Straus, David J.

7053 Background: In ECHELON-1 (NCT01712490), 6-year follow-up (FU) analyses demonstrated significant improvements in overall survival (OS) and progression-free survival (PFS) with A+AVD (brentuximab vedotin plus doxorubicin, vinblastine, and dacarbazine) versus ABVD (doxorubicin, bleomycin, vinblastine, and dacarbazine), with a comparable safety profile. Here, we report data at 7-year median FU. Methods: Analyses of OS and PFS per investigator were conducted in the intent-to-treat (ITT) population (data cut-off March 11, 2023). Patients (pts) were randomized 1:1 to receive ≤6 cycles of A+AVD (n=664) or ABVD (n=670) on days 1 and 15, every 28 days. PET scan after cycle 2 (PET2) evaluation was mandatory. Long-term safety outcomes in the safety population included resolution or improvement of peripheral neuropathy (PN), second malignancies, and pregnancies. Results: At median FU of 89.3 months (95% CI 87.0–90.2), 7-year OS rates were 93.5% (95% CI 91.1–95.2) with A+AVD and 88.8% (95% CI 85.8–91.1) with ABVD; OS favored A+AVD over ABVD (HR 0.62; 95% CI 0.42–0.90; p=0.011). Subgroup analyses showed consistent OS benefit for A+AVD, including in the age <40 years and Stage IV disease subgroups (Table). 7-year PFS rates with A+AVD vs ABVD were 82.3% (95% CI 79.1–85.0) vs 74.5% (95% CI 70.8–77.7; HR 0.68 [95% CI 0.53–0.86]; p=0.001). PN improved/resolved in most pts at last FU (A+AVD: 86%; ABVD: 87%). Median (range) time to complete resolution of PN (A+AVD vs ABVD) was 16 (0–373) vs 10 (0–343) weeks; median (range) time to improvement was 42 (2–182) vs 19 (15–142) weeks. PN was ongoing in 28% (4% grade ≥3) of A+AVD and 20% (1% grade ≥3) of ABVD pts. Second malignancies were reported in 5% of A+AVD and 6% of ABVD pts. Pts and their partners reported 84/92 livebirths/pregnancies with A+AVD and 59/73 with ABVD; no stillbirths were recorded. Conclusions: At 7-year median FU, pts with stage III/IV cHL who received A+AVD showed a sustained PFS and OS benefit vs ABVD, with PFS rates indicating potential curability. The safety profile in pts treated with A+AVD showed no new safety signals at 7 years. Clinical trial information: NCT01712490 . [Table: see text]

Abstract Rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) is considered the standard-of-care for patients with advanced-stage diffuse large B-cell lymphoma (DLBCL), despite findings that patients with nongerminal center B-cell like (non-GCB) have significantly worse outcome with this regimen. We evaluated the prognostic significance of baseline risk factors, including cell of origin (COO) classified by the Hans algorithm, within an alternative chemoimmunotherapy program. At Memorial Sloan Kettering Cancer Center (MSK), 151 patients with DLBCL received sequential R-CHOP induction and (R)-ICE (rituximab, ifosfamide, carboplatin, and etoposide) consolidation. Outcome analysis based on COO was validated with a propensity score–matched cohort treated with R-CHOP from the Mayo Clinic component of the Molecular Epidemiology Resource (MER). Among the patients with GCB (n = 69) and non-GCB (n = 69) at MSK, event-free survival (EFS) of non-GCB was superior to that of GCB (hazard ratio [HR], 0.53; 95% confidence interval [CI], 0.29-0.98). Overall survival (OS) demonstrated an association in the same direction but was not statistically significant (HR, 0.68; 95% CI, 0.33-1.42). Propensity score–matched patients from MSK (n = 108) demonstrated a small attenuation in the HRs for EFS (HR, 0.57; 95% CI, 0.27-1.18) and OS (HR, 0.76; 95% CI, 0.33-1.79) and were no longer statistically significant. In contrast, the matched MER cohort (n = 108) demonstrated an EFS association (HR, 1.17; 95% CI, 0.70-1.95) and OS association (HR, 1.13; 95% CI, 0.64-2.00) in the opposite direction, but were also not statistically significant. R-CHOP induction and (R)-ICE consolidation may overcome the negative prognostic impact of the non-GCB phenotype, per the Hans algorithm, and can be preferentially selected for this population. This trial was registered at www.ClinicalTrials.gov as #NCT00039195 and #NCT00712582.

7503 Background: To date, an overall survival (OS) benefit from upfront treatment for new treatment combinations over existing approaches has rarely been shown in first-line classical Hodgkin lymphoma (cHL). With the introduction of newer active therapies for relapsed/refractory disease, demonstration of improved OS with first-line therapy has been challenging. In ECHELON-1 (NCT01712490), 5-year follow-up analyses supported the long-term progression-free survival (PFS) benefit with first-line brentuximab vedotin, doxorubicin, vinblastine, and dacarbazine (A+AVD) vs doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD) in patients (pts) with stage III/IV cHL, independent of interim positron emission tomography status. A+AVD had a manageable long-term safety profile, with numerically fewer second malignancies and a greater number of pregnancies reported vs ABVD (Connors et al, NEJM 2018; Straus et al, Lancet Haematol 2021). We report a prespecified OS analysis after approximately 6 years’ follow-up (cut-off, June 1, 2021). Methods: Pts were randomized 1:1 to receive up to 6 cycles of A+AVD (n = 664) or ABVD (n = 670) on day 1 and 15 every 28 days. OS was the key secondary endpoint and was an event-driven, pre-specified, alpha-controlled analysis in the intention to treat population. Results: At a median follow-up of 73 months, 39 and 64 OS events occurred in A+AVD and ABVD arms, respectively: OS significantly favored A+AVD vs ABVD (HR 0.590; 95% confidence interval [CI] 0.396–0.879; p = 0.009). Estimated 6-year OS rates (95% CI) were 93.9% (91.6–95.5) vs 89.4% (86.6–91.7) with A+AVD vs ABVD, respectively. There was a consistent OS benefit for A+AVD vs ABVD across prespecified subgroups. The 6-year PFS estimate was 82.3% (79.1–85.0) vs 74.5% (70.8–77.7) with A+AVD vs ABVD, respectively (HR 0.678 [95% CI 0.532–0.863]). Overall, A+AVD had a comparable long-term safety profile to ABVD. Treatment-emergent peripheral neuropathy continued to resolve or improve in both arms, with 86% (379/443) and 87% (249/286) of cases in the A+AVD and ABVD arms either completely resolving (72% vs 79%) or improving (14% vs 8%) by last follow-up. Fewer second malignancies were reported in the A+AVD vs ABVD arm (23 vs 32). More female patients reported pregnancy (49 vs 28) or live births (42 vs 19 in females) in the A+AVD vs the ABVD arm; no stillbirths were reported. No new safety signals were identified. Conclusions: A+AVD treatment resulted in a statistically significant 41% reduction in the risk of death vs ABVD, with a manageable safety profile consistent with prior reports. These outcomes confirm A+AVD as a preferred option for pts with previously untreated stage III/IV cHL. Clinical trial information: NCT01712490.

Introduction Historically, nearly all relapses in classical Hodgkin lymphoma (cHL) occur within the first 5 years (Radford et al, BMJ 1997). In the phase 3 ECHELON-1 study (NCT01712490), treatment with brentuximab vedotin, doxorubicin, vinblastine, and dacarbazine (A+AVD) significantly improved modified progression-free survival (PFS) in patients (pts) with newly-diagnosed Stage III/IV cHL compared with doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD) (Connors et al, NEJM 2018). 3- and 4-year follow-up (Straus et al, Blood 2020; Bartlett et al, Blood 2019) reported durable PFS benefit with A+AVD vs ABVD in the intent-to-treat (ITT) population that was consistent across most key pt subgroups, irrespective of interim positron emission tomography (PET) scan status, disease stage, and baseline disease risk factor score. We report updated efficacy and safety results for pts in the ECHELON-1 study after a median follow-up of 55.6 months. Methods In this evaluation of longer follow-up, an exploratory analysis of PFS (time from randomization to relapse, progression, or death from any cause) per investigator (INV) was conducted, with a cutoff date of May 18, 2020. Pts with previously untreated Stage III or IV cHL were randomized 1:1 to receive up to six cycles of A+AVD (n=664) or ABVD (n=670) intravenously on days 1 and 15 of a 28-day cycle. An interim PET scan after cycle 2 (PET2) was required. Resolution and improvement (defined as improvement by ≥1 grade from worst grade as of the latest assessment) of peripheral neuropathy (PN) in pts with ongoing symptoms at the end of treatment (EoT) were monitored during the extended follow-up period. The rate of secondary malignancies, and the incidence and outcomes of pregnancies among pts and their partners were also assessed. Results With extended follow-up (median 55.6 months; 95% CI 55.2-56.7) estimated 5-year PFS rates were 82.0% (95% CI 78.7-84.8) for A+AVD and 75.2% (95% CI 71.5-78.4) for ABVD. Overall, PFS per INV favored A+AVD over ABVD (HR 0.691; 95% CI 0.543-0.880; p=0.003) (Table). Exploratory subgroup analyses by PET2 status and age demonstrated PFS benefits regardless of PET2 status (Table); estimated 5-year PFS per INV with A+AVD vs ABVD in the ITT population was 84.7% vs 78.8% in PET2-negative pts (HR 0.676; 95% CI 0.512-0.892; p=0.005), and 60.6% vs 45.9% in PET2-positive pts (HR 0.703; 95% CI 0.393-1.256; p=0.230). PFS benefit with A+AVD over ABVD was also independent of the number of International Prognostic Factors Project (IPFP) risk factors (Figure). After a median follow-up of almost 5-years, 84% (370/442) and 86% (245/286) of pts with treatment-emergent PN reported complete resolution or improvement of symptoms in the A+AVD and ABVD arms, respectively. Median time to complete resolution of PN events that were ongoing at EoT was 30 weeks (range 0-262) in the A+AVD arm and 16 weeks (range 0-267) in the ABVD arm; median time to improvement was 49 weeks (range 8-270) and 12 weeks (range 2-70) , respectively. Of the 132 (30%) pts with ongoing PN in the A+AVD arm, 77 (17%), 39 (9%), 15 (3%) and 1 (&lt;1%) experienced a maximum severity of grade 1, 2, 3 or 4, respectively. In the ABVD arm, PN was ongoing in 61 pts (21%); maximum severity was grade 1, 2, 3 or 4 in 40 (14%), 17 (6%), 4 (1%) and 0 pts, respectively. A total of 124 pregnancies were reported among pts and their partners (40 female and 30 male pts in the A+AVD arm; 26 female and 28 male pts in the ABVD arm). The proportion of live births was similar between arms for female pts (26/40 in the A+AVD arm and 17/26 in the ABVD arm, 65% in each arm) and for male pts' partners (19/30 [63%] in the A+AVD arm and 20/28 [71%] in the ABVD arm). No stillbirths were recorded. Additional follow-up at an estimated median of ~5 years and secondary malignancy data will be presented. Conclusions After a median follow-up of 55.6 months, A+AVD continues to demonstrate a robust and durable treatment benefit independent of disease stage, risk factor score, and PET2 status. In addition, compared with ABVD, treatment adaptation by interim PET2 status is not required and bleomycin exposure is avoided. The sustained PFS benefit with A+AVD is coupled with a manageable safety profile with symptoms of PN improving or resolving over time and similar pregnancy rates in both treatment arms. The benefits observed with A+AVD at this important milestone suggest that A+AVD is an attractive treatment option for all pts with previously untreated Stage III or IV cHL. Disclosures Straus: Karyopharm Therapeutics: Membership on an entity's Board of Directors or advisory committees; Imedex, Inc.: Speakers Bureau; Targeted Oncology: Consultancy, Speakers Bureau; NY Lymphoma Rounds: Consultancy; Takeda Pharmaceuticals: Research Funding, Speakers Bureau; OncLive: Speakers Bureau; Elsevier: Membership on an entity's Board of Directors or advisory committees, Other: CME writer; ASH: Other: Conference in December 2019 on HL to other physicians during ASH; Seattle Genetics: Consultancy, Membership on an entity's Board of Directors or advisory committees. Connors:Seattle Genetics: Other: Sponsorship to educational presentations; Takeda: Other: Sponsorship to educational presentations. Illés:Takeda, Seattle Genetics: Research Funding; Novartis, Janssen, Pfizer, Roche;: Other: Travel, Accommodations, Expenses; Janssen, Celgene, Takeda, Novartis Pharma SAS, Pfizer Pharmaceuticals Israel, Roche;: Consultancy, Honoraria; Celgene, Janssen, Novartis,Roche, Takeda: Consultancy. Lech-Marańda:Roche, Novartis, Takeda, Janssen-Cilag, Amgen, Gilead, AbbVie, Sanofi: Consultancy; Roche, Amgen, Gilead: Speakers Bureau. Feldman:KITE: Honoraria, Speakers Bureau; Abbvie: Honoraria, Speakers Bureau; Morphosis: Other: Ad board; AstraZeneca: Other: Ad board; BMS/Celgene: Consultancy, Honoraria, Speakers Bureau; Seattle Genetics: Consultancy, Speakers Bureau; Janssen: Honoraria, Speakers Bureau; Pharmacyclics: Honoraria, Speakers Bureau; Takeda: Honoraria, Speakers Bureau. Smolewski:Roche Poland: Consultancy, Honoraria; Takeda: Consultancy, Honoraria; Sandoz: Honoraria; Morphosis: Honoraria. Savage:Roche (institutional): Research Funding; Merck, BMS, Seattle Genetics, Gilead, AstraZeneca, AbbVie, Servier: Consultancy; BeiGene: Other: Steering Committee; Merck, BMS, Seattle Genetics, Gilead, AstraZeneca, AbbVie: Honoraria. Bartlett:Pfizer: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Pharmacyclics: Research Funding; Seattle Genetics: Consultancy, Research Funding; Roche/Genentech: Consultancy, Research Funding; Seattle Genetics: Membership on an entity's Board of Directors or advisory committees, Research Funding; BTG: Consultancy; Acerta: Consultancy; Affimed Therapeutics: Research Funding; ADC Therapeutics: Consultancy; Autolus: Research Funding; BMS/Celgene: Research Funding; Forty Seven: Research Funding; Immune Design: Research Funding; Janssen: Research Funding; Kite, a Gilead Company: Research Funding; Merck: Research Funding; Millennium: Research Funding. Walewski:Gilead: Consultancy, Honoraria; Servier: Consultancy, Honoraria; BMS: Consultancy, Honoraria; Celgene: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; Abbvie: Consultancy, Honoraria; Takeda: Consultancy, Honoraria, Research Funding; Roche: Consultancy, Honoraria, Other: Travel Support, Research Funding; Novartis: Consultancy, Honoraria, Research Funding; Janssen: Consultancy, Honoraria, Research Funding; GSK: Research Funding. Ramchandren:Janssen: Research Funding; Pharmacyclics LLC, an AbbVie Company: Consultancy, Research Funding. Zinzani:Eusapharma: Consultancy, Speakers Bureau; Gilead: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Portola: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Immune Design: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Kyowa Kirin: Consultancy, Speakers Bureau; MSD: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Servier: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; AbbVie: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; BMS: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Immune Design: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; TG Therapeutics, Inc.: Honoraria, Speakers Bureau; Janssen: Consultancy, Honoraria, Speakers Bureau; EUSA Pharma: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Kirin Kyowa: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; ADC Therapeutics: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Verastem: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celltrion: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Janssen-Cilag: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Sandoz: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Merck: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Sanofi: Consultancy, Membership on an entity's Board of Directors or advisory committees; Incyte: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Hutchings:Celgene, Genmab, Janssen, Novartis, F. Hoffmann-La Roche, Takeda: Research Funding; Genmab, F. Hoffmann-La Roche, Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees. Munoz:Juno/Celgene/BMS: Consultancy, Research Funding, Speakers Bureau; Alexion: Consultancy; Beigene: Consultancy, Speakers Bureau; Fosunkite: Consultancy; Innovent: Consultancy; Acrotech/Aurobindo: Speakers Bureau; Verastem: Speakers Bureau; AstraZeneca: Speakers Bureau; Kyowa: Consultancy, Honoraria, Speakers Bureau; Janssen: Consultancy, Research Funding, Speakers Bureau; Seattle Genetics: Consultancy, Honoraria, Research Funding, Speakers Bureau; Genentech/Roche: Research Funding, Speakers Bureau; AbbVie: Consultancy, Speakers Bureau; Merck: Research Funding; Portola: Research Funding; Incyte: Research Funding; Millenium: Research Funding; Pfizer: Consultancy; Kite, a Gilead Company: Consultancy, Research Funding, Speakers Bureau; Pharmacyclics: Consultancy, Research Funding, Speakers Bureau; Bayer: Consultancy, Research Funding, Speakers Bureau. Kim:JJ: Research Funding; Celltrion: Research Funding; Kyowa Kirn: Research Funding; Donga: Research Funding; Mundipharma: Research Funding; Pfizer: Research Funding; F. Hoffmann-La Roche: Research Funding. Advani:Astra Zeneca, Bayer Healthcare Pharmaceuticals, Cell Medica, Celgene, Genentech/Roche, Gilead, KitePharma, Kyowa, Portola Pharmaceuticals, Sanofi, Seattle Genetics, Takeda: Consultancy; Celgene, Forty Seven, Inc., Genentech/Roche, Janssen Pharmaceutical, Kura, Merck, Millenium, Pharmacyclics, Regeneron, Seattle Genetics: Research Funding. Ansell:Bristol Myers Squibb: Research Funding; Takeda: Research Funding; ADC Therapeutics: Research Funding; AI Therapeutics: Research Funding; Trillium: Research Funding; Affimed: Research Funding; Regeneron: Research Funding; Seattle Genetics: Research Funding. Younes:HCM: Consultancy; Daiichi Sankyo: Consultancy; Curis: Consultancy; BMS: Consultancy; Novartis: Consultancy; Epizyme: Consultancy; BioPath: Consultancy; AstraZeneca: Current Employment; Janssen: Consultancy; Takeda: Consultancy. Gallamini:Takeda: Other: Speaker. Liu:Takeda Pharmaceuticals: Current Employment. Little:Takeda: Current Employment, Current equity holder in publicly-traded company. Fenton:Seattle Genetics: Current Employment, Current equity holder in publicly-traded company. Fanale:Seattle Genetics: Current Employment, Current equity holder in publicly-traded company. Radford:GlaxoSmithKline: Current equity holder in publicly-traded company, Other: Spouse; AstraZeneca: Current equity holder in publicly-traded company, Other: Spouse; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Pfizer: Research Funding; ADCT: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; BMS: Consultancy, Honoraria, Speakers Bureau; Novartis: Consultancy, Honoraria; Seattle Genetics: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau.

Background: Diffuse large B-cell lymphoma (DLBCL) is frequently curable after frontline therapy, however, relapses can occur after achievement of a PET-negative complete remission (CR). Early detection of relapse may be associated with improved outcomes with second-line curative intent therapy or novel therapies. Controversy exists regarding the utility of post-therapy surveillance imaging which is associated with patient (pt) anxiety, radiation exposure, false-positive results, and cost. A retrospective study found that serial minimal residual disease (MRD) monitoring during DLBCL surveillance could identify pts at risk of relapse before clinical evidence of disease (Roschewski, Lancet Oncol, 2015). In this multicenter prospective study, we assessed whether a next-generation sequencing (NGS)-based MRD assay could be used for early detection of molecular relapse in DLBCL. Methods: Eligible pts with DLBCL or high-grade B-cell lymphoma (HGBCL) who received anthracycline-containing chemotherapy were enrolled across five cancer centers. In pts who achieved a PET-negative CR, serial peripheral blood samples were obtained every 3 months (mos) and CT scans every 6 mos for 2 years (yrs) post-treatment. The clonoSEQ® 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 and translocations in Bcl1/2-IgH was used. MRD positive was defined as any detectable rearrangement and MRD negative as no evidence of rearrangement. We also reported MRD positivity above the limit of detection (LOD) (observations required to have 95% reproducibility). Interim futility analysis was performed after approximately 50% of anticipated relapses occurred to assess the preliminary sensitivity of the assay. Progression-free survival (PFS) was defined as time from treatment start date to relapse or death. Results: 501 pts were enrolled and 401 were evaluable (pre-treatment tumor pathology available, completed frontline treatment, and achieved PET-negative CR at end-of-treatment). Baseline characteristics were median age of 62 yrs (range 19-95), male sex 58%, advanced stage 61%, and poor-risk by R-IPI 40% (Table 1). Histologies included DLBCL, NOS (86%), primary mediastinal B-cell lymphoma (6%), HGBCL (5%), T-cell rich B-cell lymphoma (1%), and other (1%). Pts received regimens including RCHOP x 6 cycles (36%), REPOCH x 6 cycles (20%), clinical trial (15%), combined modality therapy (RCHOP+RT) (10%), and other RCHOP variations (19%). Among the 401 evaluable pts, 44 relapses have occurred as of June 1, 2020. In 47% of pts (18/38), clinical relapse was detected using surveillance imaging alone (typically CT CAP with IV contrast) in an otherwise asymptomatic pt with a normal physical exam and laboratory evaluation. Clinical relapse was detected by clinical symptoms alone in 11% (4/28), by the evaluation of an oncologist alone in 0%, and by imaging and clinical symptoms and/or evaluation by an oncologist in 42% (16/38) (missing data in 6 pts). With a median follow-up of 2.2 yrs, the 2-yr PFS was 88.1% (84.8, 91.4) (Figure 1). Advanced age, advanced stage, and poor-risk R-IPI were associated with inferior PFS. Of the 44 relapses, 43 pts were included in the interim analysis and tumor-specific clonotypes were identified in 39 pts (91%). In 56% (22/39), the MRD assay was positive at or before clinical relapse. In 38% (15/39), the MRD assay was positive above the limit of detection at or prior to clinical relapse, with only 10 relapses detected more than 3 mos prior to relapse, reflecting the poor clinical sensitivity of the assay. The NGS-MRD assay was more sensitive in the acellular (plasma cell-free DNA) than in the cellular (circulating leukocytes) compartment. Results: Overall outcomes are excellent for DLBCL and HGBCL pts who achieve PET-negative complete remission. In interim analysis, surveillance MRD assessment using the clonoSEQ® assay fails to consistently identify pts at risk of recurrence before clinical evidence of relapse in DLBCL. In a prospective analysis, a substantial proportion (47%) of clinical relapses are detected by imaging in asymptomatic pts, supporting the value of CT surveillance imaging in DLBCL, particularly for pts with advanced stage or high-risk disease. Additional analyses are forthcoming for MRD assessment in all pts, including those in remission. Disclosures Kumar: Celgene: Research Funding; Pharmacyclics: Research Funding; Adaptive Biotechnologies,: Research Funding; AbbVie: Research Funding; Seattle Genetics: Research Funding; Celgene: Honoraria, Other: Honoraria for Advisory Board; Astra Zeneca: Honoraria, Other: Honoraria for Advisory Board; Kite Pharmaceuticals: Honoraria, Other: Honoraria for Advisory Board. Westin:Kite: Consultancy, Research Funding; Curis: Consultancy, Research Funding; Genentech: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; Amgen: Consultancy; Astra Zeneca: Consultancy, Research Funding; Morphosys: Consultancy, Research Funding; 47: Research Funding; Janssen: Consultancy, Research Funding; BMS: Consultancy, Research Funding. Nowakowski:Curis: Consultancy; Seattle Genetics: Consultancy; Nanostrings: Research Funding; MorphoSys: Consultancy, Research Funding; Roche: Consultancy, Research Funding; Celgene/BMS: Consultancy, Research Funding; Kite: Consultancy; Denovo: Consultancy; Kymera: Consultancy; Ryvu: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other. Lossos:Verastem: Consultancy, Honoraria; Seattle Genetics: Consultancy, Other; NCI: Research Funding; Stanford University: Patents & Royalties; Janssen Biotech: Honoraria; Janssen Scientific: Consultancy, Other. Batlevi:Life Sci, GLG, Juno/Celgene, Seattle Genetics, Kite: Consultancy; Janssen, Novartis, Epizyme, Xynomics, Bayer, Autolus, Roche/Genentech: Research Funding. Drullinsky:Roche: Research Funding; Novartis: Research Funding. Gerecitano:Janssen: Current Employment. Hamlin:Celgene: Consultancy; Karyopharm: Consultancy; Juno Therapeutics: Consultancy; Portola: Research Funding; Molecular Templates: Research Funding; Incyte: Research Funding; J&J Pharmaceuticals: Research Funding; Portola Pharmaceutics: Consultancy. Horwitz:ASTEX: Consultancy; Affirmed: Consultancy; Vividion Therapeutics: Consultancy; Verastem: Consultancy, Research Funding; Myeloid Therapeutics: Consultancy; Miragen: Consultancy; Kura Oncology: Consultancy; Janssen: Consultancy; GlaxoSmithKline: Consultancy; Daiichi Sankyo: Research Funding; C4 Therapeutics: Consultancy; Beigene: Consultancy; Portola: Consultancy, Research Funding; Mundipharma: Consultancy; Innate Pharma: Consultancy; Corvus: Consultancy; Trillium: Consultancy, Research Funding; Seattle Genetics: Consultancy, Research Funding; Millenium/Takeda: Consultancy, Research Funding; Kyowa Hakka Kirin: Consultancy, Research Funding; Infinity/Verastem: Research Funding; Forty Seven: Consultancy, Research Funding; Celgene: Consultancy, Research Funding; Aileron: Consultancy, Research Funding; ADCT Therapeutics: Consultancy, Research Funding. Jacob:Adaptive Biotechnologies: Current Employment, Current equity holder in publicly-traded company. Joffe:AstraZeneca: Membership on an entity's Board of Directors or advisory committees; Epizyme: Membership on an entity's Board of Directors or advisory committees. von Keudell:Bayer: Research Funding; Pharmacyclics: Research Funding; Genentech: Research Funding. Lahoud:MorphoSys: Other: Advisory Board. Matasar:Bayer: Consultancy, Honoraria, Research Funding; Seattle Genetics: Consultancy, Honoraria, Research Funding; Rocket Medical: Consultancy, Research Funding; Teva: Consultancy; F. Hoffmann-La Roche Ltd: Consultancy, Honoraria, Research Funding; GlaxoSmithKline: Honoraria, Research Funding; Takeda: Consultancy, Honoraria; Daiichi Sankyo: Consultancy; IGM Biosciences: Research Funding; Janssen: Honoraria, Research Funding; Pharmacyclics: Honoraria, Research Funding; Immunovaccine Technologies: Honoraria, Research Funding; Merck: Consultancy; Juno Therapeutics: Consultancy; Genentech, Inc.: Consultancy, Honoraria, Research Funding. Mullins:Adaptive Biotechnologies: Current Employment, Other: shareholder. Noy:Pharmacyclics: Research Funding; NIH: Research Funding; Rafael Pharma: Research Funding; Janssen: Consultancy; Pharmacyclics: Consultancy; Medscape: Consultancy; Targeted Oncology: Consultancy; Morphosys: Consultancy. Straus:Seattle Genetics: Consultancy, Membership on an entity's Board of Directors or advisory committees; ASH: Other: Conference in December 2019 on HL to other physicians during ASH; Elsevier: Membership on an entity's Board of Directors or advisory committees, Other: CME writer; OncLive: Speakers Bureau; Takeda Pharmaceuticals: Research Funding, Speakers Bureau; NY Lymphoma Rounds: Consultancy; Targeted Oncology: Consultancy, Speakers Bureau; Imedex, Inc.: Speakers Bureau; Karyopharm Therapeutics: Membership on an entity's Board of Directors or advisory committees. Younes:Takeda: Consultancy; HCM: Consultancy; AstraZeneca: Current Employment; Novartis: Consultancy; Daiichi Sankyo: Consultancy; Janssen: Consultancy; Epizyme: Consultancy; BMS: Consultancy; BioPath: Consultancy; Curis: Consultancy. Zelenetz:MEI Pharma: Research Funding; MorphoSys: Research Funding; Sandoz: Research Funding; Celgene: Research Funding; Roche: Research Funding; Gilead: Research Funding; Genentech/Roche: Consultancy; Gilead: Consultancy; Celgene: Consultancy; Janssen: Consultancy; Amgen: Consultancy; Novartis: Consultancy; Adaptive Biotechnology: Consultancy; BeiGene: Membership on an entity's Board of Directors or advisory committees.

Abstract The phase 3 ECHELON-1 study demonstrated that brentuximab vedotin (A) with doxorubicin, vinblastine, and dacarbazine (AVD; A+AVD) exhibited superior modified progression-free survival (PFS) vs doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD) for frontline treatment of patients with stage III/IV classical Hodgkin lymphoma (cHL). Maturing positron emission tomography (PET)-adapted trial data highlight potential limitations of PET-adapted approaches, including toxicities with dose intensification and higher-than-expected relapse rates in PET scan after cycle 2 (PET2)-negative (PET2−) patients. We present an update of the ECHELON-1 study, including an exploratory analysis of 3-year PFS per investigator. A total of 1334 patients with stage III or IV cHL were randomized 1:1 to receive 6 cycles of A+AVD (n = 664) or ABVD (n = 670). Interim PET2 was required. At median follow-up of 37 months, 3-year PFS rates were 83.1% with A+AVD and 76.0% with ABVD; 3-year PFS rates in PET2− patients aged &lt;60 years were 87.2% vs 81.0%, respectively. A beneficial trend in PET2+ patients aged &lt;60 years on A+AVD was also observed, with a 3-year PFS rate of 69.2% vs 54.7% with ABVD. The benefit of A+AVD in the intent-to-treat population appeared independent of disease stage and prognostic risk factors. Upon continued follow-up, 78% of patients with peripheral neuropathy on A+AVD had either complete resolution or improvement compared with 83% on ABVD. These data highlight that A+AVD provides a durable efficacy benefit compared with ABVD for frontline stage III/IV cHL, consistent across key subgroups regardless of patient status at PET2, without need for treatment intensification or bleomycin exposure. This trial was registered at www.clinicaltrials.gov as #NCT01712490 (EudraCT no. 2011-005450-60).

Introduction: As previously reported, the combination of brentuximab vedotin with doxorubicin, vinblastine and dacarbazine (A+AVD) demonstrated a statistically significant improvement in modified progression free survival (modified PFS) compared with doxorubicin, bleomycin, vinblastine and dacarbazine (ABVD) in patients with newly diagnosed Stage III or IV classical HL in the phase 3 ECHELON-1 trial (NCT01712490). The benefit of A+AVD in the ITT population observed in the primary analysis was maintained at 3-years median follow-up [3-year PFS: A+AVD: 83.1% (79.9-85.9), ABVD: 76% (72.4-79.2)] and appears independent of interim PET status, disease stage, and prognostic risk factors. Here we present the efficacy and safety results of longer follow-up at a median 43.3 months. Methods: Newly diagnosed patients with Stage III or IV cHL were randomized 1:1 to receive A+AVD (n=664) or ABVD (n=670) intravenously on days 1 and 15 of each 28-day cycle for up to 6 cycles. The primary endpoint of the study was modified PFS per independent central review. The present follow-up PFS analysis is exploratory and per investigator assessment, with a cutoff date of June 17th, 2019. Patients with ongoing peripheral neuropathy (PN) at end of treatment were followed for resolution or improvement (defined as improved by ≥1 grade from worst grade as of the latest assessment) during the post-treatment follow-up period. Results: With a median follow-up of 43.3 months, the 42-month PFS per investigator for all patients was 82.4% (95% CI, 79.1-85.2) on the A+AVD arm and 76.2% (95% CI, 72.6-79.4) on the ABVD arm [overall HR 0.697 (95% CI, 0.547-0.890)]. Exploratory subgroup analyses of PET2(+) and PET2(-) patients showed a treatment effect in favor of A+AVD. The 42-month PFS in PET2(-) patients was 85.0% (95% CI, 81.6-87.7) for A+AVD and 79.6% (95% CI, 75.9-82.8) for ABVD [overall HR 0.695 (95% CI, 0.526-0.919)]; in PET2(+) patients 42-month PFS was 68.3% (95% CI, 54.5-78.7) for A+AVD and 51.5% (95% CI, 38.2-63.4) for ABVD [overall HR 0.552 (95% CI, 0.308-0.989)]. Upon continued follow-up, 81% (356/442) of patients with PN in the A+AVD arm had either complete resolution (64%, 283/442) or improvement (17%, 73/442) of their PN events compared with 83% (236/286) with either complete resolution (74%, 212/286) or improvement (8%, 24/286) in the ABVD arm. Among patients with ongoing PN after continued follow-up, the majority were Grade 1/2 events, with 89% (141/159; 59% Grade 1) and 95% (70/74; 65% Grade 1) on the A+AVD and ABVD arms, respectively. Overall survival data are not yet mature; per protocol, the final analysis will be performed after 112 deaths have occurred. Additional follow-up at an estimated median of ~4 years, including data from prespecified subgroups, will be presented. Conclusions: With a median follow-up of 43.3 months, A+AVD continues to provide a robust, durable benefit for patients with previously untreated Stage III or IV cHL compared with ABVD; the benefit is evident regardless of patient status at interim PET [PET2(+) or PET2(-)] and without the need for treatment intensification. PN continued to completely resolve or improve in patients on the A+AVD and ABVD arms. Together, these data further support the clinical advantages of A+AVD versus ABVD as treatment for patients with previously untreated Stage III or IV cHL. Disclosures Bartlett: Affimed Therapeutics: Research Funding; Bristol-Myers Squibb: Research Funding; Celgene: Research Funding; Dynavax: Research Funding; Forty-Seven: Research Funding; Genentech: Research Funding; Gilead: Research Funding; Immune Design: Research Funding; Janssen: Research Funding; Kite Pharma: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Medimmune: Research Funding; Merck: Research Funding; Millennium: Research Funding; Novartis: Research Funding; Pfizer: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Pharmacyclics: Research Funding; Seattle Genetics, Inc.: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding. Straus:Elsevier (PracticeUpdate): Consultancy, Honoraria; Hope Funds for Cancer Research: Membership on an entity's Board of Directors or advisory committees; Seattle Genetics: Consultancy, Honoraria. Dlugosz-Danecka:Servier: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Macrogenomics: Research Funding; Roche: Honoraria, Speakers Bureau; Janssen: Consultancy, Honoraria, Speakers Bureau. Illes:Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Seattle Genetics: Research Funding; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees; Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees. Feldman:Takeda: Honoraria, Speakers Bureau; Celgene: Honoraria, Research Funding, Speakers Bureau; Cell Medica: Research Funding; Amgen: Research Funding; Viracta: Research Funding; Bayer: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Kite Pharma: Honoraria, Other: Travel expenses, Speakers Bureau; Janssen: Honoraria, Speakers Bureau; Pharmacyclics: Honoraria, Other: Travel expenses, Speakers Bureau; Pfizer: Research Funding; Portola Pharma: Research Funding; Roche: Research Funding; Eisai: Research Funding; Corvus: Research Funding; Roche: Research Funding; AbbVie: Honoraria, Other: Travel expenses, Speakers Bureau; Seattle Genetics: Consultancy, Honoraria, Other: Travel expenses, Speakers Bureau; Kyowa Hakko Kirin: Research Funding; Trillium: Research Funding. Smolewski:Roche: Other: Travel Expenses. Savage:Seattle Genetics, Inc.: Consultancy, Honoraria, Research Funding; BMS, Merck, Novartis, Verastem, Abbvie, Servier, and Seattle Genetics: Consultancy, Honoraria. Walewski:Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel Expenses, Research Funding; Takeda: Honoraria, Research Funding; Incyte: Consultancy, Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Servier: Honoraria; Gilead: Other: Travel Expenses; Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees; Bristol-Myers Squibb: Consultancy, Membership on an entity's Board of Directors or advisory committees; GlaxoSmithKline: Research Funding; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Zinzani:Portola: 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; Immune Design: 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; Servier: 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; Janssen-Cilag: 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; Celltrion: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Sanofi: Consultancy; Eusapharma: 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; Verastem: Consultancy, 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. Hutchings:Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel Expenses, Research Funding; Genmab: Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Travel Expenses, Research Funding; Novartis: Research Funding; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel Expenses, Research Funding. Radford:AstraZeneca: Equity Ownership, Research Funding; Novartis: Consultancy, Honoraria; Seattle Genetics: Consultancy, Honoraria; ADC Therapeutics: Consultancy, Research Funding; Takeda: Consultancy, Honoraria, Research Funding; BMS: Consultancy, Honoraria; GSK: Equity Ownership. Munoz:AstraZeneca: Speakers Bureau; Kite Pharma: Consultancy, Research Funding, Speakers Bureau; Pharmacyclics LLC an AbbVie Company: Consultancy, Research Funding, Speakers Bureau; Gilead: Consultancy, Speakers Bureau; Fosunkite: Speakers Bureau; Kyowa: Consultancy, Honoraria, Speakers Bureau; Bayer: Consultancy, Speakers Bureau; Seattle Genetics: Consultancy, Honoraria, Research Funding; Celgene: Research Funding; Portola: Research Funding; Incyte: Research Funding. Kim:Roche: Research Funding; Kyowa-Kirin: Research Funding; Novartis: Research Funding; J&J: Research Funding; Mundipharma: Research Funding; Celltrion: Research Funding; Donga: Research Funding. Advani:Cell Medica, Ltd: Consultancy; Pharmacyclics: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Merck: Research Funding; Kura: Research Funding; Infinity Pharma: Research Funding; Bristol-Myers Squibb: Membership on an entity's Board of Directors or advisory committees, Research Funding; Bayer: Consultancy, Membership on an entity's Board of Directors or advisory committees; Celgene: Research Funding; Celmed: Consultancy, Membership on an entity's Board of Directors or advisory committees; Autolus: Consultancy, Membership on an entity's Board of Directors or advisory committees; Agensys: Research Funding; Stanford University: Employment, Equity Ownership; Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees; Seattle Genetics: Consultancy, Research Funding; Kyowa Kirin Pharmaceutical Developments, Inc.: Consultancy; Regeneron: Research Funding; Millennium: Research Funding; Janssen: Research Funding; Roche/Genentech: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Gilead Sciences, Inc./Kite Pharma, Inc.: Consultancy, Membership on an entity's Board of Directors or advisory committees; Forty-Seven: Research Funding; AstraZeneca: Consultancy, Membership on an entity's Board of Directors or advisory committees. Ansell:Mayo Clinic Rochester: Employment; Affimed: Research Funding; Mayo Clinic Rochester: Employment; Trillium: Research Funding; Affimed: Research Funding; Seattle Genetics: Research Funding; Trillium: Research Funding; Trillium: Research Funding; Affimed: Research Funding; Bristol-Myers Squibb: Research Funding; Bristol-Myers Squibb: Research Funding; LAM Therapeutics: Research Funding; Regeneron: Research Funding; Affimed: Research Funding; Trillium: Research Funding; Mayo Clinic Rochester: Employment; Regeneron: Research Funding; Bristol-Myers Squibb: Research Funding; Bristol-Myers Squibb: Research Funding; Mayo Clinic Rochester: Employment; LAM Therapeutics: Research Funding; LAM Therapeutics: Research Funding; Seattle Genetics: Research Funding; Mayo Clinic Rochester: Employment; Mayo Clinic Rochester: Employment; Trillium: Research Funding; LAM Therapeutics: Research Funding; Seattle Genetics: Research Funding; Seattle Genetics: Research Funding; Seattle Genetics: Research Funding; Trillium: Research Funding; Affimed: Research Funding; Bristol-Myers Squibb: Research Funding; Seattle Genetics: Research Funding; LAM Therapeutics: Research Funding; Bristol-Myers Squibb: Research Funding; LAM Therapeutics: Research Funding; Regeneron: Research Funding; Regeneron: Research Funding; Seattle Genetics: Research Funding; Regeneron: Research Funding; Trillium: Research Funding; Affimed: Research Funding; Regeneron: Research Funding; LAM Therapeutics: Research Funding; Affimed: Research Funding; Trillium: Research Funding; Affimed: Research Funding; Mayo Clinic Rochester: Employment; Regeneron: Research Funding; Bristol-Myers Squibb: Research Funding; Bristol-Myers Squibb: Research Funding; Mayo Clinic Rochester: Employment; Regeneron: Research Funding; LAM Therapeutics: Research Funding; Affimed: Research Funding; Regeneron: Research Funding; LAM Therapeutics: Research Funding; Seattle Genetics: Research Funding; Seattle Genetics: Research Funding; Bristol-Myers Squibb: Research Funding; Trillium: Research Funding; Mayo Clinic Rochester: Employment. Younes:Roche: Consultancy, Honoraria, Research Funding; Janssen: Honoraria, Research Funding; Curis: Honoraria, Research Funding; Merck: Honoraria, Research Funding; Abbvie: Honoraria; Takeda: Honoraria; Pharmacyclics: Research Funding; AstraZeneca: Research Funding; Genentech: Research Funding; Biopath: Consultancy; Xynomics: Consultancy; Epizyme: Consultancy, Honoraria; Celgene: Consultancy, Honoraria; HCM: Consultancy; BMS: Research Funding; Syndax: Research Funding. Gallamini:Takeda: Consultancy; Roche: Consultancy. Miao:Millennium Pharmaceuticals, Inc., Cambridge, MA, a wholly owned subsidiary of Takeda Pharmaceutical Company Limited: Employment, Equity Ownership. Liu:Takeda: Employment. Fenton:Seattle Genetics, Inc.: Employment, Equity Ownership. Forero-Torres:Seattle Genetics: Employment, Equity Ownership, Honoraria, Research Funding.