Axicabtagene Ciloleucel in the Real World: Outcomes and Predictors of Response, Resistance and Toxicity
Authors: Jacobson Caron A. , Hunter Bradley , Armand Philippe , Kamihara Yusuke , Ritz Jerome , Rodig Scott J , Wright Kyle , Lipschitz Mikel , Redd Robert A. , Maus Marcela V. , Chen Yi-Bin , Abramson Jeremy S. , Kline Justin , Cohen Jonathon B. , Maakaron Joseph , Jaglowski Samantha , Smith Stephen D. , Maloney David G. , Gopal Ajay K. , Frigault Matthew J. , Acharya Utkarsh H. 
Published: October 2019

Abstract

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: Precision Bioscience: Consultancy; Kite: Consultancy; Pfizer: Consultancy; Bayer: Consultancy; Humanigen: Consultancy; Novartis: 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:iTeos: Research Funding; Merck: Honoraria, 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.