INTRAVENOUS IMMUNOGLOBULIN THERAPY USE IN PATIENTS WITH RELAPSED/REFRACTORY DIFFUSE LARGE B‐CELL LYMPHOMA TREATED WITH TISAGENLECLEUCEL IN THE JULIET TRIAL (2019)

Background: Tisagenlecleucel is an anti-CD19 chimeric antigen receptor (CAR)-T cell therapy that has demonstrated durable responses and a manageable safety profile in adult patients (pts) with relapsed/refractory diffuse large B-cell lymphoma (r/r DLBCL). Intravenous immunoglobulin (IVIG) is commonly used to manage hypogammaglobulinemia following stem cell transplant; hypogammaglobulinemia can also be a consequence of CD19+ B-cell depletion by anti-CD19 CAR-T cell therapy. We report use of IVIG and clinical outcomes for JULIET study pts. Methods: JULIET is a single-arm, pivotal, phase 2 trial of tisagenlecleucel in adult pts with r/r DLBCL. IgG, IgM, and IgA at baseline; d 14, 28; mo 3, 6, 9, 12; and end of follow-up, together with IVIG use and clinical outcomes, were evaluated. Hypogammaglobulinemia was defined as IgG <4 g/L. Results: At data cutoff (21 May 2018; median follow-up: 19 mo), hypogammaglobulinemia was observed in 68 of 115 pts (59%) following tisagenlecleucel infusion. Among 75 pts with IgG ≥4 g/L prior to tisagenlecleucel, 37 (49%) subsequently developed hypogammaglobulinemia, with a median duration of 70 d (range: 0-726) and median onset of 14 d (range: 14-376). CAR-T transgene levels (copies/μg DNA) were comparable between pts with or without hypogammaglobulinemia at all timepoints after infusion. Immunoglobulin recovery in the overall population according to IVIG use is summarized in the Figure. Thirty-eight of 115 pts (33%) received IVIG following tisagenlecleucel infusion; 25 of 38 pts received IVIG in the presence of hypogammaglobulinemia, while 13 received IVIG with levels of IgG ≥4 g/L. Nine of 115 pts (7.8%) received IVIG before infusion. Median start of IVIG was 55 d after tisagenlecleucel infusion (range: 5-555). IVIG use in responders vs nonresponders to tisagenlecleucel was 38.3% vs 27.3%, respectively. Within 8 weeks of tisagenlecleucel infusion, the frequency of grade 3-4 infections was similar between pts who received IVIG (n=8/38, 21%) and those who did not (n=14/77, 18%); however, at later timepoints (>8 wk to ≤1 yr and >1yr), the frequency of grade 3-4 infections was higher in pts receiving IVIG (n=11/35 [31%] and n=3/20 [15%], respectively) vs those who did not (n=7/65 [11%] and n=0/21 [0%], respectively). IgG levels in pts receiving and not receiving IVIG supplementation were comparable over time. Conclusions: Approximately one third of pts received IVIG following tisagenlecleucel infusion; use of IVIG was driven by local institutional practice, with heterogeneity in terms of indication, frequency, and duration of treatment. Although our study was not powered to address this question, no clear pattern associating IVIG use with patient characteristics and conditions was observed. Further research is needed to develop guidance for IVIG use following CAR-T infusion in pts with r/r DLBCL. Keywords: CD19; diffuse large B-cell lymphoma (DLBCL); hypogammaglobulinemia. Disclosures: 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, MSD, Novartis, Roche, Takeda Millenium, Amgen, AOP Orphan, BMS, Sandoz. Tam, C: Honoraria: Novartis. 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: Kalyera, Novartis; Stock Ownership: Cerus Corporation, Chimerix; Honoraria: Cambium Medical Technologies, Kalytera, Novartis; Research Funding: Celldex, Novartis, Pharmacyclics; Other Remuneration: Pharmacyclics. Jaglowski, S: Consultant Advisory Role: Kite Pharma, Juno; Research Funding: 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, Elsai, MSD, Takeda, Janssen, Mundipharma, Chugai, AbbVie, Bayer, Ono, Gilead, Zenyaku, Celgene, Solasia, Symbio, Astellas, Amgen, Diichi Sankyo. Schuster, S: Honoraria: Celgene, Genentech, Merck, Pharmacyclics, Novartis, Nordic Nanovector, Acerta, Pfizer, Gilead; Research Funding: Celgene, Genentech, Merck, Pharmacyclics, Novartis, Gilead. Bachanova, V: Research Funding: GAMIDA Cell, UNUM, Novartis, GT Biopharm. Maziarz, R: Consultant Advisory Role: Novartis, Incyte, Juno Therapeutics; Honoraria: Novartis, Incyte, Juno Therapeutics, Kite Therapeutics; 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: Honoraria: JUNO, ADC Therapeutics, Janssen; Research Funding: Merck, Novartis, Celgene, Astex. Corradini, P: Consultant Advisory Role: Celgene, AbbVie, Amgen, Daiichi Sankyo, Gilead, Janssen, KiowaKirin, Novartis, Roche, Sanofi, Servier, Takeda. Tiwari, R: Employment Leadership Position: Novartis. Forcina, A: Employment Leadership Position: Novartis. Pacaud, L: Employment Leadership Position: Novartis. Bishop, M: Employment Leadership Position: United Healthcare; Consultant Advisory Role: Celgene, Juneau Therapeutics, Novartis; Honoraria: Celgene, Juneau Therapeutics, Novartis.