Metabolic Kinetics of Non-Hodgkin Lymphoma Prior to CAR-T Infusion: Prognostic Factors and Risk Stratification

Abstract

<h3>Purpose/Objective(s)</h3> Chimeric antigen receptor T-cell (CAR-T) therapy is utilized for patients with active non-Hodgkin lymphoma (NHL) refractory to recent treatments, sometimes even requiring bridging therapy during CAR-T manufacturing to maintain clinically stability for CAR-T infusion. We examined the metabolic kinetics of these patients' lymphoma via F-18 fluorodeoxyglucose positron emission tomography/computed tomography (PET/CT) with the hypothesis that increasing metabolic disease parameters during CAR-T manufacturing are associated with increased rates of progressive disease (PD) and death after CAR-T. <h3>Materials/Methods</h3> Patients with NHL who received axicabtagene ciloleucel (axi-cel), an anti-CD19 CAR-T therapy, on a prospective registry at one institution were included. Lesions on PET/CT scans before leukapheresis (pre-leuk) and before lymphodepletion chemotherapy (pre-LD) were segmented with a fixed absolute SUV threshold of 2.5 using a semi-automated workflow with manual modification to exclude physiologic uptake as needed. Metabolic tumor volume (MTV), total lesion glycolysis (TLG), SUV maximum (SUVMax), and other lesion characteristics were assessed for each PET/CT, and changes between pre-leuk and pre-LD were calculated. Univariate Cox modeling was used to associate relative and directional change in metabolic and volumetric PET/CT characteristics with PD and death, after adjusting for bridging therapy. LASSO method was used for multivariable model selection. <h3>Results</h3> Axi-cel was delivered to 69 patients with NHL (64% DLBCL) from 2018-2020. Pre-leuk and pre-LD PET/CT scans were performed a median of 46 days and 7 days prior to CAR-T infusion, respectively. Forty patients (58%) received bridging therapy between scans, including 9 (13%) receiving radiotherapy. At data cut-off of December 2020 with a median follow-up of 13 months for surviving patients, 39 (57%) had died and 46 (67%) had PD. Increases from pre-leuk to pre-LD PET/CT in total MTV, total TLG, parenchymal MTV, and nodal MTV were associated with increased risk of PD. Increases in parenchymal MTV, nodal MTV, TLG of the largest lesion, and total number of lesions were associated with increased risk of death. LASSO analysis identified increasing total extranodal MTV (≥25% increase) and increasing TLG of the largest lesion (≥10% increase) as strong predictors of death (AUC 0.74, Table). <h3>Conclusion</h3> Increasing metabolic disease burden during CAR-T manufacturing is associated with increased risk of PD and death. A two variable tool using increasing extranodal disease and increasing TLG of the largest lesion may be able to stratify prognosis prior to CAR-T and inform treatment paradigms.