Kahl, Brad S.

Abstract Background: High grade B-cell Lymphoma with rearrangements of MYC and BCL2 and/or BCL6, also known as double hit lymphoma (DHL), and double expressing lymphomas (DEL; DLBCL with IHC expression of MYC and BCL2, but without double hit cytogenetics) are highly aggressive B cell non-Hodgkin lymphomas and patients (pts) often develop relapsed/refractory disease following standard first-line chemoimmunotherapy. DA-EPOCH-R is widely used in patients with DHL, and a phase 1 trial of venetoclax + DA-EPOCH-R established the dose of 600 mg for 5 days with each cycle as the recommended phase 2 dose (Rutherford, et al. Proc ASCO 2020). A051701 is a phase II/III randomized trial evaluating chemoimmunotherapy +/- the BCL2 inhibitor venetoclax in a DHL cohort (pts with DHL with BCL2 rearrangement and/or expression), and a DEL cohort. Here we report the initial results from the DHL cohort of A051701. Methods: Pts age ≥ 18 years with newly diagnosed DHL were stratified on International Prognostic Index (IPI) score and receipt of a single cycle of chemotherapy prior to registration, which was permitted, and randomized 1:1 to receive DA-EPOCH-R (Arm 1) or DA-EPOCH-R with venetoclax (Arm 2). Enrollment was based on local pathology results which were centrally confirmed. DA-EPOCH-R was administered as previously published. Venetoclax was dosed at 600 mg po daily on days 4-8 of cycle 1 and on days 1-5 of subsequent cycles for up to 6 total cycles. All cycles were supported by GCSF or peg-GCSF. For the interim analysis at the end of phase II, 53 events ensured 90% power to detect an improvement in 24-month progression-free survival (PFS) from 40% in Arm 1 to 60% in Arm 2 (HR=0.557) using a one-sided stratified log-rank test with type I error rate of 20%. The Alliance Data and Safety Monitoring Board approved the data release after accrual was stopped early due to excess toxicity in Arm 2. These data were frozen July 8, 2021. Results: 73 pts were registered (36 in Arm 1 and 37 in Arm 2) between 8/7/19 and 9/18/20. Analyses were performed for the modified intent-to-treat (mITT) population, defined as eligible pts with DHL histology confirmed (n=66; 30 Arm 1, 36 Arm 2). Median age was 65 years in both arms (range 37-80) and baseline demographic factors were well balanced. An allowed pre-protocol chemoimmunotherapy cycle was administered in 60% and 56% of Arm 1 and Arm 2 pts, respectively. The majority of pts had advanced stage disease (Arm 1 87%, Arm 2 86%), GCB immunophenotype (Arm 1 100%, Arm 2 88%), ECOG PS 0-1 (Arm 1 90%, Arm 2 86%), and high-intermediate/high risk IPI score (Arm 1 63%, Arm 2 64%). Therapy was completed per protocol in 70% and 47% of pts, respectively, for Arm 1 and 2, and disease progression on therapy occurred in 10% and 3%. Treatment was discontinued due to adverse events in 7% of pts in Arm 1 and 11% of pts in Arm 2. Consent was withdrawn after beginning treatment in 3% and 11% in Arm 1 and 2, respectively. Death on treatment occurred in 1 patient (3%; PJP pneumonia) in Arm 1 and 6 pts (17%; sepsis (n=4), cardiac arrest (n=2)) in Arm 2. The observation of excess deaths on Arm 2 prompted suspension of accrual to the DHL cohort. Treatment was discontinued for other reasons in 3 (10%) and 4 (11%) pts in Arms 1 and 2, respectively. Venetoclax was dose-reduced and/or omitted in 15 (42%) pts. Grade 4 neutropenia was not significantly different between arms (Arm 1 67%, Arm 2 71%), nor was grade ≥3 neutropenic fever (Arm 1 36%, Arm 2 40%). Sepsis occurred more frequently in Arm 2 (14% vs. 23%). The end of treatment overall and complete response rates in the mITT population were 73% and 67% in Arm 1, and 58% and 50% in Arm 2. The end of treatment overall and complete response rates among only pts evaluated for response (n=52) were 79% and 71% in Arm 1, and 88% and 75% in Arm 2. With a median follow-up of 7.4 months, the median PFS was not reached (NR) in Arm 1 (95% CI 6.1-NR) and was 6.7 months in Arm 2 (95% CI 4.5-NR) (two-sided p=0.13). The median OS was NR in Arm 1 and was 8.5 months in Arm 2 (95% CI 5.2-NR) (two-sided p=0.004). Conclusions: DA-EPOCH-R plus venetoclax in DHL pts resulted in excess treatment-related mortality compared to DA-EPOCH-R alone, prompting early discontinuation of accrual and venetoclax treatment for the study cohort. Based on these data, we recommend against combining venetoclax with DA-EPOCH-R in DHL. Robust accrual to this study shows that prospective trials are feasible in DHL, and the favorable outcome thus far in the DA-EPOCH-R arm may serve as a benchmark for future trials Figure 1 Figure 1. Disclosures Abramson: Astra-Zeneca: Consultancy; Allogene Therapeutics: Consultancy; Incyte Corporation: Consultancy; BeiGene: Consultancy; Kymera: Consultancy; Bluebird Bio: Consultancy; Genmab: Consultancy; EMD Serono: Consultancy; Bristol-Myers Squibb Company: Consultancy, Research Funding; C4 Therapeutics: Consultancy; Morphosys: Consultancy; Kite Pharma: Consultancy; Novartis: Consultancy; Seagen Inc.: Research Funding; AbbVie: Consultancy; Karyopharm: Consultancy; Genentech: Consultancy. Ruppert: Telios Pharma: Consultancy. Hsi: Seattle Genetics: Honoraria; Cytomx: Honoraria; Eli Lilly: Research Funding; AbbVie: Research Funding. Landsburg: Triphase: Research Funding; Takeda: Research Funding; Curis: Research Funding; Karyopharm: Membership on an entity's Board of Directors or advisory committees, Other: DSMB member; ADCT: Membership on an entity's Board of Directors or advisory committees; Incyte: Membership on an entity's Board of Directors or advisory committees; Morphosys: Membership on an entity's Board of Directors or advisory committees. Kahl: AbbVie, Adaptive, ADCT, AstraZeneca, Bayer, BeiGene, Bristol-Myers Squibb, Celgene, Genentech, Incyte, Janssen, Karyopharm, Kite, MEI, Pharmacyclics, Roche, TG Therapeutics, and Teva: Consultancy; AbbVie, Acerta, ADCT, AstraZeneca, BeiGene, Genentech: Research Funding. Friedberg: Acerta: Other: DSMC ; Novartis: Other: DSMC ; Bayer: Other: DSMC . Bartlett: Millennium: Research Funding; Janssen: Research Funding; Kite, a Gilead Company: Research Funding; Merck: Research Funding; Genentech: Research Funding; Celgene: Research Funding; Forty Seven: Research Funding; Bristol Myers Squibb: Research Funding; Roche/Genentech: Consultancy; Autolus: Research Funding; Seagen: Consultancy, Research Funding; Pharmacyclics: Research Funding; ADC Therapeutics: Consultancy, Research Funding. Leonard: ADC Therapeutics, AstraZeneca, Bayer, BMS/Celgene, Epizyme, Inc., Genmab, Gilead/Kite, Karyopharm, BMS/Celgene, Regeneron, MEI Pharma, Miltenyi, Roche/Genentech, Sutro: Consultancy; Roche/Genentech: Consultancy. OffLabel Disclosure: venetoclax in double hit lymphoma

Abstract BACKGROUND: E4402 was a randomized phase III study comparing two different rituximab dosing strategies for patients with previously untreated, low tumor burden follicular lymphoma (FL). The primary endpoint was time to treatment failure. The initial publication (Kahl, JCO 2014) demonstrated that a retreatment strategy utilized less drug and produced comparable time to treatment failure compared to a maintenance strategy. Here we provide long term follow up results, focusing on response duration, time to first cytotoxic therapy, overall survival, and risk of histologic transformation. METHODS: Eligible patients had untreated, low tumor burden (GELF criteria) FL. Patients received R 375 mg/m 2 weekly x 4 and responders were randomized to maintenance rituximab (MR) (single dose R q 3 months) or retreatment rituximab (RR) (R weekly x 4 doses at disease progression). Each strategy was continued until treatment failure. The primary endpoint, time to treatment failure, was defined as progression within 6 months of last R, no response to R retreatment, initiation of alternative therapy, or inability to complete protocol therapy. Secondary endpoints included time to first cytotoxic therapy, quality of life and safety. The ECOG Data Monitoring Committee recommended release of study results at a planned interim analysis in September 2011 and patients and providers were notified of results. Time to treatment failure data collection halted with release of the results but limited data collection on time to first cytotoxic therapy, response duration, and risk of histologic transformation continued. INITITIAL RESULTS: From 11/03 to 9/08, 384 patients with FL were enrolled. Complete or partial response was achieved in 289 patients (71%), who were then randomized to MR (n=146) or RR (n=143). Demographic features were similar in the two arms: median age 59 years; ECOG PS 0-1 in all patients, and FLIPI low-risk (14.9 vs. 16.4%), intermediate-risk (46.3 vs. 42.9%) and high-risk (38.8 vs. 40.7%) for MR vs. RR, respectively. At initial publication, with a median follow-up of 3.8 years, the time to treatment failure was 3.9 years for MR vs. 3.6 years for RR (p=NS). LONG TERM FOLLOW UP RESULTS: Immunoglobulin levels and risks for serious infections/late complications in MR patients will be updated at the annual meeting. For the endpoint of time to first cytotoxic therapy, the median follow up is 8.7 years. At 7 years, 83% of MR and 63% of RR remained free from first cytotoxic therapy (HR 2.37; 95% CI 1.50 - 3.76) [Figure 1]. For the endpoint of response duration, the median follow up is 12.1 years. At 10 years, 66% of the MR patients remained in their 1 st remission compared to 30% of the RR patients who remained in their 1 st remission [Figure 2]. The median response duration for RR patients receiving a single 4-week course of rituximab was 3.25 years. There was no difference in the overall survival at 10 years, 84% for MR vs. 83% for RR. There was a trend towards a lower risk of histologic transformation for patients receiving MR (n = 4) compared to RR (n = 11) (p = 0.11). CONCLUSIONS: With long term follow up, the RESORT data indicates that in previously untreated, low tumor burden, follicular lymphoma, MR was superior to RR for delaying time to first cytotoxic therapy and for response duration, with a trend towards reducing the risk of histologic transformation. MR did not improve the overall survival. The original publication concluded that the time to treatment failure is similar between the two dosing strategies. Due to study design, time to treatment failure could not be analyzed in this long term follow up analysis. Compared to the historical benchmark of 3 years median time to first cytotoxic therapy when watch and wait is utilized, single agent rituximab, administered by either dosing strategy, was highly effective at delaying the time to first cytotoxic therapy. Figure 1 Figure 1. Disclosures Kahl: AbbVie, Adaptive, ADCT, AstraZeneca, Bayer, BeiGene, Bristol-Myers Squibb, Celgene, Genentech, Incyte, Janssen, Karyopharm, Kite, MEI, Pharmacyclics, Roche, TG Therapeutics, and Teva: Consultancy; AbbVie, Acerta, ADCT, AstraZeneca, BeiGene, Genentech: Research Funding. Habermann: Incyte: Other: Scientific Advisory Board; Tess Therapeutics: Other: Data Monitoring Committee; Seagen: Other: Data Monitoring Committee; Morphosys: Other: Scientific Advisory Board; Loxo Oncology: Other: Scientific Advisory Board; Eli Lilly & Co.,: Other: Scientific Advisor. Schuster: Abbvie: Consultancy, Research Funding; Acerta Pharma: Consultancy; AstraZeneca: Consultancy; Adaptive Biotechnologies: Research Funding; BeiGene: Consultancy; Celgene: Consultancy, Honoraria, Research Funding; DTRM: Research Funding; Genetech: Consultancy, Research Funding; Roche: Consultancy, Research Funding; Incyte: Research Funding; Juno Theraputics: Consultancy, Research Funding; Loxo Oncology: Consultancy; Merck: Research Funding; Nordic Nanovector: Consultancy; Novartis: Consultancy, Honoraria, Patents & Royalties, Research Funding; Pharmaclcyclics: Research Funding; Tessa Theraputics: Consultancy; TG Theraputics: Research Funding. Fenske: TG Therapeutics: Consultancy, Speakers Bureau; Servier Pharmaceuticals: Consultancy; Seattle Genetics: Speakers Bureau; Sanofi: Speakers Bureau; Pharmacyclics: Consultancy; MorphoSys: Consultancy; Kite (Gilead): Speakers Bureau; KaryoPharm: Consultancy; CSL Therapeutics: Consultancy; Bristol-Myers Squibb: Speakers Bureau; Biogen: Consultancy; Beigene: Consultancy; AstraZeneca: Speakers Bureau; ADC Therapeutics: Consultancy; Adaptive Biotechnologies: Consultancy; AbbVie: Consultancy.

Abstract Background: Chemoimmunotherapy is considered standard initial therapy for follicular lymphoma (FL) with high tumor burden (HTB). Obinutuzumab and Bendamustine (OB) with maintenance Obinutuzumab (mO) is considered a standard therapy for the frontline treatment of HTB FL (GALLIUM, Marcus et al, NEJM 2017). Venetoclax (VEN), an oral BCL2 inhibitor, is an attractive target in FL given the high BCL2 expression; though single agent activity has been disappointing (Davids et al. JCO 2017). BCL2 inhibition is thought to be synergistic with chemotherapy. Thus, the PrE0403 study evaluated the OB-VEN combination in frontline HTB FL. Here we present end of induction (EOI) outcomes. Methods: The primary objective of this Phase II study was to estimate the complete remission (CR) rate at EOI. Potential participants must have had a histologically confirmed diagnosis of FL grade 1, 2, or 3a with HTB defined by GELF or high risk defined by FLIPI-1 criteria. They must have had adequate performance status and organ function. Notably, creatinine clearance must have been ≥50 mL/min. Participants must have not had prior treatment for FL. Eligible participants were treated with Bendamustine IV 90 mg/m2 Day (D) 1 & 2, Obinutuzumab IV 100 mg D1, 900 mg D2, 1000 mg D8 and D15 of Cycle (C) 1 then D1 of each cycle, and VEN 800 mg orally daily D1-10 every 28 days for 6 total cycles. Due to a high rate of laboratory tumor lysis syndrome (TLS) during C1 in the first 21 patients, VEN was removed from C1 and given in C2-6 only. Participants with a CR at EOI were treated with mO IV 1000 mg D1 every 8 weeks for 2 years. Those with a partial response (PR) or stable disease (SD) were treated with mO as well as VEN 800 mg orally daily for 2 years. Pneumocystis jiroveci Pneumonia (PJP) and antiviral prophylaxis was required as was G-CSF support. Response was assessed via Lugano Criteria at EOI including PET/CT and bone marrow assessment. Adverse Events (AEs) were evaluated using CTCAE v5.0. To be considered promising, OB-VEN should improve the null hypothesis CR rate of 50% (OB) to 65%. With an 85% power and a one sided 15% type I error, 56 participants would be needed with an estimated 51 eligible. Support for the study was from Genentech, Member of the Roche Group. Results A total of 56 participants were enrolled and treated between 12/2017 and 11/2020; baseline characteristics are listed in Table 1. TLS was closely monitored in C1 and 8/21 participants developed TLS when VEN was administered in C1; 0/35 when it was not. However, monitoring for TLS in C1 became less stringent when VEN was not administered. Treatment related Grade ≥3 toxicities occurred in 47/56 participants (83.9%) with serious adverse events in 31 of 56 (55.5%). Atypical infections were seen; there was one treatment related death on study due to cytomegalovirus (CMV) encephalitis as well as PJP pneumonia which occurred after induction C6. Enrollment was temporarily suspended and CMV monitoring was implemented with no further occurrences. Another participant receiving mO later developed BK virus nephropathy following mO C6 and now requires ongoing hemodialysis. Another was diagnosed with Respiratory Syncytial Virus pneumonia 30 days after C6 and later PJP pneumonia after C2 of mO. Common (incidence >10%) AEs during induction are listed in Table 2. 45 of 56 (80.4%) participants were able to receive all 6 cycles of OB-VEN. CR was seen in 41 of 56 participants (73.2%, 2 sided 95% Confidence Interval (CI) 59.7-84.2%) at the EOI. 30 participants (53.5%) went onto maintenance. With a median follow up of 20.9 months, estimated 2 year Overall Survival (OS) and Progression-Free Survival (PFS) (90% CI) is 94.4% (82.4-98.3%) and 85.8% (68.8-93.9%) respectively. Conclusions This Phase II study of OB-VEN in untreated HTB FL showed high CR rate and met its primary endpoint with early signs of prolonged PFS. Laboratory TLS was identified but it was unclear if attributed solely to VEN, as baseline laboratory TLS rate for OB is unknown. The rate of Grade ≥3 AE of 83.9% (compared to 69% for OB in GALLIUM, Hiddeman JCO 2018) and the observation of opportunistic infections including CMV encephalitis, PJP pneumonia and BK nephropathy, suggests the combination is highly immunosuppressive. Therefore, while the study met its primary outcome, the combination of OB-VEN at 800 mg for 10 days, plus mO, does not have an acceptable risk/benefit profile. Participants will continue to be followed for efficacy and safety during the maintenance phase. Figure 1 Figure 1. Disclosures Portell: Acerta/AstraZeneca: Research Funding; SeaGen: Research Funding; Pharmacyclics: Honoraria; Xencor: Research Funding; Aptitude Health: Honoraria; BeiGene: Honoraria, Research Funding; Abbvie: Research Funding; TG Therapeutics: Honoraria, Research Funding; Kite: Honoraria, Research Funding; Merck: Honoraria, Research Funding; Morphosys: Honoraria; Targeted Oncology: Honoraria; Genentech: Research Funding; VelosBio: Research Funding. Nowakowski: MorphoSys: Consultancy; Incyte: Consultancy; Kymera Therapeutics: Consultancy; TG Therapeutics: Consultancy; Blueprint Medicines: Consultancy; Nanostrings: Research Funding; Roche: Consultancy, Research Funding; Genentech: Consultancy, Research Funding; Celgene/Bristol Myers Squibb: Consultancy, Research Funding; Zai Labolatory: Consultancy; Daiichi Sankyo: Consultancy; Bantham Pharmaceutical: Consultancy; Curis: Consultancy; Karyopharm Therapeutics: Consultancy; Selvita: Consultancy; Ryvu Therapeutics: Consultancy; Kyte Pharma: Consultancy. Cohen: Janssen, Adicet, Astra Zeneca, Genentech, Aptitude Health, Cellectar, Kite/Gilead, Loxo, BeiGene, Adaptive: Consultancy; Genentech, BMS/Celgene, LAM, BioINvent, LOXO, Astra Zeneca, Novartis, M2Gen, Takeda: Research Funding. Kahl: AbbVie, Acerta, ADCT, AstraZeneca, BeiGene, Genentech: Research Funding; AbbVie, Adaptive, ADCT, AstraZeneca, Bayer, BeiGene, Bristol-Myers Squibb, Celgene, Genentech, Incyte, Janssen, Karyopharm, Kite, MEI, Pharmacyclics, Roche, TG Therapeutics, and Teva: Consultancy. OffLabel Disclosure: Venetoclax is not approved for follicular lymphoma or in combination with bendamustine and obinutuzumab

7503 Background: Optimal initial therapy for mantle cell lymphoma (MCL) remains uncertain. The randomized phase 2 NCTN trial E1411 tested if progression-free survival (PFS) is prolonged by addition of bortezomib (V) (1.6 mg/m2 SC/IV days 1, 8) to bendamustine-rituximab (BVR vs BR) induction and/or by addition of lenalidomide (L) to rituximab (LR vs R) consolidation. Here we report efficacy and toxicity of induction BVR vs BR. Methods: 373 pts, accrued 2012–16, stratified by MIPI and age (≥60) received 1 of 4 arms: A) BR induction x 6 followed by R x 2 yrs, B) BVR followed by R, C) BR followed by LR or D) BVR followed by LR. Eligible pts had untreated MCL, ≥ age 18 (amended from ≥60 when S1106 for < 65 closed), ECOG PS 0-2 and adequate hematologic and organ function. Pts without progressive disease during induction proceeded to consolidation. Primary induction objective was whether adding bortezomib (BVR) (Arms B + D) to BR (Arms A + C) improves PFS, irrespective of consolidation R vs LR. Design of 360 eligible treated pts would provide 93.8% power to detect 10% improvement in 2-yr PFS from 70% hypothesized for BR, corresponding to 37.4% reduction in hazard using stratified log-rank test at 1-sided 10% alpha. Efficacy population was 179 (BVR) and 180 (BR), induction treatment completed in 144 vs 153, progressive disease during induction 6 vs 7 and registration to consolidation 140 vs 145. Results: Baseline demographics did not differ between the groups, with median age 67 (range 42-90) and 13% < 60 yr, 73% men, ECOG PS 0-1 97%, MIPI Low/Med/Hi 37/29/34%. Estimated PFS at 2 yrs 79.6% BVR (95% CI 73.8-85.9) vs 74.5% BR (95% CI 68.2-81.4) (1-sided stratified log-rank p = 0.268). With median PFS follow-up 51 mos, median PFS estimated at 64.1 and 64.0 mos. Overall response rate (ORR) for BVR was 88.9% (CR 65.5%) vs 89.5% (CR 60.5%) BR (z-test 1 sided p = 0.577 for ORR). Treatment related deaths during induction were 2 in BVR (cardiac arrest, hepatitis) and 1 in BR (tumor lysis). Grade ≥ 3 toxicities were 88.1% (163/185) BVR vs 77.5% (145/187) BR. For BVR vs BR grade ≥ 3 neutropenia occurred in 52 vs 39 pts, though febrile neutropenia (7 vs 6), anemia (7 vs 8) and thrombocytopenia (18 vs 16) did not differ. Peripheral neuropathy (PN) grade 2 was 8 sensory for BVR vs 2 sensory/1 motor for BR, while grade 3 PN was 6 sensory/1 motor for BVR vs 0 with BR. The only non-hematologic grade ≥ 3 toxicity in > 5% of pts was rash (9 vs 12 pts). Conclusions: Bortezomib did not significantly improve the primary endpoint of PFS when added to BR as initial MCL therapy. ORR and CR rates at end of induction were also similar. Follow-up continues to assess the entire treatment regimen, including consolidation R vs LR, but the PFS > 5 yrs, high ORR and MRD negativity rate (Smith et al ASH 2019) in this BR-based trial support BR as a platform for MCL induction therapy. Clinical trial information: NCT01415752.

AbstractIntroductionWhile most patients with mantle cell lymphoma (MCL) receive therapy shortly after diagnosis, a subset of patients with indolent‐behaving disease can safely defer treatment. In this subgroup, we evaluated the importance of treatment intensity in patients with MCL who defer initial therapy.MethodsOut of 1134 patients with MCL from 12 academic centers, we analyzed 219 patients who initiated therapy at least 90 days after diagnosis. Patients who received induction with high‐dose cytarabine and/or autologous stem cell transplantation (ASCT) in first remission were considered to have received intensive therapy (n = 88) while all other approaches were non‐intensive (n = 131).ResultsThere was no difference in progression‐free (PFS; P = .224) or overall survival (OS; P = .167) in deferred patients who received non‐intensive vs. intensive therapy. Additionally, univariate and multivariate Cox proportional hazards models were performed for PFS and OS. Treatment at an academic center (HR 0.43, P = .015) was associated with improved OS in both univariate and multivariate models, while intensity of treatment was not associated with improved OS in either model.ConclusionsThese results indicate that intensified initial treatment is not associated with improved survival after deferring initial therapy, although prospective studies are needed to determine which of these patients with MCL may benefit from intensive therapy.

PURPOSE Lenalidomide combined with rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) (R2CHOP) in untreated diffuse large B-cell lymphoma (DLBCL) has shown promising activity, particularly in the activated B-cell–like (ABC) subtype. Eastern Cooperative Oncology Group (ECOG)-ACRIN trial E1412 was a randomized phase II study comparing R2CHOP versus R-CHOP in untreated DLBCL. PATIENTS AND METHODS Patients with newly diagnosed DLBCL, stage II bulky-IV disease, International Prognostic Index (IPI) ≥ 2, and ECOG performance status ≤ 2 were eligible and randomly assigned 1:1 to R2CHOP versus R-CHOP for six cycles. Tumors were analyzed using the NanoString Lymph2Cx for cell of origin. The primary end point was progression-free survival (PFS) in all patients with the co-primary end point of PFS in ABC-DLBCL. Secondary end points included overall response rate (ORR), complete response (CR) rate, and overall survival (OS). RESULTS Three hundred forty-nine patients were enrolled; 280 patients (145 R2CHOP and 135 R-CHOP) were evaluable: 94 were ABC-DLBCL, 122 germinal center B-cell–like-DLBCL, 18 unclassifiable, and 46 unknowns. Baseline characteristics were well-balanced between arms, and the median age was 66 (range, 24-92); 70% of patients had stage IV disease; 34%, 43%, and 24% had IPI 2, 3, and 4 or 5, respectively. Myelosuppression was more common in the R2CHOP arm. The ORR and CR rate were 92% and 68% in R-CHOP and 97% ( P = .06) and 73% ( P = .43) in the R2CHOP arm, respectively. The median follow-up was 3.0 years; R2CHOP was associated with a 34% reduction in risk of progression or death versus R-CHOP (hazard ratio [HR], 0.66 95% CI, 0.43 to 1.01) and 3-year PFS of 73% versus 61%, one-sided P = .03, and an improvement in OS (83% and 75% at 3 years; HR, 0.67; one-sided P = .05). The PFS HR for R2CHOP was 0.67 for ABC-DLBCL, one-sided P = .1. CONCLUSION In this signal-seeking study, the addition of lenalidomide to R-CHOP (R2CHOP) improved outcomes in newly diagnosed DLBCL including patients with ABC-DLBCL.

Introduction: FL is the most common indolent non-Hodgkin lymphoma in the Western world. FL may cause disease-related symptoms, and patients with high-risk disease usually require systemic therapy. BR is commonly used as first-line therapy for high-risk FL, and the addition of bortezomib to a BR backbone has been studied (Evens A et al. Clin Can Res 2020). Little is known about how these therapeutic options impact patients' health-related quality of life (HRQL). To fill this gap, patient-reported outcomes (PROs) were administered to patients enrolled on E2408 to quantify symptom burden and effects of BR versus BVR induction on HRQL. Methods: Patients (n=258) randomized to receive 6 cycles of BR or BVR induction completed PROs assessing neurotoxicity (FACT/GOG-Ntx) at the beginning of each treatment cycle. Additional PROs measuring fatigue (FACT-F), lymphoma-specific concerns (FACT-Lym) and HRQL (Functional Assessment of Cancer Therapy-General; FACT-G) were completed at baseline, mid-treatment (MT; cycle 3/4) and end of induction (EOI; cycle 6). Paired t-test was used to assess PRO score changes from baseline to MT and EOI within BR or BVR group. Two-sample t-test was used to compare change scores between groups at MT and EOI, respectively. Univariate analyses with a linear model identified patient baseline characteristics and clinical factors (age, sex, stage, performance status, # extra nodal sites, FLIPI, GELF, bone marrow involvement, elevated LDH, palpable splenomegaly, B-symptoms, CRIS) associated with PRO change scores from baseline to EOI, adjusting for treatment group. A multivariate model was built with backward variable selection approach for each of the PROs. Results: As shown in Figure 1, compared with baseline, patients randomized to BVR reported significantly worse FACT/GOG-Ntx scores at cycle 4, which continued to end of induction (FACT/GOG-Ntx change scores -2.91 to -3.73; p &lt; 0.001). Neurotoxicity remained stable for patients treated with BR (Ntx change scores -0.02 to -0.55). FACT-Fatigue scores indicated worse fatigue at MT compared to baseline for patients receiving BVR (-2.7, p&lt;0.05), yet they remained stable for BR. FACT-Lym scores were significantly higher at MT (BR: 2.69, p&lt;0.001; BVR: 2.71, p=0.007) and end of induction (BR: 3.32, p&lt;0.001; BVR: 3.55, p&lt;0.001) compared to baseline, signifying a reduction in lymphoma-related symptoms in both arms. FACT-G scores were comparable between treatment arms at each time-point and did not change significantly from baseline to end of induction. Univariate analyses among all patients identified older age and the absence of palpable splenomegaly at baseline as associated with worse FACT-Lym, FACT-Fatigue, and FACT-G change scores, signifying less improvement in lymphoma-related symptoms, fatigue and HRQL from baseline to end of induction (p&lt;0.01). The presence of B-symptoms at baseline was associated with a greater reduction in lymphoma-related symptoms and fatigue from baseline to end of induction (p&lt;0.01). Higher ECOG performance status was only associated with higher FACT-Fatigue change score, suggesting more improvement in fatigue for those with worse performance status at baseline. A multivariate model generated similar results. Conclusions: Despite worse treatment-related symptoms throughout induction, the addition of bortezomib was associated with comparable overall HRQL to those treated with BR. Both treatments were associated with a reduction in lymphoma-related symptoms from baseline to end of induction, likely contributing to stable HRQL throughout treatment despite treatment-related symptoms. Findings also suggest that a subgroup of patients, particularly those who are older, may experience fewer improvements in lymphoma-related symptoms. This underscores the potential need for closer monitoring and clinical management of these patients. Collectively, results are likely to be encouraging for patients experiencing lymphoma-related symptoms, for whom the symptom burden associated with treatment may be worth the trade-off given the potential for improved disease-related symptom control. Disclosures Evens: Merck: Consultancy, Honoraria, Research Funding; Seattle Genetics: Consultancy, Honoraria, Research Funding; Abbvie: Consultancy, Honoraria; Pharmacyclics: Consultancy, Honoraria; MorphoSys: Consultancy, Honoraria; Research To Practice: Honoraria, Speakers Bureau; Epizyme: Consultancy, Honoraria, Research Funding; Mylteni: Consultancy, Honoraria; Novartis: Consultancy, Honoraria. Advani:Celgene, Forty Seven, Inc., Genentech/Roche, Janssen Pharmaceutical, Kura, Merck, Millenium, Pharmacyclics, Regeneron, Seattle Genetics: Research Funding; Astra Zeneca, Bayer Healthcare Pharmaceuticals, Cell Medica, Celgene, Genentech/Roche, Gilead, KitePharma, Kyowa, Portola Pharmaceuticals, Sanofi, Seattle Genetics, Takeda: Consultancy. Ansell:Trillium: Research Funding; Affimed: Research Funding; Regeneron: Research Funding; AI Therapeutics: Research Funding; Takeda: Research Funding; Seattle Genetics: Research Funding; Bristol Myers Squibb: Research Funding; ADC Therapeutics: Research Funding. Winter:Norvartis: Consultancy, Other: DSMB; Ariad/Takeda: Consultancy; CVS/Caremark: Consultancy; Delta Fly Pharma: Consultancy; Amgen: Consultancy; Epizyme: Other: DSMB; Merck: Membership on an entity's Board of Directors or advisory committees, Other: advisory board; Karyopharm: Membership on an entity's Board of Directors or advisory committees, Other: advisory board. Cella:FACIT.org: Membership on an entity's Board of Directors or advisory committees, Other: President; Astellas: Consultancy, Honoraria; Pled Pharma: Research Funding; Janssen: Research Funding; Clovis: Research Funding; Alexion: Research Funding; Apellis: Consultancy; Pfizer: Consultancy, Research Funding; Novartis: Consultancy; Kiniksa: Consultancy; IDDI: Consultancy; BMS: Consultancy, Research Funding; ASAHI KASEI PHARMA CORP.: Consultancy; Oncoquest: Consultancy; Mei Pharma: Consultancy; Ipsen: Consultancy, Research Funding; Evidera: Consultancy; DSI: Consultancy, Research Funding; BlueNote: Consultancy; Abbvie: Consultancy, Research Funding; PROMIS Health Org: Membership on an entity's Board of Directors or advisory committees, Other. Kahl:ADC Therapeutics: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees; BeiGene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Roche Laboratories Inc: Consultancy; Pharmacyclics LLC: Consultancy; Genentech: Consultancy; Celgene Corporation: Consultancy; AstraZeneca Pharmaceuticals LP: Consultancy, Membership on an entity's Board of Directors or advisory committees; AbbVie: Consultancy; Acerta: Consultancy, Research Funding. Wagner:Celgene Inc.: Membership on an entity's Board of Directors or advisory committees; Connect Multiple Myeloma Registry: Membership on an entity's Board of Directors or advisory committees.

Background: Plasmablastic lymphoma (PBL) is a rare subtype of Non-Hodgkin Lymphoma with a well-known association with HIV infection. The outcomes of PBL patients are typically described with high relapse rates and poor prognosis. (Loghavi S, J Hematol Oncol. 2015; Morscio J, Am J of Pathol. 2014; Castillo JJ, Clin Lymphoma Myeloma Leuk. 2011; Castillo JJ, Am J Hematol. 2008) There has been a paucity of data suggesting that limited stage disease (Ann Arbor stage I-II) may have a more favorable prognosis. However, due to the rarity of this disease there have been no large-scale reviews to confirm this. Thus, many patients with limited stage disease are subject to the aggressive therapy recommendations based on the poor outcomes of PBL patients as a whole. (Loghavi S, J Hematol Oncol. 2015; NCCN Guidelines, version 2.2020; Al-Malki MM, BBMT. 2014) We attempted to determine the treatment patterns and outcomes of patients with limited stage PBL. Methods: We conducted a multi-center (13 US academic centers) retrospective study of patients with limited stage (Ann Arbor stage I-II) Plasmablastic lymphoma. Determination of limited stage and diagnosis of PBL was determined by the investigators at each individual center. Patients diagnosed between 1/1/1990 and 6/1/2018 were included. Baseline demographic, clinical, laboratory, pathology, and outcomes data were extracted by retrospective chart review. Kaplan Meier was utilized for time to event analysis. Results: Baseline characteristics are included in table 1. A total of 80 patients were identified with limited stage disease. With a median follow up of 34 months the 3-yr Progression free survival (PFS) and overall survival (OS) was 71.9% and 78.7% respectively (Figure 1A and 1B). Patients that received frontline chemotherapy with (n=29) and without RT (n=36) had a 3-yr PFS and OS of 84.6% and 96.2% as compared to 64.5% and 70.8%, respectively (Figure 2A and 2B; Figure 3A and 3B). The Hazard ratio (HR) for PFS and OS for chemo (reference) vs chemo-RT was 0.47 (95% CI 0.18-1.3; P=0.131) and 0.18 (95% CI 0.04-0.84; p=0.029) respectively. The HR for PFS and OS for CHOP (n=14, reference) vs EPOCH (n=33) based regimens was 0.37 (95% CI 0.11-1.2; p=0.106) and 0.36 (95% CI 0.079-1.6; p=0.182) respectively. Patients with stage I/IE disease (n=56) had a 3-yr PFS and OS of 73.1% and 81.2% respectively. Patients with stage II/IIE disease (n=24) had a 3-yr PFS and OS of 69.3% and 73.4% respectively. Patients that received aggressive treatment (n=17) with Hyper-CVAD based regimens and/or Auto-SCT as consolidation had a 3-yr PFS and OS of 63.6% and 72.7% respectively. Patients with concomitant HIV (n=16) had a 3-yr PFS and OS of 80.8% and 77.4% respectively. Seven patients received RT alone and 6 patients had surgical resection alone as frontline therapy; 1 patient received no therapy; 1 patient received HAART therapy only and remains in CR without any other treatment for PBL 29 months after diagnosis. There were 8 deaths (10%) related to PBL, 3 deaths (4%) related to treatment of PBL (2 during frontline chemo and 1 upon relapse with salvage chemo), and 9 deaths (11%) related to other causes. The 3-yr lymphoma free survival (LFS) of the entire cohort, pts receiving chemo alone, and pts receiving chemo-RT (without including treatment related mortality (TRM) as an event) was 89.1%, 85.2%, and 100% respectively. The 3-yr LFS survival of the entire cohort, pts receiving chemo alone, and pts receiving chemo-RT (including TRM as an event) was 85.1%, 80.0%, and 96.2% respectively. Discussion: Here we report the largest review to our knowledge of limited stage PBL. Outcomes appear to be excellent with 3-yr PFS and OS of 71.9% and 78.7% respectively and a 3-yr LFS of 89.1% (85.1% when attributing TRM as an event). There was no obvious benefit to receiving aggressive therapy with H-CVAD based regimens and/or Auto-SCT. Although this is a small, uncontrolled sample size the HR for OS was improved in patients receiving frontline chemo-RT vs chemo alone 0.18 (95% CI 0.04-0.84; p=0.029). However, this did not take into account TRM with or progression while receiving frontline chemotherapy. Patients who were HIV+ had similar PFS and OS outcomes compared to the entire cohort. This retrospective study clearly demonstrates the favorable outcomes in this patient population, especially in those able to receive definitive therapy for their disease. Disclosures Hess: ADC Therapeutics: Consultancy, Membership on an entity's Board of Directors or advisory committees; BMS, AstraZeneca: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Patel:Takeda: Consultancy, Research Funding; Precision Biosciences: Research Funding; Nektar: Consultancy, Research Funding; Celgene: Consultancy, Research Funding; Bristol Myers Squibb: Consultancy, Research Funding; Poseida: Research Funding; Cellectis: Research Funding; Oncopeptides: Consultancy; Janssen: Consultancy, Research Funding. Nowakowski:Nanostrings: Research Funding; Seattle Genetics: Consultancy; Curis: Consultancy; Ryvu: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other; Kymera: Consultancy; Denovo: Consultancy; Kite: Consultancy; Celgene/BMS: Consultancy, Research Funding; Roche: Consultancy, Research Funding; MorphoSys: Consultancy, Research Funding. Chavez:Bayer: Consultancy; AbbVie: Consultancy; BeiGene: Speakers Bureau; Morphosys: Consultancy, Speakers Bureau; Merck: Research Funding; AstraZeneca: Speakers Bureau; Celgene: Consultancy; Genentech: Speakers Bureau; Epizyme: Speakers Bureau; Gilead: Consultancy; Novartis: Consultancy; Kite, a Gilead Company: Consultancy, Speakers Bureau; Karyopharm: Consultancy; Verastem: Consultancy; Pfizer: Consultancy. Hill:Beigene: Consultancy, Honoraria, Research Funding; Abbvie: Consultancy, Honoraria, Research Funding; Genentech: Consultancy, Honoraria, Research Funding; Takeda: 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; Pharmacyclics: Consultancy, Honoraria, Research Funding; Karyopharm: Consultancy, Honoraria, Research Funding. Maddocks:Pharmacyclics: Consultancy, Honoraria; Morphosys: Consultancy, Honoraria; Celgene: Consultancy, Honoraria; Seattle Genetics: Consultancy, Honoraria; Karyopharm: Consultancy; ADC Therapeutics, AstraZeneca: Consultancy; BMS: Consultancy, Research Funding. Wagner-Johnston:ADC Therapeutics, Regeneron, CALIB-R, Verastem: Membership on an entity's Board of Directors or advisory committees. Kahl:AstraZeneca Pharmaceuticals LP: Consultancy, Membership on an entity's Board of Directors or advisory committees; AbbVie: Consultancy; Pharmacyclics LLC: Consultancy; Genentech: Consultancy; Acerta: Consultancy, Research Funding; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees; Celgene Corporation: Consultancy; ADC Therapeutics: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; BeiGene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Roche Laboratories Inc: Consultancy. Alderuccio:ADC Therapeutics: Membership on an entity's Board of Directors or advisory committees; Forma Therapeutics: Other: Family member; Agios Pharmaceuticals: Other: Family member; Oncinfo: Honoraria; Inovio Pharmaceuticals: Other: Family member; Foundation Medicine: Other: Family member; Puma Biotechnology: Other: Family member; OncLive: Honoraria. Lossos:Janssen Biotech: Honoraria; Verastem: Consultancy, Honoraria; Janssen Scientific: Consultancy, Other; Seattle Genetics: Consultancy, Other; Stanford University: Patents & Royalties; NCI: Research Funding. Portell:Bayer: Consultancy; BeiGene: Consultancy, Research Funding; Kite: Consultancy, Research Funding; Acerta/AstraZeneca: Research Funding; Amgen: Consultancy; Janssen: Consultancy; Pharmacyclics: Consultancy; AbbVie: Research Funding; TG Therapeutics: Research Funding; Infinity: Research Funding; Roche/Genentech: Consultancy, Research Funding; Xencor: Research Funding. Landsburg:Celgene: Membership on an entity's Board of Directors or advisory committees; Triphase: Research Funding; Takeda: Research Funding; Curis: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Karyopharm: Membership on an entity's Board of Directors or advisory committees; Morphosys: Membership on an entity's Board of Directors or advisory committees; Seattle Genetics: Speakers Bureau. Castillo:TG Therapeutics: Research Funding; Beigene: Consultancy, Research Funding; Kymera: Consultancy; Janssen: Consultancy, Research Funding; Abbvie: Research Funding; Pharmacyclics: Consultancy, Research Funding.

Background FDG-PET is used in staging and response assessments in patients (pts) with DLBCL. An analysis of 158 pts with DLBCL receiving R-CHOP or DA-EPOCH-R on CALGB/Alliance 50303 failed to show an association between the interim PET (iPET, after cycle 2 of therapy) visual 5-point scale score (5-PS) by central review and progression-free survival (PFS) or overall survival (OS), but did show a significant association between percent change in FDG uptake from baseline to after cycle 2 (∆SUV) and PFS/OS (Schoder et al. 2020). As central review of FDG-PET is not feasible in routine practice, we retrospectively compared local vs central readings, and determined associations from local imaging data with PFS/OS. Methods 126 pts at baseline and 109 at iPET had local imaging data submitted across 21 institutions. Visual scores 1-3 defined PET- and scores 4-5 defined PET+ disease. ∆SUV was defined as the percent change in the maximum SUV at any site (maxSUV) from baseline to iPET. Continuous ∆SUV and categorized ∆SUV (&lt;66% vs &gt;66%) were analyzed. Differences in quantitative measures were calculated as the local minus central result. The Kappa statistic estimated agreement in PET and ∆SUV groups between local and central review. PFS and OS distributions for local PET and ∆SUV groups were landmarked at iPET, estimated with the Kaplan-Meier method, and compared using the log-rank test. Results At baseline, maxSUV was reported locally and centrally in 118 pts. Median maxSUV was 24.3 (range: 5.9-77.3) by local review and 24.3 (range: 5.9-77.0) by central review. The median difference in maxSUV was 0 (range: -12.9 to 21.9), with 50% of differences between -1.1 and 0.1, and 90% of differences between -7.8 and 4.1. In 106 pts with visual iPET 5-PS results, 52 (49.1%) were PET+ by local review and 37 (34.9%) by central review. Agreement in local and central review was moderate (kappa=0.53), occurring in 81 pts (76.4%; 32 PET+ and 49 PET-). Disagreement occurred in 25 patients, 20 with local PET+ but central PET- and 5 with local PET- but central PET+. iPET maxSUV was reported locally and centrally in 90 pts. Median maxSUV was 3.4 (range: 0-18.3) by local review and 3.3 (range: 1.2-18.2) by central review. The median difference in maxSUV was 0 (range: -8.6 to 2.4), with 50% of differences between -0.3 and 0.4, and 90% of differences between -4.4 and 1.8. ∆SUV was calculated in 87 pts. Median ∆SUV was 84.6% (range: -3.0% to 95.9%) by local review and 85.1% (range: -34.9% to 95.8%) by central review. The median difference in ∆SUV was -0.3 (range: -19.6 to 31.9), with 50% of differences between -2.1 and 1.1, and 90% of differences between -7.1 and 12.3. ∆SUV was &lt;66% in 12 (13.8%) pts by local review and 12 pts by central review. Agreement in local and central review was high (kappa=0.81), occurring in 83 pts (95.4%; 10 with ∆SUV &lt;66%, 73 with ∆SUV &gt;66%). Disagreement occurred in 4 pts, 2 in each direction. Using local data, PFS and OS estimates were numerically lower in pts with iPET+ vs iPET- disease, but did not reach statistical significance (p=0.12 and p=0.15). Two-year estimates for PFS were 79% (95% CI 68-91%) and 89% (95% CI 81-98%), and 2-year estimates for OS were 84% (95% CI 75-95%) and 96% (95% CI 91-100%) in pts with iPET+ and iPET-, respectively. In contrast, ∆SUV groups were significantly associated with PFS and OS (p=0.03 and p=0.002). Two-year estimates for PFS were 56% (95% CI 34-94%) and 87% (95% CI 79-95%) and 2-year estimates for OS were 56% (95% CI 34-94%) and 93% (95% CI 88-99%) in pts with ∆SUV &lt;66% and ∆SUV &gt;66%, respectively. Conclusion Agreement in visual 5-PS at iPET was moderate; most discrepancies arose from a local PET+ result when central review called PET-. Differences in maxSUV and ∆SUV tended to be small. Grouping ∆SUV resulted in only 4 discrepancies (4.6%). Similar to the previous analysis using central data, the separation in PFS and OS curves using local data for ∆SUV was greater than by visual 5-PS. Encouragingly, the agreement in ∆SUV of &lt;66% vs ≥66% was high between local and central review. Overall agreement however may be unduly influenced by the large proportion of pts with ∆SUV ≥66%, with less certainty in agreement for pts with ∆SUV &lt;66%. Larger prospective studies comparing local and central imaging data are warranted to best determine the utility of local imaging in clinical trials. Support: P30 CA008748, U10CA180821, U10CA180882; https://acknowledgments.alliancefound.org. ClinicalTrials.gov Identifier: NCT00118209 (CALGB 50303) Disclosures Kahl: Acerta: Consultancy, Research Funding; ADC Therapeutics: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees; BeiGene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Roche Laboratories Inc: Consultancy; Pharmacyclics LLC: Consultancy; Genentech: Consultancy; Celgene Corporation: Consultancy; AstraZeneca Pharmaceuticals LP: Consultancy, Membership on an entity's Board of Directors or advisory committees; AbbVie: Consultancy. Friedberg:Astellas: Consultancy; Acerta Pharma - A member of the AstraZeneca Group, Bayer HealthCare Pharmaceuticals.: Other; Portola Pharmaceuticals: Consultancy; Seattle Genetics: Research Funding; Roche: Other: Travel expenses; Kite Pharmaceuticals: Research Funding; Bayer: Consultancy. Leonard:MEI Pharma: Consultancy; Sutro: Consultancy; Bayer: Consultancy; BMS/Celgene: Consultancy; GenMab: Consultancy; Roche/Genentech: Consultancy; Gilead/Kite: Consultancy; ADC Therapeutics: Consultancy; Regeneron: Consultancy; Epizyme: Consultancy; Miltenyi: Consultancy; AstraZeneca: Consultancy; Karyopharm: Consultancy. Bartlett:Pfizer: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Pharmacyclics: Research Funding; Millennium: Research Funding; Merck: Research Funding; Kite, a Gilead Company: Research Funding; Immune Design: Research Funding; Janssen: Research Funding; Forty Seven: Research Funding; BMS/Celgene: Research Funding; BTG: Consultancy; Seattle Genetics: Membership on an entity's Board of Directors or advisory committees, Research Funding; Roche/Genentech: Consultancy, Research Funding; Seattle Genetics: Consultancy, Research Funding; Acerta: Consultancy; Affimed Therapeutics: Research Funding; ADC Therapeutics: Consultancy; Autolus: Research Funding.

PURPOSEDiffuse large B-cell lymphoma (DLBCL) presents as a limited-stage disease in 25% to 30% of patients, with better overall survival (OS) than that for advanced-stage disease but with continuous relapse regardless of treatment approach. The preferred treatment is abbreviated rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) and radiation therapy. On the basis of promising results of positron emission tomography (PET)–directed treatment approaches, we designed a National Clinical Trials Network (NCTN) study to improve outcomes and decrease toxicity.METHODSPatients with nonbulky (< 10 cm) stage I/II untreated DLBCL received 3 cycles of standard R-CHOP therapy and underwent a centrally reviewed interim PET/computed tomography scan (iPET). Those with a negative iPET proceeded with 1 additional cycle of R-CHOP, whereas those with a positive iPET received involved field radiation therapy followed by ibritumomab tiuxetan radioimmunotherapy.RESULTSOf 158 patients enrolled, 132 were eligible and 128 underwent iPET, which was positive in 14 (11%) of the patients. With a median follow-up of 4.92 years (range, 1.1-7.7 years), only 6 patients progressed and 3 died as a result of lymphoma. Eleven patients died as a result of nonlymphoma causes at a median age of 80 years. The 5-year progression-free survival estimate was 87% (95% CI, 79% to 92%) and the OS estimate was 89% (95% CI, 82% to 94%), with iPET-positive and iPET-negative patients having similar outcomes.CONCLUSIONTo our knowledge, S1001 is the largest prospective study in the United States of limited-stage DLBCL in the rituximab era, with the best NCTN results in this disease subset. With PET-directed therapy, 89% of the patients with a negative iPET received R-CHOP × 4, and only 11% had a positive iPET and required radiation, with both groups having excellent outcomes. The trial establishes R-CHOP × 4 alone as the new standard approach to limited-stage disease for the absolute majority of patients.