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Treatment with covalent Bruton tyrosine kinase inhibitors (BTKi) represents an important advance in the management of relapsed or refractory mantle cell lymphoma, but these treatments are not curative and many patients ultimately relapse. Pirtobrutinib, a highly selective, non covalent (reversible) BTKi, inhibits both wild type and C481-mutant BTK with equal low nM potency, and has favorable oral pharmacology that enables continuous BTK inhibition throughout the dosing interval regardless of intrinsic rate of BTK turnover. Pirtobrutinib is well tolerated and has demonstrated promising efficacy in patients with poor prognosis B-cell malignancies following prior therapy, including covalent BTKi. This phase III, head-to-head, randomized study (NCT04662255) will evaluate whether pirtobrutinib is superior to investigator's choice of covalent BTKi in patients with previously treated, BTKi-naive mantle cell lymphoma.MCL is an uncommon type of B-cell non-Hodgkin lymphoma, a cancer of the immune system. It starts in the part of the lymph node called the mantle zone, where unusual B cells gather and crowd out healthy B cells in the lymph nodes, spleen, bone marrow and/or other organs. MCL can be caused by inappropriate cell signaling. BTK has been identified as a key driver of unusual cell signaling and blocking BTK has been shown to help kill the cancer cells. Covalent (not reversible) BTK inhibitors have advanced the treatment of MCL, but the effectiveness of these treatments is limited by side effects and treatment resistance. Pirtobrutinib, a non covalent (reversible) BTK inhibitor, has been shown to have manageable side effects and to be effective in patients with MCL following previous treatment, including treatment with covalent BTK inhibitors. The BRUIN MCL-321 study compares pirtobrutinib with three currently approved covalent BTK inhibitors (ibrutinib, acalabrutinib or zanubrutinib), in patients with MCL who have never received any form of BTK inhibitor. This trial will look at how many people live with the disease without it getting worse. Like other cancer treatments, pirtobrutinib may affect both healthy cells and tumor cells, which can result in side effects that will also be looked at in this study. This study is active and currently recruiting new patients who have received at least one previous therapy for MCL and have never been treated with a BTK inhibitor.

Introduction: In 2017, the US FDA granted approval of a subcutaneous (SC) injection form of rituximab as an alternative means of administration for patients with follicular lymphoma (FL), diffuse large B-cell lymphoma (DLBCL), and chronic lymphocytic leukemia (CLL). Although patients have reported a preference for SC rituximab (R-SC) over intravenous rituximab infusion (R-IV) in the clinical trial setting, patient and nurse provider preferences for R-SC vs R-IV in a real-world setting have not been studied. We report the findings of two surveys designed to assess patient and nurse treatment preferences for R-SC vs R-IV. Methods: Two descriptive, cross-sectional surveys of 70 patients and 208 oncology nurse providers were conducted via web-based questionnaires. Patients who received R-SC, and nurses who administered at least one R-IV and at least one R-SC treatment between July 1, 2017 and April 30, 2019 in US Oncology Network (USON) clinics, were eligible to participate. The surveys evaluated patients' and nurses' experience with R-SC vs R-IV, preference for SC or IV administration, convenience, and overall experience. Results: Among the 70 patients invited to participate in the patient survey, 29 (DLBCL n=12; FL n=13; CLL n=4) completed it (41% response rate). Of the respondents, the mean age was 69 years, 59% were male, 86% were Caucasian, 35% had stage IV disease, 72% had an Eastern Cooperative Oncology Group performance status of 0-1, and 69% were retired. Respondents received a mean of 4 (standard deviation [SD] 2.5) R-SC injections per patient, with the majority indicating preference for R-SC (n=20, 69%) over R-IV infusion (n=9, 31%). Among patients preferring R-SC, less time spent in the clinic (n=20, 69%) and less emotional distress (n=12, 41%) were the most common reasons for their treatment preference. A higher percentage of patients reported R-SC as being very convenient (n=18, 62%) versus R-IV (n=13, 45%). More patients required caregiver assistance during R-IV administration (n=13, 45% patients) compared with R-SC administration (n=8, 28%). Among 208 nurse providers invited to participate in the nurse provider survey, 36 completed it (17% response rate). In total, 58% (n=21) of nurse respondents preferred administering R-SC over R-IV, with time saving, convenience, and patient preference being the most common reasons. A high proportion of respondents (61%) had a positive/very positive experience with R-SC over R-IV, as a result of patient time saved, clinic/staff time saved, and quality time with patients. Most (80%) respondents reported spending 1.5 to over 2 hours of nursing time monitoring and administering R-IV for each patient, and 52% reported that 1.5 to 2 hours could be saved with each administration of R-SC as compared with R-IV. All respondents judged that chair time could be saved with each administration of R-SC compared with R-IV. Respondents reported that the time saved could be used to see more patients, complete nursing procedures, and complete administrative work, and most agreed that the quality of patient care was not impacted by the shorter administration time of R-SC. Conclusions: Although this study is limited by a small sample size, of the patients and nurses surveyed, the majority expressed a positive experience with respect to receiving and administrating R-SC over R-IV. Reduced time spent in the clinic was the main reason for R-SC preference among patients. Time saved, convenience, and patient preference contributed to the positive experience with R-SC among nurse providers. This survey-based assessment of patient and nurse preference demonstrates a majority of respondents preferring R-SC compared to R-IV. While our analysis is limited by a small sample size, it provides real-world data on patient and provider preferences of rituximab administration. Disclosures Gandhi: TG Therapeutics (Advisory board), GlaxoSmithKline (Advisory board): Membership on an entity's Board of Directors or advisory committees. Shapouri:Roche: Current equity holder in publicly-traded company; Genentech, Inc.: Current Employment. Ravelo:Genentech, Inc.: Current Employment; Roche Holdings: Current equity holder in publicly-traded company. Sudharshan:Employee of McKesson. McKesson was paid consulting fees for the conduct of this study: Consultancy; McKesson Life Sciences: Current Employment. Beeks:F. Hoffmann-La Roche Ltd: Consultancy; McKesson: Current Employment. Dawson:Genentech, Inc.: Current Employment; Roche/Genentech: Current equity holder in publicly-traded company.

Background: Bruton tyrosine kinase inhibitors (BTKis) are important tools to treat B-cell malignancies. However, duration of treatment may be limited by adverse events (AEs). Zanubrutinib (zanu) is a BTKi approved for mantle cell lymphoma (MCL) and is in development for other hematologic malignancies. Data from phase 3 head-to-head trials of zanu vs ibrutinib (ibr) in pts with Waldenström macroglobulinemia (WM) or chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) demonstrated that pts treated with zanu showed lower rates of AEs leading to discontinuation (Blood 2020;136(18):2038-50; EHA 2021 LB1900). Preliminary results from BGB-3111-215 (NCT04116437) show that zanu was well-tolerated in pts who discontinued ibr and/or acalabrutinib (acala) treatment due to AEs (EHA 2021 EP642). Here, we report updated results from the BGB-3111-215 study with a median follow-up of 9 months. Methods: This study is an ongoing US, phase 2, multicenter, single-arm, open-label study. The safety and efficacy of zanu monotherapy (160 mg twice daily or 320 mg once daily) were evaluated in pts with B-cell malignancies who met criteria for continued treatment after having become intolerant to prior BTKi therapy. Pts were divided into cohort 1 (pts who were intolerant to ibr only) and cohort 2 (pts who were intolerant to acala alone/and ibr). Pts with documented progressive disease (PD) on prior BTKi therapy were excluded. Efficacy and safety, including recurrence of intolerant AEs to the prior BTKi, were evaluated. AEs were assessed for severity, seriousness, and relation to zanu; as well as dose reductions, holds, or discontinuations. Response was assessed by investigators based on response criteria for their respective indications (Blood 2008;131:2745; J Clin Oncol 2012;30:2820; J Clin Oncol 2014;32:3059; Br J Haemtol 2013;160:171). Disease parameters from study entry were the baseline for response assessment. Mutational analysis was performed on pts who discontinued treatment, and data will be shared once available. To support clinical findings, kinase selectivity was assessed using Kinome profiling at 100X IC50 (against BTK) for zanu, ibr, acala and its major metabolite, M27 (Reaction Biology Corp). Results: As of 7 June 2021 (data cutoff), 57 pts (n=44 CLL/SLL; n=9 WM; n=2 MCL; n=2 marginal zone lymphoma [MZL]) were enrolled in cohort 1, and 7 pts were enrolled in cohort 2 (n=4 CLL; n=1 WM; n=1 MCL; n=1 MZL). All received ≥1 dose of zanu and were analyzed for safety. The median age was 71 years (range, 49-91) in cohort 1 and 71 years (range, 65-76) in cohort 2; median duration of treatment was 8.7 months (range, 0.6-17.9) in cohort 1 and 8.2 months (range, 6.4-11.4) in cohort 2; median number of prior regimens was 1 (range, 1-12) in cohort 1 and 3 (range, 2-5) in cohort 2. Within cohort 2, 5 pts were intolerant to both ibr and acala. Median number of intolerant events per pt for both cohorts 1 and 2 was 2 (range, 1-5). Overall, 73% of pts did not experience recurrence of their ibr or acala intolerant events and 79% of recurrent events recurred at a lower severity (Figure 1). At cutoff, 54 pts remained on treatment. Reasons for treatment discontinuation were AEs (n=4), PD (n=4), physician's decision (n=1), and consent withdrawal (n=1). Grade ≥3 AEs were reported in 18 pts (28%), and serious AEs occurred in 7 pts (11%). AEs requiring dose interruptions occurred in 17 pts (27%), and AEs leading to dose reduction occurred in 3 pts (5%). One death, due to COVID-19, was reported. Pts demonstrated maintained (41%) and improved (53%) response with zanu treatment from their reported best overall response on prior BTKis for a total disease control rate of 94% (including a 42% partial response rate in pts with CLL/SLL, 30% in pts with WM, and a 20% very good partial response rate in pts with WM). Zanu also demonstrated good selectivity by kinase profiling. It showed >50% inhibition on 7/370 kinases, while ibr, acala, and M27 had more off-target binding (17, 15 and 23 kinases, respectively) at their respective 100X IC50 (BTK) concentrations (Figure 2). Conclusion: In pts with B-cell malignancies intolerant to ibr and/or acala, zanu treatment resulted in continued disease control or improved response. Zanu was well-tolerated, and most AEs that led to discontinuation of previous BTKi therapy did not recur or recurred at a lower grade. In support of clinical findings, differentiation between BTKi selectivity profiles favor zanu over ibr and acala. Figure 1 Figure 1. Disclosures Shadman: Abbvie, Genentech, AstraZeneca, Sound Biologics, Pharmacyclics, Beigene, Bristol Myers Squibb, Morphosys, TG Therapeutics, Innate Pharma, Kite Pharma, Adaptive Biotechnologies, Epizyme, Eli Lilly, and Atara Biotherapeutics, Adaptimmune: Consultancy; Mustang Bio, Celgene, Bristol Myers Squibb, Pharmacyclics, Gilead, Genentech, Abbvie, TG Therapeutics, Beigene, AstraZeneca, Sunesis, Atara Biotherapeutics, GenMab: Research Funding; Abbvie, Genentech, AstraZeneca, Sound Biologics, Pharmacyclics, Beigene, Bristol Myers Squibb, Morphosys, TG Therapeutics, Innate Pharma, Kite Pharma, Adaptive Biotechnologies, Epizyme, Eli Lilly, and Atara Biotherapeutics, Adaptimmune: Membership on an entity's Board of Directors or advisory committees. Flinn: Nurix Therapeutics: Consultancy, Other: All consultancy payments made to Sarah Cannon Research Institute; Seagen: Consultancy, Other: All consultancy and research funding payments made to Sarah Cannon Research Institute, Research Funding; MorphoSys: Consultancy, Other: All consultancy and research funding payments made to Sarah Cannon Research Institute, Research Funding; Forty Seven: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Calithera Biosciences: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Verastem: Consultancy, Other: All consultancy and research funding payments made to Sarah Cannon Research Institute, Research Funding; Curis: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Takeda: Consultancy, Other: All consultancy and research funding payments made to Sarah Cannon Research Institute, Research Funding; Yingli Pharmaceuticals: Consultancy, Other: All consultancy payments made to Sarah Cannon Research Institute; IGM Biosciences: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; AbbVie: Consultancy, Other: All Consultancy and Research Funding payments made to Sarah Cannon Research Institute, Research Funding; Portola Pharmaceuticals: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Trillium Therapeutics: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Rhizen Pharmaceuticals: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Incyte: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Acerta Pharma: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Agios: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Kite, a Gilead Company: Consultancy, Other: All consultancy and research funding payments made to Sarah Cannon Research Institute, Research Funding; Gilead Sciences: Consultancy, Other: All consultancy and research funding payments made to Sarah Cannon Research Institute, Research Funding; Pharmacyclics LLC, an AbbVie Company: Consultancy, Other: All consultancy and research funding payments made to Sarah Cannon Research Institute, Research Funding; Karyopharm Therapeutics: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Forma Therapeutics: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Genentech: Consultancy, Other: All consultancy and research funding payments made to Sarah Cannon Research Institute, Research Funding; ArQule: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Triphase Research & Development Corp.: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Roche: Consultancy, Other: All consultancy and research funding payments made to Sarah Cannon Research Institute, Research Funding; Pfizer: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Teva: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Infinity Pharmaceuticals: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Unum Therapeutics: Consultancy, Other: All consultancy and research funding payments made to Sarah Cannon Research Institute, Research Funding; Celgene: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Constellation Pharmaceuticals: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Juno Therapeutics: Consultancy, Other: All consultancy and research funding payments made to Sarah Cannon Research Institute, Research Funding; AstraZeneca: Consultancy, Other: All consultancy and research funding payments made to Sarah Cannon Research Institute, Research Funding; Iksuda Therapeutics: Consultancy, Other: All consultancy payments made to Sarah Cannon Research Institute; Loxo: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Merck: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Novartis: Consultancy, Other: All consultancy and research funding payments made to Sarah Cannon Research Institute, Research Funding; Great Point Partners: Consultancy, Other: All consultancy payments made to Sarah Cannon Research Institute; BeiGene: Consultancy, Other: All consultancy and research funding payments made to Sarah Cannon Research Institute, Research Funding; Janssen: Consultancy, Other: All consultancy and research funding payments made to Sarah Cannon Research Institute, Research Funding; TG Therapeutics: Consultancy, Other: All consultancy and research funding payments made to Sarah Cannon Research Institute, Research Funding; Century Therapeutics: Consultancy, Other: All consultancy payments made to Sarah Cannon Research Institute; Hutchison MediPharma: Consultancy, Other: All consultancy payments made to Sarah Cannon Research Institute; Vincerx Pharma: Consultancy, Other: All consultancy payments made to Sarah Cannon Research Institute; Sarah Cannon Research Institute: Current Employment; Servier Pharmaceuticals: Consultancy, Other: All consultancy payments made to Sarah Cannon Research Institute; Yingli Pharmaceuticals: Consultancy, Other: All consultancy payments made to Sarah Cannon Research Institute; Seagen: Consultancy, Other: All consultancy payments made to Sarah Cannon Research Institute; Servier Pharmaceuticals: Consultancy, Other: All consultancy payments made to Sarah Cannon Research Institute; Unum Therapeutics: Consultancy, Other: All consultancy payments made to Sarah Cannon Research Institute, Research Funding; Johnson & Johnson: Current holder of individual stocks in a privately-held company; Seattle Genetics: Research Funding. Levy: Epizyme: Consultancy, Other: Promotional speaker; Amgen Inc.: Consultancy, Honoraria, Other: Promotional speaker, Speakers Bureau; Gilead Sciences, Inc.: Consultancy, Honoraria, Speakers Bureau; GSK: Consultancy, Other: Promotional speaker; Morphosys: Consultancy, Honoraria, Other: Promotional speaker, Speakers Bureau; AbbVie: Consultancy, Honoraria, Other: Promotional speaker, Speakers Bureau; Beigene: Consultancy, Honoraria, Speakers Bureau; Karyopharm: Consultancy, Honoraria, Other: Promotional speaker, Speakers Bureau; AstraZeneca: Consultancy, Honoraria, Speakers Bureau; Takeda: Consultancy, Honoraria, Other: Promotional speaker, Speakers Bureau; Novartis: Consultancy, Other: Promotional speaker; Dova: Consultancy, Other: Promotional speaker; TG Therapeutics: Consultancy, Honoraria, Speakers Bureau; Bristol Myers Squibb: Consultancy, Honoraria, Other: Promotional speaker, Speakers Bureau; Seattle Genetics: Consultancy, Honoraria, Other: Promotional speaker, Speakers Bureau; Jazz Pharmaceuticals: Consultancy, Honoraria, Speakers Bureau; Janssen Pharmaceuticals: Consultancy, Honoraria, Other: Promotional speaker, Speakers Bureau. Burke: SeaGen: Consultancy, Speakers Bureau; Beigene: Consultancy, Speakers Bureau; MorphoSys: Consultancy; Bristol Myers Squibb: Consultancy; AstraZeneca: Consultancy; Epizyme: Consultancy; Verastem: Consultancy; Kura: Consultancy; Kymera: Consultancy; AbbVie: Consultancy; Adaptive Biotechnologies: Consultancy; Roche/Genentech: Consultancy; X4 Pharmaceuticals: Consultancy. Cultrera: Beigene: Research Funding. Yimer: Astrazeneca: Speakers Bureau; Karyopharm: Current equity holder in publicly-traded company, Speakers Bureau; Janssen: Speakers Bureau; Beigene: Speakers Bureau; GSK: Speakers Bureau; Sanofi: Speakers Bureau; Amgen: Speakers Bureau; Pharmacyclics: Speakers Bureau; Texas Oncology: Current Employment. Chaudhry: Medical Oncology Associates, PS (dba Summit Cancer Centers): Current Employment; Novartis, Immunomedics: Current holder of individual stocks in a privately-held company. Gandhi: TG Therapeutics: Honoraria; Karyopharm Therapeutics: Honoraria; GlaxoSmithKline: Honoraria. Kingsley: Comprehensive Cancer Centers of Nevada: Current Employment. Tumula: Texas Oncology: Current Employment. Manda: Morphosys: Honoraria; Genmab: Current equity holder in publicly-traded company. Chen: BeiGene: Current Employment, Divested equity in a private or publicly-traded company in the past 24 months. Cohen: BeiGene: Current Employment, Current equity holder in publicly-traded company, Other: Travel, Accommodations, Expenses. By: BeiGene, Ltd: Current Employment. Xu: Beigene: Current Employment; AstraZeneca: Ended employment in the past 24 months. Liu: BeiGene Co., Ltd: Current Employment, Current equity holder in publicly-traded company. Sharman: TG Therapeutics: Consultancy; Centessa: Current holder of stock options in a privately-held company, Membership on an entity's Board of Directors or advisory committees; Pharmacyclics LLC, an AbbVie Company: Consultancy; BMS: Consultancy; AbbVie: Consultancy; BeiGene: Consultancy; AstraZeneca: Consultancy; Lilly: Consultancy.

Background: Covalent Bruton's Tyrosine Kinase (BTK) inhibitors (BTKi) have transformed the management of relapsed mantle cell lymphoma (MCL), but these treatments are not curative and the majority of patients will require additional treatment. Covalent BTKi share pharmacologic liabilities (e.g. low oral bioavailability, short half-life) that collectively may lead to suboptimal BTK target coverage especially in rapidly proliferating tumors with high BTK protein turnover such as MCL. To address these limitations, pirtobrutinib, a highly selective, non-covalent BTKi that inhibits both wild type (WT) and C481-mutated BTK with equal low nM potency was developed. In the phase 1/2 BRUIN study, pirtobrutinib achieved pharmacokinetic exposures that exceeded its BTK IC96 at trough, was well tolerated, and demonstrated promising efficacy in heavily pretreated, poor-prognosis MCL patients, most of whom had prior treatment with a covalent BTKi (Mato et al. Lancet 2021;397,10277:892-901). The purpose of this randomized study is to demonstrate the superiority of pirtobrutinib compared to investigator's choice of covalent BTKi in patients with previously treated MCL. Study Design and Methods: BRUIN MCL-321 is a randomized, open-label, global phase 3 study comparing pirtobrutinib monotherapy versus investigator's choice of covalent BTKi monotherapy (ibrutinib, acalabrutinib, or zanubrutinib) in patients with previously treated, BTKi naïve MCL. Approximately 500 patients will be randomized 1:1. Randomization will be stratified by sMIPI risk (low/intermediate vs high), comparator BTKi (ibrutinib vs acalabrutinib/ zanubrutinib), and number of prior lines of therapy (1 vs ≥ 2). Eligible patients are adults aged ≥18 years with a confirmed diagnosis of MCL (cyclin D1 overexpression, and ≥ 1 B-cell marker) who have received ≥ 1 prior line of systemic therapy for MCL that did not include a prior BTKi. Patients must have measurable disease per Lugano criteria and must have progressed on or relapsed following the most recent line of therapy prior to study enrollment. Key exclusion criteria include a history of current or prior CNS involvement, significant cardiovascular disease, stroke, or intracranial hemorrhage within 6 months of randomization, and allogeneic stem cell transplant (SCT), autologous SCT or chimeric antigen receptor (CAR) T-cell therapy within 60 days of randomization. The primary endpoint is progression-free survival (PFS) per Lugano criteria assessed by an independent review committee (IRC), with the goal of demonstrating superiority of pirtobrutinib over investigator's choice of covalent BTKi. Secondary endpoints include overall response rate (ORR), duration of response (DoR), investigator-assessed PFS per Lugano criteria, overall survival (OS), event-free survival (EFS), time to treatment failure (TTF), time to next treatment (TTNT), time from randomization to disease progression on next line of treatment or death from any cause (PFS2), safety and tolerability, and patient reported outcomes. This global study is currently enrolling patients (NCT04662255). Disclosures Eyre: Gilead/KITE: Honoraria, Other: Travel support for conferences, Research Funding, Speakers Bureau; Janssen: Honoraria; Loxo Oncology: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Incyte: Consultancy; Abbvie: Consultancy, Honoraria, Other: Travel to conferences; Roche: Consultancy, Honoraria; AstraZeneca: Honoraria, Research Funding; Beigene: Honoraria, Research Funding; Secura Bio: Consultancy, Honoraria. Shah: Miltenyi Biotec: Consultancy, Honoraria, Research Funding; Kite: Consultancy; Epizyme: Consultancy; Umoja: Consultancy; Legend: Consultancy; Incyte: Consultancy; Lily: Consultancy, Honoraria, Research Funding. Dreyling: Novartis: Consultancy, Speakers Bureau; Janssen: Consultancy, Research Funding, Speakers Bureau; Roche: Consultancy, Research Funding, Speakers Bureau; Astra Zeneca: Consultancy, Speakers Bureau; BeiGene: Consultancy; Celgene: Consultancy, Research Funding, Speakers Bureau; Amgen: Speakers Bureau; Genmab: Consultancy; Bayer HealthCare Pharmaceuticals: Consultancy, Research Funding, Speakers Bureau; Gilead/Kite: Consultancy, Research Funding, Speakers Bureau; Abbvie: Research Funding; Incyte: Consultancy, Speakers Bureau. Vandenberghe: Jansnens: Honoraria; Abbvie: Honoraria. Jurczak: Abbvie, AstraZeneca, BeiGene, Celtrion, Celgene, Debbiopharm, Epizyme, Incyte, Janssen, Loxo Oncology, Merck, Mei Pharma, Morphosys, Novo Nordisk, Roche, Sandoz, Takeda, TG Therapeutics: Research Funding; Astra Zeneca, BeiGene, Janssen, Loxo Oncology, Sandoz, Roche,: Membership on an entity's Board of Directors or advisory committees. Wang: Genentech: Research Funding; Eli Lilly: Membership on an entity's Board of Directors or advisory committees; MorphoSys: Research Funding; LOXO Oncology: Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Research Funding; InnoCare: Research Funding; Incyte: Membership on an entity's Board of Directors or advisory committees, Research Funding; TG Therapeutics: Membership on an entity's Board of Directors or advisory committees. Cheah: Loxo/Lilly: Consultancy, Honoraria, Other: advisory; Janssen: Consultancy, Honoraria, Other: advisory; Roche: Consultancy, Honoraria, Other: advisory and travel expenses, Research Funding; TG Therapeutics: Consultancy, Honoraria, Other: advisory; AstraZeneca: Consultancy, Honoraria, Other: advisory; Celgene: Research Funding; AbbVie: Research Funding; Beigene: Consultancy, Honoraria, Other: advisory; Ascentage pharma: Consultancy, Honoraria, Other: advisory; Gilead: Consultancy, Honoraria, Other: advisory; MSD: Consultancy, Honoraria, Other: advisory, Research Funding. Gandhi: Karyopharm Therapeutics: Honoraria; TG Therapeutics: Honoraria; GlaxoSmithKline: Honoraria. Sharman: AstraZeneca: Consultancy; Lilly: Consultancy; Pharmacyclics LLC, an AbbVie Company: Consultancy; Centessa: Current holder of stock options in a privately-held company, Membership on an entity's Board of Directors or advisory committees; BeiGene: Consultancy; BMS: Consultancy; TG Therapeutics: Consultancy; AbbVie: Consultancy. Andorsky: Abbvie: Consultancy, Research Funding; Celgene/BMS: Consultancy, Research Funding; Epizyme: Research Funding. Yin: Loxo Oncology at Lilly: Current Employment; AstraZeneca: Ended employment in the past 24 months. Balbas: Nektar Therapeutics: Current equity holder in publicly-traded company, Ended employment in the past 24 months; Loxo Oncology at Lilly: Current Employment, Current equity holder in publicly-traded company. Kherani: Loxo Oncology at Lilly: Current Employment, Current equity holder in publicly-traded company. Wang: AstraZeneca, Bayer Healthcare, BeiGene, CSTone, DTRM Biopharma (Cayman) Limited, Epizyme, Genentech, InnoCare, Janssen, Juno, Kite Pharma, Loxo Oncology, Miltenyi Biomedicine GmbH, Oncternal, Pharmacyclics, VelosBio: Consultancy; Acerta Pharma, AstraZeneca, BeiGene, BioInvent, Celgene, Innocare, Janssen, Juno, Kite, Pharma, Lilly, Loxo Oncology, Molecular Templates, Oncternal, Pharmacyclics, VelosBio: Research Funding; Acerta Pharma, Anticancer Association, AstraZeneca, BeiGene, CAHON, Chinese Medical Association, Clinical Care Options, Dava Oncology, Epizyme, Hebei Cancer Prevention Federation, Imbruvica, Imedex, Janssen, Kite Pharma, Miltenyi Biomedicine GmbH, Moffit : Honoraria.

Introduction Brentuximab vedotin (BV) and nivolumab are both active and well tolerated in patients (pts) with classical Hodgkin lymphoma (cHL) and were previously studied in first salvage (overall response rate [ORR] 85%; complete response [CR] 67%) (Advani 2021) and as firstline therapy in older adults (ORR 95%; CR 79%) (Yasenchak 2019). BV is approved for the treatment of adults with treatment-naïve Stage III or IV cHL in combination with doxorubicin, vinblastine, and dacarbazine (AVD) (Connors 2017) and targets CD30, a receptor expressed on the Reed-Sternberg cells. Nivolumab is approved for treatment of adults with relapsed/refractory cHL and restores antitumor immunity by blocking the PD-1 receptor on activated T-cells. The combination of BV plus nivolumab demonstrated promising activity that supports this combination when evaluated as a frontline treatment option for pts over 60 years of age with cHL (Friedberg 2018). Additionally, in pts with non-bulky Stage I or II cHL, treatment with BV plus doxorubicin and dacarbazine (AD) resulted in a CR rate of 97% at end of treatment (EOT), as well as a promising 4-year progression-free survival (PFS) estimate of 91%. Importantly, there were no cases of ≥Grade 3 peripheral neuropathy and only 9% were Grade 2 (Abramson 2021). Herein, we present preliminary safety results from Part B of this phase 2 study, where combination treatment with AN+AD (BV, nivolumab, doxorubicin, and dacarbazine) was well tolerated without excessive dose modifications or discontinuations and is consistent with the known safety profiles of the individual components of this treatment regimen. Methods SGN35-027 (NCT03646123) is an open-label, multiple part, multicenter, phase 2 clinical trial. Part B of this study enrolled pts with Ann Arbor Stage I or II cHL with bulky mediastinal disease (defined as ≥ 10 cm) or Stage III or IV cHL. Pts received up to 6 cycles of AN+AD (consisting of BV 1.2 mg/kg, nivolumab 240 mg, doxorubicin 25 mg/m 2, and dacarbazine 375 mg/m 2). All study drugs were administered by IV infusion on Days 1 and 15 of each 28-day cycle. The primary endpoint was CR rate at EOT. Secondary endpoints included safety, tolerability, overall response rate, and PFS. Disease response and progression was assessed by investigators using the Lugano Classification Revised Staging System for nodal non-Hodgkin and Hodgkin Lymphomas (Cheson 2014) and Lymphoma Response to Immunomodulatory Therapy Criteria (LYRIC) (Cheson 2016) at Cycle 2 and EOT. Results In Part B, the majority of the 58 pts enrolled were white (86%), not of Hispanic or Latino/a or Spanish origins (79%), and less than 65 years old (95%). Median age was 35 years (range: 19-78 years). Twenty-nine percent of pts had Stage II cHL with bulky mediastinal disease, while the remainder had Stage III (17%) or Stage IV (50%) cHL. Of the 58 pts enrolled, 57 received at least one dose of study treatment. Of the 57 pts who received at least one dose of study treatment, 1 pt discontinued treatment (all study drugs) by the end of Cycle 2 due to treatment-emergent adverse events (TEAEs). By end of Cycle 2, the majority of TEAEs were Grades 1 and 2; 16% of pts experienced ≥Grade 3 TEAEs. Nausea, fatigue, and alopecia were the most frequently reported treatment-related TEAEs (51%, 33%, and 26% of pts, respectively). No febrile neutropenia was observed, and there were no Grade 5 adverse events. Two pts (4%) experienced treatment-related treatment-emergent serious adverse events; 1 pt (2%) experienced hypophysitis and aseptic meningitis, and discontinued treatment, and 1 pt (2%) experienced pneumonitis. Preliminary efficacy results are anticipated for presentation. Conclusions Preliminary results demonstrate that AN+AD is well-tolerated, and no new safety signals were observed. The omission of bleomycin and vinblastine may have contributed to the absence of certain AEs, such as febrile neutropenia. This study of AN+AD is ongoing, and updated safety and efficacy results will be presented at the meeting. Disclosures Lee: BMS: Honoraria, Research Funding; Aptitude Health: Honoraria; Century Therapeutics: Consultancy; Pharmacyclics: Research Funding; Guidepoint: Honoraria; Oncternal: Research Funding; Seagen: Research Funding; Takeda: Research Funding; Celgene: Research Funding; Janssen: Honoraria. Flinn: Agios: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Curis: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; TG Therapeutics: Consultancy, Other: All consultancy and research funding payments made to Sarah Cannon Research Institute, Research Funding; Iksuda Therapeutics: Consultancy, Other: All consultancy payments made to Sarah Cannon Research Institute; Karyopharm Therapeutics: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Loxo: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; IGM Biosciences: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Seagen: Consultancy, Other: All consultancy and research funding payments made to Sarah Cannon Research Institute, Research Funding; Kite, a Gilead Company: Consultancy, Other: All consultancy and research funding payments made to Sarah Cannon Research Institute, Research Funding; Merck: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Acerta Pharma: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Trillium Therapeutics: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Genentech: Consultancy, Other: All consultancy and research funding payments made to Sarah Cannon Research Institute, Research Funding; Janssen: Consultancy, Other: All consultancy and research funding payments made to Sarah Cannon Research Institute, Research Funding; Yingli Pharmaceuticals: Consultancy, Other: All consultancy payments made to Sarah Cannon Research Institute; Portola Pharmaceuticals: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; BeiGene: Consultancy, Other: All consultancy and research funding payments made to Sarah Cannon Research Institute, Research Funding; Takeda: Consultancy, Other: All consultancy and research funding payments made to Sarah Cannon Research Institute, Research Funding; AstraZeneca: Consultancy, Other: All consultancy and research funding payments made to Sarah Cannon Research Institute, Research Funding; Verastem: Consultancy, Other: All consultancy and research funding payments made to Sarah Cannon Research Institute, Research Funding; Juno Therapeutics: Consultancy, Other: All consultancy and research funding payments made to Sarah Cannon Research Institute, Research Funding; Great Point Partners: Consultancy, Other: All consultancy payments made to Sarah Cannon Research Institute; Infinity Pharmaceuticals: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Novartis: Consultancy, Other: All consultancy and research funding payments made to Sarah Cannon Research Institute, Research Funding; Forty Seven: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Gilead Sciences: Consultancy, Other: All consultancy and research funding payments made to Sarah Cannon Research Institute, Research Funding; Celgene: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Calithera Biosciences: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Teva: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Pharmacyclics LLC, an AbbVie Company: Consultancy, Other: All consultancy and research funding payments made to Sarah Cannon Research Institute, Research Funding; AbbVie: Consultancy, Other: All Consultancy and Research Funding payments made to Sarah Cannon Research Institute, Research Funding; Constellation Pharmaceuticals: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Pfizer: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; MorphoSys: Consultancy, Other: All consultancy and research funding payments made to Sarah Cannon Research Institute, Research Funding; ArQule: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Rhizen Pharmaceuticals: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Forma Therapeutics: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Nurix Therapeutics: Consultancy, Other: All consultancy payments made to Sarah Cannon Research Institute; Roche: Consultancy, Other: All consultancy and research funding payments made to Sarah Cannon Research Institute, Research Funding; Triphase Research & Development Corp.: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Incyte: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Unum Therapeutics: Consultancy, Other: All consultancy and research funding payments made to Sarah Cannon Research Institute, Research Funding; Century Therapeutics: Consultancy, Other: All consultancy payments made to Sarah Cannon Research Institute; Hutchison MediPharma: Consultancy, Other: All consultancy payments made to Sarah Cannon Research Institute; Vincerx Pharma: Consultancy, Other: All consultancy payments made to Sarah Cannon Research Institute; Sarah Cannon Research Institute: Current Employment; Servier Pharmaceuticals: Consultancy, Other: All consultancy payments made to Sarah Cannon Research Institute; Yingli Pharmaceuticals: Consultancy, Other: All consultancy payments made to Sarah Cannon Research Institute; Seagen: Consultancy, Other: All consultancy payments made to Sarah Cannon Research Institute; Servier Pharmaceuticals: Consultancy, Other: All consultancy payments made to Sarah Cannon Research Institute; Unum Therapeutics: Consultancy, Other: All consultancy payments made to Sarah Cannon Research Institute, Research Funding; Johnson & Johnson: Current holder of individual stocks in a privately-held company; Seattle Genetics: Research Funding. Melear: Astrazeneca: Speakers Bureau; TG Therapeutics: Speakers Bureau; Janssen: Speakers Bureau. Ramchandren: curis: Research Funding; MERCK: Consultancy, Research Funding; pharmacyclics: Consultancy, Research Funding; seattle genetics: Consultancy, Research Funding; BMS: Consultancy; Trillium: Research Funding. Friedman: Seagen Inc.: Research Funding. Burke: MorphoSys: Consultancy; Beigene: Consultancy, Speakers Bureau; AbbVie: Consultancy; Epizyme: Consultancy; Adaptive Biotechnologies: Consultancy; Bristol Myers Squibb: Consultancy; Kymera: Consultancy; AstraZeneca: Consultancy; Verastem: Consultancy; Kura: Consultancy; X4 Pharmaceuticals: Consultancy; SeaGen: Consultancy, Speakers Bureau; Roche/Genentech: Consultancy. Linhares: Seagen Inc.: Research Funding. Peterson: Seagen Inc.: Research Funding. Raval: Abbvie Pharmaceuticals: Speakers Bureau; Adaptive Biotechnologies: Consultancy; ADCT Therapeutics: Consultancy, Speakers Bureau; Alexion Pharmaceuticals: Speakers Bureau; Amgen Biotechnology Company: Research Funding; Astellas Pharmaceuticals: Speakers Bureau; Astrazeneca Pharmaceuticals: Consultancy, Speakers Bureau; Beigene Pharmaceuticals: Speakers Bureau; Bristol Meyers Squibb Pharmaceuticals: Consultancy; Epizyme Pharmaceuticals: Consultancy, Speakers Bureau; Genetech Biotechnology Company: Research Funding; GlaxoSmithKline Pharmaceuticals: Consultancy; Incyte Pharmaceuticals Corporation: Speakers Bureau; Jazz Pharmaceuticals: Consultancy; Karyopharm Therapeutics: Consultancy; Morphosys Biotech Company: Speakers Bureau; Sanofi Genzyme: Consultancy; Seagen Biotechnology Company: Research Funding; Takeda Pharmaceuticals: Consultancy, Speakers Bureau. Chintapatla: Seagen Inc.: Research Funding. Feldman: Alexion, AstraZeneca Rare Disease: Honoraria, Other: Study investigator. Yimer: Janssen: Speakers Bureau; Beigene: Speakers Bureau; Astrazeneca: Speakers Bureau; Karyopharm: Current equity holder in publicly-traded company, Speakers Bureau; GSK: Speakers Bureau; Sanofi: Speakers Bureau; Amgen: Speakers Bureau; Pharmacyclics: Speakers Bureau; Texas Oncology: Current Employment. Islas-Ohlmayer: Seagen Inc.: Research Funding. Dean: Seagen Inc.: Research Funding. Rana: Seagen Inc.: Research Funding. Gandhi: GlaxoSmithKline: Honoraria; Karyopharm Therapeutics: Honoraria; TG Therapeutics: Honoraria. Renshaw: Amgen: Speakers Bureau; SeaGen: Consultancy; Jazz Pharmaceuticals: Consultancy, Speakers Bureau; AbbVie: Consultancy, Speakers Bureau; Texas Oncology: Current Employment. Gillespie-Twardy: Seagen Inc.: Research Funding. Ho: Seagen Inc.: Current Employment, Current equity holder in publicly-traded company. Fanale: Seagen, Inc: Current Employment, Current equity holder in publicly-traded company. Guo: Seagen Inc.: Current Employment, Current equity holder in publicly-traded company. Yasenchak: Seagen Inc.: Research Funding.

Introduction: Patients with diffuse large B-cell lymphoma (DLBCL) who fail immunochemotherapy (IC) and are unsuitable for autologous stem cell transplantation (ASCT) and those who relapse shortly after ASCT have extremely poor prognosis and need additional treatment options. Loncastuximab tesirine (Lonca) is an antibody-drug conjugate (ADC) composed of a humanized anti-CD19 antibody conjugated to a pyrrolobenzodiazepine dimer toxin. In a Phase 2 study (NCT03589469), Lonca demonstrated single-agent antitumor activity with manageable toxicity in patients with relapsed/refractory (R/R) DLBCL. Rituximab is a CD20-targeting monoclonal antibody used in front-line IC for DLBCL and in salvage regimens, such as rituximab/gemcitabine/oxaliplatin (R-GemOx). The addition of rituximab to a CD19-targeting pyrrolobenzodiazepine ADC appears to prolong tumor control in preclinical studies, providing the rationale for evaluating Lonca combined with rituximab (Lonca-R) as a treatment for R/R DLBCL. Study Design and Methods: This is a Phase 3, randomized, open-label, 2-part, 2-arm, multicenter study of Lonca-R versus standard IC in patients with R/R DLBCL (NCT04384484). Part 1 is a nonrandomized safety run-in with Lonca-R. The toxicity of Lonca-R will be compared with previous single-agent Lonca safety data after 20 patients have completed Cycle 1 in Part 1. Provided no significant increase in toxicity is observed, Part 2 will be initiated. Part 2 is a randomized study of Lonca-R versus R-GemOx (Figure 1). Key inclusion and exclusion criteria are reported in Table 1. The primary objective of Part 2 is to evaluate the efficacy of Lonca-R versus R-GemOx, using progression-free survival (PFS) as the primary endpoint. PFS will be defined as the time between randomization and first documentation of recurrence, disease progression or death (central review) and the primary analysis will compare PFS between treatment arms using stratified log-rank testing. Secondary objectives include evaluation of safety, pharmacokinetics, and immunogenicity of the combination, in addition to the impact of treatment on symptoms, patient-reported outcomes and patients' overall health. In Part 1 and in the Lonca-R arm of Part 2, patients will receive intravenous (iv) Lonca at 150 µg/kg on day 1 of each 21-day cycle for 2 cycles, then at 75 µg/kg on day 1 for up to 6 additional cycles. Rituximab 375 mg/m2 iv will be administered subsequent to Lonca infusion on day 1 of each cycle. Patients treated with Lonca-R will also be given dexamethasone 4 mg (oral, twice a day), where not contraindicated, on the day before, the day of, and the day after Lonca-R infusion. In the R-GemOx arm, patients will receive rituximab 375 mg/m2, gemcitabine 1000 mg/m2, and oxaliplatin 100 mg/m2 iv on day 1 of each 14-day cycle up to a total of 8 cycles. Patients will receive premedication and supportive care according to the respective prescribing information for rituximab, gemcitabine, and oxaliplatin. The trial is planned to open in Q3/Q4 2020, and target enrollment is 350 patients. Funding: This study is sponsored by ADC Therapeutics SA; https://clinicaltrials.gov/ct2/show/NCT04384484. Disclosures Linhares: Jazz Pharmaceuticals: Consultancy; ADC Therapeutics, Verastem Oncology, Bristol Myers-Squibb (Juno), AstraZeneca: Research Funding; Miami Cancer Institute, Baptist Health South Florida: Current Employment. Gandhi:TG Therapeutics (Advisory board), GlaxoSmithKline (Advisory board): Membership on an entity's Board of Directors or advisory committees. Adeleye:ADC Therapeutics: Current Employment, Current equity holder in publicly-traded company. Ungar:ADC Therapeutics: Current Employment, Current equity holder in publicly-traded company. Hamadani:ADC Therapeutics: Membership on an entity's Board of Directors or advisory committees; Sanofi Genzyme, AstraZeneca: Speakers Bureau; Janssen R&D; Incyte Corporation; ADC Therapeutics; Celgene Corporation; Pharmacyclics, Omeros, AbGenomics, Verastem, TeneoBio: Consultancy; Takeda Pharmaceutical Company; Spectrum Pharmaceuticals; Astellas Pharma: Research Funding. OffLabel Disclosure: Rituximab is licensed for treatment of NHL but is being used in combination with an unlicensed drug (loncastuximab tesirine) in this study

Relating the in vitro mitochondrial effects of drug candidates to likely in vivo outcomes remains challenging. Better understanding of this relationship, alongside improved methods to assess mitochondrial dysfunction in vivo, would both guide safer drug candidate selection and better support discovery programmes targeting mitochondria for pharmacological intervention. The aim of this study was to profile the in vivo effects of a compound with suspected complex III electron transport chain (ETC) inhibitory activity (GSK932121A) at doses associated with clinical signs, and relate findings back to in vitro data with the same compound. Control liver mitochondria or HepG2 cells were treated in vitro with GSK932121A to assess mitochondrial effects on both calcium retention capacity (CRC) and oxygen consumption rate (OCR) respectively. The same assessments were then performed on liver mitochondria isolated from Crl:CD(SD) rats, 5 hours following intraperitoneal (IP) administration of GSK932121A. Lactate/pyruvate assessment, hepatic microscopy, blood gas analysis, glutathione profiling and transcriptomics were used to characterise the acute toxicity. In vivo, GSK932121A caused hypothermia, increased levels of hepatocellular oxidative stress and a metabolic shift in energy production, resulting in an increased lactate/pyruvate ratio, liver steatosis and glycogen depletion, together with gene expression changes indicative of a fasted state. As would be expected of an ETC inhibitor, GSK932121A reduced the CRC of liver mitochondria isolated from naive control animals and the OCR of HepG2 cells when treated directly in vitro. In contrast, mitochondria isolated from animals treated with GSK932121A in vivo unexpectedly showed an increase in CRC and basal OCR. Whilst seemingly contradictory, these differences likely reflect an adapted state in vivo resulting from the initial insult in combination with compensatory changes made by the tissue to maintain energy production. Only the initial, unconfounded, response is observable in vitro. These findings improve current understanding of the toxicological and molecular consequences of ETC inhibition. Furthermore, this work highlights key differences in the way that mitochondrial perturbation is manifest in vivo versus in vitro in terms of functional endpoints and helps guide endpoint selection for future studies with potential mitochondrial toxicants or drugs designed to modulate mitochondrial function for therapeutic benefit.

BACKGROUND Double-hit lymphomas (DHLs) are collectively defined as B-cell non-Hodgkin lymphomas harboring rearrangements of MYC as well as B-cell lymphoma 2 (BCL2) and/or B-cell lymphoma 6 (BCL6). To the authors' knowledge, the impact of specific oncogene rearrangements on outcomes of patients with DHL who are treated with immunochemotherapy has not been previously described. METHODS The authors identified patients whose diagnostic tissue specimens underwent metaphase karyotyping or fluorescence in situ hybridization for MYC as well as both BCL2 and BCL6 rearrangements. Cohorts were defined by the presence (+) or absence (−) of rearrangements: MYC+/BCL2+/BCL6− (BCL2-DHL), MYC+/BCL2−/BCL6+ (BCL6-DHL), and MYC+/BCL2+/BCL6+ (triple-hit lymphoma; THL). RESULTS A total of 117 patients were included in the current analysis (76 BCL2-DHL patients, 16 BCL6-DHL patients, and 25 THL patients). Compared with patients with BCL2-DHL, those with BCL6-DHL were more likely to be classified as having a non-germinal center cell of origin, presented with extranodal disease, and appeared to achieve higher rates of complete response despite receiving intensive induction therapy less frequently. However, patients with BCL6-DHL experienced a shorter median overall survival if achieving an initial complete response compared with patients with BCL2-DHL. Patients with THL experienced survival outcomes similar to those of patients with BCL2-DHL. CONCLUSIONS Recognition of the specific oncogene rearrangements may be of prognostic value and potentially guide future therapeutic strategies for patients with DHL. Cancer 2016;122:559–564. © 2015 American Cancer Society.

Squamous-cell cancer of the head and neck is a heterogeneous malignancy with treatment predicated on a multimodality therapy involving surgery, chemotherapy, and radiation. However, this approach results in durable responses in only a subset of patients, and is associated with significant toxicity. In advanced disease, multi-agent platinum-based chemotherapy produces only modest improvements in survival. Increased insight into tumor biology has demonstrated several critical oncogenic pathways offering prospects for targeted therapy that may improve upon the existing treatment strategies. The epidermal growth factor receptor is one such target, and directed therapy with the monoclonal antibody cetuximab has been extensively studied. Lapatinib is an oral agent that targets multiple transmembrane receptors within the epidermal growth factor receptor family, and offers a promising new approach to treatment. This paper reviews the rationale for and clinical activity of lapatinib in squamous-cell cancer of the head and neck.

Introduction: The 2017 US FDA approval of a subcutaneous (SC) injection form of rituximab made available an alternative means of administering rituximab for patients with follicular lymphoma (FL), diffuse large B-cell lymphoma (DLBCL), and chronic lymphocytic leukemia (CLL). Although patients have reported a preference for SC rituximab injection (R-SC) over intravenous rituximab infusion (R-IV), nurse provider preferences for R-SC versus R-IV in the real-world setting have not been studied. Here, we report the findings of a survey designed to assess nurse treatment preferences for R-SC versus R-IV. Methods: A descriptive, cross-sectional survey of 208 oncology nurse providers was conducted via a web-based questionnaire between June 6, 2019 and July 10, 2019. Nurses who administered at least one R-IV and at least one R-SC treatment between July 1, 2017 and April 30, 2019 in US Oncology Network (USON) clinics were eligible to participate. The survey comprised 21 items, and evaluated nurses' experience with R-SC versus R-IV, preference for SC or IV administration, convenience, and overall experience. Results: Of the 208 nurse providers invited to participate in the survey, 43 completed the survey (20.7% response rate). Almost all nurses who completed the survey were familiar with administering R-IV, with 70% of the respondents administering >20 infusions in the past year. Nurses were also familiar with administering R-SC, with 56% of respondents administering 1-10 injections in the past year and 44% administering >10 injections in the past year. Fifty-three percent of respondents preferred administering R-SC over R-IV, with time saving, convenience, and patient preference chosen as the most common reasons. Most respondents (58%) had a positive/very positive experience with R-SC over R-IV, as a result of patient time saved, clinic/staff time saved, and quality time with patients. In total, 19% of respondents had a neutral experience with R-SC compared with R-IV. Of those reporting a neutral experience with R-SC, a comparable ease of administration was the most common reason. Twenty-three percent of respondents reported a negative/very negative experience with R-SC, with discomfort with the R-SC route of administration (i.e. physical effort) chosen as the most common reason for the negative experience. Eighty-four percent of respondents reported spending 1.5 to over 2 hours of nursing time monitoring and administering R-IV for each patient. The majority of respondents (98%) agreed that chair time could be saved with each administration of R-SC compared with R-IV. Respondents reported that the time saved could be used to see more patients (50%), complete nursing procedures (36%), and complete administrative work (14%). Forty-four percent of respondents reported that 1.5 to 2 hours could be saved with each administration of R-SC as compared with R-IV, with 67% of respondents agreeing that the quality of patient care was not impacted by the shorter administration time of R-SC. In terms of convenience, 63% of respondents reported R-SC is more convenient than R-IV, and 49% reported their overall impression of injecting R-SC as easy. Moreover, 49% reported that they agreed or strongly agreed that they would recommend R-SC to their medical colleagues, and 63% agreed or strongly agreed that they believe patients would prefer R-SC over R-IV. Conclusions: Based on an online survey of nurse providers with experience administering R-IV and R-SC, a majority of nurse providers preferred administering R-SC over R-IV. Time saved, convenience, and patient preference contributed to the positive experience with R-SC. Acknowledgements: This study was sponsored by Genentech, Inc. Third party editorial assistance, under the direction of Mitul Gandhi and Sheila Shapouri, was provided by Katie Buxton of Gardiner-Caldwell Communications and was funded by F. Hoffmann-La Roche Ltd. Disclosures Gandhi: Seattle Genetics: Other: Education ; Pharmacyclics: Other: Food and beverage ; AbbVie: Other: Food and beverage ; Pfizer: Other: Education ; GSK: Other: Food and beverage ; Genentech, Inc.: Other: Food and beverage ; Acerta Pharma: Research Funding. Shapouri:Genentech, Inc.: Employment; Roche: Equity Ownership. Ravelo:Genentech: Employment, Equity Ownership. Sudharshan:McKesson: Consultancy, Employment. Clark:McKesson: Consultancy, Employment, Equity Ownership. Dawson:Genentech: Employment; Roche/Genentech: Equity Ownership.

Schematic showing the toxicological and adaptive effects of drug-induced respiratory chain inhibition in vivo; also highlighting unanticipated differences from observations made in vitro (in red)., Relating the in vitro mitochondrial effects of drug candidates to likely in vivo outcomes remains challenging. Better understanding of this relationship, alongside improved methods to assess mitochondrial dysfunction in vivo, would both guide safer drug candidate selection and better support discovery programmes targeting mitochondria for pharmacological intervention. The aim of this study was to profile the in vivo effects of a compound with suspected complex III electron transport chain (ETC) inhibitory activity (GSK932121A) at doses associated with clinical signs, and relate findings back to in vitro data with the same compound. Control liver mitochondria or HepG2 cells were treated in vitro with GSK932121A to assess mitochondrial effects on both calcium retention capacity (CRC) and oxygen consumption rate (OCR) respectively. The same assessments were then performed on liver mitochondria isolated from Crl:CD(SD) rats, 5 hours following intraperitoneal (IP) administration of GSK932121A. Lactate/pyruvate assessment, hepatic microscopy, blood gas analysis, glutathione profiling and transcriptomics were used to characterise the acute toxicity. In vivo, GSK932121A caused hypothermia, increased levels of hepatocellular oxidative stress and a metabolic shift in energy production, resulting in an increased lactate/pyruvate ratio, liver steatosis and glycogen depletion, together with gene expression changes indicative of a fasted state. As would be expected of an ETC inhibitor, GSK932121A reduced the CRC of liver mitochondria isolated from naive control animals and the OCR of HepG2 cells when treated directly in vitro. In contrast, mitochondria isolated from animals treated with GSK932121A in vivo unexpectedly showed an increase in CRC and basal OCR. Whilst seemingly contradictory, these differences likely reflect an adapted state in vivo resulting from the initial insult in combination with compensatory changes made by the tissue to maintain energy production. Only the initial, unconfounded, response is observable in vitro. These findings improve current understanding of the toxicological and molecular consequences of ETC inhibition. Furthermore, this work highlights key differences in the way that mitochondrial perturbation is manifest in vivo versus in vitro in terms of functional endpoints and helps guide endpoint selection for future studies with potential mitochondrial toxicants or drugs designed to modulate mitochondrial function for therapeutic benefit.

Patients with double-hit lymphoma (DHL), which is characterized by rearrangements of MYC and either BCL2 or BCL6, face poor prognoses. We conducted a retrospective multicenter study of the impact of baseline clinical factors, induction therapy, and stem cell transplant (SCT) on the outcomes of 311 patients with previously untreated DHL. At median follow-up of 23 months, the median progression-free survival (PFS) and overall survival (OS) rates among all patients were 10.9 and 21.9 months, respectively. Forty percent of patients remain disease-free and 49% remain alive at 2 years. Intensive induction was associated with improved PFS, but not OS, and SCT was not associated with improved OS among patients achieving first complete remission (P = .14). By multivariate analysis, advanced stage, central nervous system involvement, leukocytosis, and LDH >3 times the upper limit of normal were associated with higher risk of death. Correcting for these, intensive induction was associated with improved OS. We developed a novel risk score for DHL, which divides patients into high-, intermediate-, and low-risk groups. In conclusion, a subset of DHL patients may be cured, and some patients may benefit from intensive induction. Further investigations into the roles of SCT and novel agents are needed.

Background Brentuximab vedotin (BV) is a novel antibody drug conjugate consisting of an anti- CD30 IgG1 antibody, cAC10, linked to monomethylauristatin E, a potent inhibitor of microtubule polymerization. It is approved for treatment of relapsed classical Hodgkin lymphoma (cHL) and anaplastic large cell lymphoma (ALCL) in the US (FDA; 8/2011) and Europe (EMA; 10/2012). Peripheral neuropathy was the most frequent treatment-related adverse event (AE) in phase II trials, and the most common Grade 3 or higher toxicity apart from cytopenias. Although abdominal pain has been observed in up to 25% of all patients, pancreatitis is a previously unrecognized AE. We now report 8 cases of BV-associated pancreatitis, 2 of them fatal. Methods Following a grade 5 AE from pancreatitis in a patient receiving single-agent BV on an ongoing clinical trial ([NCT01476410][1]), collaborating investigators examined their collective cases of pancreatitis associated with BV. Lymphoma specialists at other centers were solicited for additional events. IRB or Ethics Committee approval as required was obtained in all cases. AE's reported to the FDA Adverse Event Report Systems (FAERS) from 6/2011-7/2013 were also examined. Data was collected and analyzed through the Research on Adverse Drug Events and Reports Project. Immunohistochemical staining with the anti-CD30 antibody BER-H2 (DAKO) was performed on residual normal pancreas from one of the fatal cases and normal control pancreas. Results Eight cases of BV-associated pancreatitis were identified by collaborators, and one additional report with limited information was listed in FAERS. Demographic, treatment and AE information for the eight complete cases is detailed in [Table 1][2]. In all cases, BV was administered as a single agent. In seven cases, the dosing was 1.8 mg/kg every 21 days with a maximum of 180 mg; in one case, BV was administered weekly at 1.2 mg/kg (days 1,8,15, q 28). Two patients were retreated with BV after resolution of pancreatitis; one had no further evidence of pancreatitis and proceeded to a stem cell transplant, whereas the other patient, having recovered from Grade 4 pancreatitis, experienced a second episode (Grade 3). All patients demonstrated clinical evidence of pancreatitis as manifested by severe abdominal pain and nausea. In addition, all patients had biochemical and radiologic evidence of pancreatitis. Notably, no patient had an antecedent history of excess alcohol use or radiologic evidence of biliary pathology. Two patients developed progressive and fatal multiorgan dysfunction as a consequence of acute pancreatitis. An autopsy performed on one of the two fatalities showed evidence of acute necrotizing pancreatitis as the cause of death; diffuse pancreatic parenchymal necrosis and fat necrosis were seen but no cholelithiasis. Although the anti-CD30 antibody BER-H2 was previously reported to stain normal pancreas (BLOOD 1989 74:1678), routine immunohistochemical staining for CD30 on both the patient pancreas and normal pancreas controls were negative. View this table: Table 1 BV-associated pancreatitis (n = 8) Conclusion This is the first series describing pancreatitis as a rare, but serious and potentially fatal toxicity related to BV. Pancreatitis has been previously reported with other microtubule inhibitors such as taxanes and vinca alkaloids, but the mechanism, as with BV, remains unclear. Genetic factors that predispose to both acute and chronic pancreatitis have been reported and may underlie a susceptibility to this uncommon complication of treatment with BV. Clinicians prescribing BV should evaluate patients who present with abdominal pain for pancreatitis, and should consider pre-treatment biochemical assessments with serum lipase and/or amylase. Disclosures: Off Label Use: Brentuximab Vedotin is approved for relapsed, refractory Hodgkin Lymphoma in patients who have already had a transplant or are ineligible for one, or for patients with relapsed, refractory anaplastic large cell lymphoma. Patients treated on clinical trials or off label will be included in this presentation. Evens: Seattle Genetics : Consultancy, Honoraria. Fenske: Seattle Genetics: Consultancy. Hamlin: Seattle Genetics : Consultancy, Honoraria. Coiffier: Millennium Pharmaceuticals : Consultancy. Engert: Millennium Pharmaceuticals : Consultancy. Moskowitz: Seattle Genetics : Research Funding. Ghosh: Millennium Pharmaceuticals : Membership on an entity’s Board of Directors or advisory committees. Petrich: Seattle Genetics : Consultancy, Honoraria, Research Funding. Gordon: Seattle Genetics : Research Funding. Winter: Seattle Genetics : Research Funding. [1]: /lookup/external-ref?link_type=CLINTRIALGOV&access_num=NCT01476410&atom=%2Fbloodjournal%2F122%2F21%2F4380.atom [2]: #T1

Lymphoma is a well-recognized complication in patients infected with HIV. Although its incidence has declined since the advent of antiretroviral therapy, it remains higher than seen in the general population. Several recent studies have noted improvement in clinical outcomes with the use of modern chemoimmunotherapy regimens. In patients who experience relapse, however, fewer data are available on the role of immunotherapy and its impact on outcomes. This case report presents 2 patients with relapsed HIV-associated lymphoma who experienced a second complete remission after treatment with the immunotherapy agent brentuximab vedotin.

Introduction: Post-transplant lymphoproliferative disease (PTLD) encompasses a heterogeneous array of cases of lymphoma/lymphoma-like conditions arising in the setting of immunosuppression (IS) for prior organ or marrow transplant. Such pts face heightened risk of toxicity from exposure to cytotoxic chemotherapy, and may be best treated in the frontline with reduction of IS (RI) and anti-CD20 monoclonal antibody treatment (Trappe, 2012). Autoimmune (AI) disease has been associated with an increased risk of developing lymphoma; however, the relative impact of baseline clinical features, including prior IS, is unknown. Methods: We conducted a multicenter, retrospective analysis of adult pts with pre-existing AI conditions who were diagnosed with lymphoma since 1997. Baseline clinical features at diagnosis of lymphoid malignancy, including International Prognostic Index (IPI) risk factors; underlying AI disease; duration and type of IS; EBV status (by EBER in-situ hybridization); and primary therapy received (RI, rituximab [R] monotherapy, chemotherapy [+/- R]); were collected. Survival analyses were performed using Kaplan-Meier method. We then focused on those who had A) received IS other than corticosteroids (CS) alone; and B) those diagnosed with DLBCL. Those variables found to have significant correlation with OS by univariate analyses (UVA) were used to construct Cox proportional hazards model (multivariate analysis [MVA]) in order to determine which might have the strongest association with OS. Lastly, we sought to evaluate a potential role for RI and/or R as frontline therapy for those with DLBCL. Results: A total of 130 pts were included (Table 1). The most frequent AI disease was rheumatoid arthritis and for all cases, 76% had documented exposure to IS, for a median duration of 4.5 years (range 0.17-57 years) prior to diagnosis of lymphoma. The most common histologic subtype was DLBCL (52%). EBV status was reported for only 34% of pts, but was positive in 68% (25/37), all of whom had received prior exposure to IS beyond CS, and 80% of whom (20/25) were diagnosed with DLBCL. EBV status was infrequently tested in pts not previously exposed to IS (3/31). At a median follow-up of 61 months for the entire cohort, 2-year PFS and OS were 79% and 91%, respectively (Figure 1, Panel A). By UVA, age>60; PS>1; LDH> upper limit of normal (ULN); DLBCL (vs all other histologies); underlying rheumatoid arthritis (RA; vs all other AI diseases); and prior exposure to IS, each correlated with inferior OS (Table 1). By MVA, PS>1 and prior IS maintained significance (p1 (p 0.002) and prior IS (p 0.010) maintain significance (data not shown). Among 67 pts with DLBCL, median age was 61 (range 26-90), 60% had advanced stage disease, and 32% had IPI of 4 or 5. At a median follow-up of 32 months, the 2-year PFS and OS were 82% and 84%, respectively. There were no differences in frequency of any IPI factors between patients exposed to prior IS (n=53) and those who were naïve to prior IS (n=14). For those not exposed to prior IS, the 2-year OS was 100%, compared to 80% in those who received prior IS (p 0.24); corresponding 2-year PFS were 92% and 79%, respectively (p 0.41). Age>60 and PS>1 were associated with an inferior OS but use of IS was not associated with outcome (Table 2). The 2 year OS for those treated with R plus CHOP(like) chemotherapy, CHOP(like) chemotherapy (without R), R alone (+/- RI), and with RI alone were 92%, 75%, 90%, and 67%, respectively (Figure 1, Panel B; log-rank p value 0.55). Patients who received CHOP-like therapy +/- R, as compared to R and/or RI were more likely to be naïve to IS therapy (15/46 vs 0/22, p = 0.003) and have 2 or more EN sites of disease (15/46 vs 2/22, =0.041). These differences notwithstanding, the 2-year PFS for the two groups were 86% and 74% (p 0.16), and 2-year OS for the two groups were 88% and 82%, respectively (Figure 1, Panel C; p 0.91). Conclusions: Pts with immunosuppression-related lymphoma have high rates of 2-year OS and in DLBCL, IS does not appear to be associated with an inferior outcome. Similar to evolving treatment paradigms in PTLD, rituximab monotherapy and other cytotoxic chemotherapy-free regimens as well as risk-adapted approaches may warrant further evaluation in IS-related DLBCL. Disclosures Petrich: Seattle Genetics: Consultancy, Honoraria, Research Funding. Barta:Seattle Genetics: Research Funding. Feldman:Celgene: Honoraria, Speakers Bureau; Pharmacyclics/JNJ: Honoraria, Speakers Bureau; Seattle Genetics: Honoraria, Speakers Bureau. Savage:Seattle Genetics: Honoraria, Speakers Bureau; BMS: Honoraria; Infinity: Honoraria; Roche: Other: Institutional research funding.

Th e treatment of chronic myelogenous leukemia (CML) was revolutionized with the introduction of the tyrosine kinase inhibitor (TKI) imatinib [1], off ering the prospect of highly eff ective therapy predicated upon targeting of specifi c molecularly defi ned aberrations. While second-generation TKIs appear to more frequently achieve major molecular response (MMR) [2], overall survival is not conclusively better, and imatinib remains an important and widely used agent in CML. Ideally, biological and genetic factors would identify those patients who will or are unlikely to derive benefi t from imatinib, and assist in informing the appropriate therapeutic dose. Such a pharmacogenomic approach to therapy has been explored in other several disease sites. For example, single nucleotide polymorphisms (SNPs) in VEGFR3 and CYP3A5 * 1 have been shown to predict lack of effi cacy and tolerability in patients with clear cell renal cell carcinoma (RCC) treated with sunitinib [3]. Similarly, mutations in CYP1A1 and FLT have also been shown to help predict toxicity with anti

We investigated the kinetics of circulating biomarker elevation, specifically correlated with morphology in acute myocardial injury. Male Hanover Wistar rats underwent biomarker and morphologic cardiac evaluation at 0.5 to seventy-two hours after a single subcutaneous isoproterenol administration (100 or 4000 µg/kg). Dose-dependent elevations of serum cardiac troponins I and T (cTnI, cTnT), and heart fatty acid–binding protein (H-FABP) occurred from 0.5 hour, peaked at two to three hours, and declined to baseline by twelve hours (H-FABP) or forty-eight to seventy-two hours (Serum cTns). They were more sensitive in detecting cardiomyocyte damage than other serum biomarkers. The Access 2 platform, an automated chemiluminescence analyzer (Beckman Coulter), showed the greatest cTnI fold-changes and low range sensitivity. Myocardial injury was detected morphologically from 0.5 hour, correlating well with loss of cTnI immunoreactivity and serum biomarker elevation at early time points. Ultrastructurally, there was no evidence of cardiomyocyte death at 0.5 hour. After three hours, a clear temporal disconnect occurred: lesion scores increased with declining cTnI, cTnT, and H-FABP values. Serum cTns are sensitive and specific markers for detecting acute/active cardiomyocyte injury in this rat model. Heart fatty acid–binding protein is a good early marker but is less sensitive and nonspecific. Release of these biomarkers begins early in myocardial injury, prior to necrosis. Assessment of cTn merits increased consideration for routine screening of acute/ongoing cardiomyocyte injury in rat toxicity studies.

Background Although there is no standardized frontline therapy for pts with post transplant lymphoproliferative disorder (PTLD), aggressive induction with chemoimmunotherapy (CIT) is associated in this population with excess toxicity (Choquet, 2007). Recent data support a risk-stratified sequential therapy approach, in which pts receive single-agent R, with aggressive CIT reserved for those not achieving complete response (CR; Trappe, 2012). However, only about 25-30% of pts treated by this method are spared aggressive CIT. Furthermore, elderly pts (eg, EBV-related DLBCL of elderly) and those with autoimmune disorders are prone to lymphoma sharing clinicopathological characteristics with PTLD, such as EBV, CD30, and CD20 coexpression. BV is a novel antibody-drug conjugate that received accelerated FDA approval based on high response rates in pts with relapsed/refractory CD30+ lymphoma. We hypothesized that a combination of BV and R would yield higher response rates than R alone, would limit exposure to CIT, and its attendant toxicity, in these pts. Methods We initiated a Phase I-II trial of the combination of BV and R in adults with previously untreated CD20+ NHL, with co-expression of EBV and/or CD30 (all at any level). Pts with central nervous system involvement, HIV infection, and those lacking history of immunodeficiency, were excluded. Induction consisted of R 375 mg/m2 days 1, 8, 15 22, and BV 1.2 mg/kg, days 1, 8, and 15, followed by restaging. Those with progressive (PD) or stable disease (SD) were removed from protocol and treated per local investigator (CIT recommended). Pts with partial response (PR) or CR could receive a second identical induction, followed by maintenance therapy (MT), or move directly to MT without consolidation. MT consisted of BV 1.8 mg/kg every 3 weeks and R 375 mg/m2 every 6 weeks for up to one year of total therapy. A standard 3 + 3 design was employed for Phase I, with provisional dose reduction in BV to 0.8 mg/kg. Toxicity data was defined using CTCAE 4.0. Response (Cheson, 2007) was assessed, at the end of induction, consolidation (if given), and after cycles 4 and 7 of BV. The primary objective in the phase I portion was to evaluate the safety of the combination of BV and R and to determine the recommended phase II dose (RP2D) of the combination. Results Toxicity and response data are available on seven pts (six treated in Phase I). Four were female, and median age was 61. Five pts had PTLD, diagnosed between 2 and 26 years from transplant, and two had pre-existing autoimmune disease with histories of iatrogenic immunosuppression. Patient characteristics and response data are summarized in Table 1. Five patients (71%) had a CR as best response. At median follow up of 9 months, no pts had PD or had died. One pt with SD as best response achieved CR after CIT, and another with SD declined further therapy but had not progressed at last follow up. Both pts with EBV+ serum by PCR at baseline cleared the virus during therapy. The most frequent Grade 3/4 adverse events (AE) observed were lymphopenia and neutropenia. The most frequent AE of any grade were anemia, transaminitis, and lymphopenia (Table 2). A dose reduction was not required after treatment of the first cohort, but an expansion cohort was requested by the Data/Safety Monitoring Committee for an episode of hyperbilirubinemia (primarly indirect and attributed to blood transfusion). No dose reductions were required during phase I, and the starting dose was the RP2D. Conclusions The combination of BV and R has an acceptable safety profile, appears efficacious and capable of sparing pts exposure to CIT, and warrants further evaluation in patients with CD30+ and/or EBV+ lymphomas with the RP2D idenfitied above. TABLE 1 Characteristics & Outcomes Pt Histology Stage IPI EBV (Serum) CD30 (IHC) Response(Induction) Best Response(Induction or MT) 1 P 4 2 + + CR CR 2* M 1 0 - + PR CR 3 M 3 3 - + PR CR 4 HL 3 1 - + CR CR 5* TCL 1 2 + - SD SD 6 M 4 1 - + SD SD 7 M 3 3 - + CR CR P: Polymorphic; M- Monomorphic large B cell like; TCL- T cell lymphoma; HL- Hodgkin's Like Lymphoma * Immunosuppression Related Lymphoma without history of solid organ transplant TABLE 2 Adverse events occurring in 50% or more of patients (total n=7) Adverse Event Grade 1 & 2 (n) Grade 3 & 4 (n) Anemia 5 1 Abdominal Pain 4 0 Diarrhea 3 0 Nausea 3 0 Fatigue 4 0 Elevated AST 3 2 Hyperbilirubinemia 2 1 Lymphopenia 1 4 Neutropenia 1 3 Anorexia 3 0 Hypoalbuminemia 5 0 Peripheral neuropathy 2 2 Disclosures Nabhan: Celgene: Honoraria, Research Funding. Petrich:Genentech: Consultancy, Honoraria, Research Funding, Speakers Bureau; Seattle Genetics : Consultancy, Honoraria, Research Funding, Speakers Bureau.

Background Brentuximab vedotin (BV) is a novel antibody drug conjugate consisting of an anti- CD30 IgG1 antibody, cAC10, linked to monomethylauristatin E, a potent inhibitor of microtubule polymerization. It is approved for treatment of relapsed classical Hodgkin lymphoma (cHL) and anaplastic large cell lymphoma (ALCL) in the US (FDA; 8/2011) and Europe (EMA; 10/2012). Peripheral neuropathy was the most frequent treatment-related adverse event (AE) in phase II trials, and the most common Grade 3 or higher toxicity apart from cytopenias. Although abdominal pain has been observed in up to 25% of all patients, pancreatitis is a previously unrecognized AE. We now report 8 cases of BV-associated pancreatitis, 2 of them fatal. Methods Following a grade 5 AE from pancreatitis in a patient receiving single-agent BV on an ongoing clinical trial (NCT01476410), collaborating investigators examined their collective cases of pancreatitis associated with BV. Lymphoma specialists at other centers were solicited for additional events. IRB or Ethics Committee approval as required was obtained in all cases. AE's reported to the FDA Adverse Event Report Systems (FAERS) from 6/2011-7/2013 were also examined. Data was collected and analyzed through the Research on Adverse Drug Events and Reports Project. Immunohistochemical staining with the anti-CD30 antibody BER-H2 (DAKO) was performed on residual normal pancreas from one of the fatal cases and normal control pancreas. Results Eight cases of BV-associated pancreatitis were identified by collaborators, and one additional report with limited information was listed in FAERS. Demographic, treatment and AE information for the eight complete cases is detailed in Table 1. In all cases, BV was administered as a single agent. In seven cases, the dosing was 1.8 mg/kg every 21 days with a maximum of 180 mg; in one case, BV was administered weekly at 1.2 mg/kg (days 1,8,15, q 28). Two patients were retreated with BV after resolution of pancreatitis; one had no further evidence of pancreatitis and proceeded to a stem cell transplant, whereas the other patient, having recovered from Grade 4 pancreatitis, experienced a second episode (Grade 3). All patients demonstrated clinical evidence of pancreatitis as manifested by severe abdominal pain and nausea. In addition, all patients had biochemical and radiologic evidence of pancreatitis. Notably, no patient had an antecedent history of excess alcohol use or radiologic evidence of biliary pathology. Two patients developed progressive and fatal multiorgan dysfunction as a consequence of acute pancreatitis. An autopsy performed on one of the two fatalities showed evidence of acute necrotizing pancreatitis as the cause of death; diffuse pancreatic parenchymal necrosis and fat necrosis were seen but no cholelithiasis. Although the anti-CD30 antibody BER-H2 was previously reported to stain normal pancreas (BLOOD 1989 74:1678), routine immunohistochemical staining for CD30 on both the patient pancreas and normal pancreas controls were negative. Conclusion This is the first series describing pancreatitis as a rare, but serious and potentially fatal toxicity related to BV. Pancreatitis has been previously reported with other microtubule inhibitors such as taxanes and vinca alkaloids, but the mechanism, as with BV, remains unclear. Genetic factors that predispose to both acute and chronic pancreatitis have been reported and may underlie a susceptibility to this uncommon complication of treatment with BV. Clinicians prescribing BV should evaluate patients who present with abdominal pain for pancreatitis, and should consider pre-treatment biochemical assessments with serum lipase and/or amylase. Disclosures: Off Label Use: Brentuximab Vedotin is approved for relapsed, refractory Hodgkin Lymphoma in patients who have already had a transplant or are ineligible for one, or for patients with relapsed, refractory anaplastic large cell lymphoma. Patients treated on clinical trials or off label will be included in this presentation. Evens:Seattle Genetics : Consultancy, Honoraria. Fenske:Seattle Genetics: Consultancy. Hamlin:Seattle Genetics : Consultancy, Honoraria. Coiffier:Millennium Pharmaceuticals : Consultancy. Engert:Millennium Pharmaceuticals : Consultancy. Moskowitz:Seattle Genetics : Research Funding. Ghosh:Millennium Pharmaceuticals : Membership on an entity’s Board of Directors or advisory committees. Petrich:Seattle Genetics : Consultancy, Honoraria, Research Funding. Gordon:Seattle Genetics : Research Funding. Winter:Seattle Genetics : Research Funding.

Background DHL are high-grade B-cell lymphomas (BCL) characterized by dual gene rearrangements (RA) of MYC and either BCL2 or BCL6. Outcomes are typically dismal, particularly when treated with R-CHOP, as compared to those observed in patients (pts) with similar histologies without dual RA. Few reports have evaluated the use of intensive induction regimens, with or without consolidative stem cell transplantation (SCT). We sought to evaluate the role of intensive induction as well as SCT, and to investigate predictors of outcome in DHL. Methods This study was an IRB-approved retrospective analysis across 15 centers. Cases were diagnosed between 2000-2012 as aggressive BCL harboring RA, by FISH, of MYC along with RA of BCL2 and/or BCL6. Pts were treated with either R-CHOP, or one of the following intensified regimens: R-HyperCVAD, R-EPOCH, R-CODOX-M/IVAC, R-ICE. Survival was estimated using Kaplan Meier method, and comparisons made with log rank test. Multivariable analysis (MVA) was performed using the Cox proportional hazard regression. Results One hundred six pts were analyzed. Median age at diagnosis was 60; 59% were male. The majority had DHL characterized by RA of MYC and BCL2 (77%); the remainder showed RA of MYC and BCL6 (10%), or all three (12%). History of indolent lymphoma was present in 29 pts (27%). The most common histology was DLBCL in 56 pts (53%), followed by BCL unclassifiable (BCLU) in 45 (42%), and Burkitt-like in 5 (5%). Thirty six pts (33%) received R-CHOP, 33 (31%) R-EPOCH, and 28 (36%) R-Hyper-CVAD or CODOX-M/IVAC. Fourteen pts (13%) were consolidated with SCT (n=1 allo and n=13 auto SCT); all were treated with intensive induction. Three additional pts underwent SCT in partial remission or progressive disease following R-CHOP induction. The median PFS and OS for the entire cohort were 8.8 mo and 12 mo, respectively (Table 1); of the 24 pts (23%) alive and without progression, median follow-up was 19 mo. R-EPOCH was superior in achieving complete response (CR) compared with R-CHOP (P 0.01), and trended towards significance compared with pts receiving other intensive induction (P 0.07). Additionally, primary refractory disease, observed in 37 pts (34.5%), occurred less frequently in pts receiving R-EPOCH compared to R-CHOP (P .005) or other intensive regimens (P 0.03); induction regimen did not impact OS in patients not receiving SCT (P 0.7; Fig 1). SCT in first remission was associated with improved OS (P 0.02), and PFS (P 0.006) compared with induction alone. However, among pts achieving CR, SCT was not associated with improved OS compared with observation (P 0.22; Fig 2). Pts with prior history of indolent NHL did not fare worse than those with de novo DHL (P 0.5). No difference in OS was observed based on histology (P 0.2). The following factors were evaluated in MVA: prior indolent lymphoma, histological subtype, IPI>/=3, primary refractory disease, type of induction (R-CHOP vs intensified), and consolidative SCT. Only primary refractory disease (P Conclusions In this analysis of DHL, primary refractory disease was the primary predictor of OS. Pts achieving CR did not appear to benefit from consolidative SCT, though our analysis was limited by the fact that pts receiving SCT are often highly selected (for chemosensitivity, age, comorbidities) and in this study, by the low number of pts receiving SCT. R-EPOCH was associated with a decreased rate of primary refractory disease compared to other regimens, and increased rate of CR compared to R-CHOP, but the lack of clear survival benefit suggests that relapsed disease offsets early benefit. Our analysis confirms the generally poor outcomes for pts with DHL, though a subset with chemosensitive disease has an improved prognosis, likely due to favorable disease biology. Further investigation on the role of SCT and of novel agents is needed for this high-risk population. ^Three patients untreated, one received multiple regimens Disclosures: Off Label Use: Brentuximab Vedotin is approved for relapsed, refractory Hodgkin Lymphoma in patients who have already had a transplant or are ineligible for one, or for patients with relapsed, refractory anaplastic large cell lymphoma. Patients treated on clinical trials or off label will be included in this presentation. Petrich:Genetech: Consultancy, Honoraria. Fenske:Seattle Genetics : Consultancy, Honoraria. Smith:Seattle Genetics, Inc.: Research Funding; Spectrum: Consultancy; Cephalon: Consultancy, Speakers Bureau; Celgene: Consultancy, Speakers Bureau; GlaxoSmith Kline: Speakers Bureau. Evens:Seattle Genetics: Consultancy, Honoraria; Millennium: Consultancy, Honoraria, Research Funding; Ziopharm, Inc: Research Funding; Celgene: Consultancy, Honoraria.

Background: Magrolimab is a humanized monoclonal antibody that blocks the immune checkpoint CD47, a "do not eat me" signal, overexpressed on tumor cells. The binding of magrolimab to CD47 leads to phagocytosis of cancer cells from human solid tumors and hematologic malignancies. The overexpression of CD47 contributes to the pathogenesis of multiple myeloma (MM) and blocking CD47 induces immediate activation of macrophages and elimination of myeloma cells (Sun et al). Hence, a blockade of CD47 with magrolimab may have therapeutic benefit in patients with MM. Combination therapies are more effective than single-agent therapy for both newly diagnosed and relapsed/refractory MM (RRMM). In vitro studies show synergy between magrolimab and daratumumab on MM cell line phagocytosis, and complimentary mechanisms suggest potential enhanced efficacy in other combinations. The current study (NCT04892446) is investigating the efficacy of magrolimab in combination with commonly used myeloma therapies in patients with RRMM. Design and Methods: This phase 2, multi-arm study includes patients aged ≥18 years currently requiring treatment for RRMM; all participants must have received at least 3 previous lines of therapy for MM, including an immunomodulatory drug and a proteasome inhibitor. This study includes 2 phases: a safety run-in cohort and a dose-expansion cohort (Figure 1). The primary objectives of the safety run-in cohort are to evaluate the safety and tolerability of magrolimab in combination with other anticancer therapies using the occurrence of dose-limiting toxicities (DLTs) as the primary endpoint, and to determine the recommended phase 2 dose (RP2D) of magrolimab in the following combinations: magrolimab+daratumumab; magrolimab+pomalidomide+dexamethasone; and magrolimab+bortezomib (maximum of 8 prior cycles in those who previously received bortezomib)+dexamethasone. Dose expansion cohorts will evaluate the efficacy of magrolimab combinations with objective response rate (ORR) as the primary endpoint. Secondary endpoints include duration of response, progression-free survival, and overall survival. Minimal residual disease negativity, biomarker changes from baseline, immune cell signaling alterations, and the mutational profile of plasma cell clones will also be explored. Magrolimab is administered intravenously (IV) with an initial priming dose, followed by a maintenance dose on days 8, 15, 22, and 29 during cycle 1 (35 days) and days 1, 8, 15, and 22 from cycle 2 (28 days) onwards. Daratumumab, pomalidomide, dexamethasone, and bortezomib will be administered according to manufacturer's prescribing information. Dose de-escalation may occur based on DLTs per protocol. Patients will continue treatment until unacceptable toxicity, progressive disease, or patient/investigator choice to discontinue. Planned enrollment is approximately 153 patients. Status: Recruitment is ongoing. Reference: Sun J, Muz B, Alhallak K, Markovic M, Gurley S, Wang Z, Guenthner N, Wasden K, Fiala M, King J, Kohnen D, Salama NN, Vij R, Azab AK. Targeting CD47 as a novel immunotherapy for multiple myeloma. Cancers (Basel). 2020;12(2):305. Figure 1 Figure 1. Disclosures Paul: Amgen Inc.: Speakers Bureau; Bristol Myers Squibb: Divested equity in a private or publicly-traded company in the past 24 months; Genentech: Membership on an entity's Board of Directors or advisory committees; Janssen Pharmaceuticals Inc: Membership on an entity's Board of Directors or advisory committees; AbbVie: Membership on an entity's Board of Directors or advisory committees; Regeneron: Membership on an entity's Board of Directors or advisory committees. Liedtke: Celgene: Membership on an entity's Board of Directors or advisory committees; Caelum: Membership on an entity's Board of Directors or advisory committees, Other: Clinical Trial Funding; GlaxoSmithKline: Membership on an entity's Board of Directors or advisory committees; Alnylam: Membership on an entity's Board of Directors or advisory committees; Pfizer: Honoraria; Takeda: Membership on an entity's Board of Directors or advisory committees; Karyopharm: Membership on an entity's Board of Directors or advisory committees; Sanofi: Membership on an entity's Board of Directors or advisory committees; Bristol Myers Squibb: Membership on an entity's Board of Directors or advisory committees; Janssen Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees; Kite: Membership on an entity's Board of Directors or advisory committees; Kura Oncology: Membership on an entity's Board of Directors or advisory committees; Oncopeptides: Membership on an entity's Board of Directors or advisory committees. Monge: Karyopharm Therapeutics: Research Funding; Bristol Myers Squibb: Consultancy. Rifkin: Takeda: Membership on an entity's Board of Directors or advisory committees; Fresenius-Kabi: Membership on an entity's Board of Directors or advisory committees; Karyopharm: Membership on an entity's Board of Directors or advisory committees; McKesson: Current Employment, Current equity holder in publicly-traded company; Coherus: Membership on an entity's Board of Directors or advisory committees; Sanofi: Membership on an entity's Board of Directors or advisory committees; Bristol Myers Squibb (Celgene): Membership on an entity's Board of Directors or advisory committees; Amgen: Membership on an entity's Board of Directors or advisory committees. Gandhi: Karyopharm Therapeutics: Honoraria; TG Therapeutics: Honoraria; GlaxoSmithKline: Honoraria. Kovacsovics: Janssen Pharmaceuticals: Research Funding; Amgen Inc.: Research Funding; Stemline: Honoraria; Jazz Pharmaceutials: Honoraria; Novartis: Research Funding; AbbVie: Research Funding. Levy: Bristol Myers Squibb: Consultancy, Honoraria, Other: Promotional speaker, Speakers Bureau; GSK: Consultancy, Other: Promotional speaker; Novartis: Consultancy, Other: Promotional speaker; Amgen Inc.: Consultancy, Honoraria, Other: Promotional speaker, Speakers Bureau; Jazz Pharmaceuticals: Consultancy, Honoraria, Speakers Bureau; Gilead Sciences, Inc.: Consultancy, Honoraria, Speakers Bureau; Epizyme: Consultancy, Other: Promotional speaker; Morphosys: Consultancy, Honoraria, Other: Promotional speaker, Speakers Bureau; Janssen Pharmaceuticals: Consultancy, Honoraria, Other: Promotional speaker, Speakers Bureau; Beigene: Consultancy, Honoraria, Speakers Bureau; Karyopharm: Consultancy, Honoraria, Other: Promotional speaker, Speakers Bureau; Seattle Genetics: Consultancy, Honoraria, Other: Promotional speaker, Speakers Bureau; AstraZeneca: Consultancy, Honoraria, Speakers Bureau; Takeda: Consultancy, Honoraria, Other: Promotional speaker, Speakers Bureau; AbbVie: Consultancy, Honoraria, Other: Promotional speaker, Speakers Bureau; TG Therapeutics: Consultancy, Honoraria, Speakers Bureau; Dova: Consultancy, Other: Promotional speaker. Siegel: Karyopharm: Honoraria; Celularity: Membership on an entity's Board of Directors or advisory committees; GlaxoSmithKline: Honoraria, Speakers Bureau; Takeda: Honoraria; Bristol Myers Squibb: Honoraria, Speakers Bureau; Amgen Inc.: Honoraria; Janssen: Honoraria, Speakers Bureau. Silbermann: Janssen Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees; Sanofi Genzyme: Membership on an entity's Board of Directors or advisory committees, Research Funding. Byrne: Gilead Sciences, Inc.: Current Employment, Current equity holder in publicly-traded company. Ncube: Gilead Sciences, Inc.: Current Employment, Current equity holder in publicly-traded company. Murphy: Gilead Sciences, Inc.: Current Employment, Current holder of stock options in a privately-held company. Gu: Gilead Sciences, Inc.: Current Employment, Current equity holder in publicly-traded company. Rajakumaraswamy: Gilead Sciences, Inc.: Current Employment, Current equity holder in publicly-traded company. Chao: Gilead Sciences, Inc.: Current Employment; TigaTx: Membership on an entity's Board of Directors or advisory committees; Stanford University: Patents & Royalties; Hepatx Inc: Consultancy, Current equity holder in publicly-traded company, Membership on an entity's Board of Directors or advisory committees; Iconovir Bio: Current equity holder in publicly-traded company, Membership on an entity's Board of Directors or advisory committees; Leukemia and Lymphoma Society: Membership on an entity's Board of Directors or advisory committees; Stanford University Medical School: Membership on an entity's Board of Directors or advisory committees; Foresite capital: Consultancy; Bioverge: Current equity holder in publicly-traded company, Membership on an entity's Board of Directors or advisory committees; Chimera Bioengineering: Current equity holder in publicly-traded company. Usmani: Sanofi: Consultancy, Research Funding, Speakers Bureau; Janssen: Consultancy, Research Funding, Speakers Bureau; EdoPharma: Consultancy; GSK: Consultancy, Research Funding; Celgene/BMS: Consultancy, Research Funding, Speakers Bureau; Array BioPharma: Consultancy, Research Funding; SkylineDX: Consultancy, Research Funding; Merck: Consultancy, Research Funding; Pharmacyclics: Consultancy, Research Funding; Seattle Genetics: Consultancy, Research Funding; Takeda: Consultancy, Research Funding, Speakers Bureau; Janssen Oncology: Consultancy, Research Funding; Bristol-Myers Squibb: Research Funding; Amgen: Consultancy, Research Funding, Speakers Bureau; Abbvie: Consultancy. OffLabel Disclosure: Magrolimab is an investigational therapy