Axicabtagene Ciloleucel in Relapsed or Refractory Large B-Cell Lymphoma Patients in Complete Metabolic Response at Time of Infusion
Authors: Gouni Sushanth , Westin Jason R. , Mistry Haleigh , Steiner Raphael Eric , James Jinsu , Parmar Simrit , Noorani Mansoor , Fowler Nathan H. , Horowitz Sandra B. , Feng Lei , Fayad Luis E. , Iyer Swaminathan P , Green Michael R , Hawkins Misha , Flowers Christopher R. , Ahmed Sairah , Nastoupil Loretta , Neelapu Sattva S. , Nieto Yago , Strati Paolo 
Published: November 2021

Abstract
Introduction. Suboptimal CAR T-cell stimulation, expansion, and persistence is of theoretical concern in absence of CD19+ tumor B-cells. Adequate CAR T-cell expansion has been reported in the JULIET study among 7 relapsed or refractory (r/r) large B-cell lymphoma (LBCL) patients who had achieved complete metabolic remission (CMR) before tisagenlecleucel (tisa-cel) infusion. As patients in CMR at time of infusion were excluded from the ZUMA-1 trial, the efficacy of axicabtagene ciloleucel (axi-cel), whose construct and kinetics differ significantly from those of tisa-cel, remains unknown in this population.
Methods. This is a retrospective study of all patients with r/r LBCL treated with standard of care (SOC) axi-cel at MD Anderson Cancer Center between 01/2018 and 02/2021 (data cut-off 04/2021). CMR was defined as a Deauville score &lt;=3 on PET-CT scan performed before lymphodepleting chemotherapy (LDC). Patients who had any anti-lymphoma treatment, other than LDC, between PET-CT and axi-cel infusion were excluded from the analysis. Cytokine release syndrome (CRS) and immune effector cell associated neurotoxicity syndrome (ICANS) were prospectively graded according to CARTOX criteria from 01/2018 to 04/2019, and ASTCT criteria from 05/2019 onward. Response status was defined according to 2014 Lugano criteria. The Gehan-Breslow-Wilcoxon test was used for calculation of differences in survival between patient groups.
Results. Two-hundred and six patients with R/R LBCL received SOC axi-cel between 01/2018 and 02/2021. Of these, 162 had a PET-CT scan performed after bridging therapy and before LDC, 10 of whom were in CMR at time of axi-cel infusion. The immediate treatment before achievement of CMR consisted of chemoimmunotherapy in 5 patients (platinum-based in 4 patients, methotrexate-based in 1 patient), radiation therapy in 3 patients, and biological therapy in 2 patients (lenalidomide and rituximab in 1 patient, and ibrutinib in 1 patient). When comparing the 152 patients with metabolically active disease to the 10 patients without, patients with active disease had more frequently at baseline (day -5) an international prognostic index score &gt;= 3 (58% vs 10%, p=0.006), elevated lactate dehydrogenase (LDH)(70% vs 10%, p&lt;0.001), and previously refractory disease (79% vs 40%, p=0.01). On multivariate analysis, the association with active disease was maintained only for elevated LDH (odds ratio 17; 95% confidence interval, 2-140; p=0.009). No significant difference in number of prior lines of therapy (median of 3 for each group, p=0.68) and prior use of autologous stem cell transplant (26% vs 40%, p=0.46) was observed when comparing the 2 groups.
Interestingly, when comparing patients with active disease to those without, no difference for CRS of any grade (94% vs 90%, p=0.48), grade 3-4 CRS (8% vs 10%, p=0.58), ICANS of any grade (61% vs 70%, p=0.74) or grade 3-4 ICANS (38% vs 40%, p=1) was observed (Figure A).
After a median follow-up of 12 months (95% CI, 11-13 months), 87 (54%) patients progressed and/or died, and median progression-free survival (PFS) was 6 months (95% CI, 2-10 months). Median PFS was significantly longer for patients without metabolically active disease at the time of axi-cel infusion (not reached vs 5 months, p=0.04) with a 1-year PFS rate of 80% as compared to 45% (Figure B). At most recent follow-up, 57 (35%) patients died, and median overall (OS) was not reached. One-year OS rate was higher for patients without metabolically active disease at baseline (80% vs 64%), but not statistically significant (p=0.23)(Figure C).
Conclusions. Our data support the use of axi-cel in r/r LBCL patients who achieve a CMR before axi-cel infusion, warranting further investigation of its activity as consolidative strategy in future trials. Identification of effective and biologically rational bridging therapies aimed at decreasing disease burden and continue to improve outcomes in patients treated with axi-cel is needed. CAR T-cell amplification data by qPCR and pre-infusion levels of CD19+ non-tumoral B-cells in peripheral blood are being analyzed and will be presented at the conference.
Figure 1 Figure 1.

Disclosures
Westin: Genentech: Consultancy, Research Funding; Iksuda Therapeutics: Consultancy; ADC Therapeutics: Consultancy, Research Funding; Umoja: Consultancy; Bristol Myers Squibb: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; Kite, a Gilead Company: Consultancy, Research Funding; AstraZeneca: Consultancy, Research Funding; MorphoSys: Consultancy, Research Funding; Curis: Research Funding; Morphosys: Research Funding; 47 Inc: Research Funding. Steiner: Rafael Pharmaceuticals: Research Funding; Seattle Genetics: Research Funding; BMS: Research Funding. Parmar: Cellenkos Inc.: Current holder of individual stocks in a privately-held company, Membership on an entity's Board of Directors or advisory committees, Patents & Royalties, Research Funding. Fowler: BostonGene, Corp: Current Employment, Current holder of stock options in a privately-held company; Bristol Myers Squibb, F. Hoffmann-La Roche Ltd, TG Therapeutics and Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding. Flowers: Denovo: Consultancy; Burroughs Wellcome Fund: Research Funding; AbbVie: Consultancy, Research Funding; Acerta: Research Funding; Kite: Research Funding; Karyopharm: Consultancy; EMD: Research Funding; BeiGene: Consultancy; Takeda: Research Funding; Sanofi: Research Funding; Cancer Prevention and Research Institute of Texas: CPRIT Scholar in Cancer Research: Research Funding; Genmab: Consultancy; Iovance: Research Funding; Allogene: Research Funding; TG Therapeutics: Research Funding; Celgene: Consultancy, Research Funding; National Cancer Institute: Research Funding; Amgen: Research Funding; Cellectis: Research Funding; Nektar: Research Funding; Xencor: Research Funding; Spectrum: Consultancy; Ziopharm: Research Funding; Genentech/Roche: Consultancy, Research Funding; Pharmacyclics/Janssen: Consultancy; Bayer: Consultancy, Research Funding; Morphosys: Research Funding; Biopharma: Consultancy; SeaGen: Consultancy; 4D: Research Funding; Janssen: Research Funding; Gilead: Consultancy, Research Funding; Epizyme, Inc.: Consultancy; Eastern Cooperative Oncology Group: Research Funding; Guardant: Research Funding; Adaptimmune: Research Funding; Novartis: Research Funding; Pfizer: Research Funding; Pharmacyclics: Research Funding. Ahmed: Xencor: Research Funding; Merck: Research Funding; Tessa Therapeutics: Membership on an entity's Board of Directors or advisory committees, Research Funding; Seagen: Research Funding. Nastoupil: Genentech: Honoraria, Research Funding; TG Therapeutics: Honoraria, Research Funding; Pfizer: Honoraria, Research Funding; Takeda: Honoraria, Other: DSMC, Research Funding; Gilead/Kite: Honoraria, Research Funding; IGM Biosciences: Research Funding; Denovo Pharma: Other: DSMC; Bristol Myers Squibb/Celgene: Honoraria, Research Funding; Epizyme: Honoraria, Research Funding; MorphoSys: Honoraria; Caribou Biosciences: Research Funding; ADC Therapeutics: Honoraria; Janssen: Honoraria, Research Funding; Novartis: Honoraria, Research Funding; Bayer: Honoraria. Neelapu: Kite, a Gilead Company, Merck, Bristol Myers Squibb, Novartis, Celgene, Pfizer, Allogene Therapeutics, Cell Medica/Kuur, Incyte, Precision Biosciences, Legend Biotech, Adicet Bio, Calibr, Unum Therapeutics and Bluebird Bio: Honoraria; Takeda Pharmaceuticals and related to cell therapy: Patents & Royalties; Kite, a Gilead Company, Bristol Myers Squibb, Merck, Poseida, Cellectis, Celgene, Karus Therapeutics, Unum Therapeutics (Cogent Biosciences), Allogene, Precision BioSciences, Acerta and Adicet Bio: Research Funding; Kite, a Gilead Company, Merck, Bristol Myers Squibb, Novartis, Celgene, Pfizer, Allogene, Kuur, Incyte, Precision BioSciences, Legend, Adicet Bio, Calibr, and Unum Therapeutics: Other: personal fees. Strati: Roche-Genentech: Consultancy; Astrazeneca-Acerta: Research Funding.