Whole body FDG PET/MR for progression free and overall survival prediction in patients with relapsed/refractory large B-cell lymphomas undergoing CAR T-cell therapy
Therese Sjöholm, Alexander Korenyushkin, Gustav Gammelgård, Tina Sarén, Tanja Lövgren, Angelica Loskog, Magnus Essand, Joel Kullberg, Gunilla Enblad, Håkan Åhlström
Abstract
Abstract Background To find semi-quantitative and quantitative Positron Emission Tomography/Magnetic Resonance (PET/MR) imaging metrics of both tumor and non-malignant lymphoid tissue (bone marrow and spleen) for Progression Free Survival (PFS) and Overall Survival (OS) prediction in patients with relapsed/refractory (r/r) large B-cell lymphoma (LBCL) undergoing Chimeric Antigen Receptor (CAR) T-cell therapy. Methods A single-center prospective study of 16 r/r LBCL patients undergoing CD19-targeted CAR T-cell therapy. Whole body 18F-fluorodeoxyglucose (FDG) PET/MR imaging pre-therapy and 3 weeks post-therapy were followed by manual segmentation of tumors and lymphoid tissues. Semi-quantitative and quantitative metrics were extracted, and the metric-wise rate of change (Δ) between post-therapy and pre-therapy calculated. Tumor metrics included maximum Standardized Uptake Value (SUV max ), mean SUV (SUV mean ), Metabolic Tumor Volume (MTV), Tumor Lesion Glycolysis (TLG), structural volume (V), total structural tumor burden (V total ) and mean Apparent Diffusion Coefficient (ADC mean ). For lymphoid tissues, metrics extracted were SUV mean , mean Fat Fraction (FF mean ) and ADC mean for bone marrow, and SUV mean , V and ADC mean for spleen. Univariate Cox regression analysis tested the relationship between extracted metrics and PFS and OS. Survival curves were produced using Kaplan–Meier analysis and compared using the log-rank test, with the median used for dichotomization. Uncorrected p -values < 0.05 were considered statistically significant. Correction for multiple comparisons was performed, with a False Discovery Rate (FDR) < 0.05 considered statistically significant. Results Pre-therapy ( p < 0.05, FDR < 0.05) and Δ ( p < 0.05, FDR > 0.05) total tumor burden structural and metabolic metrics were associated with PFS and/or OS. According to Kaplan-Meier analysis, a longer PFS was reached for patients with pre-therapy MTV ≤ 39.5 ml, ΔMTV≤1.35 and ΔTLG≤1.35. ΔSUV max was associated with PFS ( p < 0.05, FDR > 0.05), while ΔADC mean was associated with both PFS and OS ( p < 0.05, FDR > 0.05). ΔADC mean > 0.92 gave longer PFS and OS in the Kaplan-Meier analysis. Pre-therapy bone marrow SUV mean was associated with PFS ( p < 0.05, FDR < 0.05) and OS ( p < 0.05, FDR > 0.05). For bone marrow FDG uptake, patient stratification was possible pre-therapy (SUV mean ≤ 1.8). Conclusions MTV, tumor ADC mean and FDG uptake in bone marrow unaffected by tumor infiltration are possible PET/MR parameters for prediction of PFS and OS in r/r LBCL treated with CAR T-cells. Trial registration EudraCT 2016–004043-36.