Prognostic Value of Early PET in Patients with Aggressive Non-Hodgkin Lymphoma Treated with Anti-CD19 CAR T-Cell Therapy

Introduction: Although anti-CD19 autologous chimeric antigen receptor (CAR) T-cell therapy has transformed the management of relapsed/refractory non-Hodgkin lymphoma (NHL), the majority of patients will ultimately relapse. The prognostic implications of early (1-month) metabolic response on ultimate outcome are still poorly defined, yet would have significant implications on the development of consolidation strategies.

Methods: We conducted a multi-center, retrospective study of patients with NHL who received commercial anti-CD19 CAR T-cell therapy at 5 academic medical centers between 7/2018-5/2021. All patients had a PET scan 30 (+/- 15) days following CAR T-cell infusion. Imaging responses were per investigator assessment using Lugano criteria. Cox proportional hazards models were used to identify predictors of progression free survival (PFS).

Results: A total of 193 patients were identified who received axicabtagene ciloleucel (axi-cel, n=180) or tisagenlecleucel (tisa-cel, n=13). Histologies included diffuse large B-cell lymphoma (DLBCL), NOS, n= 134 (69%), DLBCL transformed from an indolent lymphoma, n=47 (24%), primary mediastinal B-cell lymphoma (PMBCL), n=8 (4%), and Richter's syndrome (RS), n=4 (2%). The median age was 62 (range 19-80) years; 66% of patients were male; IPI was low in 28%, intermediate in 27%, and high in 42%; median prior therapies was 3 (range 1-9); 44% had an elevated LDH prior to lymphodepletion; 30% had an elevated CRP prior to CAR T-cell infusion; 10% had bulky disease (≥10 cm) prior to lymphodepleting therapy; and 40% received bridging therapy.

The median follow-up of the entire cohort was 22 months (m). Responses at 1m included complete response (CR), n= 101 (52%), partial response (PR), n=53 (27%), stable disease (SD), n=4 (2%), and progressive disease (PD), n=35 (18%). The median PFS of the entire cohort was 11m (95% CI: 6-not reached) (Figure 1B) and median overall survival (OS) was not reached. PFS for the entire cohort was 57% (95% CI: 50-65) at 6m and 49% (95% CI: 42-58) at 12m; and OS was 79% (95% CI: 73-85) at 6m and 67% (95% CI: 61-75) at 12m. The 12m PFS and OS for patients with CR at 1m was 70% (95% CI: 61-80) and 82% (95% CI: 74-91), respectively, and was 38% (95% CI: 26-55) and 69% (95% CI: 57-84) for patients with PR/SD (Figure 1C). The 12m PFS and OS based on 1m PET (Figure 1D) was 72% (95% CI: 61-85) and 82% (95% CI: 72-93), respectively, for Deauville 1/2, 68% (95% CI: 53-88%) and 82% (CI: 69-98) for Deauville 3, 55% (95% CI: 39-79) and 83 (95% CI: 69-100) for Deauville 4, and 12% (95% CI: 3-46) and 56% (95% CI: 27-56) for Deauville 5 with PR/SD.

Indicators of shorter PFS across the entire cohort included elevated LDH at lymphodepletion (HR: 2.11 (95% CI: 1.41-3.16, p<0.001)), elevated CRP at CAR T-cell infusion (HR: 1.85 (95% CI: 1.22-2.8, p=0.004)), use of bridging therapy (HR: 1.8 (95% CI: 1.21-2.70, p=0.004)), and grade 3 or higher cytokine release syndrome (HR: 2.26 (95% HR: 1.23-4.17, p=0.009)). However, among patients with PR/SD at 1m, none of those clinical variables (including bulky disease, elevated LDH or CRP, high IPI, grade 3 or higher CRS or neurotoxicity, and use of tocilizumab or steroids) predicted progression at 3m. Among patients with a CR at 1m, an elevated LDH at the time of lymphodepletion correlated with an increased risk of relapse at 3m (HR: 4.14 (95% CI: 1.20-16.56, p=0.03)).

Discussion: We demonstrate that PFS is improved in patients with a CR at day +30 PET as compared to patients with a PR or SD. Furthermore, patients with Deauville 1/2 appear to have similar outcomes as those with a Deauville 3. No independent clinical variables were able to predict which patients with a PR/SD were likely to progress at the time of their next scan. Novel biomarkers such a minimal residual disease (MRD), may be necessary to further guide treatment modification in this setting.

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