Imaging Biomarkers to Predict Outcomes in Patients with Large B-Cell Lymphoma with a Day 28 Partial Response By PET/CT Imaging Following CAR-T Therapy
Authors: Lutfi Forat , Goloubeva Olga , Kim Dong Won , Kowatli Amer , Gryaznov Anton , Margiotta Philip , Matsumoto Lisa R , Gottlieb David , Bukhari Ali , Dunne Caroline , Law Jennie Y. , Lee Seung-Tae , Ruehle Kathleen , Yared Jean A. , Kocoglu Mehmet Hakan , Atanackovic Djordje , Hardy Nancy M. , Chen Wengen , Rapoport Aaron P. , Dahiya Saurabh 
Published: November 2021

Abstract
Introduction: CD19 Chimeric Antigen Receptor T-cell (CAR-T) therapy is now a commonly used treatment for relapsed/refractory (R/R) Large B-cell Lymphoma (LBCL). However, predictors of long-term response remain poorly defined. In particular, partial response (PR) at first tumor assessment at Day 28 (D28) is a source of uncertainty both for clinicians and patients. In the pivotal CAR-T trials for LBCL, approximately half of these patients eventually achieved a complete remission (CR), while the other half experienced progressive disease (PD) (Neelapu et al, NEJM 2017). Herein, we present real-world data on 24 patients achieving a PR on D28 by PET/CT imaging following CAR-T therapy for R/R LBCL. We explore whether differences between baseline and D28 PET/CT imaging might predict progression free survival (PFS), overall survival (OS), best overall response rate (B-ORR), or last overall response rate (L-ORR).
Methods: Out of 75 patients receiving CAR-T therapy at a single institution, we retrospectively identified and reviewed 24 (32%) as achieving a PR on D28. Two independent radiologists collected baseline (pre-CAR-T therapy) and D28 PET/CT Standard Uptake Value (SUV) max and Total Tumor Metabolic Volume (TMV, in cm 3) using ROVER software. The Intraclass Correlation Coefficients (ICC) as a measure of absolute agreement between two readers was 0.99 for SUV the 0.97 for TMV. There was a strong absolute agreement between the two radiologists. For simplicity of data interpretation and given this concordance we present the results of one reviewer. Univariable Cox regression model was used to calculate PFS and OS. All statistical tests were 2-sided and conducted at the 0.05 level of significance.
Results: Of the 24 patients with PR on D28 PET/CT, median follow-up time was 1.9 years with 17 patients (71%) still alive at last follow-up (see Fig 1a). Median age was 51 years-old, 46% were female, 66.7% had stage III/IV disease, all patients had ECOG ≤2, 58% received bridging therapy, and half had ≥3 lines of prior therapy (see Table 1A).
Results of the univariable Cox regression model revealed that a lower D28 SUV max (p=0.004), lower TMV at both baseline (p=0.03), and at D28 (p=0.01) may be predictive of better OS. Longer PFS was found with lower D28 SUV max (p=0.002) and lower TMV at both baseline (p=0.01), and D28 (p=0.04).
In analysis of B-ORR achieved by PET/CT, half of patients in PR at D28 ultimately achieved a CR (see Table 1B). OS was significantly lower in those with a B-ORR of PR vs CR (p&lt;0.004) (see Fig 1b). The median SUV max at baseline was 14 in those with B-ORR of CR vs 15 in PR (Not Significant (NS)); at D28 median SUV max was 5 in CR vs 7 in PR (p=0.04). The median TMV at baseline was 210 in those with CR vs 861 with PR (p=0.07); at D28 median TMV was 12 in CR vs 26 in PR (NS). There was no significant difference in absolute or percent change between baseline and D28 in either SUV max or TMV; however, the absolute difference in TMV was notably greater in those with B-ORR of PR than CR (793 vs 201) (p=0.08).
In analysis of outcome by L-ORR by PET/CT, 11 patients were in CR, while 13 had PD (see Table 1C). The median SUV max at baseline was 14 in those in CR vs 15 in PD (NS); at D28 median SUV max was 5 in those with CR vs 6 in PD (NS). The median baseline TMV was 298 in those with CR vs 591 in PD (NS); the median TMV at D28 was 15 in those with CR vs 21 in PD (NS). There was no significant difference in absolute or percent change between baseline and D28 of either SUV max or TMV based on L-ORR.
Conclusion: In this analysis of patients in PR at D28 following CD19-directed CAR-T therapy, D28 but not baseline SUV max was significantly higher in those with a B-ORR of PR; and, in our modeling, lower D28 SUV max may predict favorable PFS and OS. Lower TMV, both at baseline and D28, may also be predictive of longer PFS and OS.
Collectively, these findings suggest that for patients achieving a PR at D28, the best predictive factor by imaging for ultimately achieving a CR is lower SUV max at D28 and lower TMV at baseline and D28. These characteristics were also associated with longer PFS and OS. These findings indicate that there may be an intrinsic quality to the tumor itself (e.g. FDG-avidity and metabolic volume) that determines the ultimate outcome from a D28 PR. While further study is warranted, we demonstrate that patients with such characteristics should be identified, monitored closely for relapse, and perhaps be considered for further early intervention.
Figure 1 Figure 1.

Disclosures
Hardy: InCyte: Membership on an entity's Board of Directors or advisory committees; Kite/Gilead: Membership on an entity's Board of Directors or advisory committees; American Gene Technologies, International: Membership on an entity's Board of Directors or advisory committees.