Advani, Ranjana H.

Abstract Autologous stem cell transplantation (ASCT) can be curative for patients with relapsed/refractory Hodgkin lymphoma (HL). Based on studies suggesting that anti-PD-1 monoclonal antibodies (mAbs) can sensitize patients to subsequent chemotherapy, we hypothesized that anti-PD-1 therapy before ASCT would result in acceptable outcomes among high-risk patients who progressed on or responded insufficiently to ≥1 salvage regimen, including chemorefractory patients who are traditionally considered poor ASCT candidates. We retrospectively identified 78 HL patients who underwent ASCT after receiving an anti-PD-1 mAb (alone or in combination) as third-line or later therapy across 22 centers. Chemorefractory disease was common, including 42 patients (54%) refractory to ≥2 consecutive systemic therapies immediately before anti-PD-1 treatment. Fifty-eight (74%) patients underwent ASCT after anti-PD-1 treatment, while 20 patients (26%) received additional therapy after PD-1 blockade and before ASCT. Patients received a median of 4 systemic therapies (range, 3-7) before ASCT, and 31 patients (41%) had a positive pre-ASCT positron emission tomography (PET) result. After a median post-ASCT follow-up of 19.6 months, the 18-month progression-free survival (PFS) and overall survival were 81% (95% CI, 69-89) and 96% (95% confidence interval [CI], 87-99), respectively. Favorable outcomes were observed for patients who were refractory to 2 consecutive therapies immediately before PD-1 blockade (18-month PFS, 78%), had a positive pre-ASCT PET (18-month PFS, 75%), or received ≥4 systemic therapies before ASCT (18-month PFS, 73%), while PD-1 nonresponders had inferior outcomes (18-month PFS, 51%). In this high-risk cohort, ASCT after anti-PD-1 therapy was associated with excellent outcomes, even among heavily pretreated, previously chemorefractory patients.

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 (<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.

SummaryIbrutinib is associated with durable responses in patients with Waldenström macroglobulinaemia (WM). We hypothesized that response depth is predictive of progression‐free survival (PFS) in WM patients treated with ibrutinib. Using landmark analyses, we evaluated response depth in two cohorts of WM patients treated with ibrutinib monotherapy. The learning cohort was composed of 93 participants from two clinical trials, and the validation cohort of 190 consecutive patients treated off clinical trial. Rates of partial response (PR) or better at six months in learning and validation cohorts were 64% and 71% respectively (P = 0·29). In the learning cohort, three‐year PFS rates for patients who attained PR or better at six monthsversusnot were 81% and 57% respectively (P = 0·009). In the validation cohort, three‐year PFS rates for patients who attained PR or better at six monthsversusnot were 83% and 54% respectively (P = 0·008). In multivariate analyses, attaining PR or better at six months was associated with superior PFS in the learning [hazard ratio (HR) 0·38;P = 0·01] and validation cohorts (HR 0·18;P = 0·004). Attaining PR at six months on ibrutinib emerges as an intermediate outcome of interest and should be validated as surrogate for PFS in clinical trials evaluating Bruton tyrosine kinase inhibitors in WM.

BACKGROUND: Odronextamab (REGN1979) is a first-in-class, hinge-stabilized, fully human IgG4-based CD3 x CD20 bispecific antibody (bsAb) that has demonstrated encouraging safety, tolerability and preliminary efficacy in a first-in-human study of patients (pts) with relapsed/refractory (R/R) B-cell non-Hodgkin lymphoma (B-NHL). We report updated safety and efficacy data from the dose escalation and early dose expansion phase of the ongoing Phase (P)1 study (NCT02290951). METHODS: Odronextamab was administered using a step-up dose schedule consisting of an initial dose at Week (W)1, an intermediate dose at W2, and thereafter, a fixed weekly dose until W12 followed by maintenance Q2W dosing. Dexamethasone premedication was used to mitigate the risk for cytokine release syndrome (CRS). Key primary objectives were to assess safety and dose-limiting toxicities (DLTs), and to establish a maximum tolerated dose (MTD) and recommended P2 dosing regimen (RP2DR). Secondary objectives included a preliminary assessment of anti-tumor activity. RESULTS: As of Jun 25, 2020, 127 pts with R/R B-NHL have been treated at doses ranging from 0.03-320 mg. The study included pts with diffuse large B-cell lymphoma (DLBCL; n=71), follicular lymphoma (FL) Grade (Gr) 1-3a (n=37), mantle cell lymphoma (MCL; n=11), marginal zone lymphoma (n=6), and other B-NHLs (n=2). Pts were highly refractory (80.3%) and had received a median of 3 (range: 1‒11) prior lines of therapy; 29 pts (22.8%) received prior CAR T therapy (FL: 2; DLBCL: 25; MCL: 2) and 85 pts (66.9%) were double refractory to alkylator and anti-CD20 antibody, in any line of therapy. Median follow-up was 3.9 (0.4‒37.6) months (mo). No DLTs were reported during dose escalation and MTD was not reached with odronextamab doses up to 320 mg weekly. The most frequent treatment-related adverse events (AEs) of any grade were pyrexia (76.4%), CRS (62.2%), and chills (48.0%). Gr 3 CRS occurred in 8 pts (6.3%) and a Gr 4 CRS occurred in 1 pt (0.8%). Most of the CRS events occurred during the first 2 weeks of step-up dosing and resolved within a median of 2 days (range 1-41) with supportive care measures. No pts discontinued odronextamab treatment due to CRS. Gr 3 neurologic AEs were noted in 5 pts, of which only 3 (2.3%) were considered treatment-related: somnolence, syncope, and encephalopathy. None of these events required treatment discontinuation. There were no Gr 4 or higher neurologic AEs. Overall, 7 pts (5.5%) discontinued treatment due to treatment-related AEs. In pts with R/R FL Gr 1-3a, odronextamab demonstrated a broad window of therapeutic activity. In pts treated at doses of ≥5 mg (n=28), objective response rate (ORR) was 92.9%, and complete response (CR) rate was 75.0%; median duration of response (DoR) was 7.7 mo (range 0+-20.9+), with 13 of 21 CRs ongoing at last tumor assessment. The median duration of complete response (DoCR) was 8.1 mo (range 0+-19.9+) and follow-up is ongoing (Table). In pts with R/R DLBCL, encouraging activity was observed at higher odronextamab dose levels. In DLBCL pts who had not received prior CAR T therapy, treated at doses ≥80 mg (n=10), ORR and CR rate were 60%; median observed DoR was 10.3 mo (range 2.9-18.6+), with 4 of 6 CRs ongoing at last tumor assessment. The median DoCR was 9.5 mo (range 2.9-18.6+) and follow-up is ongoing. In DLBCL pts who were refractory to prior CAR T therapy, treated at doses ≥80 mg (n=21), ORR was 33.3%, and CR rate was 23.8%; median observed DoR was 2.8 mo (range 0+-18.9+), with 5 of 5 CRs ongoing at last tumor assessment. The median DoCR was 4.4 mo (range 0+-18.9+) and follow-up is ongoing. Based on an evaluation of preliminary antitumor activity and PK, RP2DR was identified for dose expansion cohorts. CONCLUSIONS: Odronextamab has demonstrated encouraging single agent antitumor activity in highly refractory pts with B-NHLs. Durable CRs have been observed in both indolent and aggressive B-NHL pts, including in pts refractory to CAR T therapy. Most CRs are ongoing at time of data cutoff, and updated data will be presented. Odronextamab has an acceptable safety and tolerability profile. Dexamethasone premedication and step-up dosing mitigates the risk for CRS and allows odronextamab administration up to 320 mg weekly without DLTs. A global P2 trial investigating odronextamab in R/R B-NHL is ongoing. Disclosures Bannerji: Regeneron Pharmaceuticals: Research Funding; AbbVie: Research Funding; Sanofi-Pasteur: Other: Spouse is employee; F. Hoffmann-La Roche Ltd/Genentech, Inc and Pharmacyclics LLC, an AbbVie Company: Research Funding. Allan:Acerta, Genentech, Abbvie, Sunesis, Ascentage, Pharmacyclics, Janssen, AstraZeneca, BeiGene: Consultancy; Abbvie, Janssen, AstraZeneca, Pharmacyclics: Honoraria; Celgene, Genentech, Janssen, TG Therapeutics: Research Funding. Arnason:Regeneron: Consultancy; Juno: Consultancy. Brown:Catapult: Consultancy; Sun: Research Funding; Loxo: Consultancy, Research Funding; Verastem: Consultancy, Research Funding; TG Therapeutics: Consultancy; Sunesis: Consultancy; Rigel Pharmaceuticals: Consultancy; Pfizer: Consultancy; Octapharma: Consultancy; Novartis: Consultancy; Nextcea: Consultancy; MEI Pharma: Consultancy; Kite: Consultancy; Juno/Celgene: Consultancy; Eli Lilly and Company: Consultancy; Dynamo Therapeutics: Consultancy; BeiGene: Consultancy; Gilead: Consultancy, Research Funding; Invectys: Membership on an entity's Board of Directors or advisory committees, Other: DSMC; Acerta: Consultancy; Genentech: Consultancy; Pharmacyclics: Consultancy; Morphosys: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other; Astra-Zeneca: Consultancy; Janssen: Honoraria; AbbVie: Consultancy. 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:Bristol Myers Squibb: Research Funding; Takeda: Research Funding; Trillium: Research Funding; ADC Therapeutics: Research Funding; Affimed: Research Funding; Seattle Genetics: Research Funding; Regeneron: Research Funding; AI Therapeutics: Research Funding. O'Brien:Gilead, Pharmacyclics, TG Therapeutics, Pfizer, Sunesis: Consultancy, Research Funding; Kite, Regeneron, Acerta: Research Funding; Amgen, Astellas, Celgene, GlaxoSmithKline, Janssen Oncology, Aptose Biosciences Inc. Vaniam Group, AbbVie, Alexion, Verastem, Eisai, Juno Therapeutics, Vida Ventures: Consultancy. Duell:Morphosys: Research Funding. Martin:Sandoz: Consultancy; Karyopharm: Consultancy, Research Funding; Celgene: Consultancy; Teneobio: Consultancy; I-MAB: Consultancy; Bayer: Consultancy; Beigene: Consultancy; Cellectar: Consultancy; Incyte: Consultancy; Kite: Consultancy; Morphosys: Consultancy; Regeneron: Consultancy; Janssen: Consultancy. Li:Regeneron Pharmaceuticals, Inc: Current Employment, Current equity holder in publicly-traded company. Flink:Regeneron Pharmaceuticals, Inc: Current Employment, Current equity holder in publicly-traded company. Zhu:Regeneron Pharmaceuticals, Inc: Current Employment, Current equity holder in publicly-traded company. Weinreich:Regeneron Pharmaceuticals, Inc.: Current Employment, Current equity holder in publicly-traded company. Yancopoulos:Regeneron Pharmaceuticals, Inc.: Current Employment, Current equity holder in publicly-traded company. Sirulnik:Regeneron Pharmaceuticals, Inc.: Current Employment, Current equity holder in publicly-traded company. Chaudhry:Regeneron Pharmaceuticals, Inc: Current Employment, Current equity holder in publicly-traded company. Ambati:Regeneron Pharmaceuticals, Inc: Current Employment, Current equity holder in publicly-traded company. Topp:Amgen, Boehringer Ingelheim, KITE, Regeneron, Roche: Research Funding; Amgen, KITE, Novartis, Regeneron, Roche: Consultancy. OffLabel Disclosure: The data described in the abstract will report on use of odronextamab in a Phase 1 clinical trial of patients with B-NHL

Background: While HL is a highly curable cancer, patients (pts) with advanced stage disease experience increased risk of relapse. Delineation of prognosis is desired to compare cohorts and outcomes between trials, and to define groups of pts for whom reduction in treatment may be appropriate or where novel therapeutic approaches are needed. The International Prognostic Score (IPS), which was derived from a discovery set of 1,618 HL pts with complete data, was a seminal publication in the field (Hasenclever and Diehl NEJM 1998). However, these data were published >20 years ago with a significant minority of pts having received chemotherapy regimens no longer in clinical use. More contemporary analyses have shown altered utility of the IPS (e.g., Moccia JCO 2012; Diefenbach BJH 2015). In addition, prior studies identified bulk disease as an adverse prognostic factor in advanced stage HL (Laskar JCO 2004; Johnson JCO 2010). Our objective was to leverage individual pt data (IPD) from HoLISTIC (www.hodgkinconsortium.com) to discover a new, robust, and modern prognostication index for advanced-stage HL pts applicable to diverse settings across the world. Methods: We created a data repository of IPD from clinical trials for newly diagnosed HL pts, which includes 4,085 advanced-stage (III or IV) pts treated in 8 large, prospective studies completed in the modern era (ie, IIL HD9601: Gobbi JCO 2005; Italian HD2000: Federico JCO 2009; ECOG 2496: Gordon JCO 2013; SWOG 0816: Press JCO 2016; IIL HD0801: Zinzani JCO 2016; RATHL: Johnson NEJM 2016; GITIL HD0607: Gallamini JCO 2017; and COG AHOD 0831: Kelly BJH 2019) as well as prominent cancer registries (eg, the Mayo/Iowa Molecular Epidemiologic Resource (MER)). The discovery analysis herein included pts from the ECOG 2496, HD0801 IIL, GITIL HD0607, and SWOG 0816 studies. Furthermore, it was restricted to pts (n=1,279) on these trials with complete data for all 9 covariates of interest: age; sex; advanced stage (III vs IV); B symptoms; any bulk; and values of hemoglobin, white blood count (WBC), lymphocyte count, and albumin. Using Cox proportional hazard (PH) models, we evaluated univariate associations between 5-year progression-free survival (PFS) and overall survival (OS) with the aforementioned prognostic variables. Age was categorized based on plots and optimum model fit (c statistic). Lab values were dichotomized using cut-points from the 1998 IPS. Per convention, treatment factors were not included in the model. To identify independent prognostic factors of PFS and OS, a parsimonious Cox PH model was fit using backward selection of all potential risk factors (P<0.05). Hazard ratios (HR) with 95% confidence interval (CI) were reported. Kaplan Meier (KM) plots were also reported for risk factors in the multivariable (MVA) models to visualize differences. Results: Among all pts, characteristics included: median age of 32.9 years (IQR 25.4-44, range 15-83); 55% male; 49% stage IV; 63% B symptoms; 26% bulk >10 cm; 20% hemoglobin <10.5 g/dL; 15% WBC count ≥15,000/mm3; 9% lymphocyte count <600/mm3; and 63% with albumin <4g/dL. For analysis of age, we observed a U-shaped relationship with PFS (Fig A), which helped delineate optimal cut points of 15-24 years (23.1%), 25-49 years (61.4%), and ≥50 years (15.6%). In univariate analysis: age, stage, B symptoms, bulk, anemia, low lymphocyte count, and low albumin were associated with worse survival. In the MVA model, age >50 years, stage IV disease, B symptoms, and bulky disease were associated with worse PFS; and age >50 years, stage IV disease, bulky disease, anemia, and low albumin were associated with worse OS (Fig B). KM plots for age, stage, and bulk are presented in Fig C. Conclusions. In this international, multi-study analysis of advanced stage HL in the modern era, we identified several factors that were associated with both worse PFS and OS on MVA (ie, age, stage IV disease, and bulky disease). The finding of bulky disease as a significant prognostic factor warrants further investigation. In addition, we detected an age-related U-shaped impact on PFS with inferior outcomes for pts ages 15-25 years and ≥50 years, the latter in an increasing linear fashion. Altogether, these data will serve as a training cohort for a modern HL prognostication index that will be augmented and analyzed with a large independent validation cohort (vis-à-vis the remaining HL data in the HoLISTIC consortium), which will be presented at the ASH meeting. Disclosures Parsons: Seattle Genetics: Consultancy. 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. Federico:Spectrum: Consultancy, Membership on an entity's Board of Directors or advisory committees; Sandoz: Consultancy, Membership on an entity's Board of Directors or advisory committees; Mundipharma s.r.l.: Research Funding; Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees; Roche: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Millennium/Takeda: Research Funding; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Cephalon/Teva: Research Funding. Friedberg:Acerta Pharma - A member of the AstraZeneca Group, Bayer HealthCare Pharmaceuticals.: Other; Bayer: Consultancy; Kite Pharmaceuticals: Research Funding; Portola Pharmaceuticals: Consultancy; Roche: Other: Travel expenses; Seattle Genetics: Research Funding; Astellas: Consultancy. Hutchings:Genmab: Research Funding; Janssen: Research Funding; Roche: Consultancy; Genmab: Consultancy; Takeda: Consultancy; Roche: Research Funding; Celgene: Research Funding; Daiichi: Research Funding; Sankyo: Research Funding; Novartis: Research Funding; Sanofi: Research Funding; Takeda: Research Funding; Roche: Honoraria; Genmab: Honoraria; Takeda: Honoraria. Johnson:MorphoSys: Honoraria; Kymera: Honoraria; Kite Pharma: Honoraria; Incyte: Honoraria; Celgene: Honoraria; Epizyme: Consultancy, Research Funding; Novartis: Honoraria; Takeda: Honoraria; Oncimmune: Consultancy; Boehringer Ingelheim: Consultancy; Janssen: Consultancy; Oncimmune: Consultancy; Janssen: Consultancy; Genmab: Honoraria; Bristol-Myers: Honoraria; Epizyme: Consultancy, Research Funding. Radford:Novartis: Consultancy, Honoraria; BMS: Consultancy, Honoraria, Speakers Bureau; ADCT: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Pfizer: Research Funding; Seattle Genetics: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; 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. Zinzani:MSD: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; 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; Janssen: Consultancy, Honoraria, Speakers Bureau; Sanofi: Consultancy, Membership on an entity's Board of Directors or advisory committees; EUSA Pharma: 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; AbbVie: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Gilead: Consultancy, Honoraria, 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; Immune Design: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Eusapharma: Consultancy, Speakers Bureau; Verastem: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Kyowa Kirin: Consultancy, Speakers Bureau; TG Therapeutics, Inc.: Honoraria, Speakers Bureau; Kirin Kyowa: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Servier: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Janssen-Cilag: Consultancy, 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; BMS: Consultancy, 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; Portola: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Celgene: Consultancy, 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; Merck: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Cerhan:NanoString: Research Funding; BMS/Celgene: Research Funding. Evens:Abbvie: Consultancy, Honoraria; Seattle Genetics: Consultancy, Honoraria, Research Funding; MorphoSys: Consultancy, Honoraria; Research To Practice: Honoraria, Speakers Bureau; Novartis: Consultancy, Honoraria; Epizyme: Consultancy, Honoraria, Research Funding; Merck: Consultancy, Honoraria, Research Funding; Pharmacyclics: Consultancy, Honoraria; Mylteni: Consultancy, Honoraria.

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 < 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<0.05), yet they remained stable for BR. FACT-Lym scores were significantly higher at MT (BR: 2.69, p<0.001; BVR: 2.71, p=0.007) and end of induction (BR: 3.32, p<0.001; BVR: 3.55, p<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<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<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.

11063 Background: Dacetuzumab (SGN-40) is a humanized IgG1 monoclonal antibody that binds to CD40, mediates effector cell functions, and activates downstream apoptosis signaling pathways. Dacetuzumab has shown single-agent activity in relapsed/refractory DLBCL in phase I and phase II trials, with multiple objective responses and 1/3 of patients demonstrating tumor shrinkage, defined as a decrease in tumor volume (SPD) of at least 10%. We previously reported a 14-gene signature (ASH 2008 #1593) that was strongly associated with dacetuzumab sensitivity in DLBCL cell lines. Here, we report an initial evaluation of the gene signature as a classifier of patients likely to demonstrate tumor shrinkage after dacetuzumab therapy. Methods: The original 14 microarray probes were chosen for high correlation with in vitro dacetuzumab sensitivity (IC25) in 31 NHL cell line models. Matching qRT-PCR probes were developed and confirmed to correlate with the microarray probes in paired cell line samples. In this retrospective analysis, archived paraffin blocks from a 26 patient subset of the phase I and II trials, with a diagnosis of DLBCL and available tumor measurements, were assayed by qRT-PCR. Results: Overall, 42% of patients (11/26) exhibited decreased SPD of at least 10%. Of those who were marker +, 10 out of 13 (78%) had 10% or better decreases in SPD, whereas only 1 of 13 patients who were marker - demonstrated tumor shrinkage (8%). The overall accuracy for predicting tumor shrinkage was 85% (one-sided P=0.002, by permutation test). Among the 14 genes contributing to the multivariate signature, CD22 and VNN2 were the most strongly down-regulated in specimens from patients without at least a 10% decrease in SPD (P=0.14 and P=0.10, respectively), while IGF1R and CTSC were the most strongly up-regulated (P=0.05 and P=0.08, respectively). Conclusions: A 14-gene signature appears to predict tumor shrinkage in DLBCL patients receiving dacetuzumab in single-agent clinical trials (P=0.002). A larger clinical data set will be analyzed to further evaluate the correlation of this gene signature with objective clinical response rates.. [Table: see text]

Abstract Purpose: We sought to improve upon frontline bendamustine/rituximab (BR) induction therapy followed by rituximab maintenance in untreated high-risk follicular lymphoma (FL). Patients and Methods: Patients were randomized to BR induction followed by 2-year rituximab maintenance (BR-R), BR with bortezomib and rituximab maintenance (BVR-R), or BR followed by lenalidomide (1 year) with rituximab maintenance (BR-LR). Dual primary objectives were complete remission (CR) rate and 1-year disease-free survival (DFS); 289 patients enrolled (NCT01216683). Results: For induction, 92%, 87%, and 86% of patients randomized to BR-R, BVR-R, or BR-LR received six cycles, respectively. CR rate with BR versus BVR induction was 62% versus 75%, respectively (P = 0.04). One-year DFS rates with BR-R versus BR-LR were 85% versus 67%, respectively (P = 0.0009). This was due to an imbalance in CR rates post-BR induction and discontinuation due to adverse events (AEs). The most common grade 3–4 AEs for BVR versus BR were neutropenia and sensory neuropathy (12% vs <1%); 83% of the latter occurred with intravenous bortezomib. The most common grade 3–4 AEs related to LR versus rituximab maintenance were neutropenia 66% versus 21%, respectively (P < 0.0001), and febrile neutropenia 10% versus 2%, respectively (P = 0.05). The overall treatment-related mortality was 1.4%. With 5-year median follow-up, 3-year PFS rates for BR-R, BVR-R, and BR-LR were 77%, 82%, and 76%, respectively (P = 0.36) with OS rates of 87%, 90%, and 84%, respectively (P = 0.79). For prognostication, CR rate and POD-24 were associated with survival. Conclusions: Altogether, neither bortezomib added to BR induction nor lenalidomide added to rituximab maintenance immediately post-BR induction is recommended in untreated FL.

The NCCN Clinical Practice Guidelines in Oncology for Hodgkin Lymphoma (HL) provide recommendations for the management of adult patients with HL. The NCCN panel meets at least annually to review comments from reviewers within their institutions, examine relevant data, and reevaluate and update their recommendations. Current management of classic HL involves initial treatment with chemotherapy alone or combined modality therapy followed by restaging with PET/CT to assess treatment response. Overall, the introduction of less toxic and more effective regimens has significantly advanced HL cure rates. This portion of the NCCN Guidelines focuses on the management of classic HL.