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Tumor-intrinsic features may render large B-cell lymphoma (LBCL) insensitive to CD19-directed chimeric antigen receptor T cells (CAR-T). We hypothesized that TP53 genomic alterations are detrimental to response outcomes in LBCL treated with CD19-CAR-T. MATERIALS AND METHODS: Patients with LBCL treated with CD19-CAR-T were included. Targeted next-generation sequencing was performed on pre–CAR-T tumor samples in a subset of patients. Response and survival rates by histologic, cytogenetic, and molecular features were assessed. Within a cohort of newly diagnosed LBCL with genomic and transcriptomic profiling, we studied interactions between cellular pathways and TP53 status. RESULTS: We included 153 adults with relapsed or refractory LBCL treated with CD19-CAR-T (axicabtagene ciloleucel [50%], tisagenlecleucel [32%], and lisocabtagene maraleucel [18%]). Outcomes echoed pivotal trials: complete response (CR) rate 54%, median overall survival (OS) 21.1 months (95% CI, 14.8 to not reached), and progression-free survival 6 months (3.4 to 9.7). Histologic and cytogenetic LBCL features were not predictive of CR. In a subset of 82 patients with next-generation sequencing profiling, CR and OS rates were comparable with the unsequenced cohort. TP53 alterations (mutations and/or copy number alterations) were common (37%) and associated with inferior CR and OS rates in univariable and multivariable regression models; the 1-year OS in TP53-altered LBCL was 44% (95% CI, 29 to 67) versus 76% (65 to 89) in wild-type (P = .012). Transcriptomic profiling from a separate cohort of patients with newly diagnosed lymphoma (n = 562) demonstrated that TP53 alterations are associated with dysregulation of pathways related to CAR-T-cell cytotoxicity, including interferon and death receptor signaling pathway and reduced CD8 T-cell tumor infiltration. CONCLUSION: TP53 is a potent tumor-intrinsic biomarker that can inform risk stratification and clinical trial design in patients with LBCL treated with CD19-CAR-T. The role of TP53 should be further validated in independent cohorts.

PURPOSE Tumor-intrinsic features may render large B-cell lymphoma (LBCL) insensitive to CD19-directed chimeric antigen receptor T cells (CAR-T). We hypothesized that TP53 genomic alterations are detrimental to response outcomes in LBCL treated with CD19-CAR-T. MATERIALS AND METHODS Patients with LBCL treated with CD19-CAR-T were included. Targeted next-generation sequencing was performed on pre–CAR-T tumor samples in a subset of patients. Response and survival rates by histologic, cytogenetic, and molecular features were assessed. Within a cohort of newly diagnosed LBCL with genomic and transcriptomic profiling, we studied interactions between cellular pathways and TP53 status. RESULTS We included 153 adults with relapsed or refractory LBCL treated with CD19-CAR-T (axicabtagene ciloleucel [50%], tisagenlecleucel [32%], and lisocabtagene maraleucel [18%]). Outcomes echoed pivotal trials: complete response (CR) rate 54%, median overall survival (OS) 21.1 months (95% CI, 14.8 to not reached), and progression-free survival 6 months (3.4 to 9.7). Histologic and cytogenetic LBCL features were not predictive of CR. In a subset of 82 patients with next-generation sequencing profiling, CR and OS rates were comparable with the unsequenced cohort. TP53 alterations (mutations and/or copy number alterations) were common (37%) and associated with inferior CR and OS rates in univariable and multivariable regression models; the 1-year OS in TP53-altered LBCL was 44% (95% CI, 29 to 67) versus 76% (65 to 89) in wild-type ( P = .012). Transcriptomic profiling from a separate cohort of patients with newly diagnosed lymphoma (n = 562) demonstrated that TP53 alterations are associated with dysregulation of pathways related to CAR-T-cell cytotoxicity, including interferon and death receptor signaling pathway and reduced CD8 T-cell tumor infiltration. CONCLUSION TP53 is a potent tumor-intrinsic biomarker that can inform risk stratification and clinical trial design in patients with LBCL treated with CD19-CAR-T. The role of TP53 should be further validated in independent cohorts.

PURPOSE To improve curability and limit long-term adverse effects for newly diagnosed early-stage (ES), unfavorable-risk Hodgkin lymphoma. METHODS In this multicenter study with four sequential cohorts, patients received four cycles of brentuximab vedotin (BV) and doxorubicin, vinblastine, and dacarbazine (AVD). If positron emission tomography (PET)-4–negative, patients received 30-Gy involved-site radiotherapy in cohort 1, 20-Gy involved-site radiotherapy in cohort 2, 30-Gy consolidation-volume radiotherapy in cohort 3, and no radiotherapy in cohort 4. Eligible patients had ES, unfavorable-risk disease. Bulk disease defined by Memorial Sloan Kettering criteria (> 7 cm in maximal transverse or coronal diameter on computed tomography) was not required for cohorts 1 and 2 but was for cohorts 3 and 4. The primary end point was to evaluate safety for cohort 1 and to evaluate complete response rate by PET for cohorts 2-4. RESULTS Of the 117 patients enrolled, 116 completed chemotherapy, with the median age of 32 years: 50% men, 98% stage II, 86% Memorial Sloan Kettering–defined disease bulk, 27% traditional bulk (> 10 cm), 52% elevated erythrocyte sedimentation rate, 21% extranodal involvement, and 56% > 2 involved lymph node sites. The complete response rate in cohorts 1-4 was 93%, 100%, 93%, and 97%, respectively. With median follow-up of 3.8 years (5.9, 4.5, 2.5, and 2.2 years for cohorts 1-4), the overall 2-year progression-free and overall survival were 94% and 99%, respectively. In cohorts 1-4, the 2-year progression-free survival was 93%, 97%, 90%, and 97%, respectively. Adverse events included neutropenia (44%), febrile neutropenia (8%), and peripheral neuropathy (54%), which was largely reversible. CONCLUSION BV + AVD × four cycles is a highly active and well-tolerated treatment program for ES, unfavorable-risk Hodgkin lymphoma, including bulky disease. The efficacy of BV + AVD supports the safe reduction or elimination of consolidative radiation among PET-4–negative patients.

Background: Chimeric antigen receptor T cell therapy (CAR T) has demonstrated remarkable clinical efficacy in hematological malignancies. However, compromised T cell effector function, proliferation, and persistence can limit CAR T from reaching their full curative potential. Interleukin-2 (IL-2) is a potent stimulator of T cells, however therapeutic use of IL-2 is limited by systemic toxicity due its pleiotropy. Therefore, to provide a selective IL-2 signal to engineered T cells, we have developed a human orthogonal ligand/receptor system consisting of a half-life extended pegylated IL-2 mutein (STK-009) and a mutated IL-2 Receptor Beta (hoRb) that responds to STK-009 but not wild type IL-2. SYNCAR-001 is an autologous CAR T co-expressing a CD19 CAR and hoRb on the T cell surface. In mouse models of refractory lymphoma, STK-009 treatment led to expansion and activation of SYNCAR-001 cells with a maintenance of stem cell memory and effector T cell phenotypes. When added to SYNCAR-001, STK-009 increased complete response rate and durable responses in a dose dependent manner. In non-human primate studies, STK-009 alone demonstrated no significant biological activity in IL-2 sensitive populations (T cells or NK cells) and was tolerable without toxicity. Methods: This is a first-in-human, open-label, dose escalation study of combination SYNCAR-001 + STK-009 in adults with relapsed or refractory (r/r) CD19+ hematologic malignancies. The objectives of this study are to evaluate the safety, preliminary efficacy, pharmacokinetics, immunogenicity, and pharmacodynamics of SYNCAR-001 + STK-009. Dose escalation follows a standard 3+3 design with STK-009 being escalated while SYNCAR-001 is held at a single fixed dose. A dose extension will enroll a cohort of patients treated at a selected dose level and indication based on dose escalation findings. SYNCAR-001 is dosed intravenously (IV) once at Day 0 and STK-009 is dosed subcutaneously (SC) over the course of the study. Participants receive a single safety lead-in dose of STK-009 prior to lymphodepletion and subsequent SYNCAR-001 infusion. After SYNCAR-001 initiation, STK-009 is dosed SC weekly for 12 weeks and then monthly for 3 months. Eligible participants include individuals with r/r chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) and selected r/r B-cell non-Hodgkin lymphoma (NHL subtypes of large B cell, mantle cell, and indolent lymphoma). Prior CD19 CAR use is excluded. The primary endpoint of safety includes outcomes such as adverse events and dose-limiting toxicities. Secondary endpoints include assessments of response, pharmacokinetics, and immunogenicity. Exploratory endpoints include assessment of immune cell populations, and relevant gene/protein expression, as well as persistence, phenotype, and functionality of SYNCAR-001 in the peripheral blood and/or bone marrow in response to STK-009. Citation Format: Maria Lia Palomba, Matthew G. Mei, Paolo F. Caimi, Matthew Cortese, Marco Davila, Greg Yadnik, Nestor Huang, David Mou, Martin Oft, Paul-Joseph Aspuria, Anita Mehta-Damani, Navneet Ratti, Naiyer Rizvi, Alex Azrilevich, Ran Reshef. A Phase 1 study to evaluate the safety and tolerability of a combination autologous CD19 CAR T cell therapy (SYNCAR-001) and orthogonal IL-2 (STK-009) in subjects with relapsed or refractory CD19 expressing hematologic malignancies (NCT05665062) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 2 (Clinical Trials and Late-Breaking Research); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(8_Suppl):Abstract nr CT125.

Cytokine release syndrome (CRS) immune effector cell–associated neurotoxicity syndrome are the most notable toxicities of CD19 chimeric antigen receptor (CAR) T-cell therapy. In addition, CAR T-cell–mediated toxicities can involve any organ system, with varied impacts on outcomes, depending on patient factors and involved organs. We performed detailed analysis of organ-specific toxicities and their association with outcomes in 60 patients with diffuse large B-cell lymphoma (DLBCL) treated with CD19 CAR T cells by assessing all toxicities in organ-based groups during the first year posttreatment. We observed 539 grade ≥2 and 289 grade ≥3 toxicities. Common grade ≥3 toxicities included hematological, metabolic, infectious, and neurological complications, with corresponding 1-year cumulative incidence of 57.7%, 54.8%, 35.4%, and 18.3%, respectively. Patients with impaired performance status had a higher risk of grade ≥3 metabolic complications, whereas elevated lactate dehydrogenase was associated with higher risks of grade ≥3 neurological and pulmonary toxicities. CRS was associated with higher incidence of grade ≥3 metabolic, pulmonary, and neurologic complications. The 1-year nonrelapse mortality and overall survival were 1.7% and 69%, respectively. Only grade ≥3 pulmonary toxicities were associated with an increased mortality risk. In summary, toxicity burdens after CD19 CAR T-cell therapy were high and varied by organ systems. Most toxicities were manageable and were rarely associated with mortality. Our study emphasizes the importance of toxicity assessment, which could serve as a benchmark for further research to reduce symptom burdens and improve tolerability in patients treated with CAR T cells.

Background T-cell/histiocyte-rich large B-cell lymphoma (THRLBCL) is an uncommon variant of diffuse large B cell lymphoma (DLBCL), characterized by low content of lymphoma cells in a background of extensive infiltrate of T-cells and histiocytes. Historically, THRLBCL was considered an aggressive variant of DLBCL with poorer outcomes and a 3-year OS We aimed to describe the clinical characteristics, prognostic factors, response to treatment, and outcome among pts diagnosed with THRLBCL at Memorial Sloan Kettering Cancer Center (MSKCC) in the rituximab era. Patients and Methods We retrospectively reviewed all cases of THRLBCL who were diagnosed in our center from January 2000 to October 2019. We collected data for demographic and clinical characteristics, pathology results, disease stage and sites of involvement, treatment regimen, and outcome. Fisher's exact test was used to assess associations between patient characteristics and treatment regimen. Fisher's exact test and Wilcoxon test were used to assess associations between categorical or continuous characteristics and response to treatment, respectively. The likelihood ratio test was used to assess significance of Cox regression univariate models. Overall survival (OS) was measured from date of diagnosis until last follow up or death. Event-free survival (EFS) was measured from end of treatment to last follow up or pathology proven relapse or disease progression. Survival curves were estimated using the Kaplan Meier method. Results A total of 100 pts were diagnosed with THRLBCL at our center during the study period. We excluded 33 pts who had missing data regarding stage, frontline treatment, or response. A total of 67 pts were included for analysis in our cohort. Median follow up duration among survivors was 3.4 years (range 0.4-10.8 years). Baseline characteristics are summarized in table 1. Forty-eight were males (72%). Median age at diagnosis was 41 years (range 19-86). Fifty-three (72%) pts were diagnosed at stage IV. Thirty-five (52%) pts had involvement of more than 1 extra-nodal site. The most common extranodal site was bone (60%). Fourteen pts had a positive bone marrow biopsy (26% of those evaluated). Univariate analysis was performed for age, gender, ethnicity, stage, extra-nodal sites, presence of B symptoms, performance status, elevated LDH, IPI score>=3, and history of NLPHL. None of these factors were found significantly associated with response rate, EFS, or OS. Frontline treatment is shown in table 2 and included R-CHOP or R-CHOP based treatment in 48% (n=32), R-EPOCH in 12% (n=8), R-CHOP/R-ICE (4 cycles of R-CHOP-14 followed by 3 cycles of R-ICE, Moskowitz CH, et al. JCO 2010) in 33% (n=22) and other regimens in 7.5% (n=5). CNS prophylactic treatment was given in 19 pts. One pt had an autologous stem cell transplant and 1 pt had an allogeneic stem cell transplant as part of frontline treatment. Fifty-one (76%) pts had a complete response (CR) to frontline treatment. Among these pts, 6 relapsed. Sixteen (24%) pts had refractory disease. Among pts with relapsed or refractory disease, 18 received additional therapy. In the whole cohort, 3-year EFS was 68% and 3-year OS was 85%. In a sub-group analysis of pts who received R-CHOP/R-ICE compared to pts who were treated with R-CHOP or R-EPOCH, CR rates were 95% and 70% respectively (p=0.014). The R-CHOP/R-ICE regimen was also associated with higher 3-year EFS of 86% compared to 62% (p=0.049) and a better 3-year OS of 100% compared with 79% (p=0.016). See figures 1-2. The 2 treatment groups were not significantly different with regards to baseline characteristics. Conclusions Our study demonstrates better outcomes among pts with THRLBCL compared to available historical data from the pre-rituximab era. In addition, with the limitation of a retrospective, single-center study, our data suggests that for newly diagnosed THRLBCL, treatment with a higher intensity regimen, such as R-CHOP/R-ICE, may be associated with favorable outcome. Disclosures Batlevi: Life Sci, GLG, Juno/Celgene, Seattle Genetics, Kite: Consultancy; Janssen, Novartis, Epizyme, Xynomics, Bayer, Autolus, Roche/Genentech: Research Funding. Falchi:Roche: Research Funding; Genmab: Research Funding. Hamlin:Molecular Templates: Research Funding; Portola Pharmaceutics: Consultancy; J&J Pharmaceuticals: Research Funding; Incyte: Research Funding; Celgene: Consultancy; Juno Therapeutics: Consultancy; Karyopharm: Consultancy; Portola: Research Funding. Horwitz:Forty Seven: Consultancy, Research Funding; ADCT Therapeutics: Consultancy, Research Funding; ASTEX: Consultancy; Beigene: Consultancy; Portola: Consultancy, Research Funding; Mundipharma: Consultancy; Innate Pharma: Consultancy; Corvus: Consultancy; Trillium: Consultancy, Research Funding; Seattle Genetics: Consultancy, Research Funding; Millenium/Takeda: Consultancy, Research Funding; Verastem: Consultancy, Research Funding; GlaxoSmithKline: Consultancy; Infinity/Verastem: Research Funding; Kyowa Hakka Kirin: Consultancy, Research Funding; Aileron: Consultancy, Research Funding; Vividion Therapeutics: Consultancy; Affirmed: Consultancy; Janssen: Consultancy; Kura Oncology: Consultancy; Miragen: Consultancy; Myeloid Therapeutics: Consultancy; Celgene: Consultancy, Research Funding; C4 Therapeutics: Consultancy; Daiichi Sankyo: Research Funding. Joffe:AstraZeneca: Membership on an entity's Board of Directors or advisory committees; Epizyme: Membership on an entity's Board of Directors or advisory committees. Kumar:AbbVie: Research Funding; Astra Zeneca: Honoraria, Other: Honoraria for Advisory Board; Celgene: Honoraria, Other: Honoraria for Advisory Board; Seattle Genetics: Research Funding; Pharmacyclics: Research Funding; Celgene: Research Funding; Adaptive Biotechnologies,: Research Funding; Kite Pharmaceuticals: Honoraria, Other: Honoraria for Advisory Board. Matasar:Pharmacyclics: Honoraria, Research Funding; Immunovaccine Technologies: Honoraria, Research Funding; Janssen: Honoraria, Research Funding; IGM Biosciences: Research Funding; GlaxoSmithKline: Honoraria, Research Funding; Takeda: Consultancy, Honoraria; Daiichi Sankyo: Consultancy; Seattle Genetics: Consultancy, Honoraria, Research Funding; Rocket Medical: Consultancy, Research Funding; Teva: Consultancy; F. Hoffmann-La Roche Ltd: Consultancy, Honoraria, Research Funding; Juno Therapeutics: Consultancy; Genentech, Inc.: Consultancy, Honoraria, Research Funding; Merck: Consultancy; Bayer: Consultancy, Honoraria, Research Funding. Noy:Pharmacyclics: Research Funding; Medscape: Consultancy; NIH: Research Funding; Rafael Pharma: Research Funding; Janssen: Consultancy; Pharmacyclics: Consultancy; Morphosys: Consultancy; Targeted Oncology: Consultancy. Palomba:Genentech: Research Funding; Juno: Research Funding; Regeneron: Research Funding; Novartis: Honoraria; Merck: Honoraria; Celgene: Honoraria; Juno: Honoraria; Pharmacyclics: Honoraria. Straus:Karyopharm Therapeutics: Membership on an entity's Board of Directors or advisory committees; Targeted Oncology: Consultancy, Speakers Bureau; NY Lymphoma Rounds: Consultancy; Takeda Pharmaceuticals: Research Funding, Speakers Bureau; OncLive: Speakers Bureau; Elsevier: Membership on an entity's Board of Directors or advisory committees, Other: CME writer; ASH: Other: Conference in December 2019 on HL to other physicians during ASH; Seattle Genetics: Consultancy, Membership on an entity's Board of Directors or advisory committees; Imedex, Inc.: Speakers Bureau. Vardhana:Other: Other: SAV has received honoraria from Agios Pharmaceuticals and Rheos Pharmaceuticals, is an advisor for Immunai and has consulted for ADC Therapeutics. von Keudell:Bayer: Research Funding; Genentech: Research Funding; Pharmacyclics: Research Funding. Zelenetz:Celgene: Consultancy; Gilead: Consultancy; Genentech/Roche: Consultancy; Gilead: Research Funding; Adaptive Biotechnology: Consultancy; Sandoz: Research Funding; MorphoSys: Research Funding; Celgene: Research Funding; MEI Pharma: Research Funding; Roche: Research Funding; BeiGene: Membership on an entity's Board of Directors or advisory committees; Janssen: Consultancy; Novartis: Consultancy; Amgen: Consultancy. Moskowitz:Incyte: Research Funding; Merck: Consultancy; Seattle Genetics: Consultancy; Miragen Therapeutics: Consultancy; Imbrium Therapeutics, L.P.: Consultancy; Merck: Research Funding; Bristol-Myers Squibb: Research Funding; Seattle Genetics: Research Funding.

Romidepsin (histone deacetylase inhibitor), lenalidomide (immunomodulatory agent), and carfilzomib (proteasome inhibitor), have efficacy and lack cumulative toxicity in relapsed/refractory lymphoma. We performed two investigator initiated sequential phase I studies to evaluate the maximum tolerated dose (MTD) of romidepsin and lenalidomide (regimen A) and romidepsin, lenalidomide, and carfilzomib (regimen B) in relapsed/refractory lymphoma. Cohorts in T-cell lymphoma (TCL), B-cell lymphoma (BCL) were enrolled at the MTD. 49 patients were treated in study A (27 TCL, 17 BCL, 5 HL) and 27 (16 TCL, 11 BCL) in study B. The MTD of regimen A was romidepsin 14 mg/m2 IV on days 1, 8, and 15 and lenalidomide 25 mg oral on days 1-21 of a 28-day cycle. The MTD of regimen B was romidepsin 8mg/m2 on days 1 and 8, lenalidomide 10mg oral on days 1-14 and carfilzomib 36mg/m2 IV on days 1 and 8 of a 21-day cycle. In study A, 94% had AEs ≥Grade 3, most commonly neutropenia (49%), thrombocytopenia (53%), and electrolyte abnormalities (49%). In study B 59% had AEs ≥Grade 3, including thrombocytopenia (30%) and neutropenia (26%). In study A the ORR was 49% (50% TCL, 47% BCL, 50% HL). In study B the ORR was 48% (50% TCL, 50% BCL). For study A and B the median progression free survival (PFS) was 5.7 months and 3.4 months respectively with 11 patients proceeding to allogeneic transplant. The combinations of romidepsin and lenalidomide and of romidepsin, lenalidomide and carfilzomib showed activity in relapsed/refractory lymphoma with an acceptable safety profile. This article is protected by copyright. All rights reserved.

Anti-CD19 chimeric antigen receptor (CAR) T cell therapy has led to unprecedented responses in patients with high-risk hematologic malignancies. However, up to 60% of patients still experience disease relapse and up to 80% of patients experience CAR-mediated toxicities, such as cytokine release syndrome or immune effector cell-associated neurotoxicity syndrome. We investigated the role of the intestinal microbiome on these outcomes in a multicenter study of patients with B cell lymphoma and leukemia. We found in a retrospective cohort (n = 228) that exposure to antibiotics, in particular piperacillin/tazobactam, meropenem and imipenem/cilastatin (P-I-M), in the 4 weeks before therapy was associated with worse survival and increased neurotoxicity. In stool samples from a prospective cohort of CAR T cell recipients (n = 48), the fecal microbiome was altered at baseline compared to healthy controls. Stool sample profiling by 16S ribosomal RNA and metagenomic shotgun sequencing revealed that clinical outcomes were associated with differences in specific bacterial taxa and metabolic pathways. Through both untargeted and hypothesis-driven analysis of 16S sequencing data, we identified species within the class Clostridia that were associated with day 100 complete response. We concluded that changes in the intestinal microbiome are associated with clinical outcomes after anti-CD19 CAR T cell therapy in patients with B cell malignancies.

Patients who develop chimeric antigen receptor (CAR) T-cell–related severe cytokine release syndrome (CRS) and immune effector cell–associated neurotoxicity syndrome (ICANS) exhibit hemodynamic instability and endothelial activation. The EASIX (Endothelial Activation and Stress Index) score (lactate dehydrogenase [LDH; U/L] × creatinine [mg/dL]/platelets [PLTs; 109 cells/L]) is a marker of endothelial damage that correlates with outcomes in allogeneic hematopoietic cell transplantation. Elevated LDH and low PLTs have been associated with severe CRS and ICANS, as has C-reactive protein (CRP), while increased creatinine is seen only in a minority of advanced severe CRS cases. We hypothesized that EASIX and 2 new modified EASIX formulas (simplified EASIX, which excludes creatinine, and modified EASIX [m-EASIX], which replaces creatinine with CRP [mg/dL]), calculated peri-CAR T-cell infusion, would be associated with development of severe (grade ≥ 3) CRS and ICANS. We included 118 adults, 53 with B-acute lymphoblastic leukemia treated with 1928z CAR T cells ({"type":"clinical-trial","attrs":{"text":"NCT01044069","term_id":"NCT01044069"}}NCT01044069) and 65 with diffuse large B-cell lymphoma treated with axicabtagene ciloleucel or tisagenlecleucel. The 3 formulas showed similar predictive power for severe CRS and ICANS. However, low PLTs and high CRP values were the only variables individually correlated with these toxicities. Moreover, only m-EASIX was a significant predictor of disease response. m-EASIX could discriminate patients who subsequently developed severe CRS preceding the onset of severe symptoms (area under the curve [AUC] at lymphodepletion, 80.4%; at day −1, 73.0%; and at day +1, 75.4%). At day +3, it also had high discriminatory ability for severe ICANS (AUC, 73%). We propose m-EASIX as a clinical tool to potentially guide individualized management of patients at higher risk for severe CAR T-cell–related toxicities.

Ibrutinib is associated with durable responses in patients with Waldenstrom macroglobulinaemia (WM). We hypothesized that response depth is predictive of progression-free survival (PFS) in WM patients treated with ibrutinib. Using landmark analyses, we evaluated response depth in two cohorts of WM patients treated with ibrutinib monotherapy. The learning cohort was composed of 93 participants from two clinical trials, and the validation cohort of 190 consecutive patients treated off clinical trial. Rates of partial response (PR) or better at six months in learning and validation cohorts were 64% and 71% respectively (P = 0·29). In the learning cohort, three-year PFS rates for patients who attained PR or better at six months versus not were 81% and 57% respectively (P = 0·009). In the validation cohort, three-year PFS rates for patients who attained PR or better at six months versus not were 83% and 54% respectively (P = 0·008). In multivariate analyses, attaining PR or better at six months was associated with superior PFS in the learning [hazard ratio (HR) 0·38; P = 0·01] and validation cohorts (HR 0·18; P = 0·004). Attaining PR at six months on ibrutinib emerges as an intermediate outcome of interest and should be validated as surrogate for PFS in clinical trials evaluating Bruton tyrosine kinase inhibitors in WM.

In the light of the COVID-19 pandemic, the International Workshop on Waldenström Macroglobulinemia (IWWM) Treatment Recommendations Panel felt the need to provide a consensus statement for the management of Waldenström Macroglobulinemia (WM) patients during this challenging time. We followed the current recommendations by the American Society of Hematology, which have been modified accordingly to fit the specific realities associated with the management of WM. In this Consensus Statement, the Panel addresses questions related to treatment initiation, preferred therapies, minimizing visit to clinics and infusions centers, supportive care and guidance for WM patients in clinical trials. Finally, we also provide information on timing and appropriateness of testing and management of COVID-19 infected patients, as well as ways to get physicians and patients involved in registry studies that could help others.

Introduction: Primary cutaneous diffuse large B-cell lymphoma, leg type (PCDLBCL,LT) is a rare subtype of lymphoma that has been reported to have aggressive clinical behavior and carry a poor prognosis. However, due to the extreme scarcity of data, optimal management of this entity remains poorly defined, particularly with respect to optimal induction therapy and the role for central nervous system (CNS) prophylaxis. We therefore reviewed our institutional experience with patients with PCDLBCL,LT to better delineate their clinical course and risk of CNS relapse. Methods: We searched our electronic database and individual electronic medical records for cases of skin-only PCDLBCL,LT and analyzed the presenting characteristics, treatment approaches, use of CNS prophylaxis, and clinical outcomes, including skin, systemic, and CNS relapse. Primary cutaneous follicle center lymphoma, primary cutaneous marginal zone lymphoma, and skin-only DLBCL arising in patients with a concurrent or antecedent indolent B-cell lymphoma were excluded. Additionally, cases with DLBCL involving both skin and nodal and/or extranodal sites at diagnosis were excluded. All patients underwent staging with positron emission tomography-computerized tomography (PET-CT). Diagnostic specimens were independently reviewed by hematopathologists with expertise in cutaneous lymphoma. Results: We identified 38 patients with PCDLBCL,LT followed at Memorial Sloan Kettering Cancer Center between July 2002 and October 2020. Fifteen (39%) were female and the median age was 76 years (range, 40-96). The disease was localized to the lower extremity in 15 cases (39%) and consisted of multiple lesions in 11 cases (29%). All but one patient had IPI 0-2. By Hans algorithm 79% of the samples had a non-GCB phenotype, 79% expressed MUM-1, 3% expressed CD10, and 82% exhibited Bcl2 expression. The median Ki-67 was 85% (range, 20%-100%). According to the CNS-IPI score, 25 out of 36 evaluable patients (69%) had low-risk disease and 11 (31%) intermediate-risk disease; no patient had high-risk disease. Induction therapy consisted of R-CHOP immunochemotherapy in 13 patients (33%), R-CHOP followed by radiation therapy (RT), at doses of 30-40 Gy, in 12 (31%), and RT alone, at doses of 30-45 Gy, in 10 (26%). One patient underwent excision alone, one received rituximab after excisional biopsy, and one best supportive care. Three patients (2 treated with chemotherapy + RT and one with chemotherapy only) received CNS prophylaxis with intrathecal methotrexate. Among 35 patients evaluable for response, the objective response rate was 86%, all of which were complete responses. One patient treated with rituximab had stable disease and 4 (2 treated with chemotherapy only, one RT, and one best supportive care) progressed. At a median follow-up of 8.9 years [range, 2.9-14.7], the 5-year progression-free survival for the cohort is 42% (Figure panel A). CNS relapse occurred in 5 patients (13%) involving leptomeninges in 1 case, parenchyma in 2, and both in 2. None of these patients received CNS prophylaxis. Of note, none of the three who did receive prophylaxis experienced CNS relapse. The 2-year and 5-year cumulative risk of CNS relapse are 7% and 19%, respectively (Figure panel B). At the time of this analysis, the 5-year overall survival rate is 66% (Figure Panel A), and in all, 16 patients (42%) have died. Among the 7 patients with known cause of death, 5 succumbed to progressive disease (including 3 with CNS disease), one to sepsis, and one to secondary acute myelogenous leukemia. Conclusions: To the best of our knowledge, this is the largest study analyzing the risk of CNS relapse in PCLBCL,LT patients treated with rituximab-containing immunochemotherapy. Our findings indicate that PCLBCL,LT is a highly aggressive disease associated with poor prognosis and high risk of CNS relapse. The 13% rate of CNS relapse in a population of patients with limited-stage disease, none of whom had high-risk CNS-IPI, suggests that alternate models of risk prediction are needed for patients with PCLBCL,LT and that clinical trials aimed at improving rates of cure and reducing the risk of CNS relapse for patients with PCLBCL,LT are needed. Figure 1 Figure 1. Disclosures Falchi: Abbvie: Consultancy, Research Funding; Genmab: Consultancy, Research Funding; Roche: Research Funding; Genetech: Research Funding. Ewalt: Loxo Oncology at Lilly: Membership on an entity's Board of Directors or advisory committees; Acceleron Pharma: Membership on an entity's Board of Directors or advisory committees. Batlevi: Memorial Sloan Kettering Cancer Center: Current Employment; Pfizer: Current holder of individual stocks in a privately-held company; Viatris: Current holder of individual stocks in a privately-held company; Life Sciences: Consultancy; Bayer: Research Funding; BMS: Current holder of individual stocks in a privately-held company; Seattle Genetics: Consultancy; Kite Pharma: Consultancy; Karyopharm: Consultancy; ADC Therapeutics: Consultancy; Dava Oncology: Honoraria; TouchIME: Honoraria; Moderna: Current holder of individual stocks in a privately-held company; TG Therapeutics: Consultancy; Medscape: Honoraria; Regeneron: Current holder of individual stocks in a privately-held company; Juno/Celgene: Consultancy; GLG Pharma: Consultancy; Xynomic: Research Funding; Roche/Genentech: Research Funding; Novartis: Research Funding; Epizyme: Research Funding; Janssen: Research Funding; Autolus: Research Funding. Caron: Astra-Zeneca: Current holder of individual stocks in a privately-held company; bristol myers: Current holder of individual stocks in a privately-held company; GlaxoSmithKlein: Current holder of individual stocks in a privately-held company; Johnson and Johnson: Current holder of individual stocks in a privately-held company; Novartis: Current holder of individual stocks in a privately-held company; pfizer: Current holder of individual stocks in a privately-held company; Teva: Current holder of individual stocks in a privately-held company. Hamlin: Alexion, AstraZeneca Rare Disease (formerly Portola Pharmaceuticals): Other: Study investigator, Research Funding; Incyte, Janssen, Molecular Templates: Research Funding; Kite, Karyopharm, Celgene: Membership on an entity's Board of Directors or advisory committees. Horwitz: ADC Therapeutics: Consultancy, Research Funding; Kyowa Hakko Kirin: Consultancy, Research Funding; Myeloid Therapeutics: Consultancy; Affimed: Research Funding; Vividion Therapeutics: Consultancy; Aileron: Research Funding; Verastem: Research Funding; C4 Therapeutics: Consultancy; Janssen: Consultancy; Seattle Genetics: Consultancy, Research Funding; Millennium /Takeda: Consultancy, Research Funding; Daiichi Sankyo: Research Funding; Forty Seven, Inc.: Research Funding; Trillium Therapeutics: Consultancy, Research Funding; Acrotech Biopharma: Consultancy; ONO Pharmaceuticals: Consultancy; Shoreline Biosciences, Inc.: Consultancy; Celgene: Research Funding; Tubulis: Consultancy; SecuraBio: Consultancy, Research Funding; Kura Oncology: Consultancy. Joffe: Epizyme: Consultancy; AstraZeneca: Consultancy. Khan: Seattle Genetics: Research Funding. Kumar: Seattle Genetics: Research Funding; Kite Pharmaceuticals: Other: advisory board , Research Funding; Pharmacyclics: Research Funding; Astra Zeneca: Honoraria, Other: Advisory Board, Research Funding; Celgene: Honoraria, Other: advisory board, Research Funding; Adaptive Biotechnologies, Celgene, Abbvie Pharmaceticals, Pharmacyclics, Seattle Genetics: Research Funding; Abbvie Pharmaceuticals: Research Funding. Moskowitz: Merck: Consultancy, Research Funding; Miragen: Research Funding; Janpix Ltd.: Consultancy; Bristol-Myers Squibb: Research Funding; Incyte: Research Funding; Beigene: Research Funding; ADC Therapeutics: Research Funding; Imbrium Therapeutics L.P./Purdue: Consultancy; Takeda: Consultancy; Seattle Genetics: Consultancy, Research Funding. Noy: Pharmacyclics: Consultancy, Research Funding; Medscape: Consultancy; Targeted Oncology: Consultancy; Morphosys: Consultancy; Rafael Parhma: Research Funding; Epizyme: Consultancy; Janssen: Consultancy, Honoraria. Palomba: Pharmacyclics: Membership on an entity's Board of Directors or advisory committees; Kite Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees. von Keudell: Pharmacyclics: Consultancy, Honoraria; Merck: Consultancy, Honoraria; Incyte: Consultancy, Honoraria; AbbVie: Research Funding; Merck: Research Funding; BMS: Research Funding; Janssen: Research Funding. Zelenetz: MEI Pharma: Honoraria, Research Funding; Pharmacyclics: Honoraria; BMS/Celgene/JUNO: Honoraria, Other; Gilead: Honoraria, Research Funding; Gilead: Honoraria; Novartis: Honoraria; Verastem: Honoraria; AstraZeneca: Honoraria; MethylGene: Research Funding; MorphoSys: Honoraria; Genentech/Roche: Honoraria, Research Funding; NCCN: Other; SecuraBio: Honoraria; Amgen: Honoraria; Janssen: Honoraria; Beigene: Honoraria, Other, Research Funding; Abbvie: Honoraria, Research Funding; LFR: Other. Dogan: Takeda: Consultancy, Research Funding; Peer View: Honoraria; Physicians' Education Resource: Honoraria; Seattle Genetics: Consultancy; Roche: Consultancy, Research Funding; EUSA Pharma: Consultancy. Salles: Allogene: Consultancy; Miltneiy: Consultancy; Loxo: Consultancy; Velosbio: Consultancy; Takeda: Consultancy; Novartis: Consultancy; Rapt: Consultancy; Regeneron: Consultancy, Honoraria; Epizyme: Consultancy, Honoraria; Morphosys: Consultancy, Honoraria; Genmab: Consultancy; Incyte: Consultancy; Genentech/Roche: Consultancy; Ipsen: Consultancy; Janssen: Consultancy; Kite/Gilead: Consultancy; Debiopharm: Consultancy; BMS/Celgene: Consultancy; Beigene: Consultancy; Abbvie: Consultancy, Honoraria; Bayer: Honoraria. Matasar: Janssen: Honoraria, Research Funding; TG Therapeutics: Consultancy, Honoraria; Teva: Consultancy; Daiichi Sankyo: Consultancy; Merck Sharp & Dohme: Current holder of individual stocks in a privately-held company; Genentech, Inc.: Consultancy, Honoraria, Research Funding; F. Hoffmann-La Roche Ltd: Consultancy, Honoraria, Research Funding; GlaxoSmithKline: Honoraria, Research Funding; Bayer: Consultancy, Honoraria, Research Funding; IGM Biosciences: Research Funding; Rocket Medical: Consultancy, Research Funding; Seattle Genetics: Consultancy, Honoraria, Research Funding; ImmunoVaccine Technologies: Consultancy, Honoraria, Research Funding; Juno Therapeutics: Consultancy; Memorial Sloan Kettering Cancer Center: Current Employment; Pharmacyclics: Honoraria, Research Funding; Takeda: Consultancy, Honoraria; Merck: Consultancy.

Background: Tumor-intrinsic molecular features informing risk and resistance mechanisms in large-B-cell lymphoma (LBCL) treated with CD19-directed chimeric antigen receptor T-cells (CAR-T) are lacking. TP53 has been implicated in aberrant apoptosis signaling and immune evasion. We hypothesized that TP53-alterations are detrimental in LBCL treated with CD19-CAR-T. Methods: Patients with relapsed/refractory LBCL treated with CD19-CAR-T were included. Targeted next-generation sequencing (NGS) encompassing protein-coding exons of over 400 genes (MSK-IMPACT) was performed on pre-CAR-T tumor samples in a subset of patients. Response and survival rates by tumor-intrinsic histological, cytogenetic, and molecular markers were assessed. Interactions between genomic aberrations and cellular pathways that could contribute to CAR-T resistance were studied using publicly available datasets with genomic and transcriptomic profiling. Results: We included 136 adults with LBCL treated with CD19-CAR-T. (axicabtagene-ciloleucel [70, 51%], tisagenlecleucel [38, 28%], lisocabtagene-maraleucel [28. 21%]). Patients were heavily pre-treated (≥4 treatment lines [58%]) and primarily categorized as diffuse large B-cell lymphoma (DLBCL)-NOS (79%) followed by double/triple hit high-grade lymphoma (12%). DLBCL transformed from follicular lymphoma, high KI67-index, germinal center B-cell cell of origin, and double expressor phenotype were highly represented (43%, 47%, 50%, and 40%, respectively). Outcomes in the complete cohort echoed pivotal trials: best overall response rate 78% (Fig. A), median overall survival (OS) 22.7 months (95%CI 14.8-NR), median progression-free survival 6.2 months (3.3-12.3). A subset of 76 patients had tumor NGS profiling. Clinical features and CR and OS rates were similar across patients with and without NGS. TP53 genomic alterations were common (28, 37%). A total of 26 TP53 mutations (22 missense; 2 in-frame deletions; 2 splice sites) were identified in 23 patients. An additional five patients had TP53 homozygous deletions (i.e., copy number alterations). Two patients had concurrent TP53 mutations and homozygous deletions. Among tumor-intrinsic factors, only TP53-alterations were predictive of complete response (CR) in univariable and multivariable logistic regression; no association was observed with histological and cytogenetic features (Fig. B). TP53-alterations were also predictive of OS in univariable and multivariable Cox regression (Fig. C-D; 1-year OS in TP53-altered (48% [95% CI 32 - 71]) vs. wild-type (75% [64 - 89]), p = 0.039). Notably, in TP53-altered LBCL, axicabtagene-ciloleucel therapy was associated with superior OS compared to aggregated 41BB products (HR 3.40 [1.19-9.66]) in multivariable Cox regression adjusted for age, performance status, and primary refractory disease (Fig. E). Transcriptomic analysis of publicly available samples from newly diagnosed LBCL patients (n=562) demonstrated that TP53-alterations are associated with dysregulation of pathways related to CAR-T cell cytotoxicity, including downregulation of interferon and death receptor pathway genes, and reduced CD8 T-cell tumor infiltration (Fig. F-H). Conclusions: We show, for the first time, that TP53 alterations are a valuable prognostic and potentially predictive marker in LGBL CD19-CAR-T recipients. Gene expression profiling suggests that TP53 alterations result in an immunosuppressive tumor-microenvironment and impaired apoptosis signaling, which could lead to decreased CAR-T efficacy. Figure 1 Figure 1. Disclosures Shouval: Medexus: Consultancy. Batlevi: Life Sciences: Consultancy; Kite Pharma: Consultancy; Juno/Celgene: Consultancy; GLG Pharma: Consultancy; Pfizer: Current holder of individual stocks in a privately-held company; Medscape: Honoraria; BMS: Current holder of individual stocks in a privately-held company; Seattle Genetics: Consultancy; Memorial Sloan Kettering Cancer Center: Current Employment; Moderna: Current holder of individual stocks in a privately-held company; Regeneron: Current holder of individual stocks in a privately-held company; Viatris: Current holder of individual stocks in a privately-held company; Karyopharm: Consultancy; TG Therapeutics: Consultancy; ADC Therapeutics: Consultancy; Dava Oncology: Honoraria; Bayer: Research Funding; TouchIME: Honoraria; Xynomic: Research Funding; Roche/Genentech: Research Funding; Novartis: Research Funding; Epizyme: Research Funding; Janssen: Research Funding; Autolus: Research Funding. Dahi: Kite / Gilead: Membership on an entity's Board of Directors or advisory committees. Giralt: AMGEN: Membership on an entity's Board of Directors or advisory committees; BMS: Membership on an entity's Board of Directors or advisory committees; SANOFI: Membership on an entity's Board of Directors or advisory committees; PFIZER: Membership on an entity's Board of Directors or advisory committees; JENSENN: Membership on an entity's Board of Directors or advisory committees; GSK: Membership on an entity's Board of Directors or advisory committees; JAZZ: Membership on an entity's Board of Directors or advisory committees; CELGENE: Membership on an entity's Board of Directors or advisory committees; Actinnum: Membership on an entity's Board of Directors or advisory committees. Salles: Janssen: Consultancy; Novartis: Consultancy; Epizyme: Consultancy, Honoraria; Miltneiy: Consultancy; Regeneron: Consultancy, Honoraria; Incyte: Consultancy; Ipsen: Consultancy; Kite/Gilead: Consultancy; Morphosys: Consultancy, Honoraria; Velosbio: Consultancy; Takeda: Consultancy; Loxo: Consultancy; Genentech/Roche: Consultancy; Rapt: Consultancy; Genmab: Consultancy; Allogene: Consultancy; Debiopharm: Consultancy; BMS/Celgene: Consultancy; Beigene: Consultancy; Abbvie: Consultancy, Honoraria; Bayer: Honoraria. Sauter: Bristol-Myers Squibb: Research Funding; GSK: Consultancy; Genmab: Consultancy; Precision Biosciences: Consultancy; Kite/Gilead: Consultancy; Celgene: Consultancy, Research Funding; Gamida Cell: Consultancy; Novartis: Consultancy; Spectrum Pharmaceuticals: Consultancy; Juno Therapeutics: Consultancy, Research Funding; Sanofi-Genzyme: Consultancy, Research Funding. Scordo: i3 Health: Other: Speaker; Kite - A Gilead Company: Membership on an entity's Board of Directors or advisory committees; Angiocrine Bioscience: Consultancy, Research Funding; Omeros Corporation: Consultancy; McKinsey & Company: Consultancy. Shah: Amgen: Research Funding; Janssen Pharmaceutica: Research Funding. van den Brink: Seres: Other: Honorarium, Intellectual Property Rights, Research Fundingand Stock Options; Ceramedix: Other: has consulted, received honorarium from or participated in advisory boards ; Merck & Co, Inc: Honoraria; WindMILTherapeutics: Honoraria; MagentaTherapeutics: Honoraria; Da Volterra: Other: has consulted, received honorarium from or participated in advisory boards; Pluto Therapeutics: Current holder of stock options in a privately-held company, Other: has consulted, received honorarium from or participated in advisory boards ; GlaskoSmithKline: Other: has consulted, received honorarium from or participated in advisory boards; Forty-Seven, Inc.: Honoraria; Lygenesis: Other: has consulted, received honorarium from or participated in advisory boards ; Rheos: Honoraria; Pharmacyclics: Other; Kite Pharmaceuticals: Other; Frazier Healthcare Partners: Honoraria; Priothera: Research Funding; Wolters Kluwer: Patents & Royalties; Juno Therapeutics: Other; DKMS (nonprofit): Other; Notch Therapeutics: Honoraria; Nektar Therapeutics: Honoraria; Synthekine (Spouse): Other: has consulted, received honorarium from or participated in advisory boards; Novartis (Spouse): Other: has consulted, received honorarium from or participated in advisory boards; Jazz Pharmaceuticals: Honoraria; Therakos: Honoraria; Amgen: Honoraria. Perales: Nektar Therapeutics: Honoraria, Other; MorphoSys: Honoraria; Miltenyi Biotec: Honoraria, Other; Merck: Honoraria; Medigene: Honoraria; Kite/Gilead: Honoraria, Other; Karyopharm: Honoraria; Incyte: Honoraria, Other; Equilium: Honoraria; Cidara: Honoraria; Celgene: Honoraria; Bristol-Myers Squibb: Honoraria; NexImmune: Honoraria; Novartis: Honoraria, Other; Omeros: Honoraria; Sellas Life Sciences: Honoraria; Servier: Honoraria; Takeda: Honoraria. Palomba: Kite Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees; Pharmacyclics: Membership on an entity's Board of Directors or advisory committees.

Introduction: Cellular immunotherapy with CD19-targeted chimeric antigen receptor (CAR) T cells has provided new therapeutic options for patients with high-risk hematologic malignancies. Following this therapy, patients may experience disease relapse or CAR-mediated toxicity due to cytokine release syndrome (CRS) or immune effector cell-associated neurotoxicity syndrome (ICANS). Recent studies have confirmed that the intestinal microbiome can modulate the anti-tumor immune response to chemotherapy, immune checkpoint blockade, graft-versus-host disease after allogeneic hematopoietic cell transplantation, and adoptive cellular therapy. The contribution of the intestinal microbiome on the function of CAR T cells in vivo both with respect to their anti-tumor function and their propensity to induce toxicities is not known. Hence, in a multi-center study we analyzed the association between clinical outcomes and (1) antibiotic exposure prior to CAR T cell infusion and (2) the composition and diversity of the fecal microbiome. Methods and Results: We retrospectively collected clinical data and antibiotic exposures from patients with acute lymphoblastic leukemia (ALL, n=91) and non-Hodgkin lymphoma (NHL, n=137) treated with investigational or commercial CD19 CAR T cells at Memorial Sloan Kettering Cancer Center (MSK) and the University of Pennsylvania (Penn). We considered any antibiotic exposure between day -30 and the day of CAR T cell infusion. We focused our analysis on anaerobe-targeting antibiotics used in the setting of neutropenic fever: piperacillin-tazobactam, imipenem-cilastatin, and meropenem (here referred to as "P-I-M"). We found that forty-seven (20.6%) of 228 patients were exposed to P-I-M in the four weeks before CAR T cell infusion. Patient characteristics at the time of CAR T cell infusion were similar between the P-I-M-exposed and not-exposed groups, although a worse performance status was observed in patients with NHL treated with P-I-M. We found that overall survival (OS) was significantly decreased following CAR T cell infusion in patients exposed to P-I-M (Fig 1A; OS HR, 2.58; 95% CI, 1.68 - 3.98; p= We also prospectively collected baseline fecal samples prior to cell infusion from CD19 CAR T cells recipients (n=48) at MSK and Penn. Samples were submitted for 16S RNA sequencing of the V4-V5 region on the Illumina MiSeq platform and the amplicon sequence variants (ASVs) were annotated according to the NCBI 16S database using BLAST. In comparison to healthy controls (n=30), we found that alpha-diversity was significantly lower in fecal samples from CAR T cell patients (p= 0.0023, Fig 1B) and the composition of fecal samples was significantly different (p= Conclusion: Our results suggest that exposure to antibiotics, in particular P-I-M, in the four weeks before therapy was associated with worse survival. Profiling of the baseline fecal microbiome samples by 16S revealed that CD19 CAR T cell patients presented with evidence of an altered fecal microbiome as measured by lower alpha-diversity and a composition that is distinct from that of healthy controls. Finally, we identified bacterial taxa that were associated with Day 100 CR and CAR-mediated toxicity. Our findings indicate that the intestinal microbiome can affect the efficacy of CD19 CAR T cell therapy and provides a rationale to target the intestinal microbiome to improve clinical outcomes of patients treated with cellular therapies. Figure 1 Figure 1. Disclosures Smith: Janssen: Consultancy, Honoraria. Gomes: Xbiome: Current Employment. Schluter: Postbiotics Plus LLC: Other: cofounder. Park: Kura Oncology: Consultancy; BMS: Consultancy; Servier: Consultancy; Autolus: Consultancy; Curocel: Consultancy; Artiva: Consultancy; Kite Pharma: Consultancy; Amgen: Consultancy; Novartis: Consultancy; Affyimmune: Consultancy; Intellia: Consultancy; Innate Pharma: Consultancy; Minerva: Consultancy; PrecisionBio: Consultancy. Palomba: Pharmacyclics: Membership on an entity's Board of Directors or advisory committees; Kite Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees. Jain: Targeted Healthcare Communications: Consultancy; Bristol Myers Squibb: Other: for advisory board participation; CareDx: Other: for advisory board participation; CTI Biopharma: Research Funding; Syneos Health: Research Funding. Pennisi: Gilead Sciences: Consultancy. Perales: Miltenyi Biotec: Honoraria, Other; Novartis: Honoraria, Other; Omeros: Honoraria; NexImmune: Honoraria; Bristol-Myers Squibb: Honoraria; Merck: Honoraria; Celgene: Honoraria; Takeda: Honoraria; Kite/Gilead: Honoraria, Other; Medigene: Honoraria; Nektar Therapeutics: Honoraria, Other; Cidara: Honoraria; Servier: Honoraria; Sellas Life Sciences: Honoraria; Karyopharm: Honoraria; MorphoSys: Honoraria; Equilium: Honoraria; Incyte: Honoraria, Other. Garfall: Amgen: Honoraria; CRISPR Therapeutics: Research Funding; GlaxoSmithKline: Honoraria; Janssen: Honoraria, Research Funding; Novartis: Research Funding; Tmunity: Research Funding. Landsburg: Triphase: Research Funding; Morphosys: Membership on an entity's Board of Directors or advisory committees; Karyopharm: Membership on an entity's Board of Directors or advisory committees, Other: DSMB member; Incyte: Membership on an entity's Board of Directors or advisory committees; ADCT: Membership on an entity's Board of Directors or advisory committees; Curis: Research Funding; Takeda: Research Funding. Gerson: Kite: Consultancy; Pharmacyclics: Consultancy; Abbvie: Consultancy; TG Therapeutics: Consultancy. Svoboda: Imbrium: Consultancy; Genmab: Consultancy; Astra Zeneca: Consultancy, Research Funding; Atara: Consultancy; BMS: Consultancy, Research Funding; Adaptive: Consultancy, Research Funding; Incyte: Research Funding; Merck: Research Funding; Pharmacyclics: Consultancy, Research Funding; Seattle Genetics: Consultancy, Research Funding; TG: Research Funding. Giralt: AMGEN: Membership on an entity's Board of Directors or advisory committees; PFIZER: Membership on an entity's Board of Directors or advisory committees; BMS: Membership on an entity's Board of Directors or advisory committees; SANOFI: Membership on an entity's Board of Directors or advisory committees; CELGENE: Membership on an entity's Board of Directors or advisory committees; JAZZ: Membership on an entity's Board of Directors or advisory committees; GSK: Membership on an entity's Board of Directors or advisory committees; JENSENN: Membership on an entity's Board of Directors or advisory committees; Actinnum: Membership on an entity's Board of Directors or advisory committees. Gill: Interius Biotherapeutics: Current holder of stock options in a privately-held company, Research Funding; Novartis: Other: licensed intellectual property, Research Funding; Carisma Therapeutics: Current holder of stock options in a privately-held company, Research Funding. Rivière: FloDesign Sonics: Other: Provision of Services; Centre for Commercialization of Cancer Immunotherapy: Other: Provision of Services; Fate Therapeutics: Other: Provision of Services, Patents & Royalties; The Georgia Tech Research Corporation (GTRC): Other: Provision of Services (uncompensated); Juno Therapeutics: Patents & Royalties. Porter: Kite/Gilead: Membership on an entity's Board of Directors or advisory committees; Wiley and Sons Publishing: Honoraria; Tmunity: Patents & Royalties; Novartis: Membership on an entity's Board of Directors or advisory committees, Patents & Royalties, Research Funding; Incyte: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees; ASH: Membership on an entity's Board of Directors or advisory committees; DeCart: Membership on an entity's Board of Directors or advisory committees; Genentech: Current equity holder in publicly-traded company, Ended employment in the past 24 months; American Society for Transplantation and Cellular Therapy: Honoraria; National Marrow Donor Program: Membership on an entity's Board of Directors or advisory committees. Schuster: Abbvie: Consultancy, Research Funding; Acerta Pharma: Consultancy; AstraZeneca: Consultancy; Adaptive Biotechnologies: Research Funding; BeiGene: Consultancy; Celgene: Consultancy, Honoraria, Research Funding; DTRM: Research Funding; Genetech: Consultancy, Research Funding; Roche: Consultancy, Research Funding; Incyte: Research Funding; Juno Theraputics: Consultancy, Research Funding; Loxo Oncology: Consultancy; Merck: Research Funding; Nordic Nanovector: Consultancy; Novartis: Consultancy, Honoraria, Patents & Royalties, Research Funding; Pharmaclcyclics: Research Funding; Tessa Theraputics: Consultancy; TG Theraputics: Research Funding. Sadelain: NHLBI Gene Therapy Resource Program: Other: Provision of Services (uncompensated); Fate Therapeutics: Other: Provision of Services (uncompensated), Patents & Royalties; Atara Biotherapeutics: Patents & Royalties; Ceramedix: Patents & Royalties; Mnemo Therapeutics: Patents & Royalties; Takeda Pharmaceuticals: Other: Provision of Services, Patents & Royalties; St. Jude Children's Research Hospital: Other: Provision of Services; Juno Therapeutics: Patents & Royalties; Minerva Biotechnologies: Patents & Royalties. Frey: Novartis: Research Funding; Kite Pharma: Consultancy; Sana Biotechnology: Consultancy; Syndax Pharmaceuticals: Consultancy. Brentjens: Gracell Biotechnologies, Inc: Consultancy, Ended employment in the past 24 months; BMS: Consultancy, Patents & Royalties, Research Funding; sanofi: Patents & Royalties; Caribou: Patents & Royalties. June: AC Immune, DeCART, BluesphereBio, Carisma, Cellares, Celldex, Cabaletta, Poseida, Verismo, Ziopharm: Consultancy; Novartis: Patents & Royalties; Tmunity, DeCART, BluesphereBio, Carisma, Cellares, Celldex, Cabaletta, Poseida, Verismo, Ziopharm: Current equity holder in publicly-traded company. Pamer: Diversigen: Other: Advisory board; Bristol Myers Squibb, Celgene, Seres Therapeutics, MedImmune, Novartis and Ferring Pharmaceuticals: Honoraria. Peled: DaVolterra: Consultancy; MaaT Pharma: Consultancy; CSL Behring: Consultancy; Seres Therapeutics: Research Funding. Ruella: BMS, BAYER, GSK: Consultancy; Novartis: Patents & Royalties; AbClon: Consultancy, Research Funding; Tmunity: Patents & Royalties; viTToria biotherapeutics: Research Funding. van den Brink: WindMILTherapeutics: Honoraria; Pluto Therapeutics: Current holder of stock options in a privately-held company, Other: has consulted, received honorarium from or participated in advisory boards ; Priothera: Research Funding; Forty-Seven, Inc.: Honoraria; MagentaTherapeutics: Honoraria; GlaskoSmithKline: Other: has consulted, received honorarium from or participated in advisory boards; Ceramedix: Other: has consulted, received honorarium from or participated in advisory boards ; Merck & Co, Inc: Honoraria; Synthekine (Spouse): Other: has consulted, received honorarium from or participated in advisory boards; Kite Pharmaceuticals: Other; Amgen: Honoraria; Frazier Healthcare Partners: Honoraria; Seres: Other: Honorarium, Intellectual Property Rights, Research Fundingand Stock Options; Rheos: Honoraria; Therakos: Honoraria; Jazz Pharmaceuticals: Honoraria; Notch Therapeutics: Honoraria; Nektar Therapeutics: Honoraria; Wolters Kluwer: Patents & Royalties; Juno Therapeutics: Other; DKMS (nonprofit): Other; Pharmacyclics: Other; Da Volterra: Other: has consulted, received honorarium from or participated in advisory boards; Novartis (Spouse): Other: has consulted, received honorarium from or participated in advisory boards; Lygenesis: Other: has consulted, received honorarium from or participated in advisory boards .

Purpose/Objective(s) Chimeric antigen receptor T-cell therapies (CART) have revolutionized the treatment of aggressive B-cell lymphomas. Bridging radiotherapy (BRT) may serve two roles including cytoreduction and potential immune augmentation but has not been prospectively studied. Preclinical data suggests maximal tumor sensitization occurs roughly 4 days after irradiation, but the safety of administering RT just prior to CART is unknown. Materials/Methods This is a single arm, Phase I trial designed to describe the feasibility and safety of a standardized BRT regimen prior to standard of care, commercial, anti-CD19 CART. The BRT approach will be a novel split-course program (SC-BRT) delivered in 2 phases following apheresis to exploit BRT's dual roles. Phase I will deliver 3 Gy x 9 fractions using ISRT focally to areas requiring cytoreduction/palliation prior to conditioning chemotherapy. Later, following conditioning chemotherapy, and immediately prior to CART-T cell infusion, Phase II will deliver 3 Gy x 1 comprehensively to all sites of PET avid disease. The larger field, low-dose RT is principally to condition tumor cells to CART-mediated death. Eligible patients will have an aggressive B-cell lymphoma, be planned for any commercial CART product, and not be expected to receive any form of systemic bridging therapy. The primary aim is the safety of SC-BRT at day +30 post CART and will be structured using 3+3 rules with the possibility of an expansion cohort. Secondary aims include feasibility of using ISRT principles for comprehensive BRT and several efficacy outcomes. Exploratory outcomes include tissue and blood correlatives. Tumor biopsies will be obtained pre-BRT, post BRT Phase I and day +7 after CART, enabling mechanistic investigation of immune augmentation. Results In total, we intend to enroll 23-26 patients on this protocol with 2 years of post-treatment follow-up. The protocol is currently under IRB review and we would present the detailed design and early results at the conference. Conclusion To our knowledge, this is the first prospective study of BRT administered systematically with a cellular therapy. This study may serve as the clinical foundation for a novel, expanded role for RT in the treatment of B-cell lymphomas. Furthermore, the correlative program aims to expand our understanding of the impact of both RT and RT+CART on tumor signaling and the lymphoma microenvironment.

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

Background: Mantle cell lymphoma (MCL) is an aggressive subtype of B-cell non-Hodgkin lymphoma (NHL). Most patients with MCL relapse after first-line immunochemotherapy, with poor responses to salvage therapy. Chimeric antigen receptor (CAR) T cell therapy has shown clinical efficacy in patients with relapsed/refractory (R/R) NHL. We report the results of the dose-finding and dose-expansion parts of the ongoing phase 1 TRANSCEND NHL 001 study (NCT02631044) in patients with R/R MCL (MCL cohort) who received lisocabtagene maraleucel (liso-cel), an investigational, CD19-directed, defined composition, 4-1BB CAR T cell product administered at equal target doses of CD8+ and CD4+ CAR+ T cells. Methods: Eligible patients had confirmed MCL (cyclin D1 expression, t[11;14]) with R/R disease after ≥1 prior line of therapy. After lymphodepleting chemotherapy, patients received liso-cel infusion at 1 of 2 dose levels (DLs): DL1 (50 × 106 CAR+ T cells) or DL2 (100 × 106 CAR+ T cells). Bridging therapy was allowed between leukapheresis and initiation of lymphodepleting chemotherapy. Primary endpoints were safety and objective response rate (ORR). Secondary endpoints included complete response (CR) rate, duration of response, progression-free survival, overall survival, and pharmacokinetics (PK). Results: At data cutoff, 41 patients had undergone leukapheresis and 32 had received liso-cel (DL1, n = 6; DL2, n = 26). Among the 32 patients who received liso-cel, the median (range) age was 67 (36‒80) years and 27 patients (84%) were male. Twelve patients (37.5%) had blastoid morphology, 23 (72%) had documented Ki67 ≥30%, 7 (22%) had a TP53 mutation, and 11 (34%) had a complex karyotype. Patients had a median (range) sum of the product of perpendicular diameters before lymphodepleting chemotherapy of 28.7 (0-209.6) cm2 and median lactate dehydrogenase of 251.5 (117-811) U/L. Patients had received a median (range) of 3 (1-7) prior systemic therapies, and most (72%) were refractory to their last prior therapy. Of 28 patients (87.5%) who had received a prior Bruton tyrosine kinase inhibitor, 11 (34%) were refractory to the therapy. Seventeen patients (53%) received bridging therapy. Eighteen patients (56%) had serious treatment-emergent adverse events (TEAEs), and 27 (84%) had grade ≥3 TEAEs, primarily neutropenia (41%), anemia (34%), and thrombocytopenia (31%). Grade ≥3 thrombocytopenia was more frequent at DL2 (n = 9/26 [35%]) than at DL1 (n = 1/6 [17%]). Prolonged grade ≥3 cytopenias (present at study Day 29) occurred in 11 patients (34%). Sixteen patients (50%; DL1, n = 2/6 [33%]; DL2, n = 14/26 [54%]) had cytokine release syndrome (CRS), including 1 grade 4 event at DL2. There were no grade 3 or 5 CRS events. Median (range) time to CRS onset and resolution was 6 (2‒10) days and 4 (2‒9) days, respectively. Nine patients (28%) had neurological events (NEs), all at DL2, including 3 grade 3 NEs. No grade 4 or 5 NEs were reported. Median (range) time to NE onset and resolution was 8 (2‒25) days and 3 (1‒51) days, respectively. Ten patients (31%) received tocilizumab and/or corticosteroids for treatment of CRS and/or NEs. Grade 5 TEAEs occurred in 2 patients (at DL2): one patient with high tumor burden had tumor lysis syndrome and 1 patient had cryptococcal meningoencephalitis. DL2 was selected for dose expansion. Of 32 patients, 27 responded to liso-cel (ORR, 84%: DL1, n = 4/6 [67%]; DL2, n = 23/26 [88%]), and 19 (59%) achieved a CR (DL1, n = 2/6 [33%]; DL2, n = 17/26 [65%]). Among the 12 patients with blastoid morphology, 9 patients had a response (ORR, 75%), including 7 (58%) who achieved a CR. Overall, the median (range) time to first CR was 1 (1-6) month. At data cutoff, 20 (74%) of 27 responders were censored with an ongoing response or had completed the study. Median (range) follow-up duration was 10.9 (1.2-24.8) months for DL1 and 3.1 (0.4-23.0) months for DL2. Preliminary PK analysis indicated that median maximum expansion was higher among patients at DL2 than at DL1. Conclusions: In this phase 1 study of patients with R/R MCL, treatment with liso-cel was associated with a low incidence of grade ≥3 CRS and NEs, late onset of CRS/NEs, and promising clinical activity. Dose confirmation is ongoing at DL2 in the MCL cohort. Disclosures Palomba: Pharmacyclics: Honoraria; Juno: Honoraria; Celgene: Honoraria; Merck: Honoraria; Novartis: Honoraria; Regeneron: Research Funding; Juno: Research Funding; Genentech: Research Funding. Gordon:Zylem Biosciences: Patents & Royalties: Patents, No Royalties. Siddiqi:Juno: Membership on an entity's Board of Directors or advisory committees; Kite: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; BeiGene: Other: DMC member; Juno Therapeutics, Pharmacyclics LLC, an AbbVie Company, AstraZeneca, Celgene, Kite Pharma, and BeiGene: Consultancy; Pharmacyclics LLC, an AbbVie Company, Seattle Genetics, Janssen, and AstraZeneca: Speakers Bureau; Pharmacyclics LLC, an AbbVie Company, Juno Therapeutics, KITE Pharma, AstraZeneca, TG Therapeutics, Celgene, Oncternal, and BeiGene: Research Funding; AstraZeneca: Other: Travel/accommodations/expenses; Astrazenca: Membership on an entity's Board of Directors or advisory committees; PCYC: Membership on an entity's Board of Directors or advisory committees. Abramson:Celgene: Honoraria, Other: Scientific Advisory Board; Juno Therapeutics: Other: Scientific Advisory Board; AbbVie: Other: Scientific Advisory Board; EMD Serono: Other: Scientific Advisory Board; Genentech/Roche: Other: Scientific Advisory Board; Janssen: Other: Scientific Advisory Board; Karyopharm: Other: Scientific Advisory Board; Gilead: Other: Scientific Advisory Board; Verastem: Other: Scientific Advisory Board; Bayer: Other: Scientific Advisory Board; Merck: Other; KIte Pharma: Other; Novartis: Other; Amgen: Other; Seattle Genetics: Other; Allogene: Other; Morphosys: Other; C4 Therapeutics: Other; BeiGene: Other; AstraZeneca: Honoraria; Incyte: Honoraria. Kamdar:Seattle Genetics: Speakers Bureau; Karyopharm: Consultancy; BMS: Consultancy; Abbvie: Consultancy; AstraZeneca: Consultancy; Pharmacyclics: Consultancy. Lunning:Acrotech: Consultancy; ADC Therapeutics: Consultancy; Bristol Meyers Squibb: Consultancy, Honoraria, Research Funding; Curis: Research Funding; Gilead: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; Karyopharm: Consultancy, Honoraria; Kite: Consultancy, Honoraria; Novartis: Consultancy, Honoraria; TG Therapeutics: Research Funding; Verastem: Consultancy, Honoraria; AstraZeneca: Consultancy, Honoraria; Legend: Consultancy; Beigene: Consultancy, Honoraria; Aeratech: Consultancy, Honoraria. Maloney:Kite, a Gilead Company: Consultancy, Honoraria, Research Funding; MorphoSys: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; Pharmacyclics: Consultancy, Honoraria; Novartis: Consultancy, Honoraria; Gilead Sciences: Consultancy, Honoraria; A2 Biotherapeutics: Consultancy, Current equity holder in publicly-traded company, Honoraria; Juno Therapeutics: Consultancy, Honoraria, Patents & Royalties: Patents are pending, but not issued, licensed, no royalties, no licensees., Research Funding; Bioline Rx: Consultancy, Honoraria; Genentech: Consultancy, Honoraria; Celgene: Consultancy, Honoraria, Research Funding. Andreadis:Genentech: Other: Spouse Employee (salary and stock); Novartis: Research Funding; Celgene/Juno: Research Funding; Amgen: Research Funding; Merck: Research Funding; Gilead/Kite: Other: Advisor; Jazz Pharmaceuticals: Other: Advisor; Astellas: Other: Advisor; Seattle Genetics: Other: Advisor; Karyopharm: Other: Advisor; Incyte: Other. Arnason:Regeneron: Consultancy; Juno: Consultancy. Ghosh:Forty Seven Inc: Consultancy, Other: Research Bureau, Research Funding; Genmab: Consultancy, Speakers Bureau; AbbVie: Speakers Bureau; Karyopharm: Consultancy; Juno/Celgene/Bristol-Myers Squibb: Consultancy, Research Funding; Kite/Gilead: Consultancy, Speakers Bureau; AstraZeneca: Speakers Bureau; Roche/Genentech: Research Funding; SGN: Consultancy, Research Funding, Speakers Bureau; TG Therapeutics: Consultancy, Research Funding; Celgene/Bristol-Myers Squibb: Speakers Bureau; Janssen: Consultancy, Research Funding, Speakers Bureau; Pharmacyclics LLC, an AbbVie Company: Consultancy, Research Funding, Speakers Bureau. Mehta:Innate Pharmaceuticals: Research Funding; Kite/Gilead: Research Funding; Merck: Research Funding; Gelgene/BMS: Research Funding; Oncotartis: Research Funding; TG Therapeutics: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Seattle Genetics: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Juno Parmaceuticals/BMS: Research Funding; fortyseven Inc/Gilead: Research Funding; Takeda: Research Funding; Roche-Genentech: Research Funding; Incyte: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Affimed: Research Funding. Farazi:Juno Therapeutics, a Bristol-Myers Squibb Company: Current Employment; Bristol-Myers Squibb: Current equity holder in publicly-traded company. Garcia:Juno Therapeutics, a Bristol-Myers Squibb Company: Current Employment; Bristol-Myers Squibb Company: Current equity holder in publicly-traded company. Dehner:Juno Therapeutics, a Bristol-Myers Squibb Company: Current Employment; Bristol-Myers Squibb: Current equity holder in publicly-traded company. Ogasawara:Bristol-Myers Squibb: Current Employment; Bristol-Myers Squibb: Current equity holder in publicly-traded company. Gao:Bristol-Myers Squibb: Current equity holder in publicly-traded company; Bristol-Myers Squibb: Current Employment. Wang:Juno: Consultancy, Research Funding; Acerta Pharma: Research Funding; Loxo Oncology: Consultancy, Research Funding; AstraZeneca: Consultancy, Honoraria, Other: Travel, accommodation, expenses, Research Funding; InnoCare: Consultancy; Kite Pharma: Consultancy, Other: Travel, accommodation, expenses, Research Funding; Pharmacyclics: Consultancy, Honoraria, Other: Travel, accommodation, expenses, Research Funding; Janssen: Consultancy, Honoraria, Other: Travel, accommodation, expenses, Research Funding; MoreHealth: Consultancy; Lu Daopei Medical Group: Honoraria; Beijing Medical Award Foundation: Honoraria; OncLive: Honoraria; Molecular Templates: Research Funding; Verastem: Research Funding; Dava Oncology: Honoraria; Guidepoint Global: Consultancy; Pulse Biosciences: Consultancy; Celgene: Consultancy, Other: Travel, accommodation, expenses, Research Funding; Oncternal: Consultancy, Research Funding; Nobel Insights: Consultancy; OMI: Honoraria, Other: Travel, accommodation, expenses; Targeted Oncology: Honoraria; BioInvent: Research Funding; VelosBio: Research Funding.

Introduction: The standard approach for relapsed or refractory (RR) classical Hodgkin lymphoma (cHL) following front-line treatment failure is second line therapy (SLT) aimed to achieve complete response (CR), followed by consolidation with high dose therapy and autologous hematopoietic cell transplantation (HDT/AHCT). No one standard SLT exists and options include regimens containing platinum, gemcitabine, and more recently brentuximab vedotin (BV). Complete response rates associated with these regimens range from 50-70%. Due to the increasing use of BV in the front-line setting, development of SLT regimens that are both highly effective and BV-sparing are needed. Programmed death-1 (PD-1) inhibitors are highly active in RR cHL and have the potential to enhance the efficacy of standard chemotherapy. Here we report the results of our phase II study evaluating a novel anti-PD-1-based regimen, pembrolizumab plus gemcitabine, vinorelbine, and liposomal doxorubicin (pembrolizumab-GVD), as SLT for RR cHL. Methods: Transplant eligible patients (pts) with RR cHL following failure of 1-line of therapy were eligible. Treatment consisted of 2 to 4 cycles of pembrolizumab (200mg IV, day 1), gemcitabine (1000mg/m2 IV, days 1 and 8), vinorelbine (20mg/m2 IV, days 1 and 8) and liposomal doxorubicin (15mg/m2, days 1 and 8), given on 21-day cycles. Pts who achieved CR by PET (Deauville ≤3) after 2 or 4 cycles proceeded to HDT/AHCT. HDT/AHCT was carried out according to institutional standards and BV maintenance was allowed following HDT/AHCT. The primary endpoint was CR rate after 2 or 4 cycles of pembrolizumab-GVD. Enrollment occurred according to a Simon 2-stage design with sample size based upon a projected CR rate of 70%. In stage 1, 23 pts enrolled and 12 or more CRs were required to proceed to stage II; in stage II, an additional 16 pts enrolled. Out of a total of 39 pts, 24 CRs were required to declare this regimen promising. Results: Among 39 patients enrolled, 37 are evaluable for toxicity (2 pts have not yet started treatment) and 34 are evaluable for response (4 pts too early, 1 pt found to have composite lymphoma after enrollment). Of 37 treated pts, median age is 36 (range 21-71), 43% are male, 23 (62%) had advanced stage disease, and 15 (41%) had primary refractory disease. With regard to RR cHL risk factors (B-symptoms, extranodal disease, and relapse/refractory disease within 1 year of initial treatment), 4(11%) had no risk factors (RFs), 21 (57%) had 1 RF, 9 (24%) had 2 RFs, and 3 (8%) had all 3 RFs. Treatment was well tolerated with most adverse events being grade 1 or 2 (see figure 1). Grade 3 AEs included rash (n=1), elevated AST/ALT (n=3), oral mucositis (n=2), and neutropenia (n=3). Figure 2 shows the outcome for all 37 treated pts. Among 34 evaluable pts, 31 (91%) achieved CR after 2 cycles and 3 achieved partial response. An additional 1 pt achieved CR after 4 cycles of pembrolizumab-GVD, therefore in total, 32 of 34 (94%) achieved CR following pembrolizumab-GVD. 4 pts with CR after 2 cycles received an additional 2 cycles of pembrolizumab-GVD in order to delay HDT/AHCT during the height of the COVID-19 pandemic (n=3) or due to refusing HDT/ASCT (n=1). To date, 32 have undergone HDT/AHCT following 2 (n=27) or 4 (n=5) cycles of treatment. 1 pt is awaiting HDT/AHCT; 1 pt refused HDT/ASCT and received pembrolizumab maintenance instead. 2 pts received involved site radiation therapy to initial area of relapsed disease prior to planned HDT/AHCT and 10 pts received post-HDT/ASCT maintenance with BV. Median follow-up post-HDT/AHCT is 9 mos (range 0.03-20.9 mos) and all pts remain in remission to date. Conclusion: Second-line therapy with pembrolizumab-GVD is a highly effective and well-tolerated regimen that can efficiently bridge pts with RR cHL to HDT/AHCT. Updated results including all 39 enrolled pts will be presented at the meeting. Given the high CR rate observed with pembrolizumab-GVD, an expansion cohort evaluating 8 cycles of pembrolizumab maintenance (instead of HDT/AHCT) for patients who achieve CR after 4 cycles of pembrolizumab-GVD is planned. Disclosures Moskowitz: Merck: Consultancy; Incyte: Research Funding; Miragen Therapeutics: Consultancy; Seattle Genetics: Consultancy; Imbrium Therapeutics, L.P.: Consultancy; Merck: Research Funding; Seattle Genetics: Research Funding; Bristol-Myers Squibb: Research Funding. Shah:Amgen Inc.: Research Funding; Janssen: Research Funding. Kumar:AbbVie: Research Funding; Celgene: Honoraria, Other: Honoraria for Advisory Board; Seattle Genetics: Research Funding; Astra Zeneca: Honoraria, Other: Honoraria for Advisory Board; Celgene: Research Funding; Kite Pharmaceuticals: Honoraria, Other: Honoraria for Advisory Board; Adaptive Biotechnologies,: Research Funding; Pharmacyclics: Research Funding. Lahoud:MorphoSys: Other: Advisory Board. Batlevi:Life Sci, GLG, Juno/Celgene, Seattle Genetics, Kite: Consultancy; Janssen, Novartis, Epizyme, Xynomics, Bayer, Autolus, Roche/Genentech: Research Funding. Hamlin:J&J Pharmaceuticals: Research Funding; Portola: Research Funding; Incyte: Research Funding; Portola Pharmaceutics: Consultancy; Juno Therapeutics: Consultancy; Karyopharm: Consultancy; Celgene: Consultancy; Molecular Templates: Research Funding. Straus:Karyopharm Therapeutics: Membership on an entity's Board of Directors or advisory committees; Imedex, Inc.: Speakers Bureau; Targeted Oncology: Consultancy, Speakers Bureau; NY Lymphoma Rounds: Consultancy; Takeda Pharmaceuticals: Research Funding, Speakers Bureau; OncLive: Speakers Bureau; Elsevier: Membership on an entity's Board of Directors or advisory committees, Other: CME writer; ASH: Other: Conference in December 2019 on HL to other physicians during ASH; Seattle Genetics: Consultancy, Membership on an entity's Board of Directors or advisory committees. Horwitz:ASTEX: Consultancy; Verastem: Consultancy, Research Funding; Myeloid Therapeutics: Consultancy; Miragen: Consultancy; Kura Oncology: Consultancy; Janssen: Consultancy; GlaxoSmithKline: Consultancy; Daiichi Sankyo: Research Funding; C4 Therapeutics: Consultancy; Affirmed: Consultancy; Vividion Therapeutics: Consultancy; Beigene: Consultancy; Portola: Consultancy, Research Funding; Mundipharma: Consultancy; Innate Pharma: Consultancy; Corvus: Consultancy; Trillium: Consultancy, Research Funding; Seattle Genetics: Consultancy, Research Funding; Millenium/Takeda: Consultancy, Research Funding; Kyowa Hakka Kirin: Consultancy, Research Funding; Infinity/Verastem: Research Funding; Forty Seven: Consultancy, Research Funding; Celgene: Consultancy, Research Funding; Aileron: Consultancy, Research Funding; ADCT Therapeutics: Consultancy, Research Funding. Falchi:Genmab: Research Funding; Roche: Research Funding. Joffe:Epizyme: Membership on an entity's Board of Directors or advisory committees; AstraZeneca: Membership on an entity's Board of Directors or advisory committees. Noy:Pharmacyclics: Research Funding; Pharmacyclics: Consultancy; Janssen: Consultancy; Rafael Pharma: Research Funding; NIH: Research Funding; Morphosys: Consultancy; Medscape: Consultancy; Targeted Oncology: Consultancy. Matasar:Teva: Consultancy; Genentech, Inc.: Consultancy, Honoraria, Research Funding; Merck: Consultancy; Bayer: Consultancy, Honoraria, Research Funding; Juno Therapeutics: Consultancy; F. Hoffmann-La Roche Ltd: Consultancy, Honoraria, Research Funding; GlaxoSmithKline: Honoraria, Research Funding; IGM Biosciences: Research Funding; Janssen: Honoraria, Research Funding; Pharmacyclics: Honoraria, Research Funding; Immunovaccine Technologies: Honoraria, Research Funding; Rocket Medical: Consultancy, Research Funding; Takeda: Consultancy, Honoraria; Daiichi Sankyo: Consultancy; Seattle Genetics: Consultancy, Honoraria, Research Funding. Vardhana:Other: Other: SAV has received honoraria from Agios Pharmaceuticals and Rheos Pharmaceuticals, is an advisor for Immunai and has consulted for ADC Therapeutics. von Keudell:Genentech: Research Funding; Bayer: Research Funding; Pharmacyclics: Research Funding. Zelenetz:Novartis: Consultancy; Janssen: Consultancy; Celgene: Consultancy; Amgen: Consultancy; Adaptive Biotechnology: Consultancy; BeiGene: Membership on an entity's Board of Directors or advisory committees; Roche: Research Funding; Gilead: Research Funding; Genentech/Roche: Consultancy; Gilead: Consultancy; Sandoz: Research Funding; Celgene: Research Funding; MEI Pharma: Research Funding; MorphoSys: Research Funding. OffLabel Disclosure: Pembrolizumab as second-line therapy for Hodgkin lymphoma

Introduction: Patient-derived data can increase breadth of knowledge in rare cancers like Waldenström's Macroglobulinemia (WM), including patient-reported outcomes (PROs). WhiMSICAL (Waldenström's Macroglobulinemia Study Involving CArt-wheeL) is the only global registry capturing patient-derived data for hypothesis generation in WM. Rapidly adaptable, it has been amended to capture Coronavirus Disease 2019 (COVID-19) data. Methods: An ethically-approved WM-specific extension to www.cart-wheel.org, an online rare cancer database for patient-derived data, was developed by clinician and patient investigators. Participants complete consent, and enter symptom, pathology, treatment and PRO (EORTC-QLQ-C30, Impact of Event Scale-6) data online. Recruitment strategies utilizing social media tools are driven by the International Waldenström's Macroglobulinemia Foundation investigators. A validation study compared patient-entered data with data-manager-entered data in the Australia & New Zealand Lymphoma & Related Diseases Registry (LaRDR). To capture the impact of COVID-19, additional questions on COVID-19 testing, symptoms and therapy, as well as effect on WM management in those without COVID-19, were included in April 2020. Results: 453 patients from 19 countries have been recruited, predominantly from USA (46%) and Australia (25%), with male predominance (62%). At diagnosis, median age was 61 (range 24-83), median IgM 2620 mg/dL (IQR 1320-3850 mg/dL, n=175) and median hemoglobin 11.4 g/dL (IQR 9.5-12.9 g/dL, n=181). Of the 365 (81%) patients providing symptoms at diagnosis, fatigue/muscle weakness was most common (46%) and 30% were asymptomatic. Using the Impact of Event Scale for symptoms of post-traumatic stress disorder (PTSD) resulting from a cancer diagnosis, the mean score among 387 patients was 5.9 (no stress=0, maximal stress=24), with 39/387 (10%) scoring >13 (PPV 94% for PTSD, Thoresen et al, 2010). This proportion did not increase for scores entered after March 1st, 2020 - 12/123 (10%) - when the COVID-19 pandemic became a global crisis. Marked treatment variation was noted, with 47 different first-line therapeutic combinations documented by 302 patients. Median time from diagnosis to first treatment for USA patients was 48 days (IQR 13-404, n=133) vs Rest of World (ROW) 176 days (IQR 20-885, n=163), (p=0.01). At median follow up of 38.5 months, first-line bendamustine rituximab had superior time to next treatment outcomes compared to other first-line therapies: rituximab monotherapy, dexamethasone-rituximab-cyclophosphamide and Bruton tyrosine kinase inhibitors (BTKi, Figure 1). 51 patients exposed to BTKi had a trend to higher EORTC QLQ-C30 global scales, mean 78.6±17.7, compared to 148 not exposed: mean 73.4±22.6 (p=0.13), despite higher treatment burden: median lines of treatment 2 (IQR 1-4) and 1 (IQR 1-2), respectively (p83%. 188/453 (42%) participants responded to the impact of COVID-19 questions; 75/188 (40%) had reduced face-to-face reviews, 4/188 (2%) had delays to starting treatment and 57/188 (30%) documented no impact. Of the 188 respondents, 23 (12%) had COVID-19 testing, with two returning a positive result and neither requiring hospitalization. Conclusion: WhiMSICAL is a robust, rapidly adaptable, global patient-derived data platform, providing insight into patient symptoms, real-world therapies and PROs. It is a scientific, ethically-approved portal for contributing the patients' voice in this rare lymphoma. Disclosures Warden: Janssen Cilag: Other: Personal fees for photoshoot event. Opat:CSL Behring: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; F. Hoffmann-La Roche Ltd: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; AbbVie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Merck: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; AstraZenca: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; BeiGene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Gilead: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Epizyme: Research Funding. D'Sa:Sanofi: Honoraria; BeiGene: Honoraria, Research Funding; Janssen: Honoraria, Research Funding. Kersten:Takeda: Research Funding; Roche: Consultancy, Honoraria, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company), Research Funding; Kite/Gilead: Consultancy, Honoraria, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company); Celgene: Consultancy, Honoraria, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company), Research Funding; Miltenyi Biotech: Consultancy, Honoraria, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company); Janssen/Cilag: Consultancy, Honoraria, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company); BMS: Consultancy, Honoraria, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company); MSD: Consultancy, Honoraria, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company); Amgen: Consultancy, Honoraria, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company); Novartis: Consultancy, Honoraria, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company). Olszewski:Genentech, Inc.: Research Funding; Adaptive Biotechnologies: Research Funding; TG Therapeutics: Research Funding; Spectrum Pharmaceuticals: Research Funding. Harrington:Calithera Biosciences: Current equity holder in publicly-traded company; Bristol-Myers Squibb: Current equity holder in publicly-traded company; BeiGene: Current equity holder in publicly-traded company; Gilead: Current equity holder in publicly-traded company; Idera Pharmaceuticals: Current equity holder in publicly-traded company; AbbVie: Current equity holder in publicly-traded company. Trotman:Takeda: Research Funding; PCYC: Research Funding; F. Hoffmann-La Roche: Research Funding; Celgene: Research Funding; BeiGene: Research Funding.

7511 Background: G-len has promising activity and manageable toxicity in R/R FL (Morschhauser et al. 2019). We report the final analysis of an open-label, multicenter, Phase Ib/II trial (NCT02631577) that evaluated the immunomodulatory triplet G-atezo-len in pts with R/R FL. Methods: An initial 3+3 dose‐escalation to identify the Phase II len dose was followed by an expansion phase with G-atezo-len. Enrolled pts (aged ≥18 years) received induction with 6, 28-day cycles of G 1000 mg IV on Day [D] 1, 8, and 15 of Cycle [C] 1 and D1 of C2–6, atezo 840 mg IV on D1 and 15 of C2–6, and len 15/20 mg (dose escalation) or 20 mg (expansion) orally on D1–21 of C1–6. Responders received 24 months (mos) of maintenance with G 1000 mg D1 every 2 mos, atezo 840 mg D1–2 every mo, and len 10 mg D1–21 mos 1–12. The primary endpoint was complete response at end of induction by PET-CT assessed by Independent Review Committee (modified Lugano 2014 criteria; Morschhauser et al. ICML 2019). Exploratory endpoints described herein included progression-free survival (PFS), overall survival (OS), and duration of response (DOR). Adverse events (AEs) were also assessed. Results: At the final analysis (October 7, 2020), 38 pts had completed the trial. Median age was 62 years, 26% had a high-risk FLIPI score, 45% were refractory to their last line of therapy, and 37% had progression of disease within 24 mos of their first-line of therapy (POD24). Median treatment duration was 26 mos (range: 0.4‒30). The 36-mo PFS rate for the overall population (median observation time, 35.9 mos; range: 3‒47) was 64% (95% CI, 45‒79), OS was 85% (95% CI, 70‒93), and median DOR was 38 mos (95% CI, 35‒NE). 36-mo PFS rates for the following subgroups are provided in the table: double refractory (rituximab and an alkylator); with/without POD24; minimal residual disease (MRD) +/-. In total, 32 pts (84%) had a Grade 3/4 AE (majority hematologic), and 18 (47%) had a serious AE. Five pts (13%) during induction and six pts (16%) during maintenance had an AE that led to discontinuation of any drug. Two fatal AEs were reported (1 merkel carcinoma, 1 sarcomatoid carcinoma; both unrelated to any study drug). The most common atezo AEs of special interest were hyperthyroidism (13%), hypothyroidism (11%), increased ALT and AST (both 8%), increased lipase (8%), and hepatocellular injury (5%). Conclusions: G-atezo-len is efficacious in pts with R/R FL, with data from the final analysis suggesting a potential for improved outcomes versus the G-len doublet. AEs were consistent with the safety profile of the individual drugs. Clinical trial information: NCT02631577. [Table: see text]

As the survival of patients with mantle cell lymphoma (MCL) continues to improve, patients are increasingly being treated with multiple regimens. However, outcome after each line remains poorly characterized in the modern era. To address this knowledge gap, we retrospectively studied 404 consecutive MCL patients who were managed between 2000 and 2014 at Memorial Sloan Kettering Cancer Center. Histologic diagnosis was centrally confirmed, and patients were followed longitudinally from diagnosis throughout their disease course. Progression-free survival (PFS) and overall survival (OS) were determined by Kaplan–Meier method. The median OS and PFS after first-line treatment were 9.7 and 4.0 years, respectively. After second-line therapy, the median OS and PFS were 41.1 and 14.0 months, third line were 25.2 and 6.5 months, and fourth line were 14.4 and 5.0 months. In patients less than 65 years, stem cell transplant (SCT)-based frontline regimens were associated with improved PFS compared with non-SCT regimens (median PFS: 86.2 versus 40.0 months; P P = 0.06). Early treatment failure after first-line regimens was associated with worse OS (5.9 versus 2.5 years; P

CD19-specific chimeric antigen receptor (CAR) T cell therapy is a promising treatment for hematological malignancies however is associated with neurotoxicity. Axicabtagene ciloleucel is approved to treat adult patients with relapsed or refractory large B-cell lymphoma. Here we describe the neurological features and encephalogram (EEG) patterns of patients with refractory lymphoma treated with axicabtagene ciloleucel at Memorial Sloan Kettering Cancer Center (MSKCC). We retrospectively analyzed the neurological features and EEG patterns of the first six patients with refractory lymphoma treated at MSKCC with axicabtagine ciloleucel between February and April 2018. All six patients developed neurotoxicity, with both diffuse encephalopathy and focal neurological features.None of the patients had pre-existing neurological conditions. All patients received prophylatic levetiracetam and had a long-term video EEG performed. Two patients developed neurological findings concerning for focal status epilepticus. One patient had rhythmic right arm movements followed by weakness and the EEG showed left lateralized rhythmic delta activity (LRDA) with sharp waves and attenuation possibly reflecting a post-ictal state. The second patient had right facial and bilateral eye twitching concerning for focal motor status epilepticus. The EEG showed diffuse dysfunction - rhythmic delta activity and triphasic waves. Both patients had clinical improvement with addition of fosphenytoin. The remaining four patients had EEGs showing diffuse cerebral dysfunction. Neuroimaging in all patients was unrevealing for acute or significant structural pathology. Most patients had resolving neurologic symptoms; one patient had prolonged paraparesis. CONCLUSIONS: Axicabtagene ciloleucel can lead to transient diffuse and focal neurological findings of varying severity including focal status epilepticus. EEG is useful in characterizing cerebral dysfunction however is limited in detecting epileptic events. In patients who develop clinical status epilepticus escalation of AEDs may be warranted despite EEG not fulfilling status epilepticus criteria. Further study is needed to determine whether AED escalation can optimize patient outcomes.

Background Minimal residual disease (MRD) monitoring has been used to identify early molecular relapse and predict clinical relapse in mantle cell lymphoma (MCL). Few published data exist in MCL on the performance of next-generation sequencing–based assay of immunoglobulin gene rearrangements for MRD assessment. Patients and Methods In a prospective clinical trial (NCT01484093) with intensive induction chemotherapy and autologous stem-cell transplantation, posttreatment peripheral blood samples were collected from 16 MCL patients and analyzed with an earlier version of the Adaptive Biotechnologies MRD assay. Results Of the 7 patients whose disease remained in remission, the MRD test remained negative in 5 (71%). Of the 9 patients who experienced relapse, the MRD test was positive at least 3 months before relapse in 6 patients (67%) and positive at the time of relapse in 1 patient (11%). All patients with at least 2 positive MRD tests experienced relapse. Conclusion The next-generation sequencing–based MRD assay identified early molecular relapse, and we observed more sensitivity in the cellular (circulating leukocytes) versus acellular (plasma cell-free DNA) compartment. This observation may be due to availability of tumor target or a limitation of the assay.

Waldenström's macroglobulinemia (WM) is a B-cell non-Hodgkin's lymphoma (B-NHL) characterized by immunoglobulin M (IgM) monoclonal gammopathy and the medullary expansion of clonal lymphoplasmacytic cells. Neoplastic transformation has been partially attributed to hyperactive MYD88 signaling, secondary to the MYD88 L265P mutation, occurring in the majority of WM patients. Nevertheless, the presence of chronic active B-cell receptor (BCR) signaling, a feature of multiple IgM+ B-NHL, remains a subject of speculation in WM. Here, we interrogated the BCR signaling capacity of primary WM cells by utilizing multiparametric phosphoflow cytometry and found heightened basal phosphorylation of BCR-related signaling proteins, and augmented phosphoresponses on surface IgM (sIgM) crosslinking, compared with normal B cells. In support of those findings we observed high sIgM expression and loss of phosphatase activity in WM cells, which could both lead to signaling potentiation in clonal cells. Finally, led by the high-signaling heterogeneity among WM samples, we generated patient-specific phosphosignatures, which subclassified patients into a 'high' and a 'healthy-like' signaling group, with the second corresponding to patients with a more indolent clinical phenotype. These findings support the presence of chronic active BCR signaling in WM while providing a link between differential BCR signaling utilization and distinct clinical WM subgroups.

8037 Background: Currently approved CAR T cell therapies are generally administered as inpatient (inpt) treatment at university medical centers due to concerns about frequency, onset, severity, and management of AEs, including cytokine release syndrome (CRS) and neurologic events (NEs). We sought to characterize whether patients (pts) could be safely monitored in the outpatient (outpt) setting after receiving liso-cel, an investigational, CD19-directed CAR T cell product administered at equal target doses of CD8+ and CD4+ CAR+ T cells, across university and non-university sites in TRANSCEND NHL 001 (NCT02631044), OUTREACH (NCT03744676), and PILOT (NCT03483103). Methods: Eligible pts had R/R LBCL after systemic chemoimmunotherapy; moderately impaired organ function was allowed. For outpt infusion of liso-cel, pts were required to receive safety monitoring education, have a caregiver and stay within 1 h travel to site of care for 30 d post-treatment. All study sites had a multidisciplinary CAR T cell team and standard operating procedures for toxicity monitoring and management. Results: At data cutoff, 53 pts had received liso-cel on Study Day 1 and were monitored as outpts (university, n = 33; non-university, n = 20), including pts ≥65 y of age (n = 23) and with high tumor burden (SPD ≥50 cm2; n = 16). Any grade CRS and NEs were reported in 18 (34%) and 14 pts (26%), respectively. Severe CRS and/or NEs occurred in only 2 pts (4%) and were reversible. Median (range) time to onset of CRS and NEs was 5 (2–9) and 8.5 (3–22) d, respectively. Tocilizumab and/or corticosteroids for treatment of CRS and/or NEs were required in 8 pts (15%). Overall, 30 pts (57%) required hospitalization post-treatment, with a median (range) time to hospitalization post-treatment of 5.5 (2–22) d; 9 pts (17%) were hospitalized Study Day 4 or earlier. Two pts required ICU-level care. There were no grade 5 treatment-emergent AEs. Safety in pts monitored as outpts was comparable across types of sites. Overall response rate was 81% (95% CI, 68–91). Safety and efficacy were consistent with data from inpts across the 3 studies (N = 270). Conclusions: Pts with R/R LBCL were successfully treated with liso-cel and monitored for CAR T cell-related toxicity in the outpt setting across different types of sites. Incidences of severe CRS, NEs, and early hospitalization were low; 43% of pts did not require hospitalization. A larger dataset will be presented, including comparisons of outpts vs inpts and sites of care. Clinical trial information: NCT02631044 (TRANSCEND NHL 001), NCT03744676 (OUTREACH), NCT03483103 (PILOT) .

e20017 Background: FDG avidity above liver on interim PET (PET2) during frontline ABVD is considered a marker of impending treatment failure and an indication to switch to an intensified regimen. However, in clinical practice the utility of PET2 for treatment decisions is less clear. We describe outcomes of patients with positive PET2 who continued treatment with ABVD in the clinical setting. Methods: A retrospective study of all patients with newly diagnosed advanced-stage Hodgkin lymphoma treated with frontline ABVD at Memorial Sloan Kettering Cancer Center between 2008-2017. Eligibility criteria were set to correspond with the RATHL inclusion criteria (stage IIB - IV, or IIA bulky or ≥ 3 involved sites). We identified all PET2 reports indicating suspected residual uptake. All positive PET2 images were then reviewed by a single study radiologist. To increase reproducibility and avoid selection of borderline cases, we defined as PET2 positive only those cases with a lesion-to-liver (mean) SUV ratio ≥ 1.3. We also used a recently published stringent criterion of lesion-to-liver (max) ratio ≥ 1.4 (mPET2+). Progression-free and overall survival (PFS, OS) were calculated from the date of initial treatment until progression or death of any cause. Consolidative radiation was not considered a PFS event, and all progressions were verified by biopsy. Results: We identified 227 patients fitting RATHL inclusion criteria treated with ABVD. Median age was 34, with 25% (58) ≥ 45 years, 12% (26) had an IPS ≥ 4; 28% (64) stage II (5% II-X) and 38% (87) with extranodal involvement. 57 (25%) patients had a PET2 report indicating suspected residual lymphoma (PET2+), however, only 32 (14%) met the more stringent mPET2+ criterion. Most patients with PET2+ continued ABVD (84%, 48), and 9 switched to escBEACOPP (this subset of patients had substantially worse disease and are not the focus of this analysis). 21 (9%) patients received consolidative radiation. With a median follow-up of 47 months (42-54m), PET2+ patients who continued ABVD had a 3yPFS of 70% (58-85%, n = 48); mPET+ had a 3yPFS of 71% (55-92%, n = 24). Overall survival was excellent regardless of PET2 status (5yOS 97%). Conclusions: The outcome of PET2+ patients in this analysis was better than previously reported and the continuation of ABVD was appropriate for most patients. Use of a confirmatory biopsy is important for identifying true progressions. Patients with PET2+ had an excellent OS. Evaluation of the superiority of alternative regimens in PET2+ patients requires an ABVD comparator arm.

e20046 Background: Clinical studies of liso-cel show low incidences of severe CRS and NEs. Pts with high tumor burden and inflammation are at higher risk of CRS and NEs (Borrega, Hemasphere 2019). Here, we characterize the presenting symptoms, timing, and management of CRS and NEs in pts with R/R LBCL treated with liso-cel in TRANSCEND NHL 001 (NCT02631044). A deeper understanding of CRS/NEs after liso-cel treatment may help clinicians identify and manage these toxicities. Methods: Pts with R/R LBCL and ≥2 lines of therapy received liso-cel after lymphodepletion (LD) with fludarabine and cyclophosphamide. Bridging therapy was allowed for pts with PET-positive disease before LD (Abramson, ASH 2019 #241). Investigators were educated on prospectively identifying liso-cel–related NEs and CRS, which were collected and graded per NCI CTCAE v4.03 (NEs) or 2014 Lee criteria (CRS). Timing and severity of individual CRS/NE symptoms and interventions were also collected. Results: The analysis included 269 pts (median age, 63 y): 38% had sum of perpendicular diameters ≥50 cm2 or lactate dehydrogenase ≥500 U/L, and 59% received bridging therapy. CRS and NEs had delayed onset (median, 5 and 9 d, respectively) and a low incidence of grade (Gr) ≥3 events (CRS 2%; NE 10%). CRS occurred before NEs in most pts and was Gr 1/2 at onset in all but 2 pts (Table). The most common CRS symptoms were pyrexia (40%), hypotension (20%), and tachycardia (18%). Overall, 20% of pts received tocilizumab and/or corticosteroids for CRS (10% tocilizumab only; 2% corticosteroids only; 8% both); 3% received vasopressors. The most common NE symptoms were confusional state (11%), tremor (9%), and aphasia (8%); most were low grade. A total of 17% of pts received tocilizumab and/or corticosteroids for NEs (13% corticosteroids only; < 1% tocilizumab only; 3% both); < 1% received vasopressors. Overall, 4% of pts were admitted to the ICU for CRS and/or NEs. Additional analyses on timing of intervention and type/severity of initial symptoms will be presented. Conclusions: In pts with high-risk, aggressive R/R LBCL, liso-cel treatment was associated with a low incidence of severe CRS/NEs, late onset of mostly low-grade events at presentation, and low use of tocilizumab/corticosteroids. Clinical trial information: NCT02631044 . [Table: see text]

8006 Background: Venetoclax (Ven)-Obinutuzumab (O) is approved for chronic lymphocytic leukemia (CLL) achieving frequent undetectable minimum residual disease (uMRD; Fischer NEJM 2019). Ven-Ibrutinib is synergistic with frequent uMRD but with grade >3 neutropenia in 33-48% patients (pts; Tam ASH 2019; Jain NEJM 2019). Zanubrutinib (B) is a highly specific BTK inhibitor that demonstrated 100% occupancy in lymphoid tissues, so may be preferred to combine with OVen. We hypothesize that treatment (tx) with BOVen using an MRD driven discontinuation strategy will achieve frequent uMRD and durable responses. Methods: In this multicenter, investigator initiated phase 2 trial (NCT03824483), eligible pts had previously untreated CLL requiring tx per iwCLL, ECOG PS 1, PLT >75 (ANC >0, PLT >20 if due to CLL). BOVen was administered in 28D cycles: B 160 mg PO BID starting D1; O 1000 mg IV D1 or split D1-2, 8, 15 of C1, D1 of C2-8; Ven ramp up initiated C3D1 (target 400 mg QD). Tx duration was determined by a prespecified uMRD endpoint (min 8 cycles). MRD was assessed in peripheral blood (PB; flow cytometry, sensitivity >10−4) starting C7D1 then every 2 cycles. Once PB uMRD was determined and confirmed in bone marrow (BM), tx continued 2 additional cycles. Adverse events (AE) were assessed per CTCAE v5. Median (med) time to uMRD (primary endpoint) was estimated using the Kaplan-Meier method. Results: The study accrued 39 pts (3-10/19): med age 59 years (23-73), 3:1 male, CLL IPI >4 26/39 (67%), unmutated IGHV 28/39 (72%), 17p del/ TP53 mutated 4/39 (10%), all pts were evaluable for toxicity with 37 evaluable for efficacy. At a med follow up of 8 months (mo; 3-10), 25/37 (68%) pts achieved PB uMRD. Med time to PB uMRD is 6 mo (4-8+). Another 8/37 (22%) had PB MRD < 0.1%. Of 25 with PB uMRD, 19 had BM uMRD with 10/19 completing 2 additional cycles and discontinued; 3 had BM MRD (all

Introduction: The standard therapy for early stage, unfavorable risk Hodgkin lymphoma (HL) with disease bulk is combined modality therapy, typically 4-6 cycles of ABVD followed by 30Gy involved-site radiotherapy (ISRT) (Eich JCO 2010). In this pilot study with four sequential cohorts, we studied whether consolidative radiotherapy could be reduced or eliminated in early stage, unfavorable risk HL patients treated with brentuximab vedotin (BV) and AVD chemotherapy. In the first cohort, we demonstrated that BV+AVD and 30Gy ISRT had an acceptable safety profile without significant pulmonary toxicity and promising efficacy (Kumar Blood 2016). In subsequent cohorts, we tested whether the ISRT dose could be reduced to 20Gy (cohort 2), the RT field could be reduced with consolidation volume radiation (CVRT; cohort 3), and whether radiation therapy could be eliminated (cohort 4). Methods: Patients received 4 cycles of BV 1.2 mg/kg with AVD chemotherapy every 2 weeks, followed by 30 Gy ISRT in cohort 1, 20Gy ISRT in cohort 2, 30 Gy CVRT in cohort 3, and no radiotherapy in cohort 4. CVRT targets PET-negative residual masses greater than 1.5cm on post-chemotherapy CT imaging. Eligible patients in cohorts 1-2 included untreated stage I/II, classical HL with any one of the following unfavorable risk factors: bulky disease (MSK criteria: maximal transverse or coronal diameter >7 cm on CT), elevated ESR, extranodal involvement, >2 lymph node sites, or infradiaphragmatic disease. In cohort 3-4, early stage patients with bulky disease by MSK criteria were eligible. PET/CT after 2 and 4 cycles and after ISRT were interpreted with the 5-point Deauville scale (negative=1-3). The primary endpoint of cohort 1 was to evaluate safety and tolerability of the treatment combination, with special attention to pulmonary toxicity; the primary endpoint of cohorts 2-4 was to evaluate preliminary efficacy with the rate of complete responses (CRs) at end of treatment (EOT). Results: In June 2019, the study was fully accrued with 117 patients enrolled across four cohorts. Patients had a median age of 32 (range 18-59), 98% stage II, 86% with MSK-defined disease bulk (>7cm in transverse or coronal dimension), 27% with traditionally defined bulk (>10cm in transverse dimension), 50% elevated ESR, 38% B-symptoms, 21% extranodal involvement, 56% >2 involved lymph node sites, and 3.4% infradiaphragmatic disease. 26 patients (22%) had advanced stage disease by German Hodgkin Study Group criteria: IIBX (n=16), IIBE (n=5), and IIBXE (n=6). Of the patients enrolled in cohorts 1-3 with interim PET imaging, 85% and 91% achieved a negative PET scan after 2 and 4 cycles of therapy, respectively, and 95% achieved a CR at EOT. In cohort 4, 24 of the 29 enrolled patients have completed 4 cycles of therapy. Thus far, 93% of patients achieved a negative PET-2 scan (25 of 27 patients), 77% of patients achieved a negative PET-4 scan (17 of 22 patients), and 91% achieved a CR at EOT (20 of 22 patients). The remaining two patients with equivocal PET-4 results will have repeat short-interval scans to clarify EOT response. The overall median follow-up of survivors is 29 months: 56 months for cohort 1, 38 months for cohort 2, 24 months for cohort 3, and 5 months for cohort 4. Seven events have occurred in the study thus far. In cohort 1, two patients had primary refractory disease after chemotherapy and were treated off study. In cohort 2, one patient in remission died in a motor vehicle accident and one late relapse occurred at 34 months. In cohort 3, two patients had primary refractory HL after CVRT and one relapse occurred at 9 months. Overall, the 2-year PFS is 94% (95% CI 0.90, 0.99), see Figure. Across all 4 cohorts, the BV+AVD treatment was well-tolerated; the most common toxicities were peripheral neuropathy, abdominal pain, and neutropenia that were generally mild-moderate in severity, reversible, and manageable. Conclusion: BV+AVD x 4 cycles is an active treatment program for early stage, unfavorable risk HL, including patients with bulky disease. The efficacy of BV+AVD in this setting has facilitated a safe reduction in radiation dose and field evidenced by excellent and similar outcomes across the first 3 cohorts. With substantial follow-up, 20Gy ISRT appears equivalent to 30Gy ISRT following BV+AVD. The preliminary outcomes from the final cohort with chemotherapy alone are also promising, however, follow-up is short. Updated response data will be presented at the meeting. Disclosures Kumar: Seattle Genetics: Research Funding. Casulo:Gilead: Honoraria, Other: Travel, accommodation, expenses; Roche: Other: Travel, accommodation, expenses; Celgene: Research Funding. Advani:Kyowa Kirin Pharmaceutical Developments, Inc.: Consultancy; Cell Medica, Ltd: Consultancy; Kura: Research Funding; Merck: Research Funding; Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees; Pharmacyclics: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Stanford University: Employment, Equity Ownership; Seattle Genetics: Consultancy, Research Funding; Agensys: Research Funding; AstraZeneca: Consultancy, Membership on an entity's Board of Directors or advisory committees; Autolus: Consultancy, Membership on an entity's Board of Directors or advisory committees; Bayer: Consultancy, 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, Research Funding; Celgene: Research Funding; Infinity Pharma: Research Funding; Forty-Seven: Research Funding; Gilead Sciences, Inc./Kite Pharma, Inc.: Consultancy, Membership on an entity's Board of Directors or advisory committees; Regeneron: Research Funding; Janssen: Research Funding; Millennium: Research Funding; Roche/Genentech: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Celmed: Consultancy, Membership on an entity's Board of Directors or advisory committees. Budde:F. Hoffmann-La Roche Ltd: Consultancy. Barr:Janssen: Consultancy; Astra Zeneca: Consultancy, Research Funding; Verastem: Consultancy; Gilead: Consultancy; AbbVie: Consultancy; Pharmacyclics LLC, an AbbVie company: Consultancy, Research Funding; TG Therapeutics: Consultancy, Research Funding; Celgene: Consultancy; Merck: Consultancy; Seattle Genetics: Consultancy; Genentech: Consultancy. Batlevi:Juno Therapeutics: Consultancy, Membership on an entity's Board of Directors or advisory committees. Friedberg:Acerta: Other: Data & Safety Monitoring Committee; Bayer: Honoraria, Other: Data & Safety Monitoring Committee. Horwitz:Corvus Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Mundipharma: Consultancy; Mundipharma: Consultancy; Aileron: Research Funding; Infinity/Verastem: Consultancy, Research Funding; Seattle Genetics: Consultancy, Research Funding; Innate Pharma: Consultancy; Innate Pharma: Consultancy; Seattle Genetics: Consultancy, Research Funding; Millennium/Takeda: Consultancy, Research Funding; Astex: Consultancy; Infinity/Verastem: Consultancy, Research Funding; Seattle Genetics: Consultancy, Research Funding; Trillium: Research Funding; Celgene: Consultancy, Research Funding; Astex: Consultancy; Kyowa Hakko Kirin: Consultancy; Trillium: Research Funding; Affimed: Consultancy; Innate Pharma: Consultancy; Affimed: Consultancy; Corvus Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Miragen: Consultancy; Corvus Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Astex: Consultancy; Celgene: Consultancy, Research Funding; Infinity/Verastem: Consultancy, Research Funding; Infinity/Verastem: Consultancy, Research Funding; Innate Pharma: Consultancy; Kura: Consultancy; Kyowa Hakko Kirin: Consultancy; Kyowa Hakko Kirin: Consultancy; Millennium/Takeda: Consultancy, Research Funding; Millennium/Takeda: Consultancy, Research Funding; Affimed: Consultancy; Miragen: Consultancy; Miragen: Consultancy; Portola: Consultancy; Trillium: Research Funding; Mundipharma: Consultancy; Portola: Consultancy; Astex: Consultancy; Aileron: Research Funding; Aileron: Research Funding; Celgene: Consultancy, Research Funding; Forty-Seven: Research Funding; Trillium: Research Funding; Forty-Seven: Research Funding; Forty-Seven: Research Funding; Aileron: Research Funding; Portola: Consultancy; ADCT Therapeutics: Research Funding; Affimed: Consultancy; Mundipharma: Consultancy; ADCT Therapeutics: Research Funding; ADCT Therapeutics: Research Funding; ADCT Therapeutics: Research Funding; Portola: Consultancy; Forty-Seven: Research Funding; Miragen: Consultancy; Kura: Consultancy; Kura: Consultancy; Kura: Consultancy; Kyowa Hakko Kirin: Consultancy; Millennium/Takeda: Consultancy, Research Funding; Corvus Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Consultancy, Research Funding; Seattle Genetics: Consultancy, Research Funding. Matasar:Genentech, Inc.: Consultancy, Honoraria, Other: Travel, accommodation, expenses , Research Funding; Bayer: Consultancy, Honoraria, Other; Roche: Consultancy, Honoraria, Other: Travel, accommodation, expenses , Research Funding; Merck: Consultancy, Equity Ownership; Juno Therapeutics: Consultancy; Teva: Consultancy; Rocket Medical: Consultancy, Research Funding; Bayer: Other: Travel, accommodation, expenses; Janssen: Honoraria, Research Funding; Pharmacyclics: Consultancy, Honoraria, Research Funding; GlaxoSmithKline: Honoraria, Research Funding; Daiichi Sankyo: Consultancy; Seattle Genetics: Consultancy, Honoraria, Other: Travel, accomodation, expenses, Research Funding. Moskowitz:Erytech Pharma: Consultancy; Erytech Pharma: Consultancy; Cell Medica: Consultancy; Cell Medica: Consultancy; Kyowa Hakko Kirin Pharma: Consultancy, Research Funding; Takeda Pharmaceuticals: Consultancy; ADC Therapeutics: Consultancy; ADC Therapeutics: Consultancy; Merck: Research Funding; Takeda Pharmaceuticals: Consultancy; Erytech Pharma: Consultancy; ADC Therapeutics: Consultancy; Takeda Pharmaceuticals: Consultancy; Takeda Pharmaceuticals: Consultancy; Seattle Genetics: Consultancy, Honoraria, Research Funding; Seattle Genetics: Consultancy, Honoraria, Research Funding; Kyowa Hakko Kirin Pharma: Consultancy, Research Funding; Merck: Research Funding; ADC Therapeutics: Consultancy; ADC Therapeutics: Consultancy; Kyowa Hakko Kirin Pharma: Consultancy, Research Funding; Merck: Research Funding; Bristol-Myers Squibb: Consultancy, Research Funding; Bristol-Myers Squibb: Consultancy, Research Funding; Bristol-Myers Squibb: Consultancy, Research Funding; Bristol-Myers Squibb: Consultancy, Research Funding; Merck: Research Funding; Merck: Research Funding; Merck: Research Funding; Seattle Genetics: Consultancy, Honoraria, Research Funding; Merck: Research Funding; Bristol-Myers Squibb: Consultancy, Research Funding; Erytech Pharma: Consultancy; Bristol-Myers Squibb: Consultancy, Research Funding; Incyte: Research Funding; miRagen Therapeutics Inc: Consultancy, Research Funding; miRagen Therapeutics Inc: Consultancy, Research Funding; Incyte: Research Funding; miRagen Therapeutics Inc: Consultancy, Research Funding; Incyte: Research Funding; Incyte: Research Funding; Incyte: Research Funding; Incyte: Research Funding; Incyte: Research Funding; Incyte: Research Funding; miRagen Therapeutics Inc: Consultancy, Research Funding; Seattle Genetics: Consultancy, Honoraria, Research Funding; Kyowa Hakko Kirin Pharma: Consultancy, Research Funding; Kyowa Hakko Kirin Pharma: Consultancy, Research Funding; Kyowa Hakko Kirin Pharma: Consultancy, Research Funding; Merck: Research Funding; Merck: Research Funding; Erytech Pharma: Consultancy; ADC Therapeutics: Consultancy; Seattle Genetics: Consultancy, Honoraria, Research Funding; Seattle Genetics: Consultancy, Honoraria, Research Funding; Seattle Genetics: Consultancy, Honoraria, Research Funding; Merck: Research Funding; Bristol-Myers Squibb: Consultancy, Research Funding; ADC Therapeutics: Consultancy; Takeda Pharmaceuticals: Consultancy; Seattle Genetics: Consultancy, Honoraria, Research Funding; Incyte: Research Funding; Kyowa Hakko Kirin Pharma: Consultancy, Research Funding; Bristol-Myers Squibb: Consultancy, Research Funding; Bristol-Myers Squibb: Consultancy, Research Funding; Bristol-Myers Squibb: Consultancy, Research Funding; miRagen Therapeutics Inc: Consultancy, Research Funding; miRagen Therapeutics Inc: Consultancy, Research Funding; miRagen Therapeutics Inc: Consultancy, Research Funding; miRagen Therapeutics Inc: Consultancy, Research Funding; miRagen Therapeutics Inc: Consultancy, Research Funding; ADC Therapeutics: Consultancy; Takeda Pharmaceuticals: Consultancy; Takeda Pharmaceuticals: Consultancy; Takeda Pharmaceuticals: Consultancy; Takeda Pharmaceuticals: Consultancy; Takeda Pharmaceuticals: Consultancy; Takeda Pharmaceuticals: Consultancy; Takeda Pharmaceuticals: Consultancy; Kyowa Hakko Kirin Pharma: Consultancy, Research Funding; Erytech Pharma: Consultancy; Bristol-Myers Squibb: Consultancy, Research Funding; Erytech Pharma: Consultancy; Kyowa Hakko Kirin Pharma: Consultancy, Research Funding; Cell Medica: Consultancy; miRagen Therapeutics Inc: Consultancy, Research Funding; Cell Medica: Consultancy; Cell Medica: Consultancy; miRagen Therapeutics Inc: Consultancy, Research Funding; ADC Therapeutics: Consultancy; ADC Therapeutics: Consultancy; Cell Medica: Consultancy; Kyowa Hakko Kirin Pharma: Consultancy, Research Funding; Kyowa Hakko Kirin Pharma: Consultancy, Research Funding; Kyowa Hakko Kirin Pharma: Consultancy, Research Funding; Takeda Pharmaceuticals: Consultancy; Cell Medica: Consultancy; Cell Medica: Consultancy; ADC Therapeutics: Consultancy; ADC Therapeutics: Consultancy; Merck: Research Funding; Erytech Pharma: Consultancy; Erytech Pharma: Consultancy; Erytech Pharma: Consultancy; Erytech Pharma: Consultancy; Cell Medica: Consultancy; Cell Medica: Consultancy; Cell Medica: Consultancy; Cell Medica: Consultancy; Cell Medica: Consultancy; Cell Medica: Consultancy; Incyte: Research Funding; Incyte: Research Funding; Incyte: Research Funding; Incyte: Research Funding; Takeda Pharmaceuticals: Consultancy; Cell Medica: Consultancy; Merck: Research Funding; Seattle Genetics: Consultancy, Honoraria, Research Funding; Kyowa Hakko Kirin Pharma: Consultancy, Research Funding; Kyowa Hakko Kirin Pharma: Consultancy, Research Funding; Kyowa Hakko Kirin Pharma: Consultancy, Research Funding; Seattle Genetics: Consultancy, Honoraria, Research Funding; Takeda Pharmaceuticals: Consultancy; Seattle Genetics: Consultancy, Honoraria, Research Funding; Seattle Genetics: Consultancy, Honoraria, Research Funding; miRagen Therapeutics Inc: Consultancy, Research Funding; miRagen Therapeutics Inc: Consultancy, Research Funding; Bristol-Myers Squibb: Consultancy, Research Funding; Bristol-Myers Squibb: Consultancy, Research Funding; Bristol-Myers Squibb: Consultancy, Research Funding; Merck: Research Funding; Erytech Pharma: Consultancy; Bristol-Myers Squibb: Consultancy, Research Funding; miRagen Therapeutics Inc: Consultancy, Research Funding; Incyte: Research Funding; Incyte: Research Funding; miRagen Therapeutics Inc: Consultancy, Research Funding; Erytech Pharma: Consultancy; ADC Therapeutics: Consultancy; Merck: Research Funding; Merck: Research Funding; Erytech Pharma: Consultancy; Erytech Pharma: Consultancy; ADC Therapeutics: Consultancy; Seattle Genetics: Consultancy, Honoraria, Research Funding; Seattle Genetics: Consultancy, Honoraria, Research Funding; Seattle Genetics: Consultancy, Honoraria, Research Funding; ADC Therapeutics: Consultancy. Noy:Prime Oncology: Honoraria; NIH: Research Funding; Medscape: Honoraria; Janssen: Consultancy; Pharamcyclics: Research Funding; Raphael Pharma: Research Funding. Palomba:Pharmacyclics: Membership on an entity's Board of Directors or advisory committees; STRAXIMM: Membership on an entity's Board of Directors or advisory committees; Kite Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees; Evelo: Equity Ownership; MSK (IP for Juno and Seres): Patents & Royalties; Noble Insights: Consultancy; Merck & Co Inc.: Consultancy; Seres Therapeutics: Equity Ownership, Membership on an entity's Board of Directors or advisory committees; Hemedicus: Speakers Bureau. Straus:Elsevier (PracticeUpdate): Consultancy, Honoraria; Seattle Genetics: Consultancy, Honoraria; Hope Funds for Cancer Research: Membership on an entity's Board of Directors or advisory committees. Younes:Roche: Consultancy, Honoraria, Research Funding; Janssen: Honoraria, Research Funding; Curis: Honoraria, Research Funding; Merck: Honoraria, Research Funding; Abbvie: Honoraria; Takeda: Honoraria; Pharmacyclics: Research Funding; AstraZeneca: Research Funding; Genentech: Research Funding; Biopath: Consultancy; Xynomics: Consultancy; Epizyme: Consultancy, Honoraria; Celgene: Consultancy, Honoraria; HCM: Consultancy; BMS: Research Funding; Syndax: Research Funding. Zelenetz:Beigene: Consultancy, Membership on an entity's Board of Directors or advisory committees; Genentech/Roche: Consultancy, Membership on an entity's Board of Directors or advisory committees; MEI Pharma: Consultancy, Membership on an entity's Board of Directors or advisory committees; Pharmacyclics/AbbVie: Consultancy, Membership on an entity's Board of Directors or advisory committees; Pfizer: Consultancy, Membership on an entity's Board of Directors or advisory committees; Karyopharm: Consultancy, Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees; Pfizer: Consultancy, Membership on an entity's Board of Directors or advisory committees; Verastem: Consultancy, Membership on an entity's Board of Directors or advisory committees; Gilead: Consultancy, Membership on an entity's Board of Directors or advisory committees; Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees; Gilead: Consultancy, Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees; Morphosys: Consultancy, Membership on an entity's Board of Directors or advisory committees; Astra-Zeneca: Consultancy, Membership on an entity's Board of Directors or advisory committees; Karyopharm: Consultancy, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees; Pharmacyclics/AbbVie: Consultancy, Membership on an entity's Board of Directors or advisory committees; Verastem: Consultancy, Membership on an entity's Board of Directors or advisory committees; Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees; Astra-Zeneca: Consultancy, Membership on an entity's Board of Directors or advisory committees; DAVA Oncology: Consultancy, Membership on an entity's Board of Directors or advisory committees; Bayer: Consultancy, Membership on an entity's Board of Directors or advisory committees; Genentech/Roche: Consultancy, Membership on an entity's Board of Directors or advisory committees; Beigene: Consultancy, Membership on an entity's Board of Directors or advisory committees; Bayer: Consultancy, Membership on an entity's Board of Directors or advisory committees; MEI Pharma: Consultancy, Membership on an entity's Board of Directors or advisory committees; Morphosys: Consultancy, Membership on an entity's Board of Directors or advisory committees; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees; DAVA Oncology: Consultancy, Membership on an entity's Board of Directors or advisory committees. Moskowitz:ADC Therapeutics: Research Funding; Merck: Consultancy, Research Funding; Seattle Genetics, Inc.: Consultancy, Research Funding; Genentech: Consultancy, Research Funding; Celgene: Consultancy; Pharmacyclics: Research Funding.

Background: To date, CAR T cell therapy has generally been limited to inpatient treatment at university medical centers. However, most patients (pts) in the US with R/R diffuse large B cell lymphoma receive therapy at non-university medical centers where outpatient delivery of cancer therapy is common. Infusion and management of CAR T cell therapies in the outpatient setting may lead to wider utilization in community/non-university centers and improve access. In TRANSCEND NHL 001, lisocabtagene maraleucel (liso-cel), an investigational, anti-CD19, defined composition, 4-1BB, CAR T cell product administered at target doses of CD4+ and CD8+ CAR T cells, demonstrated efficacy as ≥3rd-line therapy in pts with R/R large B cell NHL. With fewer than half of pts developing cytokine release syndrome (CRS) and/or neurological events (NE) and its delayed onset (median 5 and 10 days, respectively; Abramson, ASCO 2018; 7505) outpatient treatment was allowed with hospitalization at the first sign of fever or neurological symptoms. We report on pts with R/R large B cell NHL who were treated with liso-cel in the outpatient setting in TRANSCEND NHL 001 (NCT02631044) and in two phase 2 studies assessing the safety and efficacy of liso-cel, as ≥3rd-line therapy (OUTREACH; NCT03744676) or as therapy for 2nd-line transplant noneligible (TNE) pts (PILOT; NCT03483103). Methods: Eligible pts had R/R large B cell NHL, adequate organ function, and prior systemic chemoimmunotherapy (TRANSCEND and OUTREACH: ≥2 prior lines of therapy and ECOG PS ≤1; PILOT: 1 prior line of therapy and deemed TNE for autologous hematopoietic stem cell transplantation based on ECOG PS, organ function, and/or age). After lymphodepletion with fludarabine/cyclophosphamide, liso-cel was administered at 1 of 3 dose levels (DL) (DL1 = 50 × 106, DL2 = 100 × 106, DL3 = 150 × 106 total CAR+ T cells) in TRANSCEND and at DL2 in OUTREACH and PILOT. All studies allowed outpatient treatment at non-university (OUTREACH) or at both university and non-university medical centers (TRANSCEND, PILOT). Outpatient treatment required pts to have a caregiver for 30 days post-liso-cel infusion, receive safety-monitoring education (recognizing critical adverse events; eg, fever), and to stay within 1 h travel to the site of care. Outpatient treatment was at the discretion of the investigator. All sites had a multidisciplinary CAR T cell therapy team and standard operating procedures for outpatient administration and toxicity monitoring. CRS (Lee criteria, 2014) and NEs (defined as related to liso-cel; CTCAE criteria) were managed in the hospital. Results: At data cutoff, 37 pts across studies had received liso-cel on study Day 1 and were monitored as outpatients, including pts ≥65 yr old and those with high tumor burden. Patient characteristics are shown in the Table. The most frequent grade ≥3 treatment-emergent AEs were cytopenias (neutropenia 43%, anemia 30%, thrombocytopenia 14%). Sixteen pts had any grade CRS and 12 had any grade NE (19 pts had CRS and/or NE). Severe CRS and/or NE occurred in only 2 pts and were reversible (Table). Three pts received tocilizumab and corticosteroids and 4 pts received corticosteroids alone for CRS and/or NE. No pts received tocilizumab alone. Twenty-two of the 37 pts (59%) required hospitalization at any time; all pts were from TRANSCEND or OUTREACH. Three of those pts (8%) were admitted on study Day 3 or earlier, all for CRS; 1 patient required ICU-level care (length of stay, 3 days). Median (range) time to hospitalization post treatment was 5 (2‒22) days and median (range) length of stay was 6 (2‒23) days. Fifteen (41%) of the 37 pts, including all 5 pts from PILOT, were not admitted to hospital in the first 29 days post liso-cel infusion. Across all 3 studies, most pts achieved an objective response, including CR (Table). Median time to peak CAR+ T cell expansion in each study was 10 days (range: 3-21 in TRANSCEND; 7-10 in OUTREACH; 7-10 in PILOT). Conclusions: A subset of pts with R/R large B cell NHL were successfully treated with liso-cel and monitored for CAR T cell-related toxicity in the outpatient setting, including elderly pts and pts with high tumor burden. Severe CRS and NEs occurred with low incidence. The number of early hospitalizations was low, and 41% of pts did not require hospitalization in the first month post liso-cel infusion. Most pts (65%) achieved an objective response. Updated data with longer follow-up will be presented. Disclosures Bachier: Sanofi: Speakers Bureau; Viracyte: Consultancy; Kadmon Corporation, LLC: Consultancy. Palomba:Noble Insights: Consultancy; Pharmacyclics: Membership on an entity's Board of Directors or advisory committees; Hemedicus: Speakers Bureau; Merck & Co Inc.: Consultancy; Seres Therapeutics: Equity Ownership, Membership on an entity's Board of Directors or advisory committees; STRAXIMM: Membership on an entity's Board of Directors or advisory committees; Kite Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees; Evelo: Equity Ownership; MSK (IP for Juno and Seres): Patents & Royalties. Abramson:AbbVie Inc, Amgen Inc, Bayer HealthCare Pharmaceuticals, Celgene Corporation, EMD Serono Inc, Genentech, Gilead Sciences Inc, Janssen Biotech Inc, Juno Therapeutics, a Celgene Company, Karyopharm Therapeutics, Kite Pharma Inc, Merck, Novartis, Seattle Gen: Consultancy. Andreadis:Roche: Equity Ownership; Novartis: Research Funding; Celgene: Research Funding; Juno: Research Funding; Pharmacyclics: Research Funding; Merck: Research Funding; Kite: Consultancy; Genentech: Consultancy, Employment; Gilead: Consultancy; Jazz Pharmaceuticals: Consultancy. Sehgal:Juno/Celgene: Research Funding; Kite/Gilead: Research Funding; Merck: Research Funding. Hildebrandt:Juno Therapeutics: Equity Ownership; crispr therapeutics: Equity Ownership; CVS Health: Equity Ownership; Immunomedics: Equity Ownership; IDEXX laboratories: Equity Ownership; Pfizer: Equity Ownership, Membership on an entity's Board of Directors or advisory committees, Other: Travel; Cellectis: Equity Ownership; Clovis Oncology: Equity Ownership; Aetna: Equity Ownership; Bluebird Bio: Equity Ownership; Celgene: Equity Ownership; Abbvie: Equity Ownership; Cardinal Health: Equity Ownership; Johnson & Johnson: Equity Ownership; Insys Therapeutics: Equity Ownership; Axim Biotechnologies: Equity Ownership; Axim Biotechnologies: Equity Ownership; Novartis: Equity Ownership; Kite Pharma: Equity Ownership, Membership on an entity's Board of Directors or advisory committees, Other: Travel; Sangamo: Equity Ownership; Procter & Gamble: Equity Ownership; Vertex: Equity Ownership; Bristol-Myers-Squibb: Equity Ownership; Bayer: Equity Ownership; Scotts-Miracle: Equity Ownership; Incyte: Membership on an entity's Board of Directors or advisory committees, Other: Travel; Jazz Pharmaceuticals: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Research Funding; Takeda: Research Funding; Pharmacyclics: Research Funding; Astellas: Other: Travel; Endocyte: Equity Ownership; GW Pharmaceuticals: Equity Ownership; Kite Pharma: Equity Ownership, Membership on an entity's Board of Directors or advisory committees, Other; Novartis: Equity Ownership. Siddiqi:PCYC: Consultancy, Research Funding, Speakers Bureau; AstraZeneca: Consultancy, Research Funding, Speakers Bureau; Janssen: Speakers Bureau; Seattle Genetics: Speakers Bureau; Kite, A Gilead Company: Research Funding; TG Therapeutics: Research Funding; Celgene: Research Funding; BeiGene: Research Funding; Juno Therapeutics: Consultancy, Other: travel support, Research Funding. Stevens:Astellas: Consultancy. Farazi:Juno Therapeutics/A Celgene Company: Employment. Kostic:Juno Therapeutics, a Celgene Company: Employment. Trede:Celgene Corporation: Employment, Equity Ownership. Wang:Celgene Corporation: Employment. Lymp:Celgene Corporation: Employment, Equity Ownership. Thelen:Celgene Corporation: Employment. Ogasawara:Celgene Corporation: Employment, Equity Ownership. Maloney:Juno Therapeutics: Honoraria, Patents & Royalties: patients pending , Research Funding; Celgene,Kite Pharma: Honoraria, Research Funding; A2 Biotherapeutics: Honoraria, Other: Stock options ; BioLine RX, Gilead,Genentech,Novartis: Honoraria.

Introduction Chimeric Antigen Receptor (CAR) T cells are associated with unique toxicities, including cytokine release syndrome (CRS) and immune effector cells-associated neurotoxicity syndrome (ICANS). Patients (pts) with severe CRS and ICANS exhibit hemodynamic instability and coagulopathy with evidence of endothelial activation and increased blood brain barrier permeability. Increases in inflammatory cytokines and biomarkers of endothelial activation in serum and CSF have been associated with severe CRS and ICANS. The EASIX (Endothelial Activation and Stress Index) score [lactate dehydrogenase (LDH) (U/L) × creatinine (mg/dl) / platelets (PLT) (109 cells/L)] correlates with severe fluid overload and survival in allogeneic transplant pts. Elevated LDH and low PLT levels have been associated with severe ICANS development, and high IL-6 levels are seen in severe CRS and ICANS. We hypothesized that the EASIX and a newly proposed version of it, the modified-EASIX (mEASIX), in which creatinine is replaced by CRP (mg/dL) as an easily available surrogate for IL6, would be associated with CRS and ICANS in CAR T cells pts. Methods We analyzed 2 different populations of adult CAR T cells pts treated at our institution: 1) B-cell acute lymphoblastic leukemia (B-ALL) pts treated with CD1928z CAR T cells from 2010 to 2016 (NCT01044069), and 2) aggressive diffuse large B-cell lymphoma (DLBCL) pts treated with axicabtagene ciloleucel (axi-cel) or tisagenlecleucel (tisa-cel) after FDA approval starting from 2018. EASIX and mEASIX scores were calculated for each patient daily from start of lymphodepletion conditioning to day +14. A log transformation using base 2 (log2) was applied to all EASIX/mEASIX variables to reduce skew. CRS and ICANS were graded according to the ASTCT grading system. Results 87 pts, B-ALL (n=53) and DLBCL (n=34), were analyzed. According to ASTCT grading, 83% (72/87) experienced CRS and 54% (47/87) developed ICANS, grade ≥3 in 23% (20/87) and 40% (35/87) of pts, respectively. When analyzed by disease, CRS and ICANS rates were 87% (46/53) and 55% (29/53) for B-ALL and 76% (26/34) and 53% (18/34) for DLBCL, respectively. CRS and ICANS were grade ≥3 in 28% (15/53) and 45% (24/53) of B-ALL pts and in 15% (5/34) and 32% (11/34) of DLBCL pts, respectively. Median time of onset of CRS after CAR T cell infusion was day +2 and median onset of ICANS was day +6 for the overall population and the subgroups. High EASIX and mEASIX scores at start of conditioning were both associated with development of any grade CRS [OR=1.81 (95% CI 1.09-3.36) p=0.038 and OR=1.94 (95% CI 1.32-3.38) p=0.005] and grade ≥3 CRS [OR=1.47 (95% CI 1.05-2.29) p=0.049 and OR=1.34 (95% CI 1.07-1.80) p=0.024], respectively (Table). Following CAR T cell infusion, high scores of both EASIX [OR=1.60 (95% CI 1.12-2.43) p=0.017] and mEASIX [OR=1.32 (95% CI 1.07-1.69) p=0.014] on day +1 were associated with development of grade ≥3 CRS. Moreover, both high EASIX [OR=1.43 (95% CI 1.08-1.96) p=0.018] and mEASIX [OR=1.29 (95% CI 1.07-1.60) p=0.010] scores on day +3 were associated with grade ≥3 ICANS. When analyzed by disease, results were confirmed for severe CRS and ICANS in B-ALL patients, while in the DLBCL group only mEASIX at start of conditioning and at day +1 was associated with development of any grade CRS. EASIX and mEASIX scores were not associated with response rates to CAR T cells therapy. Conclusions EASIX and mEASIX scores calculated at baseline (before lymphodepletion) are associated with development of CRS and severe CRS. Moreover, both high EASIX and mEASIX scores on day +1 and day +3 are associated with occurrence of grade ≥3 CRS and grade ≥3 ICANS, respectively. We conclude that EASIX and mEASIX, as markers of endothelial damage and inflammation, could be useful as early predictors in guiding treatment decisions before the onset of severe symptoms. Table Disclosures Batlevi: Juno Therapeutics: Consultancy, Membership on an entity's Board of Directors or advisory committees. Brentjens:JUNO Therapeutics: Consultancy, Patents & Royalties, Research Funding; Celgene: Consultancy. Giralt:Miltenyi: Research Funding; Spectrum Pharmaceuticals: Consultancy; Novartis: Consultancy; Jazz Pharmaceuticals: Consultancy; Celgene: Consultancy, Research Funding; Johnson & Johnson: Consultancy, Research Funding; Takeda: Consultancy, Research Funding; Amgen: Consultancy, Research Funding; Actinium: Consultancy, Research Funding; Kite: Consultancy. Palomba:Pharmacyclics: Membership on an entity's Board of Directors or advisory committees; Noble Insights: Consultancy; Seres Therapeutics: Equity Ownership, Membership on an entity's Board of Directors or advisory committees; STRAXIMM: Membership on an entity's Board of Directors or advisory committees; Kite Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees; Evelo: Equity Ownership; MSK (IP for Juno and Seres): Patents & Royalties; Hemedicus: Speakers Bureau; Merck & Co Inc.: Consultancy. Santomasso:Kite/Gilead: Consultancy; Juno/Celgene: Consultancy; Novartis: Consultancy. Sauter:GSK: Consultancy; Kite/Gilead: Consultancy; Celgene: Consultancy; Juno Therapeutics: Consultancy, Research Funding; Sanofi-Genzyme: Consultancy, Research Funding; Spectrum Pharmaceuticals: Consultancy; Novartis: Consultancy; Genmab: Consultancy; Precision Biosciences: Consultancy. Scordo:Angiocrine Bioscience, Inc.: Consultancy; McKinsey & Company: Consultancy. Shah:Amgen: Research Funding; Janssen Pharmaceutica: Research Funding. Park:Allogene: Consultancy; Amgen: Consultancy; AstraZeneca: Consultancy; Autolus: Consultancy; GSK: Consultancy; Incyte: Consultancy; Kite Pharma: Consultancy; Novartis: Consultancy; Takeda: Consultancy. Perales:Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees; Abbvie: Honoraria, Membership on an entity's Board of Directors or advisory committees; Bellicum: Honoraria, Membership on an entity's Board of Directors or advisory committees; Bristol-Meyers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees; Incyte: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Servier: Membership on an entity's Board of Directors or advisory committees; Kyte/Gilead: Research Funding; Miltenyi: Research Funding; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees; Omeros: Honoraria, Membership on an entity's Board of Directors or advisory committees; Nektar Therapeutics: Honoraria, Membership on an entity's Board of Directors or advisory committees; Merck: Consultancy, Honoraria; Medigene: Membership on an entity's Board of Directors or advisory committees; NexImmune: Membership on an entity's Board of Directors or advisory committees; MolMed: Membership on an entity's Board of Directors or advisory committees.

The development of chimeric antigen receptor T cell (CAR T) therapy has revolutionized the treatment of relapsed refractory diffuse large b-cell lymphoma (DLBCL). However, its impact in vulnerable older patients, especially those with multi-morbidity and functional limitations, has not been explored. Moreover, the Centers for Medicare & Medicaid Services (CMS) has recently proposed Coverage with Evidence Development for CAR T, emphasizing the need for evidence in older patients. We retrospectively examined outcomes of older patients referred for commercial CAR T products, axicabtagene ciloleucel and tisagenlecleucel, at our institution from January 2018 to March 2019. Forty-two consecutive older patients (≥65yo) were included in the analysis of post-relapse (last documented relapse or refractory state) overall survival (PR-OS) accounting for time of CAR T entry. Geriatric assessment, including comorbidity, basic and instrumental activities of daily living, prior falls, and weight loss, was performed either by a geriatrician prior to admission, or by interdisciplinary clinical staff on the day of admission. In parallel, we compared the safety and toxicities of CAR T between older (≥65yo, n=24) and younger ( Among the 42 patients ≥65yo, 18 did not receive CAR T due to clinical ineligibility and/or death during the pre-requisite clinical evaluation. Their gender distribution, comorbidity burden, measured by Deyo/Charlson Comorbidity Index (DCI/CCI), and Karnofsky Performance Status (KPS) were comparable to the 24 older patients who received a CAR T product. With a median follow-up of 291 days (range 162 - 572) for survivors, the PR-OS favored the group of older patients who had received CAR T with estimated 1-year PR-OS of 0.67 (95% CI: 0.43, 0.99) versus 0.44 (95% CI: 0.27, 0.75) for patients who did not receive CAR T (p=0.04) (Figure). We next compared the safety and toxicity profiles among older (≥65yo, n=24) versus younger patients ( Although limited by small sample size, retrospective design, and possible patient selection bias regarding disease biology, our results highlight potential benefits of CAR T in selected older patients even with functional limitation, multi-morbidity, and significant tumor burden; and the lack of excessive CRS, NT, and other high-grade toxicities. These findings extend beyond published results of older patients in ZUMA-1 and JULIET trials, and support that, with meticulous management of CAR T toxicities, older patients should not be excluded from CAR T based on chronologic age alone. Detailed geriatric assessment and correlation with toxicities should allow better selection of older adults who could benefit from this curative treatment. In addition, the biology of CAR T response in older adults may warrant additional investigation in the context of aging-associated changes in the immune system. Disclosures Batlevi: Juno Therapeutics: Consultancy, Membership on an entity's Board of Directors or advisory committees. Giralt:Jazz Pharmaceuticals: Consultancy; Miltenyi: Research Funding; Takeda: Consultancy, Research Funding; Amgen: Consultancy, Research Funding; Celgene: Consultancy, Research Funding; Johnson & Johnson: Consultancy, Research Funding; Actinium: Consultancy, Research Funding; Spectrum Pharmaceuticals: Consultancy; Novartis: Consultancy; Kite: Consultancy. Noy:Medscape: Honoraria; Prime Oncology: Honoraria; NIH: Research Funding; Janssen: Consultancy; Pharamcyclics: Research Funding; Raphael Pharma: Research Funding. Palomba:Noble Insights: Consultancy; Hemedicus: Speakers Bureau; Merck & Co Inc.: Consultancy; Seres Therapeutics: Equity Ownership, Membership on an entity's Board of Directors or advisory committees; Pharmacyclics: Membership on an entity's Board of Directors or advisory committees; STRAXIMM: Membership on an entity's Board of Directors or advisory committees; Kite Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees; Evelo: Equity Ownership; MSK (IP for Juno and Seres): Patents & Royalties. Santomasso:Kite/Gilead: Consultancy; Novartis: Consultancy; Juno/Celgene: Consultancy. Sauter:Juno Therapeutics: Consultancy, Research Funding; Sanofi-Genzyme: Consultancy, Research Funding; Spectrum Pharmaceuticals: Consultancy; Novartis: Consultancy; Genmab: Consultancy; Precision Biosciences: Consultancy; Kite/Gilead: Consultancy; Celgene: Consultancy; GSK: Consultancy. Scordo:Angiocrine Bioscience, Inc.: Consultancy; McKinsey & Company: Consultancy. Shah:Janssen Pharmaceutica: Research Funding; Amgen: Research Funding. Perales:Abbvie: Honoraria, Membership on an entity's Board of Directors or advisory committees; Bellicum: Honoraria, Membership on an entity's Board of Directors or advisory committees; Servier: Membership on an entity's Board of Directors or advisory committees; Medigene: Membership on an entity's Board of Directors or advisory committees; Merck: Consultancy, Honoraria; NexImmune: Membership on an entity's Board of Directors or advisory committees; MolMed: Membership on an entity's Board of Directors or advisory committees; Miltenyi: Research Funding; Nektar Therapeutics: Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees; Bristol-Meyers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees; Incyte: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Kyte/Gilead: Research Funding; Omeros: Honoraria, Membership on an entity's Board of Directors or advisory committees; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees.

Background : CAR T cell therapies have demonstrated high response rates in patients (pts) with R/R B cell NHL. Liso-cel is an investigational anti-CD19, defined composition, 4-1BB CAR T cell product administered at target doses of CD4+ and CD8+ CAR T cells. The seamless phase 1 TRANSCEND NHL 001 study evaluated liso-cel in pts with R/R large B cell NHL (NCT02631044). We present data with long-term follow-up from pts treated in the DLBCL cohort. Methods: Pts aged ≥18 yrs in the DLBCL cohort had R/R DLBCL not otherwise specified (NOS; including transformed from any indolent lymphoma), high-grade B cell lymphoma (HGBCL) with MYC and BCL2 and/or BCL6 rearrangements, primary mediastinal B cell lymphoma (PMBCL), or follicular lymphoma grade 3B (FL3B). Pts had R/R disease after ≥2 lines of therapy and ECOG PS 0‒2. Pts with grade 3/4 cytopenias, mild-moderate organ dysfunction, and secondary CNS lymphoma were eligible. Bridging therapy was allowed, but pts had to have PET-positive disease before lymphodepletion (LD) with fludarabine and cyclophosphamide. Liso-cel was administered at 1 of 3 target dose levels (DLs) of 50×106 (DL1), 100×106 (DL2), or150×106 (DL3) viable CAR+ T cells in the dose-finding cohorts. All dose levels were expanded, and DL2 was chosen as the target DL for dose confirmation. Primary endpoints were treatment-emergent adverse events (TEAEs) and overall response rate (ORR). Secondary endpoints included CR rate, DOR, PFS, PFS ratio, and OS. TEAEs, including investigator-identified neurological events (NE) related to liso-cel, were graded using CTCAE criteria; CRS was graded per the Lee criteria (2014). ORR was assessed by independent review using the Lugano criteria. Data from all liso-cel-treated pts in the DLBCL cohort were analyzed across DLs. Results: A total of 342 pts were leukapheresed; 268 pts received liso-cel (DL1, n=51; DL2, n=176; DL3, n=41). Twenty-four pts received nonconforming product; product could not be manufactured for 2 pts. Pts did not receive liso-cel primarily due to death (n=33). In the optimized manufacturing process, median time from leukapheresis to liso-cel availability was 24 days. Median age was 63 (range, 18‒86) yrs, including older subpopulations (≥65 yrs, 41%; ≥75 yrs, 10%); 65% of pts were male. At screening, 58% had ECOG PS 1. Pts were heavily pretreated and had aggressive disease: 26% had ≥4 prior lines of systemic therapy (median of 3; range, 1‒8); 34% underwent prior auto-HSCT and 3% prior allo-HSCT; 67% were chemorefractory; and 44% had never achieved CR. 59% required bridging therapy. 22% had LDH ≥500 U/L and 28% had SPD ≥50 cm2 before LD. Outcomes were similar between DLs; therefore, data were pooled. Twenty-five pts were treated in the outpatient setting. Safety analysis showed 79% of pts had grade ≥3 TEAEs, primarily cytopenias (neutropenia, 60%; anemia, 37%; thrombocytopenia, 27%). CRS or NE occurred in 47% of pts. Any grade CRS occurred in 42% of pts at a median onset of 5 days; only 2% had grade ≥3 CRS. NEs occurred in 30% of pts (grade ≥3, 10%) at a median onset of 9 days (Table). 19% of pts received tocilizumab and 21% received corticosteroids for CRS and/or NEs. Four grade 5 TEAEs related to liso-cel and LD occurred (diffuse alveolar damage, pulmonary hemorrhage, multiple organ dysfunction syndrome, cardiomyopathy). Prolonged grade ≥3 cytopenia (based on laboratory assessment at Day 29) was reported in 37% of pts. Safety was similar between age groups, histologies, and pts with organ dysfunction. The study met all primary and secondary efficacy endpoints. Among pts evaluable for efficacy (n=255), ORR was 73% (95% CI, 67‒78); the CR rate was 53% (95% CI, 47‒59). Responses were similar across all pt subgroups (Table). Median DOR was 13.3 mo (95% CI, 8.2‒not reached [NR]) with 10.8 mo of median follow-up; median DOR for pts in CR was NR (13.3‒NR). Median PFS was 6.8 mo (95% CI, 3.3‒11.8). Median OS was 19.9 mo (95% CI, 10.9‒NR). Overall, PFS after liso-cel infusion was substantially longer than PFS from the immediate prior therapy. Conclusions: Liso-cel demonstrated durable clinical activity with a favorable safety profile in this large study of CAR T cell therapy in R/R large B cell NHL. Low incidence and late onset of CRS and NE allowed for outpatient administration. Clinically meaningful efficacy was observed across histologic subgroups and those with poor prognosis, including pts who were refractory, elderly, comorbid, and/or had high tumor burden. Disclosures Abramson: AbbVie Inc, Amgen Inc, Bayer HealthCare Pharmaceuticals, Celgene Corporation, EMD Serono Inc, Genentech, Gilead Sciences Inc, Janssen Biotech Inc, Juno Therapeutics, a Celgene Company, Karyopharm Therapeutics, Kite Pharma Inc, Merck, Novartis, Seattle Gen: Consultancy. Palomba:Kite Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees; Merck & Co Inc.: Consultancy; MSK (IP for Juno and Seres): Patents & Royalties; Noble Insights: Consultancy; Pharmacyclics: Membership on an entity's Board of Directors or advisory committees; Seres Therapeutics: Equity Ownership, Membership on an entity's Board of Directors or advisory committees; STRAXIMM: Membership on an entity's Board of Directors or advisory committees; Evelo: Equity Ownership; Hemedicus: Speakers Bureau. Gordon:Gilead: Other: Advisory Board; Bayer: Other: Advisory Board; Juno/Celgene: Other: Advisory Board, Research Funding; Zylem LLC: Other: co-founder; research in nanoparticles in cancer. Lunning:Spectrum: Consultancy; Seattle Genetics: Consultancy; Portola: Consultancy; OncLive: Consultancy; Novartis: Consultancy; Kite: Consultancy; Gilead Sciences, Inc.: Consultancy; DAVA: Consultancy; Bayer: Consultancy; AbbVie: Consultancy; TG Therapeutics: Consultancy, Research Funding; MiRagen: Research Funding; Juno Therapeutics: Consultancy, Research Funding; Janssen Scientific Affairs, LLC: Consultancy, Research Funding; Curis: Research Funding; VANIUM: Consultancy; Verastem: Consultancy. Wang:Janssen: Consultancy, Honoraria, Research Funding, Speakers Bureau; Pharmacyclics: Honoraria, Research Funding; AstraZeneca: Consultancy, Honoraria, Research Funding, Speakers Bureau; MoreHealth: Consultancy, Equity Ownership; Acerta Pharma: Consultancy, Research Funding; Kite Pharma: Consultancy, Research Funding; Guidepoint Global: Consultancy; BioInvent: Consultancy, Research Funding; VelosBio: Research Funding; Loxo Oncology: Research Funding; Celgene: Honoraria, Research Funding; Juno Therapeutics: Research Funding; Aviara: Research Funding; Dava Oncology: Honoraria. Arnason:Celgene/Juno: Consultancy; Regeneron Pharmaceuticals, Inc.: Consultancy. Mehta:Pharmacyclics: Consultancy, Speakers Bureau; Celgene: Consultancy, Speakers Bureau; Spectrum: Consultancy, Speakers Bureau; Imbrium therapeutics: Consultancy; Roche-Genentech: Research Funding; Incyte: Research Funding; Kite/Gilead: Research Funding, Speakers Bureau; Takeda: Research Funding; Rhizen: Research Funding; ADC therapeutics: Research Funding; Forty Seven Inc: Research Funding; Juno/Celgene: Research Funding; Affimed: Research Funding; Seattle Genetics: Research Funding, Speakers Bureau; Astex: Research Funding; TG Therapeutics: Research Funding; miRagen: Research Funding; Kyowa-Kirin: Consultancy, Speakers Bureau; Astra-Zeneca: Speakers Bureau; Sanofi: Consultancy. Maloney:Celgene,Kite Pharma: Honoraria, Research Funding; Juno Therapeutics: Honoraria, Patents & Royalties: patients pending , Research Funding; BioLine RX, Gilead,Genentech,Novartis: Honoraria; A2 Biotherapeutics: Honoraria, Other: Stock options . Andreadis:Juno: Research Funding; Pharmacyclics: Research Funding; Genentech: Consultancy, Employment; Kite: Consultancy; Gilead: Consultancy; Jazz Pharmaceuticals: Consultancy; Roche: Equity Ownership; Novartis: Research Funding; Celgene: Research Funding; Merck: Research Funding. Sehgal:Merck: Research Funding; Juno/Celgene: Research Funding; Kite/Gilead: Research Funding. Ghosh:AstraZeneca: Honoraria, Speakers Bureau; Bristol-Myers Squibb: Honoraria, Speakers Bureau; Gilead: Consultancy, Honoraria, Speakers Bureau; Janssen: Consultancy, Honoraria, Research Funding, Speakers Bureau; Pharmacyclics LLC, an AbbVie Company: Consultancy, Honoraria, Research Funding, Speakers Bureau; SGN: Consultancy, Honoraria, Research Funding, Speakers Bureau; TG Therapeutics: Consultancy, Honoraria, Research Funding; Celgene: Consultancy, Research Funding; Genentech: Research Funding; Forty Seven Inc: Research Funding. Albertson:Juno Therapeutics, a Celgene Company: Employment, Equity Ownership. Garcia:Celgene: Employment, Equity Ownership. Kostic:Juno Therapeutics, a Celgene Company: Employment. Li:Juno Therapeutics, a Celgene Company: Employment. Kim:Juno Therapeutics, a Celgene Company: Employment. Siddiqi:TG Therapeutics: Research Funding; Kite, A Gilead Company: Research Funding; Seattle Genetics: Speakers Bureau; Janssen: Speakers Bureau; AstraZeneca: Consultancy, Research Funding, Speakers Bureau; PCYC: Consultancy, Research Funding, Speakers Bureau; Juno Therapeutics: Consultancy, Other: travel support, Research Funding; Celgene: Research Funding; BeiGene: Research Funding.