Analysis of PET-CT Derived Radiomic Biomarkers with Efficacy, Safety, and Expansion of Axicabtagene Ciloleucel (Axi-Cel) in Patients with Relapsed or Refractory Large B-Cell Lymphoma (LBCL)
Authors: Bharadwaj Sushma , Lau Eric , Hashmi Ayesha , Hamilton Mark P. , Jensen Alexandria , Goyal Anmol , Marar Mallika , Lee Caroline , Ananth Snegha , Sahaf Bita , Mallampet Jayasindhu , Ehlinger Zachary , Syal Shriya , Patil Sunita , Guo Henry , Smith Melody , Weng Wen-Kai , Frank Matthew J. , Binkley Michael S. , Miklos David B. , Dahiya Saurabh 
Published: December 2023

Introduction
In LBCL, the presence of bulky disease is known to be an adverse prognostic factor, indicating poorer outcomes. The ZUMA-1 clinical trial (Neelapu, NEJM 2017) showed that high tumor burden, as measured by the sum of the product of diameters (SPD), was associated with lower durable response after Chimeric Antigen Receptor T-Cell Therapy (CAR T ). Radiomic biomarkers such as metabolic tumor volume (MTV) and total lesion glycolysis (TLG) have been recently studied to assess three-dimensional measurement of tumor activity and metabolic volume in LBCL. There is a paucity of understanding on the impact of radiomic biomarkers on outcomes and CAR T expansion kinetics in LBCL CAR T recipients. We studied the association of these radiomic biomarkers with efficacy, toxicity, and CAR T expansion in this single institution retrospective study of patients with LBCL who received axi-cel.
Methods
189 patients with relapsed or refractory LBCL who were treated with axi-cel from 12/2017 to 5/2022 were studied. The closest PET-CT scan to CAR T leukapheresis date was identified for each patient. After excluding cases with unavailable pre-apheresis PET-CT scans, 172 patients were included in the statistical analysis. Two reviewers independently used a semi-automated contouring software (MIM, v. 7.1.2) to measure maximum standardized uptake value (SUV Max), mean SUV, total MTV and TLG values of malignant lesions. CD19 CAR T expansion was measured by real-time flow cytometry with anti-idiotype-FMC63 conjugated to Dylight 65013. Areas under the curve (AUCs) were calculated for CAR T expansion in the 28 days following infusion using the linear trapezoidal method on raw values, and the results were transformed using a base-10 logarithm. Patients were categorized into high and low biomarker groups based on whether their values exceeded or were below the respective median. For univariate analyses, continuous variables were compared using a Mann-Whitney U-test, categorical using a Chi-square test, and time-to-event using a log-rank test. Within a multivariable framework, regressions (linear, logistic, Cox) were fit to control for potential confounders.
Results
Median duration of follow up was 33 months (IQR: 17.9, 44.7). MTV was highly correlated with TLG (r=0.87). High MTV was associated with bulky disease defined as &gt;10cm (p&lt;0.01), high IPI at apheresis (p&lt;0.04), bridging treatment (p&lt;0.01), pre-lymphodepletion lactate dehydrogenase (p&lt;0.01), and autologous stem cell transplant (p=0.02).
Complete response (CR) rate was greater for those in the low MTV group (79.3%) compared to high MTV group (52.3%), (p&lt;0.01), as well as those with high TLG (77.9%) compared to low TLG group (46%), (p&lt;0.01). Low MTV was significantly associated with better progression free survival (PFS) in a univariate analysis (p=0.03); median PFS was 33.5 months (IQR 3.06, 39.55) for low MTV versus 6.1 months (IQR 6.38, NA) for high MTV. Low MTV was also significantly associated with better overall survival (OS) in a univariate analysis (p&lt;0.01); median OS was not reached for the low MTV group but was 31.8 months for the high MTV group (IQR 16.5, NA) (Figure 1). After multivariable regression analysis, PFS was no longer different by MTV biomarker level ( p= 0.07), but OS was still significantly different ( p= 0.01). Neither PFS nor OS were significantly associated with the binary TLG variable.
The proportion of cytokine release syndrome (CRS) or immune cell associated neurologic toxicity syndrome (ICANS) of any grade or severe grade ICANS were significantly higher for the high MTV and TLG groups as compared to their respective low groups. Length of stay was significantly longer for those in the high MTV and TLG groups (Table 1).
A higher day 14 CAR T cell expansion was seen in the high TLG as compared to the low group (0.89 vs 0.63 cells/μL, p=0.002). However, there was no statistically significant difference in CAR T expansion as measured by AUC between the high and low MTV or TLG cohort.
Conclusion
Our study demonstrates poor outcomes for efficacy, safety, and healthcare utilization endpoints in patients with high tumor bulk as measured by volumetric tumor assessment on PET-CT. Furthermore, we show a differential peripheral day 14 CAR T expansion with higher expansion seen in patients with higher tumor bulk. Strategies like tumor debulking prior to CAR T therapy and earlier referral in patients with high tumor bulk may improve clinical outcomes.