Citations

Abstract Introduction: Mantle cell lymphoma (MCL) is an uncommon hematological malignancy with an estimated incidence of 1 per 100,000 persons per year in the United States and represents only about 5% of all non-Hodgkin lymphomas. Several studies have shown that treatment at academic centers and a higher hospital case volume are associated with improved outcomes for uncommon hematological malignancies, probably due to increased provider expertise and access to novel therapies. Treatment of MCL can be complex given the heterogenous nature of the disease and a frequent need for autologous stem cell transplantation in eligible patients. However, the impact of treatment at an academic center and facility patient volume on the survival of patients with MCL has not been well studied in large cohorts. In this study, we utilized the National Cancer Database (NCDB) to investigate the impact of treatment at an academic center and treatment facility volume on the overall survival (OS) of patients with MCL. Methods: The NCDB was used to identify adult patients (≥ 18 years) with newly diagnosed MCL from 2004 through 2017. For facility patient volume analysis, patients were divided into groups based on the average number of new MCL patients seen annually: Tercile 1 [T1] (1-3 patients/year), Tercile 2 [T2] (4-5 patients/year) and Tercile 3 [T3] (≥6 patients/year). Treating centers were divided into Academic and Non-academic using the NCDB definitions. Academic centers were defined as centers that accessions more than 500 newly diagnosed cancer cases per year, participate in postgraduate medical education in at least four program areas including internal medicine and surgery and participates in cancer-related clinical trials. The primary endpoint was overall survival (OS). Survival analysis was performed using the Kaplan-Meier method and Cox hazards proportional model. Statistical analysis was performed using SPSS version 25. Results: We identified 22,752 patients with MCL during the study period. 9,484 (42%) patients were treated at academic centers and 13,070 (57%) were treated at non-academic centers. In terms of facility patient volume 10,948 patients (48%) were in the T1 group, 4,637 (20%) were in the T2 group and 7,166 (31%) were in the T3 group. No significant differences were found in baseline demographics (age, gender, race/ethnicity, comorbidity scores), socioeconomical variables (insurance type, median income, area of residence) and disease-related factors (B-symptoms, Ann Arbor stage) between patients treated academic vs nonacademic centers, or between patients in T1 vs T2 vs T3 groups. Notably, compared to lower volume facilities, T3 facilities were more likely to be academic centers (T3: 81% vs T2: 42% vs T1: 16%, p<0.001) . After a median follow-up of 3.4 years, the median overall survival (OS) was 5.6 years for the entire cohort. The median OS was inferior for patients treated at lower volume facilities (4.1 years for T1, 5.1 years for T2 and 9.0 years for T3, p<0.001) (Figure 1A). Similarly, the median OS was shorter for patients treated at non-academic centers vs academic centers (4.3 years vs 7.5 years respectively, p<0.001) (Figure 1B). In a multivariate analysis, treatment at a lower patient volume facility (Hazard ratio [HR] Q1= 1.26 [95%CI = 1.18-1.34]) and treatment at a non-academic center (HR = 1.1, 95%CI = 1.01-1.12) were both independent prognostic factors of inferior OS, after adjusting for demographics (age, gender, ethnicity, area of residence) and socioeconomic variables (income and insurance status). Conclusion: Patients with MCL treated at academic and higher volume facilities had a higher OS compared to patients treated at non-academic and lower volume facilities.. Additional research is needed to fully understand the mechanisms behind these differences. Patients with MCL may benefit from an early referral to academic and high-volume centers. Figure 1 Figure 1. Disclosures Munoz: Merck: Research Funding; Portola: Research Funding; Genentech: Research Funding; Incyte: Research Funding; Janssen: Research Funding; Seattle Genetics: Research Funding; Pharmacyclics/Abbvie, Bayer, Gilead/Kite Pharma, Pfizer, Janssen, Juno/Celgene, BMS, Kyowa, Alexion, Beigene, Fosunkite, Innovent, Seattle Genetics, Debiopharm, Karyopharm, Genmab, ADC Therapeutics, Epizyme, Beigene, Servier: Consultancy; Gilead/Kite Pharma, Kyowa, Bayer, Pharmacyclics/Janssen, Seattle Genetics, Acrotech/Aurobindo, Beigene, Verastem, AstraZeneca, Celgene/BMS, Genentech/Roche.: Speakers Bureau; Millennium: Research Funding; Pharmacyclics: Research Funding; Celgene: Research Funding; Physicians' Education Resource: Honoraria; Gilead/Kite Pharma: Research Funding; Kyowa: Honoraria; Bayer: Research Funding; Seattle Genetics: Honoraria; OncView: Honoraria; Targeted Oncology: Honoraria. Paludo: Karyopharm: Research Funding. Habermann: Seagen: Other: Data Monitoring Committee; Incyte: Other: Scientific Advisory Board; Tess Therapeutics: Other: Data Monitoring Committee; Morphosys: Other: Scientific Advisory Board; Loxo Oncology: Other: Scientific Advisory Board; Eli Lilly & Co.,: Other: Scientific Advisor. Nowakowski: Daiichi Sankyo: Consultancy; Zai Labolatory: Consultancy; TG Therapeutics: Consultancy; Blueprint Medicines: Consultancy; Nanostrings: Research Funding; MorphoSys: Consultancy; Kymera Therapeutics: Consultancy; Incyte: Consultancy; Ryvu Therapeutics: Consultancy; Kyte Pharma: Consultancy; Genentech: Consultancy, Research Funding; Roche: Consultancy, Research Funding; Celgene/Bristol Myers Squibb: Consultancy, Research Funding; Selvita: Consultancy; Curis: Consultancy; Karyopharm Therapeutics: Consultancy; Bantham Pharmaceutical: Consultancy. Wang: Novartis: Research Funding; LOXO Oncology: 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; Genentech: Research Funding; Eli Lilly: Membership on an entity's Board of Directors or advisory committees; MorphoSys: Research Funding; InnoCare: Research Funding; Incyte: Membership on an entity's Board of Directors or advisory committees, Research Funding.

Abstract Background: BCL-2 inhibition with venetoclax has proved to be highly effective treatment for patients with CLL. However, when administered to patients with CLL who have a high tumor burden, venetoclax is associated with an elevated risk of tumor lysis syndrome (TLS). Because of this risk, venetoclax is initiated with a gradual, 5-week dose ramp-up, requiring close laboratory monitoring over an extended period. Lisaftoclax (APG-2575) is a novel, potent, selective BCL-2 inhibitor under clinical development for hematologic malignancies (HMs). Preliminary data in 18 patients with CLL treated in a first-in-human study suggested the feasibility of an abbreviated ramp-up of lisaftoclax that might also result in a lower incidence of neutropenia (Ailawadhi et al, J Clin Oncol 39, 2021; abstr 7502). Methods: This new study is a global, open-label, multicenter, two-part phase 1b dose escalation and dose expansion study to assess the safety and tolerability of lisaftoclax (Part 1) and lisaftoclax combined with rituximab or acalabrutinib (Part 2), including dose-limiting toxicity (DLT) and maximum tolerated dose (MTD). The trial is enrolling adults with (1) histologically confirmed CLL/SLL (by 2018 iwCLL criteria) that is relapsed or refractory to ≥ 1 prior therapy and requires treatment (also by 2018 iwCLL criteria); (2) adequate bone marrow function (in the absence of growth factors), including absolute neutrophils ≥ 1.0 × 10 9/L in patients without bone marrow involvement (not required in CLL/SLL patients with bone marrow involvement); and (3) adequate renal and hepatic function. Exclusion criteria: (1) recent history of allogeneic stem cell transplantation or CAR T-cell therapy (< 90 days); (2) prior treatment with a BCL-2 inhibitor (unless patient discontinued such therapy without disease progression); (3) treatment with vitamin K anticoagulants or previous discontinuation of treatment due to acalabrutinib toxicity (in acalabrutinib plus lisaftoclax cohort); (4) active Richter's syndrome; (5) infection (e.g. HIV, hepatitis); (6) CNS involvement; (7) prior cancer that has recurred within 2 years of screening and requires treatment (apart from adequately treated cervical or breast carcinoma in situ); (8) uncontrolled and other serious concomitant illnesses, including cardiovascular disease and diabetes; (9) failure to recover adequately after surgical procedures; and (10) active graft-vs-host disease or a requirement for immunosuppressive treatment. In a standard "3+3" dose escalation design (Part 1), lisaftoclax is being administered orally once daily in a 28-day cycle, with full doses of 200 to 1,200 mg (by 200-mg increments at 4 dose levels (400, 600, 800, and 1,000 mg) in parallel. The ramp-up is performed in the hospital with close monitoring for TLS and consists of the following doses and days of lisaftoclax treatment: 20 mg on Day 1, 50 mg on Day 2, 100 mg on Day 3, 200 mg on Day 4, 400 mg on Day 5, 600 mg on Day 6, 800 mg on Day 7, and 1,000 mg on Day 8. Patients who experience TLS on any of these days have their dose held until resolution of TLS before proceeding to the next dose. Part 2 includes a further standard 3+3 dose escalation of lisaftoclax combined with rituximab or acalabrutinib (in separate cohorts), with a further planned dose expansion at recommended phase 2 doses of these combination regimens. Primary outcome measures are (1) DLTs observed during cycle 1; and (2) MTD (measured over the same interval). DLT criteria are defined as grade 4 thrombocytopenia or neutropenia lasting > 7 days, grade 3 ≥ thrombocytopenia with bleeding, grade 4 febrile neutropenia, or grade 3 ≥ non-hematologic toxicities. As of July 19, 2021, 71 patients have been enrolled (of 144 planned). Clinicaltrial.gov identifier: NCT04215809. Disclosures Davids: Ascentage Pharma: Consultancy, Research Funding; Astra-Zeneca: Consultancy, Research Funding; BMS: Consultancy, Research Funding; Genentech: Consultancy, Research Funding; MEI Pharma: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; Pharmacyclics: Consultancy, Research Funding; TG Therapeutics: Consultancy, Research Funding; Verastem: Consultancy, Research Funding; Surface Oncology: Research Funding; AbbVie: Consultancy; Adaptive Biotechnologies: Consultancy; BeiGene: Consultancy; Celgene: Consultancy; Eli Lilly and Company: Consultancy; Janssen: Consultancy; MEI Pharma: Consultancy; Merck: Consultancy; Research to Practice: Consultancy; Takeda: Consultancy. Siddiqi: Kite Pharma: Membership on an entity's Board of Directors or advisory committees; Juno therapeutics: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; BMS: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Abbvie: Membership on an entity's Board of Directors or advisory committees; AstraZeneca: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; BeiGene: Other: DSM Member, Speakers Bureau; PCYC: Speakers Bureau; Jannsen: Speakers Bureau; Dava Oncology: Honoraria; ResearchToPractice: Honoraria. Pagel: Gilead: Consultancy; AstraZeneca: Consultancy; BeiGene: Consultancy; Incyte/MorphoSys: Consultancy; Epizyme: Consultancy; Kite, a Gilead Company: Consultancy; Actinium Pharmaceuticals: Consultancy; MEI Pharma: Consultancy; Pharmacyclics/AbbVie: Consultancy. Pylypenko: Communal nonprofit enterprise "Cherkasy regional oncology dispensary of Cherkasy oblast council: Current Employment. Kriachok: Takeda, Roche, Abbivie, Janssen, MSD: Consultancy; Takeda, Roche, Abbvie, Janssen, MSD, Pfizer: Honoraria, Speakers Bureau. Usenko: Abbvie: Honoraria; Acerta: Honoraria; Ascentage: Honoraria; AstraZeneca: Honoraria; Celgene: Honoraria; Il Yang: Honoraria; Janssen: Honoraria; Karyopharm: Honoraria; Oncopeptides: Honoraria; Rigel: Honoraria; Takeda: Honoraria; UCB: Honoraria. Chen: Ascentage Pharma (Suzhou) Co., Ltd: Current Employment, Current equity holder in publicly-traded company. Huang: Ascentage Pharma (Suzhou) Co., Ltd.: Current Employment, Current equity holder in publicly-traded company. Li: Ascentage Pharma (Suzhou) Co., Ltd.: Current Employment, Current equity holder in publicly-traded company. Ahmad: Ascentage Pharma Group Inc.: Current Employment, Current equity holder in publicly-traded company. Mudenda: Ascentage Pharma Group Inc.: Current Employment, Current equity holder in publicly-traded company. Yang: Ascentage Pharma (Suzhou) Co., Ltd: Current Employment, Current equity holder in publicly-traded company, Other: Leadership and other ownership interests, Patents & Royalties, Research Funding. Zhai: Ascentage Pharma (Suzhou) Co., Ltd.: Current Employment, Current equity holder in publicly-traded company, Other: Leadership and other ownership interests, Patents & Royalties, Research Funding; Ascentage Pharma Group Inc.: Current Employment, Current equity holder in publicly-traded company, Other: Leadership and other ownership interests, Patents & Royalties, Research Funding.

Abstract Background :COVID-19 adversely affects individuals with cancer. Several studies have found that seroconversion rates among patients with hematologic malignancies are suboptimal when compared to patients without cancer. Among patients with hematologic malignancies, seroconversion rates also appear to be influenced by recent treatment and the type of treatment they have received. Patients with non-Hodgkin lymphoma (NHL) and multiple myeloma (MM) are immunocompromised due to impaired humoral and cellular immunity in addition to prescribed immunosuppressive therapy. Chimeric antigen receptor T-cell (CAR T) therapy is now widely used for NHL and MM, but little is known about seroconversion rates after COVID-19 vaccination among these populations. Current national guidelines recommend COVID-19 vaccination to be offered to CAR T recipients as early as three months thereafter. We retrospectively evaluated SARS-CoV-2 spike-binding IgG antibody levels following COVID-19 vaccination among NHL and MM CAR T therapy recipients. Methods:This retrospective study was conducted at three Mayo Clinic sites on NHL and MM patients that received CAR T infusions from Sept 2016 to June 2021. Baseline characteristics were ascertained from medical records. All NHL and MM patients who had received CAR T at any point and were alive at the time that the COVID-19 vaccine first became available were eligible for inclusion for antibody response evaluation. For antibody response to vaccination, antibody spike values > 0.80 U/mL were considered positive. Results: Out of 104 CAR T infusions, 73 patients are alive at the time of this submission. We have had 7 patients with known COVID-19 pre-CAR T and all 7 are currently alive (5 have antibody titers and 2 have not been tested yet). Nineteen patients developed known COVID infection post-CAR T (13 alive and 6 deceased). The mortality of COVID post-CAR T in our sample was 31.5%. Furthermore, of the 13 patients that survived COVID-19, they received CAR T an average of 416 days prior to COVID-19 infection (median = 337, range = 54 - 1406); the 6 patients who died from COVID-19 had received CAR T an average of 250 days prior to COVID-19 infection (median = 164, range = 7 - 846). All 6 deceased patients did not receive COVID-19 vaccination pre-CAR T. Out of 17 CAR T patients tested for antibody spike titers post COVID-19 vaccination, 76.4% were able to mount an antibody response. More patients with MM had a higher titer response to the vaccine (>250 U/mL) compared to the NHL counterparts (0.80-249 U/mL). All patients that received the vaccine, regardless of antibody response, were alive at the time of this submission. Conclusions:The majority of CAR T recipients with NHL and MM are able to mount an antibody response following COVID-19 vaccination in our relatively small sample. The frequency of seroconversion among CAR T recipients seems to be similar to patients with hematologic malignancy who had received a hematopoietic cell transplant reported elsewhere. These findings are limited by our small sample size and may be influenced by the timing of vaccination relative to CAR T. Furthermore, almost half of our patients received IVIG post CAR T which could potentially cause false positive antibody results as pooled immunoglobulin preparations may contain COVID-19 antibodies from vaccinated healthy donors. To better understand the characteristics of the immunologic response against SARS-CoV-2 in patients post-CAR T, larger multicenter studies exploring both humoral and cellular immunity will be needed. JEWN, MI and JM are co-first authors and PV, HM and AR are co-senior authors. Figure 1 Figure 1. Disclosures Munoz: Physicians' Education Resource: Honoraria; Seattle Genetics: Honoraria; Bayer: Research Funding; Gilead/Kite Pharma: Research Funding; Celgene: Research Funding; Merck: Research Funding; Portola: Research Funding; Incyte: Research Funding; Genentech: Research Funding; Pharmacyclics: Research Funding; Seattle Genetics: Research Funding; Janssen: Research Funding; Millennium: Research Funding; Gilead/Kite Pharma, Kyowa, Bayer, Pharmacyclics/Janssen, Seattle Genetics, Acrotech/Aurobindo, Beigene, Verastem, AstraZeneca, Celgene/BMS, Genentech/Roche.: Speakers Bureau; Pharmacyclics/Abbvie, Bayer, Gilead/Kite Pharma, Pfizer, Janssen, Juno/Celgene, BMS, Kyowa, Alexion, Beigene, Fosunkite, Innovent, Seattle Genetics, Debiopharm, Karyopharm, Genmab, ADC Therapeutics, Epizyme, Beigene, Servier: Consultancy; Targeted Oncology: Honoraria; OncView: Honoraria; Kyowa: Honoraria. Bergsagel: Oncopeptides: Consultancy, Honoraria; Novartis: Consultancy, Honoraria, Patents & Royalties: human CRBN mouse; Pfizer: Consultancy, Honoraria; Celgene: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; Genetech: Consultancy, Honoraria; GSK: Consultancy, Honoraria. Wang: Incyte: Membership on an entity's Board of Directors or advisory committees, Research Funding; LOXO Oncology: Membership on an entity's Board of Directors or advisory committees, Research Funding; Genentech: Research Funding; InnoCare: Research Funding; Novartis: Research Funding; MorphoSys: Research Funding; Eli Lilly: Membership on an entity's Board of Directors or advisory committees; TG Therapeutics: Membership on an entity's Board of Directors or advisory committees. Fonseca: Juno: Consultancy; Kite: Consultancy; Aduro: Consultancy; OncoTracker: Consultancy, Membership on an entity's Board of Directors or advisory committees; GSK: Consultancy; AbbVie: Consultancy; Patent: Prognosticaton of myeloma via FISH: Patents & Royalties; Caris Life Sciences: Membership on an entity's Board of Directors or advisory committees; Scientific Advisory Board: Adaptive Biotechnologies: Membership on an entity's Board of Directors or advisory committees; BMS: Consultancy; Amgen: Consultancy; Sanofi: Consultancy; Merck: Consultancy; Mayo Clinic in Arizona: Current Employment; Celgene: Consultancy; Takeda: Consultancy; Bayer: Consultancy; Janssen: Consultancy; Novartis: Consultancy; Pharmacyclics: Consultancy. Palmer: Sierra Oncology: Consultancy, Research Funding; CTI BioPharma: Consultancy, Research Funding; Protagonist: Consultancy, Research Funding; Incyte: Research Funding; PharmaEssentia: Research Funding. Dingli: Novartis: Research Funding; GSK: Consultancy; Apellis: Consultancy; Alexion: Consultancy; Sanofi: Consultancy; Janssen: Consultancy. Kapoor: Sanofi: Research Funding; AbbVie: Research Funding; Takeda: Research Funding; Karyopharm: Consultancy; Cellectar: Consultancy; BeiGene: Consultancy; Pharmacyclics: Consultancy; Sanofi: Consultancy; Amgen: Research Funding; Ichnos Sciences: Research Funding; Regeneron Pharmaceuticals: Research Funding; Glaxo SmithKline: Research Funding; Karyopharm: Research Funding. Kumar: Roche-Genentech: Consultancy, Research Funding; Oncopeptides: Consultancy; Abbvie: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; BMS: Consultancy, Research Funding; Beigene: Consultancy; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Research Funding; Adaptive: Membership on an entity's Board of Directors or advisory committees, Research Funding; Astra-Zeneca: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Tenebio: Research Funding; Merck: Research Funding; Carsgen: Research Funding; KITE: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Amgen: Consultancy, Research Funding; Bluebird Bio: Consultancy; Antengene: Consultancy, Honoraria; Sanofi: Research Funding. Paludo: Karyopharm: Research Funding. Bennani: Kymera: Other: Advisory Board; Vividion: Other: Advisory Board; Kyowa Kirin: Other: Advisory Board; Daichii Sankyo Inc: Other: Advisory Board; Purdue Pharma: Other: Advisory Board; Verastem: Other: Advisory Board. Ansell: Bristol Myers Squibb, ADC Therapeutics, Seattle Genetics, Regeneron, Affimed, AI Therapeutics, Pfizer, Trillium and Takeda: Research Funding. Lin: Kite, a Gilead Company: Consultancy, Research Funding; Merck: Research Funding; Gamida Cell: Consultancy; Takeda: Research Funding; Juno: Consultancy; Bluebird Bio: Consultancy, Research Funding; Celgene: Consultancy, Research Funding; Novartis: Consultancy; Janssen: Consultancy, Research Funding; Sorrento: Consultancy; Legend: Consultancy; Vineti: Consultancy. Murthy: CRISPR Therapeutics: Research Funding.

Abstract Background: SUMOylation, a post-translational modification analogous to ubiquitination, attaches a small, ubiquitin-like modifier (SUMO) to target proteins. SUMOylation plays a central role in the immune system by regulating type I interferon (IFN-I) expression, thereby functioning to constrain the innate immune response (Decque Nat Immunol 2016), and limit tumor immune surveillance. The SUMOylation pathway is often overexpressed in multiple myeloma (MM) and is associated with poor outcomes (Driscoll Blood 2010). TAK-981 is a first-in-class, small-molecule inhibitor of SUMO-activating enzyme, which blocks the SUMOylation cascade (Langston J Med Chem 2021) and increases IFN-I production and signaling in innate immune cells (Nakamura AACR 2019). In ex vivo assays, TAK-981 activated the IFN-I pathway, increased phagocytic activity of monocyte-derived macrophages, and increased natural killer (NK) cell cytotoxicity via IFN-I signaling (Nakamura AACR 2019). The ability of TAK-981 to promote activation of macrophages and NK cells provides a mechanistic rationale for its use in combination with monoclonal antibodies (mAbs) reliant on antibody-dependent cellular cytotoxicity and phagocytosis; in vivo experiments have demonstrated synergistic activity between TAK-981 and rituximab, and between TAK-981 and the anti-CD38 mAbs daratumumab (dara) (Nakamura SITC 2020) or mezagitamab (meza; TAK-079; Figure 1). Patients with MM who have disease refractory to the three most effective classes of anti-myeloma therapies (proteasome inhibitors [PIs], immunomodulatory drugs [IMiDs], and anti-CD38 mAbs) have a poor prognosis, with median survival 9.2 months (Gandhi Leukemia 2019). Given the incurable nature of advanced MM and the highly complex mechanisms of resistance, continued efforts to better understand MM biology at the time of relapse and to translate this into effective treatment combinations are needed. Combination therapies that engage the immune system to treat MM may offer substantial clinical benefit. Methods: To be eligible for this multicenter, open-label, Phase 1b/2 trial (NCT04776018), patients must have failed at least 3 prior lines of anti-myeloma therapy, have MM disease that is triple-class refractory (defined as refractory/intolerant to ≥1 PI and ≥1 IMiD, and refractory to ≥1 anti-CD38 mAb), and have demonstrated disease progression on their last therapy. Prior CAR-T therapy is allowed. Patients will be assigned to TAK-981 plus subcutaneous (SC) meza (Phase 1 Part 1) or SC dara (dara and hyaluronidase-fihj; Phase 1 Part 2). The primary objectives of Phase 1b are to determine safety and tolerability, and to select the recommended Phase 2 dose (RP2D) and schedule for TAK-981 with each mAb; secondary objectives are to evaluate preliminary antitumor activity, to characterize TAK-981 pharmacokinetics (PK), and to explore pharmacodynamic (PD) markers of TAK-981 target engagement and SUMOylation pathway inhibition. Approximately 30 patients will participate in the Phase 1b Part 1 dose escalation of TAK-981 plus meza (~15 patients per dosing schedule), and ~15 patients will participate in the Phase 1b Part 2 dose escalation of TAK-981 plus SC dara. The primary objective of Phase 2 is to evaluate the efficacy of TAK-981 at the RP2D in combination with an anti-CD38 mAb; ~36 patients will be enrolled. In Phase 1b, patients will receive TAK-981 via a 1-hour intravenous infusion either on days 1, 4, 8, 11, and 15 (twice weekly; BIW) or on days, 1, 8, 15, and 22 (weekly; QW) for 2x 28-day cycles, then 8x every other week, then monthly. Meza 600 mg SC or dara 1800 mg SC will be given 8x weekly, 8x every other week, then monthly, in a 28-day cycle (Figure 2). Treatment will continue until disease progression or unacceptable toxicity (max. 24 cycles). TAK-981 dose escalation will proceed from 60 mg BIW, a dose shown to be pharmacologically active in a first-in-human, single-agent TAK-981 study (TAK-981-1002; data on file). Dose escalation will be guided by Bayesian Optimal Internal Design with Informative Prior (iBOIN) plus consideration of other safety, clinical, PK, and PD data. The iBOIN design selects the true maximum tolerated dose (if any) with high accuracy by allocating more patients to dose levels with a prior dose-limiting toxicity probability closest to the target of 0.3. This study is currently enrolling patients, with the first patient dosed in May 2021. Figure 1 Figure 1. Disclosures Lonial: AMGEN: Consultancy, Honoraria; Takeda: Consultancy, Honoraria, Research Funding; Janssen: Consultancy, Honoraria, Research Funding; GlaxoSmithKline: Consultancy, Honoraria, Research Funding; TG Therapeutics: Membership on an entity's Board of Directors or advisory committees; BMS/Celgene: Consultancy, Honoraria, Research Funding; Merck: Honoraria; Abbvie: Consultancy, Honoraria. Boccia: BMS: Consultancy, Honoraria, Research Funding, Speakers Bureau; Janssen: Consultancy, Honoraria, Speakers Bureau; Abbvie: Consultancy, Honoraria, Speakers Bureau; Takeda: Honoraria, Research Funding, Speakers Bureau; Amgen: Research Funding, Speakers Bureau; Epizyme: Honoraria, Speakers Bureau; Morphosis: Honoraria, Speakers Bureau. Yimer: Beigene: Speakers Bureau; Astrazeneca: Speakers Bureau; Karyopharm: Current equity holder in publicly-traded company, Speakers Bureau; Janssen: Speakers Bureau; GSK: Speakers Bureau; Sanofi: Speakers Bureau; Amgen: Speakers Bureau; Pharmacyclics: Speakers Bureau; Texas Oncology: Current Employment. Levy: Jazz Pharmaceuticals: Consultancy, Honoraria, Speakers Bureau; Morphosys: Consultancy, Honoraria, Other: Promotional speaker, Speakers Bureau; Karyopharm: Consultancy, Honoraria, Other: Promotional speaker, Speakers Bureau; Dova: Consultancy, Other: Promotional speaker; Janssen Pharmaceuticals: Consultancy, Honoraria, Other: Promotional speaker, Speakers Bureau; Amgen Inc.: Consultancy, Honoraria, Other: Promotional speaker, Speakers Bureau; GSK: Consultancy, Other: Promotional speaker; Epizyme: Consultancy, Other: Promotional speaker; Novartis: Consultancy, Other: Promotional speaker; AbbVie: Consultancy, Honoraria, Other: Promotional speaker, Speakers Bureau; Beigene: Consultancy, Honoraria, Speakers Bureau; Bristol Myers Squibb: Consultancy, Honoraria, Other: Promotional speaker, Speakers Bureau; AstraZeneca: Consultancy, Honoraria, Speakers Bureau; Gilead Sciences, Inc.: Consultancy, Honoraria, Speakers Bureau; Seattle Genetics: Consultancy, Honoraria, Other: Promotional speaker, Speakers Bureau; Takeda: Consultancy, Honoraria, Other: Promotional speaker, Speakers Bureau; TG Therapeutics: Consultancy, Honoraria, Speakers Bureau. Abonour: Takeda: Research Funding; GSK: Consultancy, Honoraria, Research Funding; Celgene-BMS: Membership on an entity's Board of Directors or advisory committees, Research Funding; Jensen: Honoraria, Research Funding. Mohan: Medical College of Wisconsin: Current Employment. Girnius: BMS: Honoraria, Speakers Bureau; Celgene: Speakers Bureau; Genentech: Honoraria; GSK: Honoraria, Speakers Bureau; Takeda: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Beigene: Speakers Bureau. Rosenbaum: Takeda: Honoraria; Akcea: Honoraria; Janssen: Honoraria. Nadeem: Karyopharm: Membership on an entity's Board of Directors or advisory committees; BMS: Membership on an entity's Board of Directors or advisory committees; Adaptive Biotechnologies: Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees; GSK: Membership on an entity's Board of Directors or advisory committees. Berg: Takeda: Current Employment, Current equity holder in publicly-traded company, Current holder of stock options in a privately-held company. Chao: Takeda: Current Employment. Berger: Takeda Development Center Americas, Inc.: Current Employment. Nakamura: Takeda Development Center Americas, Inc.: Current Employment. Zhang: Takeda: Current Employment. Song: Takeda Pharmaceuticals International Co.: Current Employment. Ward: Takeda: Current Employment. Proscurshim: Takeda Pharmaceuticals: Current Employment, Current holder of individual stocks in a privately-held company. Kumar: Novartis: Research Funding; Tenebio: Research Funding; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Antengene: Consultancy, Honoraria; Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Roche-Genentech: Consultancy, Research Funding; Astra-Zeneca: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Abbvie: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; BMS: Consultancy, Research Funding; Beigene: Consultancy; Bluebird Bio: Consultancy; KITE: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Merck: Research Funding; Oncopeptides: Consultancy; Amgen: Consultancy, Research Funding; Carsgen: Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Adaptive: Membership on an entity's Board of Directors or advisory committees, Research Funding; Sanofi: Research Funding. OffLabel Disclosure: Study of the investigational agent TAK-981 in combination with daratumumab and hyaluronidase-fihj or the investigational agent mezagitamab (TAK-079).

Abstract Introduction: Acquired thrombotic thrombocytopenic purpura (aTTP) due to an acquired deficiency in the enzyme ADAMTS13 leads to ultra-large von Willebrand multimers, thrombocytopenia and microangiopathic hemolytic anemia. Complications include microvascular and macrovascular thrombosis. We present an unusual case of a patient with a history of refractory aTTP who experienced relapsed aTTP following COVID-19 vaccine. Case Description: A 57-year-old African-American male with a history of refractory aTTP experienced a relapse following 3 years of remission after receiving COVID-19 vaccination. The patient was initially diagnosed with aTTP in 2016, after presenting with symptoms of dark urine, mild headaches and transient episodes of aphasia and paresthesia. Due to symptoms and persistently low ADAMTS13 levels, he required prolonged and extensive treatment including over 5 weeks of daily therapeutic plasma exchange (TPE), followed by gradual reduction in frequency of TPE sessions, as well as trials of rituximab, eculizumab, steroids, mycophenolate mofetil and bortezomib. Ultimately, he achieved remission after 9 months of intermittent TPE, 3 months of weekly bortezomib 1 mg/m 2, mycophenolate mofetil up-titrated to 1,750 mg twice daily, and then slowly tapered off over a 2-year period. The patient was doing well for 3 years without manifestations of aTTP (2 years off all therapeutics), until he developed a petechial rash 7 weeks after receiving the second dose of the Moderna COVID-19 vaccine. He was found to have acute thrombocytopenia with platelets of 38 x 10 9/L (normal range 135-317 x 109/L), from a baseline of 200-300 x 10 9/L. He was referred to the emergency department, where additional labs were notable for mildly elevated LDH of 508 U/L (normal range 122-222 U/L), hemoglobin of 12.4 g/dL (normal range 13.2-16.6 g/dL), creatinine at baseline, and peripheral blood smear showing 1-3 schistocytes per high-powered field. ADAMTS13 activity level was t <5% (normal >/= 70%), with positive ADAMTS13 inhibitor screen and titer of 1.5 (normal <0.4), consistent with relapsed aTTP. The patient was admitted to the hospital, and initiated on daily TPE, with steroids and diphenhydramine prior to each TPE session. He quickly improved with TPE alone , but given his history of refractory aTTP, he was discharged on weekly rituximab for 4 weeks and caplacizumab 11 mg daily for 30 days. His platelets remained stable within the upper limit of normal during his 30 day course of caplacizumab. However, 3 weeks after completion of caplacizumab, he had an acute drop in his platelets to 23 x 10 9/L. His ADAMTS13 level was again found to be <5%, and inhibitor level was the highest that it had ever been at 11.4. He was again hospitalized and underwent 8 sessions of daily TPE, as well as re-initiation of caplacizumab, mycophenolate mofetil 500 mg bid (with increasing taper), and a prednisone taper. Intravenous Cyclophosphamide 750 mg/m 2 was also added every 3 weeks. With this regimen, patient's platelet count normalized and remain stable, and his ADAMTS13 activity level has reached 52-59%. Discussion: Cases of vaccine-induced immune thrombotic thrombocytopenia (VITT) have been described as a complication following vaccination with formulations containing replication-defective adenoviral vectors (AstraZeneca-Oxford and Johnson&Johnson COVID-19 vaccines)(Arepally and Ortel 2021, Simpson, Shi et al. 2021). VITT and aTTP are both immune-mediated, however, VITT is distinct and pathogenically linked to autoimmune heparin-induced thrombocytopenia (HIT), given the presence of anti-platelet factor 4 antibodies in these patients, whereas aTTP is due to reduction in ADAMTS13 level, secondary to an antibody inhibitor of ADAMTS13 (Arepally and Ortel 2021). Recently, cases have been reported of de novo aTTP developing shortly after COVID-19 vaccination with all available vaccines, except the Moderna (mRNA-1273) vaccine (Al-Ahmad, Al-Rasheed et al. 2021, de Bruijn, Maes et al. 2021, Maayan, Kirgner et al. 2021, Ruhe, Schnetzke et al. 2021, Waqar, Khan et al. 2021, Yocum and Simon 2021). Additionally, cases of relapsed aTTP have been described following only the BNT162B2 (Pfizer-BioNTech) vaccine (Maayan, Kirgner et al. 2021, Sissa, Al-Khaffaf et al. 2021). This is the first case, to our knowledge, reported in the literature of aTTP following vaccination with Moderna's mRNA-1273 vaccine. Disclosures No relevant conflicts of interest to declare.

Abstract Background: Diffuse large B-cell lymphoma (DLBCL) is frequently curable after frontline therapy, however, relapses can occur after achievement of a PET-negative complete remission (CR). Early detection of relapse may be associated with improved outcomes, particularly given the development of more active therapies for relapsed, refractory DLBCL. Controversy exists regarding the utility of post-therapy surveillance imaging which is associated with patient (pt) anxiety, radiation exposure, false-positive results, and cost, without clear overall survival benefit in retrospective studies (Thompson JCO 2014). A retrospective study found that serial minimal residual disease (MRD) monitoring during DLBCL surveillance could identify pts at risk of relapse before clinical evidence of disease (Roschewski Lancet Oncol 2015). In this multicenter prospective study, we assessed whether a next-generation immunosequencing (IS) MRD assay could be used for early detection of molecular relapse in DLBCL. Methods: Eligible pts with DLBCL or high-grade B-cell lymphoma (HGBCL) who received anthracycline-containing chemotherapy were enrolled across five cancer centers. In pts who achieved a PET-negative CR, serial peripheral blood samples were obtained every 3 months (mos) and CT scans every 6 mos for 2 years (yrs) post-treatment. The IS MRD assay (Adaptive Biotechnologies, Seattle, WA) that leverages multiplex PCR followed by NGS to identify and track rearrangements of IgH, V-J, D-J and IgK/L loci and translocations in Bcl1/2-IgH was used. MRD positive was defined as any detectable rearrangement and MRD undetectable as no evidence of rearrangement. Results: 500 pts were enrolled and 400 were evaluable (pre-treatment tumor pathology available, completed frontline treatment, and achieved PET-negative CR at end-of-treatment). Baseline characteristics were median age of 62 yrs (range 19-95), male sex 58%, advanced stage 61%, and poor-risk by R-IPI 42%. Histologies included DLBCL, NOS (88%), primary mediastinal B-cell lymphoma (6%), HGBCL (5%), T-cell rich B-cell lymphoma (3%), and other (1%). Pts received regimens including RCHOP x 6 cycles (37%), REPOCH x 6 cycles (20%), clinical trial (15%), combined modality therapy (RCHOP+RT) (9%), and other RCHOP variations (19%). Among the 400 evaluable pts, 44 relapses have occurred as of July 1, 2021. In 45% of pts (20/44), clinical relapse was detected using surveillance imaging alone (typically CT CAP with IV contrast) in an otherwise asymptomatic pt with a normal physical exam and laboratory evaluation . In 10% of pts (4/44), relapse was detected by patient-reported clinical symptoms alone. In 45% of pts (20/44), relapse was detected by imaging, clinical symptoms, and/or evaluation by an oncologist. With a median follow-up of 34 months, the 2-year PFS was 88.9% (85.8, 92.1). Advanced age, advanced stage, and poor-risk R-IPI were associated with inferior PFS. Of the 44 relapses, tumor-specific clonotypes were identified in 39 pts (4 failed quality control (QC), 1 failed calibration) and 38 pts had ≥1 sample available within 90 days of relapse. Of 356 patients in ongoing CR, tumor-specific clonotypes were identified in 279 patients (29 failed QC, 33 failed calibration, and 15 are pending sequencing). The patient-level prospective MRD results are shown in Figure 1. The overall sensitivity, specificity, positive predictive value, and negative predictive value of the IS MRD assay was 63% (24/38), 78% (218/279), 28% (24/85), and 94% (218/232), respectively. Plasma MRD detection had improved sensitivity and specificity compared with circulating cells. Among the 24 relapsed patients with a positive MRD result at or before relapse, the median anticipation of the test was 3 months (range 0 to 24 months). Conclusion: Overall outcomes are excellent for DLBCL and HGBCL pts who achieve PET-negative CR. In this multicenter prospective analysis with standardized follow up, a substantial proportion (45%) of clinical relapses are detected radiographically in asymptomatic pts, supporting the value of CT surveillance imaging in DLBCL, particularly for pts with advanced stage or high-risk disease. MRD assessment using the IS MRD assay had suboptimal sensitivity and specificity in the post-treatment surveillance setting in DLBCL. Further study of the clinical context and its correlation with test performance is ongoing. Figure 1 Figure 1. Disclosures Kumar: Kite Pharmaceuticals: Other: advisory board , Research Funding; Abbvie Pharmaceuticals: Research Funding; Celgene: Honoraria, Other: advisory board, Research Funding; Adaptive Biotechnologies, Celgene, Abbvie Pharmaceticals, Pharmacyclics, Seattle Genetics: Research Funding; Pharmacyclics: Research Funding; Astra Zeneca: Honoraria, Other: Advisory Board, Research Funding; Seattle Genetics: Research Funding. Westin: Novartis: Consultancy, Research Funding; Genentech: Consultancy, Research Funding; Curis: Research Funding; Morphosys: Research Funding; ADC Therapeutics: Consultancy, Research Funding; Iksuda Therapeutics: Consultancy; Umoja: Consultancy; MorphoSys: Consultancy, Research Funding; Kite, a Gilead Company: Consultancy, Research Funding; AstraZeneca: Consultancy, Research Funding; Bristol Myers Squibb: Consultancy, Research Funding; 47 Inc: Research Funding. Schuster: TG Theraputics: Research Funding; Incyte: Research Funding; Adaptive Biotechnologies: Research Funding; Pharmacyclics: Research Funding; Merck: Research Funding; Genentech/Roche: Consultancy, Research Funding; Tessa Theraputics: Consultancy; Loxo Oncology: Consultancy; Juno Theraputics: Consultancy, Research Funding; BeiGene: Consultancy; Alimera Sciences: Consultancy; Acerta Pharma/AstraZeneca: Consultancy; Novartis: Consultancy, Honoraria, Patents & Royalties, Research Funding; Abbvie: Consultancy, Research Funding; Nordic Nanovector: Consultancy; Celgene: Consultancy, Honoraria, Research Funding. Nowakowski: Celgene, NanoString Technologies, MorphoSys: Research Funding; Celgene, MorphoSys, Genentech, Selvita, Debiopharm Group, Kite/Gilead: Consultancy, Membership on an entity's Board of Directors or advisory committees. Lossos: Lymphoma Research Foundation: Membership on an entity's Board of Directors or advisory committees; Seattle Genetics: Consultancy; Janssen: Consultancy, Honoraria; NCI: Research Funding; University of Miami: Current Employment; NIH grants: Research Funding; Stanford University: Patents & Royalties; Verastem: Consultancy, Honoraria. Jacob: Adaptive Biotechnologies: Current Employment. Mullins: Adaptive Biotechnologies: Current Employment. Zelenetz: AstraZeneca: Honoraria; Amgen: Honoraria; Beigene: Honoraria, Other, Research Funding; Gilead: Honoraria, Research Funding; SecuraBio: Honoraria; Genentech/Roche: Honoraria, Research Funding; BMS/Celgene/JUNO: Honoraria, Other; Janssen: Honoraria; LFR: Other; MEI Pharma: Honoraria, Research Funding; Abbvie: Honoraria, Research Funding; Verastem: Honoraria; MethylGene: Research Funding; NCCN: Other; Pharmacyclics: Honoraria; Novartis: Honoraria; Gilead: Honoraria; MorphoSys: Honoraria.

Abstract Objectives: We identified a case of follicular lymphoma (FL) that transformed into a morphologic diffuse large B-cell lymphoma (DLBCL), which by gene expression profiling showed a primary mediastinal (PMBL)-like gene expression profile (GEP) (Lymph3Cx; Blood 2018;132:2401-5). A search identified 4 additional transformed FL (tFL) cases with a PMBL-like GEP, which we further studied to determine how similar these tFLs were to classic cases of PMBL. Methods: The morphology and previously reported immunophenotype were reviewed, and CD30, CD23, MAL, CD273/PDL2, and CD200 immunohistochemical stains (IHC) were performed. Whole exome sequencing (WES) and copy number analysis (CNA) to evaluate genes typically altered in FL and PMBL were performed. Results: None of the tFLs arose in the mediastinum or had a previous history of mediastinal disease. All cases showed typical centroblastic DLBCL cytology, with fine sclerosis typical of PMBL. 3/3 were GCB by the Hans IHC algorithm, 1/3 were MYC+, 3/3 BCL2+, 1/5 CD30+, 3/5 CD23+, 4/5 MAL+, 0/5 CD273/PDL2+, 1/5 CD200+, and 0/2 EBER+. Rearrangements of MYC, BCL2, or BCL6 were identified by FISH in 0/3, 1/3, and 2/3 cases, respectively. WES demonstrated sequence variants in genes associated with both FL (CREBBP [60%], KMT2D [40%], and TNFRSF14 [40%]) and PMBL (JAK-STAT pathway genes [80%], B2M [20%], and CD58 [20%]). 2 of the mutations identified in the tFLs have previously been shown to result in JAK-STAT activation (STAT6 p.E372K [PNAS 2016;113:13015-20] and SOCS1 p.F101L [Oncogene 2002;21:4351-62] identified in 1/5 cases each). CNA showed gains/amplification of REL in 3/5 cases, gains/amplification of STAT6 in 2/5, gains of large sections of chromosome 16, including IL4R, in 2/5, and both deletions and gains of 11q in 1/5. See Figure demonstrating the 5 cases on the Y-axis and the chromosomes on the X-axis. Conclusions: The tFLs in this small series seem to represent PMBL-like DLBCLs, rather than classic PMBLs, and have a blended pattern of immunophenotypic and genomic features between FL/DLBCL and PMBL. Although the cases express some PMBL-associated markers (CD23 and MAL), there is less frequent staining for others (CD30, CD273/PDL2, and CD200). The cases harbor both FL-associated and PMBL-associated sequence variants, including 40% with mutations known to activate the JAK-STAT pathway. This frequency of mutations in JAK-STAT pathway genes is higher than that seen in typical FL/DLBCL, but perhaps lower than in classic PMBL (Blood 2019;134:802-13). PMBL also frequently has gains/amplifications of 9p24.1, which was not seen in our cohort. However, gains/amplification of REL/2p, which is seen in approximately 50% of PMBL, was identified in 60% of the tFLs. The 11q aberration identified in 1 case would be unusual for PMBL, and is instead more commonly associated with a subset of aggressive lymphomas with Burkitt-like features (Haematologica 2019;104:1822-9). Recently, lymphomas with similar blended features between DLBCL and PMBL, which were not arising in the setting of tFL, have been reported (Duns G, et al. Blood 2021). Our study extends the types of biological transformations, in addition to more classic DLBCL, that can be seen in FL. These tFLs with blended PMBL-DLBCL biology may have implications for therapeutic decision making including targeted therapies used in PMBL. Figure 1 Figure 1. Disclosures Rimsza: NanoString Technologies: Other: Fee-for-service contract. Steidl: Curis Inc.: Consultancy; Trillium Therapeutics: Research Funding; Bayer: Consultancy; Epizyme: Research Funding; Seattle Genetics: Consultancy; AbbVie: Consultancy; Bristol-Myers Squibb: Research Funding.

Abstract Introduction: VEXAS syndrome (vacuoles, E1 ubiquitin ligase, X-linked, autoinflammatory, somatic) is a newly recognized inflammatory disorder caused by somatic mutations in the UBA1 gene. Bone marrows from these patients reveal a range of morphological changes in hematopoietic precursor cells. In this study, we aim to assess the laboratory indices and morphologic spectrum of bone marrow pathology in VEXAS syndrome. Methods: We identified 16 cases of VEXAS syndrome. All cases had confirmed UBA1 mutation. We reviewed bone marrow biopsies corresponding to the date of diagnosis. This study was approved by the Mayo Clinic Institutional Review Board. Results: All patients were male with a median age of 73 years - associated autoimmune disorders included Sweet syndrome, inflammatory arthritis, relapsing polychondritis and granulomatosis with polyangiitis. 14/16 patients had anemia with median hemoglobin of 10.4 (Range: 6.7- 14.1 g/dL). 15/16 had macrocytosis with median MCV 110.4 (Range: 94.8- 123.1 /fL). 5/16 had thrombocytopenia with median platelet count 174 (Range: 20- 500 x10^9/L). 7/16 had leukopenia with median WBC 3.65 (Range: 2.4- 11.6 x10^9/ L). The ESR and CRP medians were 61.0 mm/hr and 81.5 mg/L, respectively. Karyotype was performed in 12 patients of which 11 were normal and the remaining case showed a complex karyotype. An NGS panel targeting the most frequent myeloid disorder associated gene mutations was negative in 10/15 cases. GS for myeloid mutations revealed pathogenic mutations in 5 patients, involving genes TET2 (2/5), DNMT3A (2/5), and TP53 (1/5). Conclusions: Bone marrow findings in VEXAS syndrome, in this series of 16 patients, are individually non-specific, yet when taken altogether in the overtly abnormal cases, are very suggestive when the clinical index of suspicion is high. In such scenarios, the combined clinical and bone marrow findings should prompt discussion and consideration for UBA1 mutation testing given the significant clinical implications for patient management and prognosis. Disclosures Patnaik: StemLine: Research Funding; Kura Oncology: Research Funding. Warrington: Eli Lilly: Research Funding; Kiniksa: Research Funding.

Abstract Background Patients (pts) with aggressive B-cell non-Hodgkin lymphoma (NHL) progressing after anti-CD19 chimeric antigen receptor T (CART) cell therapy have poor prognosis and may benefit from new therapy options through clinical trials. However, in a single center report, only 12% of such pts were treated in trials (Chow et al. Am J Hematol, 2019). Identifying the reasons for this low enrollment is needed to design future studies for this population. Here, we evaluated the eligibility criteria for recent landmark trials for relapsed/refractory aggressive B-cell NHL to learn what eligibility barriers are present. Methods Pts with aggressive B-cell NHL who received FDA-approved CART cell therapy at Mayo Clinic (Rochester, Arizona, Florida) since 2018 and progressed after CART cell therapy were identified. The potential eligibility for the following key trials was evaluated: a) polatuzumab + bendamustine + rituximab, b) tafasitamab + lenalidomide, c) selinexor and d) loncastuximab. The eligibility for each trial was retrospectively assessed at the time of disease progression after CART cell therapy based on hemoglobin (Hb), absolute neutrophils count (ANC), platelet count (Plt), renal and liver function tests, ECOG performance status (PS), and central nervous system (CNS) involvement. Results Seventy-five pts had disease progression to axicabtagene ciloleucel (N=73, 97%) or tisagenlecleucel (N=2, 3%) and are included in this analysis. Median time to progression after CART was 2.1 months (IQR: 1.0 - 3.1). Thirteen (17%) pts were treated in clinical trials after progression following CART cell therapy, while 46 (61%) were treated off trials, and 16 (22%) pts never received any treatment after progression. At a median follow-up of 13.6 months (IQR: 9.1 - 26.7) from CART progression, the median overall survival (mOS) from CART progression was 5.8 months (95% CI 3.5 - 10.1) and 53 (71%) pts died. Thirty-eight pts (51%) did not meet eligibility criteria for any of the 4 recent landmark trials. Hematologic impairment was the most common barrier to inclusion of these patients in clinical trials: Hb < 9 g/dL n=23 (31%) or Hb < 10 g/dL n=36 (48%), ANC < 1.0 x 10 9/L n=19 (25%) or ANC < 1.5 x 10 9/L n=32 (43%), and Plt < 75 x 10 9/L n=30 (40%) or Plt < 90 x 10 9/L n=34 (45%). Renal (n=11, 15%) or liver dysfunction (n=5, 7%), CNS involvement (n=8, 11%) and ECOG PS > 2 (n=3, 4%) were less common reasons leading to exclusion from trials. Post CART trial ineligible pts had significantly shorter time to progression (median 1.7 months, IQR: 1.0 - 2.6 vs. 3.0 months IQR: 1.9 - 3.4, p < 0.01) and inferior overall response to CART (45% vs 67%, p = 0.06) compared to pts who met trial eligibility post CART. Baseline Hb (median Hb 9.5 g/dL, IQR: 8.5 - 10.5 vs. 10.9 g/dL, IQR: 9.7 - 12.2, p < 0.01) and Plt (median Plt 106 x 10 9/L IQR: 54 - 165 vs. 201 x 10 9/L IQR: 141 - 243, p < 0.01) were also significantly lower in pts ineligible for trials post CART. There were no significant differences between pts eligible or ineligible for trials with regards to age (median 59 vs. 60 years), number of prior therapies (median 3 vs. 3), prior autologous stem cell transplant (41% vs. 37%), bridging therapy (65% vs. 63%), baseline ANC (median 4,1 vs. 3,0 x10 9/L), or high-grade (grade ≥ 2) cytokine release syndrome (19% vs. 21%) or neurotoxicity (32%, vs. 42%), respectively. Survival after CART progression was significantly shorter (mOS 2.5 months, 95% CI: 1.6 - 5.1) for the 38 pts ineligible for trials compared to pts eligible for trials (mOS 10.6 months, 95% CI: 8.9 - NA), (p < 0.01). In the 59 pts who received therapy post CART progression, the mOS of pts treated on (n = 13) or off (n = 46) trials was 13.8 months (95% CI: 9.2 - NA) vs. 6.6 months (4.9 - 10.7), respectively (p = 0.047). Conclusion Approximately half of the pts (51%) with aggressive B-cell NHL progressing after CART cell therapy would have be excluded from landmark clinical trials. The current hematologic exclusion criteria are a major barrier to enrollment in clinical trials, which would exclude many pts who have disease progression within 3 months of CART cell therapy (ie, primary refractory disease), in whom cytopenia as a toxicity from therapy is prevalent. Given the known delayed hematologic recovery after CART cell therapy and the unmet need of pts progressing to CART cell therapy, the hematologic exclusion criteria should be adjusted to increase trial participation of this population, especially of those with primary refractory disease. Figure 1 Figure 1. Disclosures Munoz: Gilead/Kite Pharma, Kyowa, Bayer, Pharmacyclics/Janssen, Seattle Genetics, Acrotech/Aurobindo, Beigene, Verastem, AstraZeneca, Celgene/BMS, Genentech/Roche.: Speakers Bureau; Janssen: Research Funding; Pharmacyclics/Abbvie, Bayer, Gilead/Kite Pharma, Pfizer, Janssen, Juno/Celgene, BMS, Kyowa, Alexion, Beigene, Fosunkite, Innovent, Seattle Genetics, Debiopharm, Karyopharm, Genmab, ADC Therapeutics, Epizyme, Beigene, Servier: Consultancy; Seattle Genetics: Research Funding; Millennium: Research Funding; Pharmacyclics: Research Funding; Genentech: Research Funding; Incyte: Research Funding; Portola: Research Funding; Merck: Research Funding; Celgene: Research Funding; Gilead/Kite Pharma: Research Funding; Bayer: Research Funding; Seattle Genetics: Honoraria; Physicians' Education Resource: Honoraria; Targeted Oncology: Honoraria; OncView: Honoraria; Kyowa: Honoraria. Murthy: CRISPR Therapeutics: Research Funding. Maurer: Morphosys: Membership on an entity's Board of Directors or advisory committees, Research Funding; Nanostring: Research Funding; Kite Pharma: Membership on an entity's Board of Directors or advisory committees; Celgene: Research Funding; Genentech: Research Funding; Pfizer: Consultancy, Membership on an entity's Board of Directors or advisory committees. Bennani: Purdue Pharma: Other: Advisory Board; Daichii Sankyo Inc: Other: Advisory Board; Kyowa Kirin: Other: Advisory Board; Vividion: Other: Advisory Board; Kymera: Other: Advisory Board; Verastem: Other: Advisory Board. Paludo: Karyopharm: Research Funding. Wang: Genentech: Research Funding; Incyte: Membership on an entity's Board of Directors or advisory committees, Research Funding; MorphoSys: Research Funding; TG Therapeutics: Membership on an entity's Board of Directors or advisory committees; Eli Lilly: Membership on an entity's Board of Directors or advisory committees; LOXO Oncology: Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Research Funding; InnoCare: Research Funding. Ansell: Bristol Myers Squibb, ADC Therapeutics, Seattle Genetics, Regeneron, Affimed, AI Therapeutics, Pfizer, Trillium and Takeda: Research Funding. Witzig: Karyopharm Therapeutics, Celgene/BMS, Incyte, Epizyme: Consultancy, Membership on an entity's Board of Directors or advisory committees; Celgene/BMS, Acerta Pharma, Kura Oncology, Acrotech Biopharma, Karyopharm Therapeutics: Research Funding. Nowakowski: Celgene, NanoString Technologies, MorphoSys: Research Funding; Celgene, MorphoSys, Genentech, Selvita, Debiopharm Group, Kite/Gilead: Consultancy, Membership on an entity's Board of Directors or advisory committees. Lin: Vineti: Consultancy; Takeda: Research Funding; Sorrento: Consultancy; Novartis: Consultancy; Juno: Consultancy; Legend: Consultancy; Janssen: Consultancy, Research Funding; Bluebird Bio: Consultancy, Research Funding; Celgene: Consultancy, Research Funding; Merck: Research Funding; Gamida Cell: Consultancy; Kite, a Gilead Company: Consultancy, Research Funding.

Abstract Background Diffuse large B-cell lymphoma (DLBCL) that fails to achieve a complete response (CR) or relapses early after standard immunochemotherapy (IC, e.g., R-CHOP or similar) is referred to as primary refractory DLBCL and has a poor prognosis. The clinical course with regards to frontline IC is heterogenous, and different definitions have been used in literature, e.g., progressive or refractory during therapy (narrow definition), or not achieving complete remission at the end of IC, or relapsing within 6 or 12 months after completing IC (broad definition). A small proportion of patients may still have chemosensitive disease and be able to achieve durable disease control with salvage chemotherapy followed by autologous stem cell transplant (ASCT). However, it is challenging to identify such patients, with clinical and molecular predictors highly needed. In this study, we examined the association of time to refractory status with survival outcomes in patients with primary refractory disease. Methods Adult patients with newly diagnosed DLBCL between 2002 and 2015 and seen at Mayo Clinic Rochester were identified from the prospective Molecular Epidemiology Resource (MER) cohort study of the University of Iowa/Mayo Clinic Lymphoma SPORE. The current study included patients with primary refractory disease, which was defined as no response to frontline IC (primary progression), partial response (PR) at end of treatment (EOT PR), or relapse with 12 months after achieving CR at EOT (early relapse). Clinical characteristics, treatment and response data, and follow-up data were abstracted from MER and collected by medical record review if needed. Clinical characteristics between groups were compared using Chi-square test. Overall survival (OS) was defined as the time from confirmation of refractory disease to the time of death from any cause and was analyzed using the Kaplan-Meier method. Results Out of 949 newly diagnosed DLBCL patients, 122 (12.8%) had primary refractory disease, 36 with primary progression, 36 with EOT PR, and 50 with early relapse. The baseline clinical characteristics are summarized in Table 1. No significant differences in age, gender, ECOG performance status, number of extranodal sites, stage, International Prognostic Index, or cell of origin were found between the 3 groups. The proportion of MYC2 and BCL2/BCL6 rearrangements or Myc/Bcl2 double expressor was small and not different among the 3 groups. Salvage therapies were mainly platinum based high-dose chemotherapy (e.g., R-ICE, R-DHAP, or similar) for systemic disease, MTX-based therapy for CNS relapse, or radiotherapy or resection for localized disease (Table 1). The response to salvage chemotherapy was significantly different between the 3 groups. The CR/PR rate was 8.6%/28.6% for patients with primary progression, 16.7%/46.7% for patients with EOT PR, and 35.6%/33.3% for patients with early relapse (P<0.01, Table 1). At a median follow-up time (of living patients) of 113 months, 93 patients had died. The 2-year OS was 13.9% for patients with primary progression, which was significantly worse compared to that of patients with EOT PR (2-year OS 41.7%) or early relapse (2-year OS 44%), (P=0.001)(Figure 1A). In patients with early relapse, the 2-year OS was not significantly different among those who relapsed with 3 months, between 3-6 months, or between 6-12 months (Figure 1B). Conclusion Our data suggest that broadly defined primary refractory DLBCL has heterogenous survival outcomes. DLBCL patients with primary progressive disease represent an ultra-high risk group that has particularly poor survival outcomes with current standard salvage regimens. Novel therapies such CAR T-cell therapy or targeted agents should be studied in this patient population. In contrast, patient who only achieve PR at EOT and those who relapse within 1 year of achieving CR had better OS. A fraction of these patients may still have chemosensitive disease and benefit from salvage chemotherapy and ASCT. The survival difference in the two groups also has important implications for clinical trial design. The definition of primary refractory DLBCL in clinical trials should be carefully and clearly defined. When evaluating novel therapies in single arm trials, the benchmark for efficacy (i.e., historical outcomes) may differ according to the population included in the trial (e.g., time to refractory status). Figure 1 Figure 1. Disclosures Maurer: BMS: Research Funding; Genentech: Research Funding; Morphosys: Membership on an entity's Board of Directors or advisory committees, Research Funding; Kite Pharma: Membership on an entity's Board of Directors or advisory committees; Pfizer: Membership on an entity's Board of Directors or advisory committees; Nanostring: Research Funding. Bennani: Vividion: Other: Advisory Board; Kyowa Kirin: Other: Advisory Board; Daichii Sankyo Inc: Other: Advisory Board; Verastem: Other: Advisory Board; Purdue Pharma: Other: Advisory Board; Kymera: Other: Advisory Board. Cerhan: Celgene/BMS: Other: Connect Lymphoma Scientific Steering Committee, Research Funding; NanoString: Research Funding; Regeneron Genetics Center: Other: Research Collaboration; Genentech: Research Funding. Witzig: Celgene/BMS, Acerta Pharma, Kura Oncology, Acrotech Biopharma, Karyopharm Therapeutics: Research Funding; Karyopharm Therapeutics, Celgene/BMS, Incyte, Epizyme: Consultancy, Membership on an entity's Board of Directors or advisory committees. Habermann: Seagen: Other: Data Monitoring Committee; Incyte: Other: Scientific Advisory Board; Tess Therapeutics: Other: Data Monitoring Committee; Morphosys: Other: Scientific Advisory Board; Loxo Oncology: Other: Scientific Advisory Board; Eli Lilly & Co.,: Other: Scientific Advisor. Wang: Genentech: Research Funding; TG Therapeutics: Membership on an entity's Board of Directors or advisory committees; Novartis: Research Funding; Eli Lilly: Membership on an entity's Board of Directors or advisory committees; Incyte: Membership on an entity's Board of Directors or advisory committees, Research Funding; InnoCare: Research Funding; MorphoSys: Research Funding; LOXO Oncology: Membership on an entity's Board of Directors or advisory committees, Research Funding. Nowakowski: Celgene, MorphoSys, Genentech, Selvita, Debiopharm Group, Kite/Gilead: Consultancy, Membership on an entity's Board of Directors or advisory committees; Celgene, NanoString Technologies, MorphoSys: Research Funding.