ALBERT

Description: Background Tisagenlecleucel is a CD19-directed genetically modified autologous T-cell immunotherapy approved for the treatment of patients up to 25 years of age with B-cell ALL that is refractory or in second or later relapse. In the pivotal ELIANA trial, 79 patients were treated with tisagenlecleucel. The best overall response rate (CR/CRi) was 82%; 98% of patients who achieved CR/CRi were also negative for minimal residual disease (MRD). With a median follow-up of 24 months, the median duration of remission was not reached. Grade 3 or higher cytokine release syndrome (CRS) by UPenn criteria and neurotoxicity within the first 8 weeks after infusion occurred in 49% and 13%, respectively (Grupp, et al. Blood 2018, Abstr 895). The CIBMTR CT Registry was developed to collect long-term safety and efficacy information on recipients of cellular immunotherapies and it is utilized for a post marketing study of tisagenlecleucel in the real world setting. Methods Clinical data from the CT registry were analyzed for baseline information. Efficacy and safety data were presented among patients with a minimum of 3 months follow-up. CRS and immune effector cell-associated neurotoxicity syndrome (ICANS) were reported as per the ASTCT consensus criteria. Additionally, manufacturing product characteristics of tisagenlecleucel were compared to clinical outcomes. The association of number of cells administered, cell viability, potency, and transduction efficiency of tisagenlecleucel to overall response, CRS and ICANS grades was performed using descriptive summaries and univariate logistic regression analyses. Results Forty centers in the U.S. contributed data for refractory or relapsed pediatric or young adult patients with B-cell ALL through the CIBMTR CT registry as of May 31, 2019. Baseline information was available for 159 patients; 105 patients had at least the first follow up assessment reported at 3 months (Table 1). The median follow-up of survivors was 5.8 months (2.6-16.9 months). All patients received cells in the approved range for their weight with a median of 1.9 x 106/kg (range 0.2-4.6 x 106/kg) for children ≤ 50 kg and 0.9 x 108 (range 0.1-2.3 x 108) for children and young adults 〉 50 kg. The best overall response rate (CR) was 88% (95% CI 80%-94%). MRD was collected in 52 patients after tisagenlecleucel; all were negative. Importantly, among the 4 patients age 〈 3 years of age with more than 3 months of follow-up, all attained a CR. The 6-month duration of response, event-free survival and overall survival (OS) was 77%, 68% and 94%, respectively. After bridging therapy, there were 35 patients who attained CR and 63 patients who did not attain CR at the time of tisagenlecleucel infusion. The 6-month OS rate was 100% and 90.2% for patients attaining CR and not attaining CR, respectively. The rate of grade 3 or higher CRS and ICANS was 13.3% and 8.6%, respectively and was similar for patients age 〈 3 years. Clinically significant infections within the first 3 months occurred in 35.2% of patients; bacterial infections were most common. Deaths within 30 days following infusion occurred in 2 patients (due to disease progression and cerebral hemorrhage) and no deaths were attributed directly to tisagenlecleucel. Secondary malignancy was reported in 1 patient (myeloproliferative neoplasm). None of the manufacturing characteristics (cell viability, potency, nor transduction efficiency) or cell dose were associated with efficacy or safety. Importantly, analysis of cell viability showed no association with best overall response (Table 2). Conclusions The CIBMTR CT registry represents real world data for the treatment of pediatric patients with relapsed/refractory ALL and will allow follow up of these patients for 15 years. Tisagenlecleucel therapy in the real world setting demonstrated similar efficacy and safety compared to the pivotal ELIANA trial. None of the manufacturing characteristics analyzed (including % cell viability) correlated with response rates, CRS or ICANS. Updated results will be presented at the meeting. Disclosures Grupp: CBMG: Consultancy; Novartis: Research Funding; Kite: Research Funding; Servier: Research Funding; Novartis: Consultancy, Research Funding; Roche: Consultancy; GSK: Consultancy; Cure Genetics: Consultancy; Humanigen: Consultancy; Jazz: Other: study steering committees or scientific advisory boards; Adaptimmune: Other: study steering committees or scientific advisory boards. Pulsipher:Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Jazz: Other: Education for employees; Adaptive: Membership on an entity's Board of Directors or advisory committees, Research Funding; CSL Behring: Membership on an entity's Board of Directors or advisory committees; Amgen: Other: Lecture; Bellicum: Consultancy; Miltenyi: Research Funding; Medac: Honoraria. Margossian:Novartis: Membership on an entity's Board of Directors or advisory committees. Curran:Novartis: Consultancy; Juno Therapeutics: Consultancy, Research Funding. Nikiforow:Kite/Gilead: Honoraria; Novartis: Honoraria; NKarta: Honoraria. Chawla:Novartis Pharma AG: Employment. Horowitz:Actinium: Other: Unrestricted educational and research grant; Mesoblast: Other: Unrestricted educational and research grant, Research Funding; CSL Behring: Other: Unrestricted educational and research grant, Research Funding; Daiichi Sankyo: Other: Unrestricted educational and research grant; Magenta: Consultancy, Other: Unrestricted educational and research grant; GlaxoSmithKline: Other: Unrestricted educational and research grant; Miltenyi Biotech: Other: Unrestricted educational and research grant, Research Funding; Bristol-Myers Squibb: Other: Unrestricted educational and research grant, Research Funding; Oncoimmune: Other: Unrestricted educational and research grant; Chimerix: Other: Unrestricted educational and research grant; Amgen: Other: Unrestricted educational and research grant; Shire: Other: Unrestricted educational and research grant; Gamida Cell: Other: Unrestricted educational and research grant, Research Funding; Janssen: Other: Unrestricted educational and research grant, Research Funding; Kite Pharma/Gilead: Other: Unrestricted educational and research grant, Research Funding; Pharmacyclics: Other: Unrestricted educational and research grant; Regeneron: Other: Unrestricted educational and research grant; Sanofi: Other: Unrestricted educational and research grant, Research Funding; Seattle Genetics: Other: Unrestricted educational and research grant. Bleickardt:Novartis: Employment. Pasquini:Novartis: Research Funding; Kit Pharma: Research Funding; BMS: Research Funding; Pfizer: Other: Advisory Board; Amgen: Consultancy; Medigene: Consultancy.

Description: Introduction Tisagenlecleucel is a CD19-directed genetically modified autologous T-cell immunotherapy approved for the treatment of adult patients with relapsed or refractory large B-cell lymphoma after two or more lines of systemic therapy including diffuse large B-cell lymphoma not otherwise specified (DLBCL-NOS), high grade B-cell lymphoma and DLBCL arising from follicular lymphoma. In the pivotal JULIET trial, 115 patients received tisagenlecleucel treatment; the best overall response rate (ORR) was 54% and complete response (CR) rate was 40%. At a median follow-up of 24 months, the median duration of response was not reached. Grade 3 or higher cytokine release syndrome (CRS) (UPenn scale) and neurotoxicity within the first 8 weeks after infusion occurred in 22.6% and 11.3%, respectively (Bachanova et. al. Hematol Oncol. Abstr 2019). CIBMTR CT Registry was developed to collect long-term safety and efficacy information on recipients of cellular immunotherapies and it is utilized for a post marketing study of tisagenlecleucel in the real-world setting. Methods Clinical data from the registry were analyzed for baseline information. Efficacy and safety data were collected from patients with a minimum of 3 months follow-up. CRS and immune effector cell-associated neurotoxicity syndrome (ICANS) were reported as per the consensus ASTCT criteria. Important manufacturing product characteristics of tisagenlecleucel were compared to clinical outcomes obtained by the CIBMTR CT registry. The association of number of cells administered, cell viability, potency, and transduction efficiency to overall response, CRS and ICANS grade was performed using descriptive summaries and univariate logistic regression analyses. Tisagenlecleucel cell product characterization by immunophenotyping was also compared to clinical outcomes in the CIBMTR Registry. Results Twenty-six centers contributed data for relapsed/refractory DLBCL patients through the CIBMTR CT registry as of May 31, 2019. Baseline information was available in 70 patients while outcomes ≥ 3 months post-infusion was available on 47 patients (Table 1). All patients received cells in the FDA approved range (0.6 to 6 x 108 CAR+ viable T cells) with a median of 1.7 x 108 (range 0.6-3.5 x 108). The median follow-up time for survivors was 5.8 months (0.9-8.9 months). The overall response rate (ORR) was 59.6% (28 of 47 patients) including 38.3% (18 patients) achieving a CR. The rate of grade 3 or higher CRS and ICANS was 4.3% and 4.3%, respectively. Tocilizumab and corticosteroids were administered in 40.9% and 9.1% among patients who had CRS. The median time to onset of CRS was 4.5 days and lasted for an average of 5 days. A total of 14 (29.8%) patients died after treatment, all due to disease progression and no deaths were attributed to toxicities from tisagenlecleucel. A secondary malignancy was reported in 1 patient (basal cell carcinoma) that was present prior to CAR-T cell infusion. Out of the products manufactured for these 47 patients, 21 were out-of-commercial specification (OOS) because of low cell viability (〈 80%), however, efficacy and safety outcomes were similar to those with batches meeting viability specifications. None of the manufacturing characteristics analyzed (such as cell viability, potency or transduction efficiency) correlated with either efficacy (ORR) or safety (CRS or ICANS). Importantly, analysis of cell viability showed no association with best overall response (Table 2). Conclusions The CIBMTR CT registry represents real-world data for the treatment of adults with DLBCL and allows capture of long-term follow up (15 years). The efficacy and safety in the real world setting demonstrate similar efficacy and safety as compared with the pivotal JULIET trial. Cell product characteristics analyzed, including percentage of viable cells, do not correlate with response rates, CRS or ICANS. Updated results, including tisagenlecleucel cell product characterization, will be presented at the meeting. Disclosures Kamdar: Seattle Genetics: Speakers Bureau; Pharmacyclics: Consultancy; Celgene: Consultancy; AstraZeneca: Consultancy; University of Colorado: Employment. Perales:Medigene: Membership on an entity's Board of Directors or advisory committees; Servier: Membership on an entity's Board of Directors or advisory committees; Kyte/Gilead: Research Funding; Miltenyi: Research Funding; Merck: Consultancy, Honoraria; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees; MolMed: Membership on an entity's Board of Directors or advisory committees; NexImmune: 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; 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; Omeros: Honoraria, Membership on an entity's Board of Directors or advisory committees. Nikiforow:Kite/Gilead: Honoraria; Novartis: Honoraria; NKarta: Honoraria. Jeschke:Novartis: Employment. Chawla:Novartis Pharma AG: Employment. Horowitz:Mesoblast: Other: Unrestricted educational and research grant, Research Funding; Gamida Cell: Other: Unrestricted educational and research grant, Research Funding; Chimerix: Other: Unrestricted educational and research grant; Janssen: Other: Unrestricted educational and research grant, Research Funding; Pharmacyclics: Other: Unrestricted educational and research grant; Daiichi Sankyo: Other: Unrestricted educational and research grant; Miltenyi Biotech: Other: Unrestricted educational and research grant, Research Funding; CSL Behring: Other: Unrestricted educational and research grant, Research Funding; Regeneron: Other: Unrestricted educational and research grant; Sanofi: Other: Unrestricted educational and research grant, Research Funding; Bristol-Myers Squibb: Other: Unrestricted educational and research grant, Research Funding; Seattle Genetics: Other: Unrestricted educational and research grant; Actinium: Other: Unrestricted educational and research grant; GlaxoSmithKline: Other: Unrestricted educational and research grant; Amgen: Other: Unrestricted educational and research grant; Kite Pharma/Gilead: Other: Unrestricted educational and research grant, Research Funding; Magenta: Consultancy, Other: Unrestricted educational and research grant; Shire: Other: Unrestricted educational and research grant; Oncoimmune: Other: Unrestricted educational and research grant. Bleickardt:Novartis: Employment. Pasquini:Pfizer: Other: Advisory Board; Amgen: Consultancy; Medigene: Consultancy; BMS: Research Funding; Kit Pharma: Research Funding; Novartis: Research Funding.

Description: Introduction Axi-cel is approved in the US for the treatment of adult patients with relapsed or refractory large B cell lymphoma after 2 or more lines of systemic therapy. A post-marketing study is ongoing in the US utilizing the infrastructure created by the Center for International Blood and Marrow Transplant (CIBMTR) for post-approval safety and efficacy assessment and to follow these patients for 15 years through the established cellular therapy registry. This is the first year analysis of this study. Methods From October 18, 2017 to May 1, 2019, 453 axi-cel recipients were voluntarily reported to the CIBMTR. Of these, 295 patients from 43 US centers that have at least the first follow-up assessment submitted at 3 months were included in this analysis. Median follow-up was 6 months (range, 1-14 months). Results The median age overall was 61 years, 101 (34%) patients were ≥ 65 years, and 197 (67%) patients were male (Table 1). Baseline clinical characteristics included Eastern Cooperative Oncology Group (ECOG) performance score 0-1 (77%), transformed lymphoma (27%), double-hit lymphoma (36%), prior autologous transplant (34%), and chemotherapy-resistant disease (66%) prior to axi-cel. The median time from diagnosis to axi-cel infusion was 18 months (range 2-274 months). Overall response rate (ORR) was 70% (complete response [CR] 52% and partial response [PR] 18%). Patients ≥ 65 years were generally comparable vs younger patients with a slightly better CR rate (62% vs 46%, p=0.03) but similar overall response rate (CR+PR, 75% vs 67%, p=0.26). Cytokine release syndrome (CRS) of any grade was reported in 83% of patients. Incidence of Grades ≥ 3 CRS according to Lee et al 2014 was 11%, and was 14% according to American Society for Transplantation and Cellular Therapy (ASTCT) Consensus Grading (Table 2). Two patients died due to CRS. Median time to any grade CRS was 3 days (range, 1-17 days), and 94% of CRS cases resolved with a median duration of 7 days (range, 1-121 days). Among patients with CRS, tocilizumab, corticosteroids and siltuximab were used in 70%, 26% and 1% of cases, respectively. Neurologic adverse events (AEs) of any grade occurring after axi-cel infusion were reported in 181 (61%) patients. One patient was reported to die from cerebral edema. Additional information on neurologic AE severity will be presented. The median time to onset of any grade neurologic AEs was 6 days (range, 1-82 days), and 88% resolved by time of data submission with a median duration of 8 days (range, 1 to 105 days). Corticosteroids were used in 56% of patients for treatment. Patients ≥ 65 years had comparable CRS (85% vs 82%, p=0.62), grades ≥ 3 CRS (13% vs 9%, p=0.62), and neurologic AEs (68% vs 58%, p=0.13) vs patients 〈 65 years of age. Prolonged cytopenias (thrombocytopenia and neutropenia), as defined by an inability to recover within 30 days after the administration of axi-cel, occurred in 7% of patients. Preliminary data reveals 6 patients (2%) reported subsequent neoplasms: myelodysplasia (n=3), lung cancer (n=1), neuroendocrine tumor (n=1), and cutaneous squamous cell carcinoma (n=1); additional details, including pre-existing risk factors, will be addressed when the updated analysis is presented. Conclusion Post-approval axi-cel use reported in this registry study in the US, when compared to the registrational ZUMA-1 trial, includes a larger proportion of older patients, patients with transformed or double-hit lymphoma, and patients with a worse performance status. Despite these differences, best responses and toxicities are comparable to those reported for the ZUMA-1 trial. CRS severity assessment varied based on the grading method utilized, with a slightly higher rate of grade 3 CRS based on ASTCT Consensus Grading compared with Lee et al 2014. The safety and efficacy outcomes of patients ≥ 65 years at this early stage are comparable to those of younger patients, although further analysis with more follow-up is warranted. Disclosures Pasquini: Novartis: Research Funding; Kit Pharma: Research Funding; BMS: Research Funding; Pfizer: Other: Advisory Board; Amgen: Consultancy; Medigene: Consultancy. Locke:Cellular BioMedicine Group Inc.: Consultancy; Kite: Other: Scientific Advisor; Novartis: Other: Scientific Advisor. Herrera:Pharmacyclics: Research Funding; Kite Pharma: Consultancy, Research Funding; Immune Design: Research Funding; Merck: Consultancy, Research Funding; Genentech, Inc.: Consultancy, Research Funding; Seattle Genetics: Consultancy, Research Funding; AstraZeneca: Research Funding; Adaptive Biotechnologies: Consultancy; Bristol-Myers Squibb: Consultancy, Research Funding; Gilead Sciences: Consultancy, Research Funding. Siddiqi:Seattle Genetics: Speakers Bureau; BeiGene: Research Funding; Celgene: Research Funding; TG Therapeutics: Research Funding; Kite: Research Funding; Astra Zeneca: Consultancy, Other: Travel, Accommodations, Expenses, Research Funding, Speakers Bureau; Pharmacyclics LLC, an AbbVie company: Consultancy, Research Funding, Speakers Bureau; Juno: Consultancy, Research Funding; Janssen: Speakers Bureau. Ghobadi:Celgene: Consultancy; Wugen: Consultancy; Kite Pharma a Gilead Company: Consultancy, Research Funding, Speakers Bureau; EUSA: Consultancy. Dong:Gilead Inc: Other: Own Stock; Kite Pharma: Employment. Nikiforow:Kite/Gilead: Honoraria; Novartis: Honoraria; NKarta: Honoraria. Purdum:Kite Pharma: Employment. Horowitz:Sanofi: Other: Unrestricted educational and research grant, Research Funding; Chimerix: Other: Unrestricted educational and research grant; CSL Behring: Other: Unrestricted educational and research grant, Research Funding; Regeneron: Other: Unrestricted educational and research grant; Kite Pharma/Gilead: Other: Unrestricted educational and research grant, Research Funding; Daiichi Sankyo: Other: Unrestricted educational and research grant; GlaxoSmithKline: Other: Unrestricted educational and research grant; Janssen: Other: Unrestricted educational and research grant, Research Funding; Gamida Cell: Other: Unrestricted educational and research grant, Research Funding; Actinium: Other: Unrestricted educational and research grant; Amgen: Other: Unrestricted educational and research grant; Bristol-Myers Squibb: Other: Unrestricted educational and research grant, Research Funding; Magenta: Consultancy, Other: Unrestricted educational and research grant; Mesoblast: Other: Unrestricted educational and research grant, Research Funding; Miltenyi Biotech: Other: Unrestricted educational and research grant, Research Funding; Oncoimmune: Other: Unrestricted educational and research grant; Pharmacyclics: Other: Unrestricted educational and research grant; Seattle Genetics: Other: Unrestricted educational and research grant; Shire: Other: Unrestricted educational and research grant. Hooper:Kite Pharma Inc: Employment, Other: Owner Stock. Kawashima:Kite: Employment. Jacobson:Bayer: Consultancy, Other: Travel Expenses; Novartis: Consultancy, Honoraria, Other: Travel Expenses; Kite, a Gilead Company: Consultancy, Honoraria, Other: Travel Expenses, Research Funding; Precision Biosciences: Consultancy, Other: Travel Expenses; Pfizer: Consultancy, Research Funding; Humanigen: Consultancy, Other: Travel Expenses; Celgene: Consultancy, Other: Travel Expenses.