Prognostic Value of Early PET in Patients with Aggressive Non-Hodgkin Lymphoma Treated with Anti-CD19 CAR T-Cell Therapy
Authors: Crombie Jennifer L. , Redd Robert A. , Chow Victor A. , Gauthier Jordan , Mullane Erin , Shouse Geoffrey , Herrera Alex F. , Romancik Jason , Cohen Jonathon B. , Saucier Anna , Houot Roch , Jacobson Caron , Armand Philippe , Hess Brian T. 
Published: November 2021

Abstract
Introduction: Although anti-CD19 autologous chimeric antigen receptor (CAR) T-cell therapy has transformed the management of relapsed/refractory non-Hodgkin lymphoma (NHL), the majority of patients will ultimately relapse. The prognostic implications of early (1-month) metabolic response on ultimate outcome are still poorly defined, yet would have significant implications on the development of consolidation strategies.
Methods: We conducted a multi-center, retrospective study of patients with NHL who received commercial anti-CD19 CAR T-cell therapy at 5 academic medical centers between 7/2018-5/2021. All patients had a PET scan 30 (+/- 15) days following CAR T-cell infusion. Imaging responses were per investigator assessment using Lugano criteria. Cox proportional hazards models were used to identify predictors of progression free survival (PFS).
Results: A total of 193 patients were identified who received axicabtagene ciloleucel (axi-cel, n=180) or tisagenlecleucel (tisa-cel, n=13). Histologies included diffuse large B-cell lymphoma (DLBCL), NOS, n= 134 (69%), DLBCL transformed from an indolent lymphoma, n=47 (24%), primary mediastinal B-cell lymphoma (PMBCL), n=8 (4%), and Richter's syndrome (RS), n=4 (2%). The median age was 62 (range 19-80) years; 66% of patients were male; IPI was low in 28%, intermediate in 27%, and high in 42%; median prior therapies was 3 (range 1-9); 44% had an elevated LDH prior to lymphodepletion; 30% had an elevated CRP prior to CAR T-cell infusion; 10% had bulky disease (≥10 cm) prior to lymphodepleting therapy; and 40% received bridging therapy.
The median follow-up of the entire cohort was 22 months (m). Responses at 1m included complete response (CR), n= 101 (52%), partial response (PR), n=53 (27%), stable disease (SD), n=4 (2%), and progressive disease (PD), n=35 (18%). The median PFS of the entire cohort was 11m (95% CI: 6-not reached) (Figure 1B) and median overall survival (OS) was not reached. PFS for the entire cohort was 57% (95% CI: 50-65) at 6m and 49% (95% CI: 42-58) at 12m; and OS was 79% (95% CI: 73-85) at 6m and 67% (95% CI: 61-75) at 12m. The 12m PFS and OS for patients with CR at 1m was 70% (95% CI: 61-80) and 82% (95% CI: 74-91), respectively, and was 38% (95% CI: 26-55) and 69% (95% CI: 57-84) for patients with PR/SD (Figure 1C). The 12m PFS and OS based on 1m PET (Figure 1D) was 72% (95% CI: 61-85) and 82% (95% CI: 72-93), respectively, for Deauville 1/2, 68% (95% CI: 53-88%) and 82% (CI: 69-98) for Deauville 3, 55% (95% CI: 39-79) and 83 (95% CI: 69-100) for Deauville 4, and 12% (95% CI: 3-46) and 56% (95% CI: 27-56) for Deauville 5 with PR/SD.
Indicators of shorter PFS across the entire cohort included elevated LDH at lymphodepletion (HR: 2.11 (95% CI: 1.41-3.16, p&lt;0.001)), elevated CRP at CAR T-cell infusion (HR: 1.85 (95% CI: 1.22-2.8, p=0.004)), use of bridging therapy (HR: 1.8 (95% CI: 1.21-2.70, p=0.004)), and grade 3 or higher cytokine release syndrome (HR: 2.26 (95% HR: 1.23-4.17, p=0.009)). However, among patients with PR/SD at 1m, none of those clinical variables (including bulky disease, elevated LDH or CRP, high IPI, grade 3 or higher CRS or neurotoxicity, and use of tocilizumab or steroids) predicted progression at 3m. Among patients with a CR at 1m, an elevated LDH at the time of lymphodepletion correlated with an increased risk of relapse at 3m (HR: 4.14 (95% CI: 1.20-16.56, p=0.03)).
Discussion: We demonstrate that PFS is improved in patients with a CR at day +30 PET as compared to patients with a PR or SD. Furthermore, patients with Deauville 1/2 appear to have similar outcomes as those with a Deauville 3. No independent clinical variables were able to predict which patients with a PR/SD were likely to progress at the time of their next scan. Novel biomarkers such a minimal residual disease (MRD), may be necessary to further guide treatment modification in this setting.
Figure 1 Figure 1.

Disclosures
Crombie: Karyopharm: Consultancy; Incyte: Consultancy; Merck: Research Funding; Abbvie: Research Funding; Bayer: Research Funding; Roche: Research Funding. Chow: AstraZeneca: Research Funding; ADC Therapeutics: Current holder of individual stocks in a privately-held company, Research Funding. Gauthier: Janssen: Membership on an entity's Board of Directors or advisory committees; Legend Biotech: Membership on an entity's Board of Directors or advisory committees; Multerra Bio: Consultancy; Larvol: Consultancy; JMP: Consultancy; Eusapharma: Consultancy. Shouse: Beigene: Honoraria; Kite Pharma: Speakers Bureau. Herrera: Kite, a Gilead Company: Research Funding; ADC Therapeutics: Consultancy, Research Funding; Tubulis: Consultancy; Takeda: Consultancy; Seagen: Consultancy, Research Funding; Bristol Myers Squibb: Consultancy, Research Funding; Genentech: Consultancy, Research Funding; Merck: Consultancy, Research Funding; Gilead Sciences: Research Funding; AstraZeneca: Consultancy, Research Funding; Karyopharm: Consultancy. Cohen: Janssen, Adaptive, Aptitude Health, BeiGene, Cellectar, Adicet, Loxo/Lilly, AStra ZenecaKite/Gilead: Consultancy; Genentech, Takeda, BMS/Celgene, BioInvent, LAM, Astra Zeneca, Novartis, Loxo/Lilly: Research Funding. Jacobson: Lonza: Consultancy, Honoraria, Other: Travel support; Precision Biosciences: Consultancy, Honoraria, Other: Travel support; Pfizer: Consultancy, Honoraria, Other: Travel support, Research Funding; Axis: Speakers Bureau; Kite, a Gilead Company: Consultancy, Honoraria, Other: Travel support; Celgene: Consultancy, Honoraria, Other: Travel support; Humanigen: Consultancy, Honoraria, Other: Travel support; Novartis Pharmaceuticals Corporation: Consultancy, Honoraria, Other: Travel support; Nkarta: Consultancy, Honoraria; AbbVie: Consultancy, Honoraria; Clinical Care Options: Speakers Bureau. Armand: Otsuka: Research Funding; Sigma Tau: Research Funding; Infinity: Consultancy; Kite: Research Funding; Pfizer: Consultancy; IGM: Research Funding; Tensha: Research Funding; Roche: Research Funding; Genentech: Consultancy, Research Funding; AstraZeneca: Consultancy; Epizyme: Consultancy; Regeneron: Consultancy; Enterome: Consultancy; C4: Consultancy; GenMab: Consultancy; Tessa Therapeutics: Consultancy; Miltenyi: Consultancy; Daiichi Sankyo: Consultancy; Morphosys: Consultancy; Celgene: Consultancy; ADC Therapeutics: Consultancy; Adaptive: Consultancy, Research Funding; Affimed: Consultancy, Research Funding; BMS: Consultancy, Honoraria, Research Funding; Merck: Consultancy, Honoraria, Research Funding. Hess: BMS: Speakers Bureau; ADC Therapeutics: Consultancy.