CORRELATIVE ANALYSES OF CYTOKINE RELEASE SYNDROME AND NEUROLOGICAL EVENTS IN TISAGENLECLEUCEL‐TREATED RELAPSED/REFRACTORY DIFFUSE LARGE B‐CELL LYMPHOMA PATIENTS (2019)

Background: Tisagenlecleucel (anti-CD19 CAR-T cell therapy) has shown durable responses and a manageable safety profile in adult patients (pts) with relapsed/refractory diffuse large B-cell lymphoma (r/r DLBCL). We report a 24 mo clinical update and correlative analyses between cytokine release syndrome (CRS)/neurological events (NE) and inflammatory/lab analyte markers. Methods: JULIET (NCT02445248) is a single-arm, pivotal, phase 2 trial of tisagenlecleucel in adult pts with r/r DLBCL. The primary endpoint was overall response rate (ORR: complete [CR] + partial response). Peak (within 1 mo of infusion) serum cytokine levels/lab parameters were correlated with rate/grade (gr) of CRS (by Penn) and NE (by CTCAE v4.03) within 8 wk of infusion. Results: As of 11 Dec 2018, 115 pts were infused (99 evaluable for efficacy). ORR remained 54% (95% CI: 43, 64), CR rate was 40%, and median duration of response was not reached (NR; 95% CI: 10, –) at a max follow-up of almost 24 mo from onset of response. Of 31 pts with CR at 6 mo, 3 relapsed between 6-12 mo and 1 relapsed beyond 12 mo. Median overall survival for all 115 pts was 10.3 mo (NR for pts in CR). Severe (gr 3/4) CRS and NE occurred in 23% and 11%, respectively. 83% of pts with any gr NE also had CRS; 62% of pts with severe NE had severe CRS. Median time to onset of CRS and NE was 3 and 6 d, respectively. Peak cytokine levels within 1 mo of infusion were increased in pts with CRS/NE and the trend was more noticeable in pts with severe CRS and severe NE. Higher CRP, ferritin, interferon-ɣ (IFNG), IL2, IL6, and IL10 were observed in pts with severe CRS; severe NE showed similar trends of a lesser degree, except for IFNG. In pts with CRS, cytokines peaked on d 6-9, with early increase of IL2, IL6, and IFNG in the first 2 d post-infusion with severe CRS. Low platelet count, elevated lactate dehydrogenase, and below-normal albumin levels were seen after lymphodepleting chemotherapy; these trends continued post-infusion in pts with severe CRS. As CRS progressed, hepatic and kidney dysfunction-related analytes trended toward an increase, peaking 2 wk post-infusion in pts with severe CRS. Additional univariate/multivariate analyses using pts’ disease and clinical characteristics in an attempt to predict CRS/NE severity are ongoing. Conclusions: With almost 24 mo max follow-up, tisagenlecleucel continued to demonstrate durable efficacy. Severe NE appeared to correlate with severe CRS. Trends in peak levels of several markers were noted with severe CRS and – to a lesser extent – severe NE. Keywords: CD19; cytokines; diffuse large B-cell lymphoma (DLBCL). Disclosures: Bachanova, V: Consultant Advisory Role: Novartis; Research Funding: GAMIDA Cell, UNUM, Novartis, GT Biopharm. Westin, J: Consultant Advisory Role: Novartis, Kite Pharma, Juno, Celgene, Janssen, Genentech. Tam, C: Honoraria: Novartis. Borchmann, P: Honoraria: Novartis. Jaeger, U: Honoraria: AbbVie, Bioverativ, Celgene, Gilead, Janssen, MSD, Novartis, Roche, Takeda Millenium, Amgen, AOP Orphan, BMS, Sandoz; Research Funding: Bioverativ, Celgene, Gilead, Janssen, MSD, Novartis, Roche; Other Remuneration: AbbVie, Celgene, Gilead, Janssen, MAD, Novartis, Roche, Takeda Millenium, Amgen, AOP Orphan, BMS, Sandoz. McGuirk, J: Honoraria: Kite Pharma; Research Funding: Novartis, Kite Pharma, Fresenius Biotech, Astellas Pharma, Bellicum Pharmaceuticals, Gamida Cell, Pluristem Ltd. Holte, H: Consultant Advisory Role: Novartis; Honoraria: Novartis. Waller, E: Employment Leadership Position: Cambium Medical Technologies; Consultant Advisory Role: Kalytera, Novartis; Stock Ownership: Cerus Corporation, Chimerix; Honoraria: Cambrium Medical Technologies, Kalytera, Novartis; Research Funding: Celldex, Novartis, Pharmacyclics. Jaglowski, S: Honoraria: Kite Pharma, Juno; Research Funding: Novarits. Bishop, M: Employment Leadership Position: United Healthcare; Honoraria: Celgene, Jeneau Therapeutics, Novartis. Andreadis, C: Honoraria: Novartis, Genentech, Seattle Genetics, Gilead, Astellas; Research Funding: Novartis, Cellerant Therapeutics, Incyte, Pharmacyclics, Amgen, Genentech. Fleury, I: Honoraria: Gilead, Novartis, Roche, Seattle Genetics, Janssen, AbbVie. Teshima, T: Honoraria: Novartis; Research Funding: Novartis. Mielke, S: Consultant Advisory Role: Celgene, KIADIS Pharma, Miltenyi Biotec, DGHO, EHA. Salles, G: Consultant Advisory Role: Novartis; Honoraria: Novartis. Ho, P: Other Remuneration: Novartis, Celgene, La Jolla Pharmaceuticals. Izutsu, K: Honoraria: Novartis, Eisal, Kyowa Hakko Kirin, MSD, Takeda, Janssen, Bristol Myers Squib, Dainihon Sumitomo, Mundipharma, Nihon Mediphysics, Chugai, AstraZeneca, AbbVie, Bayer, Ono, Celgene; Research Funding: Novartis, Eisal, MSD, Takeda, Janssen, Mundipharma, Chugai, AbbVie, Bayer, Ono, Gilead, Zenyaku, Celgene, Solasia, Symbio, Astellas, Astellas Amgen, Diichi Sankyo. Maziarz, R: Consultant Advisory Role: Novartis, Incyte, Juno Therapeutics; Honoraria: Novartis, Incyte, Juno Therapeutics, Kite Therapeutics; Research Funding: Novartis; Other Remuneration: Athersys, Inc. Van Besien, K: Research Funding: Novartis. Kersten, M: Consultant Advisory Role: Roche, Celgene, Takeda, Novartis, Kite, BMS; Honoraria: Roche, Celgene, Takeda, Novartis, Kite; Research Funding: Roche, Celgene, Takeda. Wagner-Johnston, N: Consultant Advisory Role: Juno, ADC Therapeutics, Janssen. Corradini, P: Consultant Advisory Role: Celgene, AbbVie, Amgen, Daiichi Sankyo, Gilead, Janssen, Kiowakirin, Novartis, Roche, Sanofi, Servier, Takeda. Han, X: Employment Leadership Position: Novartis. Agoulnik, S: Employment Leadership Position: Novartis. Chu, J: Employment Leadership Position: Novartis. Eldjerou, L: Employment Leadership Position: Novarits. Pacaud, L: Employment Leadership Position: Novartis. Schuster, S: Honoraria: Celgene, Genentech, Merck, Pharmacyclics, Novartis, Nordic Nanovector, Acerta, Pfizer, Gilead; Research Funding: Celgene, Genentech, Merck, Pharmacyclics, Novartis, Gilead.