ALBERT

Description: BACKGROUND: CD19-specific chimeric antigen receptor (CAR) T-cell therapy has proven to be highly effective in patients with relapsed or refractory large B-cell lymphomas, yielding early complete response (CR) rates of ~40%, which are typically sustained. Unfortunately, most patients will not experience prolonged disease control. Despite this fact, little data exist defining the outcomes and impact of subsequent therapies for such individuals. Limited data also exist on the ability for such patients to pursue further clinical trials or allogeneic hematopoietic stem-cell transplant (HSCT). This project details the specific interventions and outcomes of this population to better inform the management of patients who suffer progressive disease (PD) after CD19-specific CAR T-cell therapy. METHODS: Adults with diffuse large B-cell lymphoma (DLBCL), transformed follicular lymphoma (tFL), primary mediastinal B-cell lymphoma (PMBCL), and high-grade B-cell lymphomas (HGBCL) who received CD19-specific CAR T-cells at the University of Washington/Seattle Cancer Care Alliance were included in this analysis. Patients who received CAR T-cell therapy in conjunction with additional protocol-specified therapy were excluded. Those who exhibited PD or persistent lymphoma after CAR T-cell therapy were the focus of this study. We defined initial PD as patients who had evidence of disease progression on the initial response assessment. Delayed PD was defined as achieving a CR, partial response (PR), or stable disease (SD) on the initial response assessment, but eventually progressed or received subsequent anti-lymphoma therapy. Baseline characteristics and all data were retrieved from the electronic medical record up until date of death or date of last contact in our system, including subsequent interventions and outcomes. Primary endpoint of this analysis was overall survival (OS). RESULTS: Between October 2013 and May 2018, we identified 51 patients with PD following CD19-specific CAR T-cell therapy. Baseline characteristics are listed in the Table 1. Histologies included DLBCL (29), HGBCL (11), tFL (8) and PMBCL (3). Median age was 60 years (range 26-75), 65% were male, median prior regimens was 3 (range 1-8). Median time from CAR T infusion to PD was 42 days (range 11-609), with 27 (53%) patients exhibiting initial PD. Median follow up after time of progression was 4.2 months. Initial PD was associated with a higher risk of death (HR 2.376, 95% CI 1.19-4.75, p=0.0143, Figure 1). The median OS for those with initial PD and delayed PD was 5.1 months (95% CI 2.0-9.3) and 13.6 months (4.1-not reached) respectively. 39 (76%) patients received ≥ 1 subsequent therapies after PD. Initial therapies included: 2nd CAR T infusion (14), targeted therapy (10), chemotherapy +/- rituximab (7), other immunotherapy (3), radiotherapy (3), intrathecal chemotherapy (1) and allogeneic HSCT (1). 12 (24%) patients received no further therapy despite PD. Those who received ≥ 1 subsequent therapies after PD had a lower risk of death (HR 0.344, 95% CI 0.149-0.793, P=0.0122) compared to those who did not. There was no difference in survival if 2nd CAR T infusion was the next line therapy compared to others (p=0.449), targeted therapy compared to others (p=0.417), or chemotherapy compared to others (p=0.565). 5 (10%) patients enrolled onto a clinical trial as next line therapy. 4 (8%) patients eventually received an allogeneic HSCT after PD, 2 of whom are still alive. We identified 8 patients who were alive for ≥ 12 months after progression without evidence of lymphoma. Last line of therapy for these patients included allogeneic HSCT (2), subsequent CD19-specific CAR-T cell infusion (2), ibrutinib (2), lenalidomide/rituximab (1), and radiotherapy (1). CONCLUSIONS: Patients with PD post anti-CD19 CAR T-cell therapy, particularly those exhibiting initial PD, have poor long-term outcomes. Patients receiving at least one anti-lymphoma therapy after PD had improved overall survival, although no single approach appeared to confer a survival benefit. Few enrolled onto a clinical trial or received an allogeneic HSCT. These data reinforce the need to both further improve the durable CR rate after CAR T-cell therapy and to develop effective strategies for those not achieving a CR. Figure 1 Figure 1. Disclosures Gopal: Spectrum: Research Funding; Pfizer: Research Funding; BMS: Research Funding; Seattle Genetics: Consultancy, Research Funding; Merck: Research Funding; Takeda: Research Funding; Brim: Consultancy; Janssen: Consultancy, Research Funding; Asana: Consultancy; Gilead: Consultancy, Research Funding; Aptevo: Consultancy; Incyte: Consultancy; Teva: Research Funding. Maloney:Juno Therapeutics: Research Funding; Roche/Genentech: Honoraria; Janssen Scientific Affairs: Honoraria; Seattle Genetics: Honoraria; GlaxoSmithKline: Research Funding. Turtle:Caribou Biosciences: Consultancy; Adaptive Biotechnologies: Consultancy; Nektar Therapeutics: Consultancy, Research Funding; Bluebird Bio: Consultancy; Precision Biosciences: Equity Ownership, Membership on an entity's Board of Directors or advisory committees; Juno Therapeutics / Celgene: Consultancy, Patents & Royalties, Research Funding; Eureka Therapeutics: Equity Ownership, Membership on an entity's Board of Directors or advisory committees; Aptevo: Consultancy; Gilead: Consultancy. Smith:Genentech: Research Funding; Acerta Pharma BV: Research Funding; Incyte Corporation: Research Funding; Merck Sharp and Dohme Corp.: Consultancy, Research Funding; Pharmacyclics: Research Funding; Portola Pharmaceuticals: Research Funding; Seattle Genetics: Research Funding. Shadman:TG Therapeutics: Research Funding; Mustang Biopharma: Research Funding; Acerta Pharma: Research Funding; AstraZeneca: Consultancy; Verastem: Consultancy; Gilead Sciences: Research Funding; AbbVie: Consultancy; Qilu Puget Sound Biotherapeutics: Consultancy; Beigene: Research Funding; Genentech: Research Funding; Pharmacyclics: Research Funding; Genentech: Consultancy; Celgene: Research Funding. Cassaday:Seattle Genetics: Other: Spouse Employment, Research Funding; Incyte: Research Funding; Jazz Pharmaceuticals: Consultancy; Pfizer: Consultancy, Research Funding; Kite Pharma: Research Funding; Merck: Research Funding; Amgen: Consultancy, Research Funding; Adaptive Biotechnologies: Consultancy. Till:Mustang Bio: Patents & Royalties, Research Funding. Shustov:Seattle Genetics: Research Funding. Acharya:Juno Therapeutics: Research Funding; Teva: Honoraria. Lynch:Takeda Pharmaceuticals: Research Funding; T.G. Therapeutics: Research Funding; Rhizen Pharmaceuticals S.A.: Research Funding; Johnson Graffe Keay Moniz & Wick LLP: Consultancy; Incyte Corporation: Research Funding.

Description: Introduction: CD19-specific chimeric antigen receptor (CAR) T-cell therapy is FDA approved in patients with relapsed or refractory large B-cell lymphomas. While 35-40% of patients may achieve a durable complete response (CR), the toxicity incurred with CAR-T therapy could impact the ability to receive subsequent treatment in those who progress after CAR-T infusion. Our prior data suggested that patients who experienced early progression had inferior overall survival. We now update our results and evaluate the impact of laboratory abnormalities and comorbidities at the time of progression on overall survival. Methods: Adults with large B-cell lymphomas who received CD19-specific CAR T-cells at the University of Washington/Seattle Cancer Care Alliance were included. Patients who received CAR T-cell therapy with additional concurrent protocol-specified therapy were excluded. Those who exhibited progressive disease (PD) or persistent lymphoma after CAR T-cell therapy were the focus of this study. We defined patients who progressed or received additional lymphoma directed therapy after last CAR-T cell infusion as early PD, with all other patients defined as late PD. We collected laboratory data closest to the date of progression. We defined an absolute neutrophil count 〈 1000, platelet count 〈 75K, Creatinine 〉 upper limit of normal (ULN), INR 〉 ULN, AST/ALT 〉 2.5x ULN, total bilirubin 〉 ULN, and LDH 〉 ULN as abnormal. Primary endpoint of this analysis was overall survival (OS) landmarked to date of progression. Secondary endpoints include sub-group analyses based on early PD as well as lab abnormalities at the time of progression. A multi-variate analysis with select baseline and progression variables was also performed. Results: We identified 66 patients who met the above criteria. Median follow up for the entire cohort is 30.4 months (range 0.1-64 months) by reverse KM method. Median time from last planned CAR infusion to progression was 43.5 days (range 11-658). Median OS of the entire cohort was 5.43 months (95% CI 3.75-12.2). 25 (38%) patients experienced early PD, which was associated with inferior OS (median 3.75 vs. 10.4 months, P=0.02). LDH 〉 ULN at the time of progression defined a group with inferior outcomes (median OS 3.16 vs. 17.5 months, P ULN at progression (7.01, 95% CI 2.89-17.013), and abnormal creatinine at progression (5.32, 95% CI 1.71-16.53), as factors associated with increased risk of death. Conclusions: Patients with PD post CD19-specific CAR T-cell therapy, particularly those with early PD, elevated LDH, or renal failure experience extremely poor outcomes. These data can inform discussion of prognosis for patients who progress after CAR T-cell therapy and may predict which patients may benefit from additional anti-lymphoma therapy. Figure Disclosures Lynch: Johnson Graffe Keay Moniz & Wick LLP: Consultancy; Juno Therapeutics: Research Funding; Takeda Pharmaceuticals: Research Funding; T.G. Therapeutics: Research Funding; Incyte Corporation: Research Funding; Rhizen Pharmaceuticals S.A: Research Funding. Maloney:A2 Biotherapeutics: Honoraria, Other: Stock options ; Celgene,Kite Pharma: Honoraria, Research Funding; Juno Therapeutics: Honoraria, Patents & Royalties: patients pending , Research Funding; BioLine RX, Gilead,Genentech,Novartis: Honoraria. Turtle:Nektar Therapeutics: Other: Ad hoc advisory board member, Research Funding; Juno Therapeutics: Patents & Royalties: Co-inventor with staff from Juno Therapeutics; pending, Research Funding; Eureka Therapeutics: Equity Ownership, Membership on an entity's Board of Directors or advisory committees; Caribou Biosciences: Equity Ownership, Membership on an entity's Board of Directors or advisory committees; Novartis: Other: Ad hoc advisory board member; Precision Biosciences: Equity Ownership, Membership on an entity's Board of Directors or advisory committees; T-CURX: Membership on an entity's Board of Directors or advisory committees; Allogene: Other: Ad hoc advisory board member; Kite/Gilead: Other: Ad hoc advisory board member; Humanigen: Other: Ad hoc advisory board member. Smith:Portola Pharmaceuticals: Research Funding; Pharmacyclics: Research Funding; Ignyta (spouse): Research Funding; Genentech: Research Funding; Denovo Biopharma: Research Funding; Ayala (spouse): Research Funding; Bristol-Myers Squibb (spouse): Research Funding; AstraZeneca: Membership on an entity's Board of Directors or advisory committees, Research Funding; Acerta Pharma BV: Research Funding; Merck Sharp & Dohme Corp: Consultancy, Research Funding; Seattle Genetics: Research Funding; Incyte Corporation: Research Funding. Shadman:TG Therapeutic: Research Funding; Mustang Bio: Research Funding; Atara Biotherapeutics: Consultancy; Pharmacyclics: Consultancy, Research Funding; Genentech: Consultancy, Research Funding; AbbVie: Consultancy, Research Funding; Sunesis: Research Funding; Verastem: Consultancy; Astra Zeneca: Consultancy; ADC Therapeutics: Consultancy; Sound Biologics: Consultancy; Celgene: Research Funding; Gilead: Consultancy, Research Funding; BeiGene: Research Funding; Acerta Pharma: Research Funding. Ujjani:Pharmacyclics: Honoraria; Atara: Consultancy; Gilead: Consultancy; Genentech: Honoraria; Astrazeneca: Consultancy; AbbVie: Honoraria, Research Funding; PCYC: Research Funding. Cassaday:Amgen: Consultancy, Research Funding; Pfizer: Consultancy, Honoraria, Research Funding; Incyte: Research Funding; Kite/Gilead: Research Funding; Merck: Research Funding; Seattle Genetics: Research Funding; Seattle Genetics: Other: Spouse's disclosure: employment, stock and other ownership interests. Till:Mustang Bio: Patents & Royalties, Research Funding. Shustov:Seattle Genetics, Inc.: Research Funding. Gopal:Seattle Genetics, Pfizer, Janssen, Gilead, Sanofi, Spectrum, Amgen, Aptevo, BRIM bio, Acerta, I-Mab-pharma, Takeda, Compliment, Asana Bio, and Incyte.: Consultancy; Seattle Genetics, Pfizer, Janssen, Gilead, Sanofi, Spectrum, Amgen, Aptevo, BRIM bio, Acerta, I-Mab-pharma, Takeda, Compliment, Asana Bio, and Incyte: Honoraria; Teva, Bristol-Myers Squibb, Merck, Takeda, Seattle Genetics, Pfizer, Janssen, Takeda, and Effector: Research Funding.

Description: Background: Chemorefractory diffuse large B-cell lymphoma (DLBCL) is associated with poor outcomes. Recent Car-T therapy trials, including Zuma-1 which led to the first FDA approval of Car-T for DLBCL (Neelapu NEJM), have shown sustained complete remission, disease control, and long-term survival in a proportion of patients. As with all trials, results must be interepreted in context of study definitions and eligibility parameters. While selection bias is often discussed, little published data regarding specific eligibility requirements on accrual of DLBCL trials exists. To better understand factors influencing Car-T trial eligibility in DLBCL, and context for observed survival rates in Car-T trials, we examined chemorefractory DLBCL patients seen from 2011-2015 at our center, applying key eligibility criteria from Zuma-1 and describing likely reasons for trial exclusion. Methods: Pts with DLBCL seen at our institution from 2011-2015, who had received at least 2 lines of therapy, were reviewed under IRB approval to determine chemorefractory status based on ZUma-1 definition, and potential eligibility for the Zuma-1 trial. Chemorefractory status per Zuma 1 was defined as stable disease (lasting 6 months or less) or progressive disease as best response to most recent chemotherapy, or disease progression within 12 months of autologous stem cell transplant. "Chemorefractory date" was identified by the chart reviewed, based on biopsy or imaging showing progression, and served as the reference date for reviewing potential Zuma-1 eligibility in detail. Specifically, clinical data (ECOG, labs, organ function) within 8 weeks of chemorefractory date was examined to estimate potential Zuma-1 eligibility. On occasion, more remote studies (e.g., an echocardiogram 〉8 weeks prior) were applied when data appeared relevant. Descriptive statistics and a Kaplan-Meier survival estimate were performed, with a comparison between those potentially Zuma-1 eligible and those not. No attempt was made to compare outcomes among pts receiving specific therapies for chemorefractory DLBCL. The specific eligibility factors examined were: histology (DLBCL, PMBCL and tFL); prior therapy including history of allogeneic SCT; CNS involvement, performance status (ECOG 01- vs 2 or higher), laboratory parameters, cardiac disease, infectious comorbidities; history of second malignancy other than nonmelanoma skin cancer/in situ cance or FL; need for urgent therapy due to tumor mass effect or rapid progression. Results: Of 404 in our DLBCL database from 2011-2015, 163 had received at least 2 therapies and were examined. 36 had inadequate follow up, leaving 127 for detailed analysis. Of these 127, 78 were determined chemorefractory as per Zuma-1. Of these 78 chemorefractory pts, median age was 63 (18-82), 17 had transformed lymphoma, 30 underwent transplant (20 auto, 2 allo, 8 auto-allo), 18 relapsed within 1 year of autologous transplant, and 30 had primary refractory disease. 43 patients (55%) were deemed ineligible for Zuma-1 by retrospective review, for reasons given in Table 1. Figure 1 shows survival. Among "eligible" pts vs not: Median OS was 15 vs 8 months (eligible vs not, p=.04). 1 yr OS was 56% vs 33%, and 2 yrs OS 40% vs 22%. Conclusion: When applied to a historical cohort, about half of chemorefractory DLBCL pts met eligibility criteria for Zuma-1. The survival of "eligible" patients appears significantly better than others. A need for acute therapy (for rapid progression), ECOG performance status 2 or greater, and non-FL transformation (Richter's/CLL history) were the most common reasons for exclusion. Since these three features may not impact safety of Car-T therapy, but are associated with agrgessive disease, broadening eligibility around these criteria could represent a step toward testing Car-T therapies among those with greatest unmet need. Disclosures Lynch: T.G. Therapeutics: Research Funding; Rhizen Pharmaceuticals S.A.: Research Funding; Incyte Corporation: Research Funding; Takeda Pharmaceuticals: Research Funding; Johnson Graffe Keay Moniz & Wick LLP: Consultancy. Shadman:TG Therapeutics: Research Funding; AstraZeneca: Consultancy; Genentech: Research Funding; Verastem: Consultancy; Mustang Biopharma: Research Funding; Celgene: Research Funding; Gilead Sciences: Research Funding; AbbVie: Consultancy; Qilu Puget Sound Biotherapeutics: Consultancy; Acerta Pharma: Research Funding; Pharmacyclics: Research Funding; Genentech: Consultancy; Beigene: Research Funding. Till:Mustang Bio: Patents & Royalties, Research Funding. Shustov:SPECTRUM PHARMACEUTICALS: Consultancy, Research Funding. Gopal:Janssen: Consultancy, Research Funding; Asana: Consultancy; Takeda: Research Funding; Merck: Research Funding; BMS: Research Funding; Spectrum: Research Funding; Teva: Research Funding; Pfizer: Research Funding; Seattle Genetics: Consultancy, Research Funding; Gilead: Consultancy, Research Funding; Brim: Consultancy; Aptevo: Consultancy; Incyte: Consultancy. Smith:Pharmacyclics: Research Funding; Genentech: Research Funding; Acerta Pharma BV: Research Funding; Incyte Corporation: Research Funding; Merck Sharp and Dohme Corp.: Consultancy, Research Funding; Portola Pharmaceuticals: Research Funding; Seattle Genetics: Research Funding.

Description: Background: Patients infected with HIV have an 8 to 150-fold risk of lymphoma compared to HIV uninfected patients, with certain aggressive non-Hodgkin lymphoma (NHL) histologies being AIDS-defining. Despite the decrease in incidence of both NHL and Hodgkin lymphoma (HL) in the current anti-retroviral treatment (ART) era, HIV-infected patients remain at significantly increased risk of lymphoma compared to the general population. Over the last decade, advances have been made in the treatment of both NHL and HL with 18 agents approved since 2009. Unfortunately, safety and efficacy data in the HIV-infected population have been lacking in part due to exclusion of such patients from clinical trials. As such, the optimal treatment of HIV-associated lymphomas is unknown. In 2017, the National Comprehensive Care Network (NCCN) and the American Society of Clinical Oncology (ASCO) advocated expanding clinical trial opportunities for HIV-infected patients. However, exclusion criteria precluding HIV-infected patient participation likely persist. We sought to document and describe the current status of clinical trial exclusion criteria for NHL and HL as they relate to HIV infection. Methods We extracted data from the National Institute of Health's (NIH) registry of clinical trials (ClinicalTrials.gov) using the search term 'lymphoma' and reviewed all clinical trials (independent of funding source) in the United States that were recruiting or not yet recruiting adult patients for therapeutic trials (phase 1, 2, or 3) as of June 2019. A total of 734 trials met the above criteria; of these 206 were excluded as they were not primarily adult lymphoma trials (allogeneic transplant [n=87], leukemia [n=79], pediatric [n=87], lung cancer [n=12], and other [n=12]). As such, 526 clinical trials were included in the final sample. The primary outcome measure was whether HIV infection was an exclusion criterion for participation in the clinical trial. With the exception of the sample size, which was measured as a continuous variable, explanatory variables were dichotomized and included funding source (NIH vs. non-NIH), phase (phase 1 vs. phase 2 or 3), start date (start date prior to January 2018 vs. start date on or after January 2018), and recruitment status (recruiting vs. not yet recruiting). If the lymphoma under study was an aggressive subtype it was dichotomized as an AIDS-defining malignancy (aggressive NHL vs. other). We assessed whether these explanatory variables were associated with the primary outcome measure. We utilized bivariate analyses to identify measures with p 〈 0.20 for inclusion in a multivariate logistic regression model. Results: Of the 526 lymphoma-related trials, 352 (66.9%) excluded HIV-infected patients. Among all studies, the target sample sizes of these studies ranged from 6 to 6,542 (median 52) and were primarily phase 1 (219; 41.6%) or phase 2 (277; 52.7%) studies. Only 30 of the clinical trials were phase 3 (5.7%). The majority of studies (493; 93.7%) were actively recruiting and were initiated prior to January 1, 2018 (302; 57.4%). The majority of the 526 trials (320; 60.8%) included patients with aggressive NHL. The remaining trials included patients with indolent lymphoma, HL, or NHL with an unspecified subtype. Only 39 (7.4%) of all studies were funded strictly by NIH; the remainder were funded strictly by industry (192; 36.5%), 'other' (107; 20.3%), or a combination (188; 35.7%).[Table 1] Of the explanatory variables, funding source, sample size, and a start date on or after January 1, 2018 were associated with the outcome measure in the bivariate analysis and were included in a multivariate model. In the multivariate analyses, NIH-funded studies (OR 0.34 [0.17, 0.67], studies which began recruitment after January 1, 2018 (OR 0.66 [0.45, 0.97]) and larger studies (OR 0.998 [0.996, 0.999] were less likely to exclude HIV-infected patients. [Table 2] Conclusions: Despite support from ASCO and specific NCCN guidance which advocates that the participation in cancer clinical trials of patients living with HIV/AIDS "should be encouraged whenever feasible," the majority of interventional clinical trials for the treatment of lymphoma currently exclude participants based on infection with HIV. This goal of inclusion could be accomplished by adding an additional HIV-specific safety and efficacy cohort to most studies which could potentially be mandated by the FDA for all registrational trials. Disclosures Lynch: Rhizen Pharmaceuticals S.A: Research Funding; Takeda Pharmaceuticals: Research Funding; T.G. Therapeutics: Research Funding; Incyte Corporation: Research Funding; Johnson Graffe Keay Moniz & Wick LLP: Consultancy; Juno Therapeutics: Research Funding. Shadman:Sound Biologics: Consultancy; Acerta: Research Funding; Pharmacyclics: Consultancy, Research Funding; Celgene: Research Funding; Gilead: Research Funding; TG Therapeutics: Research Funding; Atara: Consultancy; Verastem: Consultancy; Mustang Biopharma: Research Funding; Bigene: Research Funding; ADC Therapeutics: Consultancy; Merck: Research Funding; AbbVIe: Consultancy, Research Funding; Sunesis: Research Funding; Genentech, Inc.: Consultancy, Research Funding; Emergent: Research Funding; AstraZeneca: Consultancy. Shustov:Spectrum Pharmaceuticals: Consultancy, Research Funding. Smith:AstraZeneca: Membership on an entity's Board of Directors or advisory committees, Research Funding; Acerta Pharma BV: Research Funding; Merck Sharp & Dohme Corp: Consultancy, Research Funding; Denovo Biopharma: Research Funding; Genentech: Research Funding; Ignyta (spouse): Research Funding; Bristol-Myers Squibb (spouse): Research Funding; Ayala (spouse): Research Funding; Pharmacyclics: Research Funding; Portola Pharmaceuticals: Research Funding; Seattle Genetics: Research Funding; Incyte Corporation: Research Funding. Till:Mustang Bio: Patents & Royalties, Research Funding. Ujjani:PCYC: Research Funding; Pharmacyclics: Honoraria; Pharmacyclics: Honoraria; Genentech: Honoraria; PCYC: Research Funding; Gilead: Consultancy; Gilead: Consultancy; Astrazeneca: Consultancy; Astrazeneca: Consultancy; Atara: Consultancy; Genentech: Honoraria; Atara: Consultancy; AbbVie: Honoraria, Research Funding; AbbVie: Honoraria, Research Funding. Uldrick:Roche: Other: commercial research support through a CTA with Fred Hutchinson Cancer Research Center; Merck: Other: drug for a clinical trial from Merck through a CRADA with the NCI; Celgene: Other: research support from Celgene through a CRADA at the NCI; Patent: Patents & Royalties: co-inventor on US Patent 10,001,483 entitled . Gopal:Seattle Genetics, Pfizer, Janssen, Gilead, Sanofi, Spectrum, Amgen, Aptevo, BRIM bio, Acerta, I-Mab-pharma, Takeda, Compliment, Asana Bio, and Incyte.: Consultancy; Seattle Genetics, Pfizer, Janssen, Gilead, Sanofi, Spectrum, Amgen, Aptevo, BRIM bio, Acerta, I-Mab-pharma, Takeda, Compliment, Asana Bio, and Incyte: Honoraria; Teva, Bristol-Myers Squibb, Merck, Takeda, Seattle Genetics, Pfizer, Janssen, Takeda, and Effector: Research Funding.

Description: Introduction: CD19-specific chimeric antigen receptor (CAR) T-cell therapy is FDA-approved in patients with relapsed or refractory large B-cell lymphomas and can lead to long-term remissions in 35-40% of patients. Outcomes in patients who progress after CAR T-cell therapy is poor, with a median overall survival (OS) of 5.3 months with few long-term survivors (Chow et al. AJH 2019). Achieving quality end of life (EOL) care for patients with hematologic malignancies has been a challenge, and widespread consensus on what are acceptable metrics is lacking (Odejide et al JCO 2016). EOL care among large B-cell lymphoma patients who progressed after CAR-T cell therapy has not been previously examined. Methods: Adults with large B-cell lymphomas who received CD19-specific CAR T-cells at the University of Washington/Seattle Cancer Care Alliance since 2011 who subsequently progressed and ultimately died were included. Patients who received CAR T-cell therapy with additional concurrent protocol-specified therapy were excluded. We also examined a similar cohort of chemorefractory large B-cell lymphoma patients who did not receive CAR T-cell therapy and later died of their disease (Smith et al. AJH 2019). EOL metrics including death in an acute care facility, transfusion or hospice admission within 7 days of death, lymphoma treatment (excluding steroids) within 14 days of death, ED visit, and hospitalization, or ICU admission within 30 days of death were abstracted from medical records under IRB approval. We also analyzed data based on death ≤90 days or 〉 90 days after CAR T-cell therapy or date determined chemorefractory in the cohort receiving non-CAR T-cell treatments. Statistical analyses were descriptive, with univariate analyses performed between the subsets mentioned above. P-values were calculated using Fisher's Exact test for categorical variables, and Wilcoxon Rank Sum test for continuous variables. Results: We identified 49 patients who progressed after CD19-specific CAR T-cell treatment and subsequently died, and 31 patients with chemorefractory DLBCL who did not receive CAR T-cells. 37 of 49 post-CAR patients, and 17 of 31 chemorefractory patients had adequate data for analysis. Baseline characteristics were balanced between the two groups except that post-CAR patients had more median prior therapies (4 (range 1-9) vs. 3 (range 2-3), p = 0.005). There was no significant difference in EOL measures between the post-CAR and chemorefractory subsets. While few patients received chemotherapy (8.1% vs. 11.8%) or oral therapy (10.8% vs. 17.6%) within 14 days of death, there were high rates of ED visits and hospitalizations (73.0% vs. 82.4%), as well as hospice enrollment within 7 days of death (43.8% vs. 50.0%). When we stratified post-CAR patients by death ≤ 90 days vs 〉 90 days after progression, we found that late death was associated with increased rates of ICU stays within 30 days of death (55.0% vs. 11.8%, p = 0.014), hospice enrollment within 7 days of death (73.3% vs. 17.6%, p = 0.004), death in an acute care facility (45.0% vs. 11.8%, p = 0.036), and inability to meet all EOL measures (95.0% vs. 64.7%, p = 0.033). No significant differences were seen in chemorefractory patients when stratified by time of death. Conclusions: Patients who succumb to refractory DLBCL received aggressive care at the EOL, including high rates of ED/hospital visits and ICU stays near death, whether treated with CAR T-cell therapy or alternative treatments at our center. In particular, patients with death more than 90 days after relapse from CAR T-cell therapy rarely achieved standard EOL measures. While these data require validation in other cohorts, improvements in EOL care and planning appear critical in the setting of refractory DLBCL. Disclosures Lynch: Juno Therapeutics: Research Funding; Rhizen Pharmaceuticals S.A: Research Funding; T.G. Therapeutics: Research Funding; Incyte Corporation: Research Funding; Johnson Graffe Keay Moniz & Wick LLP: Consultancy; Takeda Pharmaceuticals: Research Funding. Maloney:Juno Therapeutics: Honoraria, Patents & Royalties: patients pending , Research Funding; Celgene,Kite Pharma: Honoraria, Research Funding; BioLine RX, Gilead,Genentech,Novartis: Honoraria; A2 Biotherapeutics: Honoraria, Other: Stock options . Turtle:Humanigen: Other: Ad hoc advisory board member; Novartis: Other: Ad hoc advisory board member; T-CURX: Membership on an entity's Board of Directors or advisory committees; Kite/Gilead: Other: Ad hoc advisory board member; Juno Therapeutics: Patents & Royalties: Co-inventor with staff from Juno Therapeutics; pending, Research Funding; Nektar Therapeutics: Other: Ad hoc advisory board member, Research Funding; Precision Biosciences: Equity Ownership, Membership on an entity's Board of Directors or advisory committees; Eureka Therapeutics: Equity Ownership, Membership on an entity's Board of Directors or advisory committees; Caribou Biosciences: Equity Ownership, Membership on an entity's Board of Directors or advisory committees; Allogene: Other: Ad hoc advisory board member. Shadman:Sunesis: Research Funding; Atara Biotherapeutics: Consultancy; TG Therapeutic: Research Funding; Gilead: Consultancy, Research Funding; BeiGene: Research Funding; Acerta Pharma: Research Funding; Sound Biologics: Consultancy; AbbVie: Consultancy, Research Funding; Mustang Bio: Research Funding; Pharmacyclics: Consultancy, Research Funding; Genentech: Consultancy, Research Funding; Verastem: Consultancy; Astra Zeneca: Consultancy; Celgene: Research Funding; ADC Therapeutics: Consultancy. Ujjani:AbbVie: Honoraria, Research Funding; Pharmacyclics: Honoraria; PCYC: Research Funding; Genentech: Honoraria; Gilead: Consultancy; Astrazeneca: Consultancy; Atara: Consultancy. Cassaday:Merck: Research Funding; Amgen: Consultancy, Research Funding; Pfizer: Consultancy, Honoraria, Research Funding; Incyte: Research Funding; Kite/Gilead: Research Funding; Seattle Genetics: Research Funding; Seattle Genetics: Other: Spouse's disclosure: employment, stock and other ownership interests. Till:Mustang Bio: Patents & Royalties, Research Funding. Shustov:Seattle Genetics, Inc.: Research Funding. Gopal:Seattle Genetics, Pfizer, Janssen, Gilead, Sanofi, Spectrum, Amgen, Aptevo, BRIM bio, Acerta, I-Mab-pharma, Takeda, Compliment, Asana Bio, and Incyte: Honoraria; Teva, Bristol-Myers Squibb, Merck, Takeda, Seattle Genetics, Pfizer, Janssen, Takeda, and Effector: Research Funding; Seattle Genetics, Pfizer, Janssen, Gilead, Sanofi, Spectrum, Amgen, Aptevo, BRIM bio, Acerta, I-Mab-pharma, Takeda, Compliment, Asana Bio, and Incyte.: Consultancy. Smith:Ignyta (spouse): Research Funding; Ayala (spouse): Research Funding; AstraZeneca: Membership on an entity's Board of Directors or advisory committees, Research Funding; Acerta Pharma BV: Research Funding; Merck Sharp & Dohme Corp: Consultancy, Research Funding; Denovo Biopharma: Research Funding; Genentech: Research Funding; Pharmacyclics: Research Funding; Seattle Genetics: Research Funding; Portola Pharmaceuticals: Research Funding; Incyte Corporation: Research Funding; Bristol-Myers Squibb (spouse): Research Funding.