The Post-CAR Prognostic Index (PC-PI): A New Prognostic Score to Predict Overall Survival in Large B-Cell Lymphoma Patients Progressing after Chimeric Antigen Receptor T-Cell Therapy

Abstract

Introduction: Chimeric antigen receptor (CAR) T-cell therapy fails to achieve durable responses in 60% of relapsed/refractory (R/R) large B-cell lymphoma (LBCL) patients in the third or later line setting. There is no standard treatment after CAR T-cell therapy progression and a wide range of outcomes are observed in this patient population. Besides the interval between CAR T-cell infusion and progressive disease (PD), data regarding prognostic factors at time of progression are scarce. Our aim was to develop a new prognostic tool to predict overall survival (OS) after CAR T-cell therapy progression with easily-available markers from routine clinical practice. Methods: First, we performed a retrospective data collection at 12 Spanish centers of R/R LBCL patients who progressed after CAR T-cell therapy in the third or later line setting from September 2018 until June 2022 (training cohort, TC). We analyzed a total of 15 variables, including pre-CAR T-cell therapy characteristics (gender, histology, primary refractory disease, previous hematopoietic transplant, number of previous lines) and values collected at time of progression to CAR T-cells (age, stage, extranodal sites, ECOG, hemoglobin, neutrophils, platelets, LDH, best response to CAR T-cells, time from CAR T-cell infusion to PD). The primary endpoint was OS from date of progression to CAR T-cell therapy. A stratified Cox model was used to estimate hazard ratios (HRs) using post-progression treatment as a stratification factor. We used LASSO regression with minimum lambda to identify which variables had the highest prognostic impact on OS. Additionally, the factors with a lower contribution were eliminated to create a parsimonious model. The C-statistic was used to evaluate its discrimination. We examined the performance of the International Prognostic Index (IPI) score and Revised IPI (R-IPI) in this setting. Finally, we tested the score in an external validation cohort (VC) which included a comparable patient population from 3 European countries. Results: Among the 216 LBCL patients included in the TC, most were male (66%), had an ECOG of 1 (48%) and stage IV disease (71%) at time of CAR T-cell therapy progression. Median time from CAR T-cell infusion to PD was 2.5 months (95CI% 1.9-2.9) and median follow-up from progression was 15 months. Salvage treatment was classified into 3 subgroups, including immunotherapy or targeted agents (43%), chemotherapy or radiotherapy (20%) and palliative care (38%). To build the prognostic score, a total of 5 variables were selected. Each marker received 1 point (given the similar HR [1.48-1.77]), if they met defined criteria: ECOG (>0), hemoglobin (<10 g/dL), LDH (>2 x upper normal limit), number of extranodal sites (>1) and time from CAR T-cell infusion to PD (<4 months). Patients with 0-1 points were classified as low risk, 2 points as intermediate-low risk, 3 points as intermediate-high risk and 4 or 5 points as high risk. In the TC, the 4 risk groups showed statistically significant differences in OS (Figure 1). In the low-risk group (n=39 [18%]), the median OS [mOS] was not reached; in the intermediate-low risk (n=56 [26%]) mOS was 7.3 months (HR=2.89, p=0.002); in the intermediate-high risk (n=57 [26%]) mOS was 4.9 months (HR=4.81, p<0.001) and in the high risk (n=64 [30%]) mOS was 1.8 months (HR=6.69, p<0.001). In terms of post-relapse therapies, both the chemo/radiotherapy and the immunotherapy groups showed a balanced patient distribution, from low to high risk (32%, 35%, 14% and 19% vs 22%, 32%, 30% and 16%, respectively). The VC included 204 patients with a similar patient distribution in the 4 prognostic risk groups (35%, 25%, 12%, 27%). The mOS for each of these groups was 15.2, 5.3, 2.9 and 0.9 months, respectively. Each group had distinct OS outcomes when compared with all the other risk groups (p<0.05 for each comparison) (Figure 2). Finally, our model presented a C-index of 0.712 for the TC and 0.811 for the VC, outperforming both the IPI (0.647 [TC] and 0.691 [VC]) and R-IPI (0.632 [TC] and 0.683 [VC]). Conclusions: The Post-CAR Prognostic Index (PC-PI) is a clinically useful tool for OS prediction and risk-adapted treatment planning in LBCL patients progressing after CAR T-cell therapy. In addition, our results will help stratification in clinical trials which include patients with prior CAR T-cell therapy.