arm). In the R2 arm, the median number of treatment cycles was 12 for both the &lt; 70 y vs ≥ 70 y subgroups; however, fewer older pts completed 12 cycles of lenalidomide (76% vs 57%), and more started lenalidomide at the lower dose of 10 mg (6% vs 35%) because of low creatinine clearance, respectively. In the R2 &lt; 70 y and ≥ 70 y subgroups, the average daily dose of lenalidomide was 17.9 mg/d (range, 5.6-20.0) and 14.4 mg/d (range 4.2-20.0), and median relative dose intensity was 95% and 86%, respectively. Conclusions: Similar to the results in the original population, R2 showed superior efficacy vs rituximab monotherapy (plus placebo) as measured by the primary end point of PFS and secondary end points of ORR and CR in pts with R/R FL grade 1-3a and MZL irrespective of age. The efficacy and safety profiles of R2 and R-placebo in pts ≥ 70 y were similar to those reported in the overall population. Older pts treated with R2 vs R-placebo had superior mPFS (24.9 vs 14.3 mo). They were more likely to start lenalidomide at a lower dose and had lower median dose intensity which may have contributed to their shorter mPFS vs younger pts receiving R2. These data show that R2 maintained efficacy improvements vs R-placebo in pts ≥ 70 y, despite higher unfit status and lower overall lenalidomide treatment/exposure. Thus, R2 is an effective and available treatment option for pts with iNHL, including those with advanced age. Disclosures Trněný: Amgen: Consultancy, Honoraria; F. Hoffmann-La Roche: Consultancy, Honoraria; Abbvie: Consultancy, Honoraria; Takeda: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; Celgene: Consultancy; MorphoSys: Consultancy, Honoraria; Incyte: Consultancy, Honoraria; Bristol-Myers Squibb: Consultancy, Honoraria; Gilead Sciences: Consultancy, Honoraria. Leonard:Nordic Nanovector: Consultancy; Genentech, Inc./F. Hoffmann-La Roche Ltd: Consultancy; AstraZeneca: Consultancy; Celgene: Consultancy; Bayer Corporation: Consultancy; Epizyme, Inc: Consultancy; Karyopharm Therapeutics: Consultancy; Sutro Biopharma: Consultancy; Merck: Consultancy; Gilead: Consultancy; BeiGene: Consultancy; ADC Therapeutics: Consultancy; Sandoz: Consultancy; Akcea Therapeutics: Consultancy; Miltenyi: Consultancy; MorphoSys: Consultancy. Nowakowski:F. Hoffmann-La Roche Ltd: Research Funding; NanoString: Research Funding; Selvita: Membership on an entity's Board of Directors or advisory committees; Curis: Research Funding; Bayer: Consultancy, Research Funding; Celgene: Consultancy, Research Funding; Genentech, Inc.: Research Funding; MorphoSys: Consultancy, Research Funding. Izutsu:Chugai, Celgene, Daiichi Sankyo, Astra Zeneca, Eisai, Symbio, Ono, Bayer, Solasia, Zenyaku, Incyte, Novartis, Sanofi, HUYA Bioscience, MSD, Astellas Amgen, Abbvie, ARIAD, Takeda, Pfizer: Research Funding; Kyowa Kirin, Eisai, Takeda, MSD, Chugai, Nihon Medi-physics, Janssen, Ono, Abbvie, Dainihon Sumitomo, Bayer, Astra Zeneca, HUYA Japan, Novartis, Bristol-Byers Squibb, Mundi, Otsuka, Daiichi Sankyo, Astellas, Asahi Kasei: Honoraria; Celgene: Consultancy; Eisai, Symbio, Chugai, Zenyaku: Research Funding; Eisai, Chugai, Zenyaku: Honoraria. Fowler:TG Therapeutics: Membership on an entity's Board of Directors or advisory committees, Research Funding; Abbvie: Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Roche: Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Membership on an entity's Board of Directors or advisory committees, Research Funding. 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. Zinzani:Verastem: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; MSD: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Eusapharma: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Sanofi: Consultancy; Celltrion: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Gilead: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Janssen-Cilag: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; BMS: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Servier: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Sandoz: Membership on an entity's Board of Directors or advisory committees; Immune Design: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celgene: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Portola: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Roche: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Kyowa Kirin: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; TG Therapeutics: Honoraria, Speakers Bureau. Kalambakas:Celgene Corporation: Employment, Equity Ownership. Czuczman:Celgene Corporation: Employment, Equity Ownership. Fustier:Celgene Corporation: Employment, Equity Ownership. Wu:Celgene Corporation: Employment, Equity Ownership. Gribben:Janssen: Consultancy, Honoraria, Research Funding; Acerta/Astra Zeneca: Consultancy, Honoraria, Research Funding; Abbvie: Consultancy, Honoraria, Research Funding; Celgene: Consultancy, Honoraria, Research Funding.

Abstract Background: Southwest Oncology Group (SWOG) S0016 was a phase III randomized study that compared safety and efficacy of cyclophosphamide, doxorubicin, vincristine, prednisone and rituximab (CHOP-R) with CHOP followed by consolidation with (131) iodine-tositumomab radioimmunotherapy (CHOP-RIT) for previously untreated follicular lymphoma (FL) patients. As reported previously, the study demonstrated excellent outcomes in both arms with 2-year progression-free survival (PFS) of 76% and 80% and 2-year overall-survival (OS) of 97% and 93% in the CHOP-R and CHOP-RIT arms, respectively. (Press. et al. JCO, 2012) We now report the long term outcome of patients who were treated on the S0016 study. Methods: Between 2001 and 2008, 531 previously untreated advanced follicular lymphoma patients were randomized to receive either 6 cycles of CHOP every 3 weeks with 6 doses of rituximab (CHOP-R) or 6 cycles of CHOP every 3 weeks followed by RIT. Patients with advanced-stage disease (bulky stage II, III or IV) with any pathologic grade (1, 2 or 3) were eligible. Results: Patients on CHOP-R (n=264) and CHOP-RIT (n=267) arms had balanced baseline characteristics including age (median 54.5 vs. 53.4 years), presence of B symptoms (29% vs. 26%), pathologic grade 3 (8% vs. 9%), "high" FLIPI risk group (22% vs. 26%), stage IV disease (59% vs. 63%), elevated β2M (53% vs. 55%), bone marrow involvement (56% vs. 55%) and bulky disease (24% vs. 26%). Objective remissions were documented in 226 of 267 eligible patients treated with CHOP-R (85%) and in 226 of 264 patients with CHOP-RIT (86%). Complete remission (CR) rate was 40% in the CHOP-R and 45% in the CHOP-RIT arm. Neutropenia was the most common adverse event (AE) in both arms (48% vs. 51%). Rate of grade 3-5 AEs were not different except for thrombocytopenia which was more common in the CHOP-RIT group (18% vs. 2%). After a median follow-up of 9.6 years (range 0.1 - 14.4 years), the estimated 10-year PFS was 42% (95% CI: 35.6%, 48.5%) in the CHOP-R arm and 57% (95% CI: 50.5%, 63.2%) in the CHOP-RIT arm (p-value = 0.01). 51% of responders on the CHOP-R arm and 38% of responders on the CHOP-RIT arm have relapsed (p-value= 0.01). The estimated 2-year relapse-free survival was 76% for CHOP-R patients and 81% for CHOP-RIT patients (p-value=0.15). There were 48 deaths in the CHOP+R arm and 59 deaths in the CHOP-RIT arm with an estimated 10-year OS of 82% (95% CI: 76.3%, 86.4%) with CHOP-R and 77% (95% CI: 70.5%, 81.4%) with CHOP-RIT (p-value = 0.18). (Figure-1) During the follow-up, 41 patients (15.4%) in the CHOP-R arm and 37 patients (14%) in the CHOP-RIT arm developed secondary malignancies. MDS/AML were more common in the CHOP-RIT arm (11 patients; 4.2%) compared to CHOP-R arm (5 patients; 1.9%) with a relative risk of 2.2 (95% CI: 0.8-6.3) (P-value 0.12). Conclusion: With almost 10 years of follow-up, patients with FL treated on protocol S0016 show outstanding survival in both CHOP-R and CHOP-RIT arms, and represent the best published long-term outcomes to date in this disease. Indeed, almost half of patients enrolled still remain progression-free, confirming registry experiences. While CHOP-RIT provided significantly longer PFS and lower relapse rate compared to CHOP-R in our study, the OS rate was not different between 2 arms due in part to higher incidence of fatal MDS/AML in the CHOP-RIT group, emphasizing the importance of long-term follow-up, and calling into question the validity of PFS as a surrogate for OS in this setting. Given these outstanding outcomes, we believe chemoimmunotherapy should remain the standard induction approach for patients with high-risk FL until long-term follow-up of alternative approaches demonstrates superiority. Support: NIH/NCI grants CA180888, CA180819, CA180821 and in part by GlaxoSmithKline Disclosures Shadman: Emergent: Research Funding; Acerta: Research Funding; Gilead: Honoraria, Research Funding; Pharmacyclics: Honoraria, Research Funding. Rimsza:NCI/NIH: Patents & Royalties: L.M. Rimsza is a co-inventor on a provisional patent, owned by the NCI of the NIH, using Nanostring technology for determining cell of origin in DLBCL.. Gopal:Paid Consultancy- Gilead, Janssen, Seattle Genetics, Spectrum, Research funding- Gilead, Janssen, Pfizer, BMS, Merck, Teva, Takeda, Spectrum, Seattle Genetics: Consultancy, Honoraria, Research Funding. Maloney:Juno Therapeutics: Research Funding; Genentech/Roche: Honoraria. Cheson:Gilead: Research Funding; Pharmacyclics: Membership on an entity's Board of Directors or advisory committees, Research Funding; Acerta: Membership on an entity's Board of Directors or advisory committees, Research Funding. Smith:Amgen: Other: Educational lecture to sales force; TGTX: Consultancy; Celgene: Consultancy; Pharmacyclics: Consultancy; Genentech: Consultancy, Other: on a DSMB for two trials ; Portola: Consultancy; Juno: Consultancy; Gilead: Consultancy; AbbVie: Consultancy. Fisher:Seattle Genetics: Consultancy; Gilead: Consultancy; Johnson and Johnson: Consultancy. Friedberg:Bayer: Other: Data Safety Monitoring Committee. Press:Roche / Genentech: Consultancy, Research Funding.

Background: Standard first-line treatment for patients diagnosed with diffuse large B-cell lymphoma (DLBCL) is the R-CHOP regimen. Despite numerous efforts to improve on this regimen, in all comers and specifically in those with activated B-cell (ABC)-type DLBCL, results from large randomized studies have failed to show a significant clinical advantage above this standard. Recently, 2 large clinical trials in previously untreated DLBCL evaluated the combination of lenalidomide/R-CHOP (R2-CHOP) vs standard R-CHOP and demonstrated discordant results. We analyzed data from these trials to identify differences that may have impacted the disparate trial outcomes while identifying patient characteristics associated with benefit from the addition of lenalidomide across the trials. Methods: The 2 trials included in this evaluation are ROBUST, an international, randomized, double-blinded, placebo-controlled, phase III study of R2-CHOP vs placebo/R-CHOP, and the Intergroup ECOG-ACRIN 1412 (E1412) trial, a US-only, randomized, open-label, phase II study of R2-CHOP vs R-CHOP. Additional key study design differences included dosing, and subtype timing and inclusion (both studies used gene expression profiling [GEP] by NanoString). R-CHOP dosing differed only for prednisone, which was a flat 100 mg dose, d1-5 in ROBUST and 100 mg/m2, d1-5 in E1412. The lenalidomide dose and schedule varied between studies: 15 mg/d, d1-14/21 for ROBUST (210 mg/cycle) and 25 mg/d, d1-10/21 (250 mg/cycle) for E1412. ROBUST enrolled only patients prospectively identified with the ABC subtype, whereas E1412 enrolled all otherwise eligible patients and retrospectively evaluated for ABC-type with prespecified ABC-type accrual and power parameters. Both studies enrolled patients with IPI status ≥ 2, ECOG PS 0-2, and Ann Arbor stage II-IV (E1412 stage II with mass > 10 cm). The primary endpoint in both was progression-free survival (PFS; central review for ROBUST and investigator-assessed for E1412). Secondary endpoints included event-free survival (EFS; key for ROBUST), overall and complete response rates, overall survival (OS), and safety. Results: ROBUST enrolled 570 ABC patients and E1412 enrolled 280 GCB, ABC, and unclassified DLBCL patients. Patient profiles in both studies (ROBUST [ABC]/E1412 [all COO]) were similar in terms of median ages (65 y/66 y), male sex (58%/61%), and ECOG PS 1-2 (55%/63%). Patients in E1412 were more high risk: IPI 2 (42% ROBUST/34% E1412), IPI ≥ 3 (58%/66%), and Ann Arbor stage III/IV disease (87%/97%). Importantly, there was a notable difference in the time from patient diagnosis to treatment: median 31 days for ROBUST and 21 days (22% > 31 d) for E1412. Only 6% of patients in ROBUST were treated within 2 weeks of diagnosis vs 30% in E1412. At a median follow-up of ~2.5 y for both studies, E1412 met its primary endpoint of improvement in PFS with 34% reduction in the risk of PD/death (2-y PFS: 76% vs 70%) for all patients, but did not reach statistical significance in ABC-DLBCL patients for 2-y PFS (71% vs 61%) or 2-y OS (88% vs 76%). ROBUST showed no significant improvement in the primary PFS endpoint (2-y PFS: 67% vs 64%) or 2-y OS (79% vs 80%) in ABC patients. Subgroup analyses of PFS comparing R2-CHOP vs R-CHOP control within each study suggested that certain baseline factors favor the R2-CHOP arm, including: female sex, high IPI score (≥ 3), non-bulky disease (< 7 cm), and high Ann Arbor stage IV disease. Conclusion: While the ROBUST study design integrated state-of-the-art, real-time GEP to prospectively identify ABC-DLBCL patients with rapid lab turnaround time, cases of logistical delays in tissue submission for central analysis and staging procedures may have resulted in accrual of patients with lower-risk DLBCL and prolonged time from diagnosis to treatment. In contrast, E1412 retrospectively stratified patients by COO through GEP and was able to accrue higher-risk patients irrespective of COO within a shorter time from diagnosis to treatment, which among other differences (eg, smaller population size, study phase), could contribute to the improvement over R-CHOP control. Our comparative findings have significant implications for the design of future biomarker-driven trials and provide momentum for studies of novel combinations with R-CHOP in DLBCL. Further investigation into other factors, including dose intensity and their correlation with outcomes, will be presented. Disclosures Nowakowski: Celgene: Consultancy, Research Funding; NanoString: Research Funding; MorphoSys: Consultancy, Research Funding; Genentech, Inc.: Research Funding; F. Hoffmann-La Roche Ltd: Research Funding; Selvita: Membership on an entity's Board of Directors or advisory committees; Curis: Research Funding; Bayer: Consultancy, Research Funding. Chiappella:Servier: Other: advisory board, Speakers Bureau; Roche: Speakers Bureau; Teva: Speakers Bureau; Celgene: Other: advisory board, Speakers Bureau; Janssen: Other: advisory board, Speakers Bureau. Hong:Dana Farber Cancer Institute: Employment; Merck: Consultancy. Scott:Roche/Genentech: Research Funding; Celgene: Consultancy; Janssen: Consultancy, Research Funding; NanoString: Patents & Royalties: Named inventor on a patent licensed to NanoSting [Institution], Research Funding. Amengual:Appia Pharmaceuticals: Research Funding; Epizyme: Speakers Bureau. Leonard:BeiGene: Consultancy; Miltenyi: Consultancy; Sandoz: Consultancy; Gilead: Consultancy; Celgene: Consultancy; ADC Therapeutics: Consultancy; MorphoSys: Consultancy; ADC Therapeutics: Consultancy; Epizyme, Inc: Consultancy; Miltenyi: Consultancy; Genentech, Inc./F. Hoffmann-La Roche Ltd: Consultancy; Karyopharm Therapeutics: Consultancy; Akcea Therapeutics: Consultancy; Merck: Consultancy; Nordic Nanovector: Consultancy; Akcea Therapeutics: Consultancy; Bayer Corporation: Consultancy; Sandoz: Consultancy; MorphoSys: Consultancy; Gilead: Consultancy; BeiGene: Consultancy; AstraZeneca: Consultancy; Nordic Nanovector: Consultancy; Sutro Biopharma: Consultancy; Merck: Consultancy. Friedberg:Bayer: Honoraria, Other: Data & Safety Monitoring Committee; Acerta: Other: Data & Safety Monitoring Committee. Kostakoglu:F. Hoffman-La Roche: Consultancy; Genentech: Consultancy. Jurczak:Morphosys: Research Funding; Bayer: Research Funding; Roche: Research Funding; Incyte: Research Funding; Gilead: Research Funding; Celgene Corporation: Research Funding; Sandoz: Membership on an entity's Board of Directors or advisory committees, Research Funding; AstraZeneca: Membership on an entity's Board of Directors or advisory committees, Research Funding; Novo Nordisk: Research Funding; Servier: Research Funding; Takeda: Research Funding; TG Therapeutics: Research Funding; Celtrion: Research Funding; Janssen: Membership on an entity's Board of Directors or advisory committees, Research Funding; Loxo: Membership on an entity's Board of Directors or advisory committees, Research Funding. Yamamoto:Bristol-Myers Squibb: Consultancy, Honoraria; Bayer: Research Funding; Celgene Corporation: Consultancy, Honoraria, Research Funding; Mundipharma: Consultancy, Honoraria, Research Funding; Astra-Zeneca: Consultancy, Research Funding; Eisai: Consultancy, Honoraria, Research Funding; Meiji Seika Pharma: Consultancy, Honoraria; ARIAD: Research Funding; MSD: Consultancy, Honoraria; Gilead Sciences: Research Funding; Ono: Consultancy, Honoraria, Research Funding; SymBio: Research Funding; HUYA/IQVIA Services Japan: Consultancy, Honoraria; AbbVie: Consultancy, Research Funding; Chugai: Consultancy, Honoraria, Research Funding; Pfizer: Honoraria; Sumitomo Dainippon: Honoraria; Incyte: Research Funding; Janssen: Honoraria; Kyowa Kirin: Honoraria; Novartis: Honoraria, Research Funding; Otsuka: Honoraria; Sanofi: Honoraria; Solasia Pharma: Research Funding; Takeda: Consultancy, Honoraria, Research Funding. Czuczman:Celgene Corporation: Employment, Equity Ownership. Russo:Celgene Corporation: Employment, Equity Ownership. Hudak:Celgene Corporation: Employment, Equity Ownership; Novartis: Employment, Equity Ownership. Zhang:Celgene Corporation: Employment, Equity Ownership. Wade:Celgene: Employment, Equity Ownership. Kahl:ADC Therapeutics: Consultancy, Research Funding; BeiGene: Consultancy; TG Therapeutics: Consultancy; Seattle Genetics: Consultancy. Vitolo:Abbvie: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; F. Hoffmann-La Roche: Speakers Bureau; Juno Therapeutics: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Kite: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Gilead: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Janssen: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celgene: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. OffLabel Disclosure: Yes, these trials discuss off-label clinical trial investigation of lenalidomide plus R-CHOP in patients with newly diagnosed diffuse large B-cell lymphoma.