Prognostic Value of Baseline and Early Response FDG-PET/CT Combined with Cellular Dynamics in Patients with Refractory and Relapsed Mantle Cell Lymphoma (MCL) Undergoing Chimeric Antigen Receptor (CAR)-T Cell Therapy
Authors: Krauß Simon M , Seiffert Sabine , Perez Fernandez Carmen , Georgi Thomas Walter , Kirchberg Janine , Bach Enrica , Brueckner Mandy , Jentzsch Madlen , Herling Carmen , Merz Maximilian , Metzeler Klaus H , Herling Marco , Franke Georg-Nikolaus , Boldt Andreas , Tiepolt Solveig , Kluge Regine , Koehl Ulrike , Denecke Timm , Sabri Osama , Sack Ulrich , Platzbecker Uwe , Kurch Lars , Vucinic Vladan 
Published: December 2024

Background
Brexucabtagene autoleucel (brexu-cel) is a CAR-T cell treatment option for patients with relapsed or refractory (r/r) mantle cell lymphoma (MCL). The prognosis of patients who relapse after CAR-T cell treatment remains poor, necessitating the identification of predictive factors for treatment outcomes. 18F-Fluorodeoxyglucose positron emission tomography/computed tomography (FDG-PET/CT) is the most informative method for response assessment in patients with lymphoma with confirmed prognostic relevance in the context of CAR-T cell treatment of aggressive lymphomas. This unicentric retrospective analysis aimed to assess the predictive value of pre-treatment and early post-treatment FDG-PET/CT as well as cellular dynamics in patients with MCL undergoing treatment with brexu-cel.
Methods
15 patients with r/r MCL treated with brexu-cel underwent FDG-PET/CT before (PET-0) and 1 month after infusion of CAR-T cells (PET-1). Metabolic parameters like standard uptake value (SUV) max and mean, and metabolic tumor volume (MTV; Cut: SUV4) were measured at both timepoints. PET-1 was classified as complete metabolic response (CMR, Deauville score 1-3) or partial metabolic response (PMR, Deauville score 4-5).
The patients underwent longitudinal detection of CAR-T and bystander T-cells per flow-cytometry at lymphodepletion, 7, 14, 28 and 100 days after brexu-cel. We studied associations of the aforementioned parameters with progression-free survival (PFS).
Results
The median age at brexu-cel infusion was 64y (range 50-79), and all but one were male. The patients had at least 2 prior treatment lines, and all were treated with ibrutinib. One patient was treated for cerebral involvement, one had a history of allogeneic stem cell transplantation.
PET-0 showed active disease in 8/15 (53%) patients, PET-1 in 3/15 (20%). After a median follow up of 21.8 months (m), 4 patients relapsed, and 1 with CMR died due to an infection.
One-year PFS was 73% (95% CI: 53-100) for the whole group and was significantly better in patients with CMR in PET-1 (n=12) with 83% (95% CI: 63-100) compared to 33% (95% CI: 7-100) with PMR in PET-1 (n=3) (p=0.04).
11/12 patients with CMR remained in remission. One out of 12 with CMR along with the 3 cases with PMR relapsed after 3.7 m (median; range, 1-6).
One-year PFS for patients with CMR in PET-0 was higher than for patients with non-CMR at PET-0 with 86% (95% CI: 63-100) vs. 63% (95% CI: 37-100) but was not statistically significant (p=0.38). An MTV of 0 ml at PET-0 was not associated with significantly superior PFS, but patients with 0 ml MTV in PET-1 showed higher PFS rates with 81% (95% CI: 60-100) compared to 33% (95% CI: 7-100; p=0.06). SUVmax at PET-0 was significantly higher in relapsing patients with 11.7 (median; range, 0-32.9) compared to non-relapsing patients with 0 (range, 0-19.7; p=0.03).
After adjustment for multiple testing, we did not identify specific cell subpopulations associated with adverse outcome.
Cytokine release syndrome (CRS) occurred in 10 patients (67%). Of these, 8 were treated with tocilizumab. Immune effector cell associated neurotoxicity syndrome (ICANS) was present in 5/15 (33%) patients and was treated with steroids in all cases. We observed higher numbers of CD3+CD4+ activated CAR T cells in patients developing CRS on day 7 (median x106/L [ranges]; 12.0 [2.9-57.8] vs 1.6 [0-18.2]; p=0.05), day 14 (11.6 [0-34.4]vs 4.9 [0.2-10.0]; p=0.37) and day 28 (10.8 [0-38.1] vs 0 [0-1.6]; p=0.04) after brexu-cel. This was also observed in CRS patients in need for tocilizumab and was most prominent on day 28 (12.2 [0.3-38.1] vs 0 [0-1.6]; p=0.007).
One-year PFS of patients with CRS was significantly better with 90% (95% CI: 73-100) compared to 30% (95% CI: 6-100) without CRS (p=0.04). The application of tocilizumab or presence of ICANS had no effect on one-year PFS (p=0.22 and 0.13, respectively).
Conclusion
Our results indicate significance of PET-1 in patients with MCL after CAR-T. Non-CMR in PET-1 is associated with worse outcomes and a need for early intervention. Higher MTV prior to CAR T therapy does not necessarily associate with inferior outcome, thus also patients with high tumor load may benefit from this therapy. The occurrence of CRS was associated with better outcomes. Furthermore, we detected increased counts of activated CD3+CD4+ CAR cells in patients with CRS, esp. in need for tocilizumab. Further prospective studies are needed to validate our results.