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92 Axicabtagene Ciloleucel in the Real World: Outcomes and Predictors of Response, Resistance and ToxicityClinically Relevant Abstract

Program: Oral and Poster Abstracts
Type: Oral
Session: 627. Aggressive Lymphoma (Diffuse Large B-Cell and Other Aggressive B-Cell Non-Hodgkin Lymphomas)—Results from Retrospective/Observational Studies: Outcomes With CD19 CAR T Therapy and Checkpoint Blockade in the Real World Setting
Hematology Disease Topics & Pathways:
Diseases, Biological, Therapies, CAR-Ts, Biological Processes, B-Cell Lymphoma, Lymphoid Malignancies, immune mechanism
Saturday, December 1, 2018: 9:45 AM
Pacific Ballroom 20 (Marriott Marquis San Diego Marina)

Caron A. Jacobson, MD1, Bradley Hunter, MD, MPH2*, Philippe Armand, MD, PhD3, Yusuke Kamihara, MD, PhD4*, Jerome Ritz, MD, PhD5, Scott J Rodig, MD6, Kyle Wright, M.D., Ph.D.6*, Mikel Lipschitz, M.S.2*, Robert A. Redd, MS7*, Marcela V. Maus, MD, PhD8, Yi-Bin Chen, MD9, Jeremy S. Abramson, MD, MMSc8, Justin Kline, MD10, Jonathon B. Cohen, MD, MS11, Joseph Maakaron, MD12, Samantha Jaglowski, MD, MPH13, Stephen D. Smith, MD14, David G. Maloney, MD, PhD15, Ajay K. Gopal, MD16, Matthew J. Frigault, MD17* and Utkarsh H. Acharya, DO15,18,19*

1Department of Medical Oncology, Dana Faber Cancer Institute, Boston, MA
2Dana-Farber Cancer Institute, Boston, MA
3Dana Farber Cancer Institute, Boston, MA
4Division of Hematologic Malignancies, Dana-Farber Cancer Institute, Boston, MA
5Dana-Farber/Boston Children’s Cancer and Blood Disorders Center, Harvard Medical School, Boston, MA
6Department of Pathology, Brigham and Women's Hospital, Boston, MA
7Department of Biostatistics and Computational Biology, Dana-Farber Cancer Institute, Boston, MA
8Massachusetts General Hospital Cancer Center, Boston, MA
9Blood and Marrow Transplant Program, Massachusetts General Hospital, Needham, MA
10Department of Medicine, Section of Hematology/Oncology, University of Chicago, Chicago, IL
11Emory University, Atlanta, GA
12Ohio State University, Columbus, OH
13Hematology, The Ohio State University, Columbus, OH
14Seattle Cancer Care Alliance, University of Washington, Seattle, WA
15Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA
16University of Washington/Fred Hutchinson Cancer Research Center, Seattle, WA
17Massachusetts General Hospital, Boston, MA
18Medical Oncology, Dana Farber Cancer Institute / Brigham and Women’s Hospital, Boston, MA
19Department of Medicine, University of Washington, Seattle, WA

Introduction:

CD19 CAR T cells lead to durable responses in 40% of r/r aggressive B cell NHL patients. We performed a multicenter retrospective study of axicabtagene ciloleucel given in a real world setting where eligibility/management considerations may diverge from clinical trials. We evaluate efficacy and safety, and patient/disease factors associated with response and toxicity.

Methods:

Patient and treatment characteristics were summarized descriptively. Response and toxicity were reported with 95% exact binomial CIs. CyTOF was performed on frozen PBMCs using 38 metal-tagged mAbs. Multiplex IF was performed on FFPE tissue with standard, primary Abs sequentially, paired with a unique fluorochrome per published protocols. Standard IHC was done on FFPE whole tissue.

Results:

In total, 76 patients, median age 64, were included (Table 1). The majority had an ECOG PS ≤ 2. Twenty-one percent of patients had double/triple hit cytogenetics. Nearly half had an IPI ≥3 at treatment. Nearly 1/3 had a prior autologous transplant, 25% had prior ibrutinib, and 11% had prior lenalidomide. Twelve percent had bulky disease and 36% received bridging therapy following pheresis.

Seventy-three patients were evaluable for response (Table 2). At 4m median f/u, best ORR and CRR was 64% and 41% among those treated. Six patients had 6m f/u, all PRs at 1m: 3 converted to CR and 3 had PD. Eleven patients (13%) were pheresed but not treated due to PD (6), infection (2), or non-conforming cells (3). By ITT analysis, the ORR and CRR were 57% and 36%. OS at 4m among those treated was 84%; PFS will be calculated with longer f/u. In univariate analysis, PS, tumor bulk, IPI, baseline CRP and prior ibrutinib were significantly associated with lack of response (Table 3). There was no association between response and double/triple hit cytogenetics, grade 3+ CRS or NT, or the use of tocilizumab/steroids.

Among treated patients, 96% experienced CRS; in 17% this was ≥ grade 3. Two patients died from CRS (3%). Median time to onset was 1d; median duration was 6d (0-14d). NT was seen in 76% of patients; in 38% this was ≥ grade 3. One case of NT was fatal. Median time to onset was 5d; median duration was 8d (0-34d). Tocilizumab and steroids were given to 67% and 78% of patients. ICU care occurred in 30% of patients. Eleven treated patients have died: 6 from PD and 5 from toxicity. In univariate analysis, peak ferritin was associated with grade 3+ CRS and NT; peak ALC was associated with grade 3+ CRS, and peak CRP and prior autologous transplant were associated with grade 3+ NT (Table 4).

Three of 4 patients who had a biopsy with CD19 staining after relapse were positive (Fig 1). All 3 patients with PDL1+ tumors were refractory to CAR T cell therapy. Multiplex IF and IHC were performed on 2 primary refractory patients at progression (Fig 1). One was CD19-/PDL1+; multiplex IF showed an abundance of CAR+ T-cells (Fig 1A,B). The second was CD19+/PDL1- and multiplex IF showed no CAR+ T-cells (Fig 1C,D). CyTOF analysis of PBMCs at serial timepoints was performed on 6 patients (4 CRs, 1 PD, 1 PD after CR)(Fig 2, Table 5). Peak CAR T cell levels were seen at day 7 in all patients with increased expression of PD1, 41BB, and Ki67, as well as CC3 indicating apoptosis, followed by a reduction in CAR T cells by day 14. Immune subsets that associate with response will be evaluated and reported. Results from additional patients and longer f/u will be presented.

Conclusion:

Retrospective analysis of a multicenter cohort treated in the real world with axi-cel reveals important distinctions from ZUMA-1. The ORR and CR rate are lower than the 82% and 54% reported on ZUMA-1. This may reflect inclusion of sicker patients with a poorer PS, and/or with different histologies (ie transformation from non-FL). Outcomes were significantly worse in high risk lymphomas, reflected by IPI, PS, tumor bulk, and baseline CRP. Rates of CRS and NT were similar to ZUMA-1, but toxicity was not associated with tumor bulk or response. It was associated with higher peak inflammatory markers and ALC, which may reflect peak CAR T cell levels, as shown previously. Progression biopsies highlight 3 potential resistance mechanisms: loss of target antigen, an inhibitory tumor/TME, and lack of CAR T cell tumor infiltration. Immunomodulatory molecules on CAR T cells that may affect their activity and survival are upregulated early. This suggests that unique combination approaches are necessary for specific patients/tumors.

Disclosures: Jacobson: Humanigen: Consultancy; Celgene: Consultancy; Novartis: Consultancy; Pfizer: Consultancy; Bayer: Consultancy; Precision Bioscience: Consultancy; Kite: Consultancy. Rodig: Merck: Research Funding; Affimed: Research Funding; Bristol Myers Squibb: Research Funding; KITE: Research Funding. Maus: novartis: Consultancy; agentus: Consultancy, Research Funding; crispr therapeutics: Consultancy, Research Funding; kite therapeutics: Consultancy, Research Funding; windmil therapeutics: Consultancy; adaptimmune: Consultancy. Chen: Incyte: Consultancy, Membership on an entity's Board of Directors or advisory committees; Magenta Therapeutics: Consultancy; REGiMMUNE: Consultancy; Takeda Pharmaceuticals: Consultancy. Abramson: Verastem: Consultancy; Amgen: Consultancy; Merck: Consultancy; Karyopharm: Consultancy; Humanigen: Consultancy; Bayer: Consultancy; Gilead: Consultancy; Celgene: Consultancy; Seattle Genetics: Consultancy; Novartis: Consultancy; Juno Therapeutics: Consultancy. Kline: Merck: Honoraria, Research Funding; iTeos: Research Funding. Cohen: Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees; AbbVie: Consultancy, Membership on an entity's Board of Directors or advisory committees; Infinity Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees; Infinity Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees; Seattle Genetics: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Research Funding; Bristol-Myers Squibb: Research Funding; Bristol-Myers Squibb: Research Funding; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees; Janssen: Research Funding; Millennium: Consultancy, Membership on an entity's Board of Directors or advisory committees; Millennium: 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, Research Funding; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Pharmacyclics: Consultancy, Membership on an entity's Board of Directors or advisory committees; Takeda: Research Funding; Pharmacyclics: Consultancy, Membership on an entity's Board of Directors or advisory committees; BioInvent: Consultancy; Seattle Genetics: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Takeda: Research Funding; BioInvent: Consultancy. Jaglowski: Novartis Pharmaceuticals Corporation: Consultancy, Research Funding; Kite Pharma: Consultancy, Research Funding; Juno: Consultancy. Smith: Merck Sharp and Dohme Corp.: Consultancy, Research Funding; Acerta Pharma BV: Research Funding; Pharmacyclics: Research Funding; Genentech: Research Funding; Incyte Corporation: Research Funding; Portola Pharmaceuticals: Research Funding; Seattle Genetics: Research Funding. Maloney: Janssen Scientific Affairs: Honoraria; Seattle Genetics: Honoraria; Juno Therapeutics: Research Funding; Roche/Genentech: Honoraria; GlaxoSmithKline: Research Funding. Gopal: Spectrum: Research Funding; Seattle Genetics: Consultancy, Research Funding; Merck: Research Funding; Janssen: Consultancy, Research Funding; Takeda: Research Funding; Gilead: Consultancy, Research Funding; Pfizer: Research Funding; BMS: Research Funding; Brim: Consultancy; Teva: Research Funding; Aptevo: Consultancy; Incyte: Consultancy; Asana: Consultancy. Acharya: Teva: Honoraria; Juno Therapeutics: Research Funding.

*signifies non-member of ASH