Paper Details

ABSTRACT

Introduction: CD19-directed CAR-T has transformed outcomes for relapsed/refractory mantle cell lymphoma (r/r MCL), yet a substantial proportion of patients relapse early or develop severe toxicity. Existing prognostic tools are largely anchored at lymphodepletion or infusion, when opportunities to modify patient selection, bridging therapy, or logistical planning are exhausted. We therefore sought to identify prognostic parameters obtained prior to leukapheresis, enabling risk assessment early enough to meaningfully influence clinical decision-making with CD19-directed CAR-T.

Methods: In this multicenter observational study, demographic, laboratory, disease characteristics, and prior treatment history were examined in a training cohort of 263 r/r MCL patients treated with brexucabtagene autoleucel across 10 academic sites in 4 countries. Candidate predictors were assessed before apheresis. Missing covariate data was addressed by multiple imputation by chained equations (m=20). The primary endpoint was progression-free survival (PFS) from time of CAR-T infusion. Lasso-penalized Cox regression was applied to each imputed dataset with the penalty parameter determined as the median of 20 repeated ten-fold cross-validations; variables selected in ≥95% of imputed datasets were retained. The resulting continuous score was divided into three risk groups by recursive partitioning.

Results: Median age was 68 years (IQR 61-74). Patients received a median of 3 prior lines (IQR 2-4); 83% were BTKi-exposed and 59% had progression within 24 months of frontline therapy (POD24). Blastoid or pleomorphic morphology was present in 38%, TP53 aberration in 49% (76/155 evaluable), complex karyotype (CK) in 35% (50/142 evaluable). With a median follow-up of 31.3 months post-infusion, median PFS was 21.0 months (95% CI 14.8-30.7), median overall survival (OS) was 46.0 months (95% CI 33.7-not reached), and 1-year non-relapse mortality (NRM) was 12.8% (95% CI 8.7-16.9).

Lasso-penalized Cox regression identified 8 pre-apheresis prognostic parameters, which formed the Stratification of CAR-T Outcomes at Pre-apheresis Evaluation (SCOPE-MCL) score: ECOG performance status (PS), Ann Arbor stage, number of prior lines, exposure and response to holding therapy, Ki-67 proliferation index, LDH ratio (LDH divided by the upper limit of normal), hemoglobin, and log-transformed ferritin. The model achieved a c-index of 0.70 for PFS prediction, with time-dependent AUCs of 77%, 75%, and 73% at 6, 12, and 24 months, respectively. This compared favorably with c-indices of 0.61 for MIPI and 0.56 for CAR-HEMATOTOX in the same cohort. Notably, age, POD24, blastoid morphology, TP53 aberration and CK showed no univariable association with PFS, though TP53 and CK data were missing in ~40% of patients.

SCOPE-MCL stratified patients into three risk groups (low: 86, intermediate: 130, high: 47) with distinct outcomes (12-month PFS 87%, 54%, and 26%; p<0.001; median PFS not reached, 15.0, and 3.5 months). Twelve-month OS was 89%, 73%, and 52% across groups (p<0.001). SCOPE-MCL was associated with an increased rate of grade ≥3 early ICAHT (10%, 26%, 44%; p<0.001) and a numeric trend towards more frequent grade ≥3 CRS (4%, 10%, 11%; p=0.09). One-year NRM increased across groups (5%, 15%, 21%; p=0.09), as did relapse-related mortality (5%, 12%, 27%; p<0.001). Of interest, after inspection of PFS distribution within the high-risk group, an ultra-high-risk subgroup was identified by recursive partitioning (n=30, 11% of all patients). These patients showed a dismal 12-month PFS of 10%, 12-month OS of 40%, and substantial 12-month NRM of 20%.

In a sensitivity analysis, a simplified five-parameter score (ECOG PS, Ki-67, LDH ratio, hemoglobin, log-transformed ferritin) retained a c-index of 0.66 in the training set. Finally, initial results from an independent external cohort of 107 patients across 5 additional centers (74 brexu-cel, 33 liso-cel) confirmed prognostic discrimination of SCOPE-MCL for PFS, with significant separation of risk groups.

Conclusions: SCOPE-MCL uses eight pre-apheresis parameters to stratify efficacy and toxicity outcomes before CD19-directed CAR T-cell therapy in r/r MCL. This early pre-apheresis assessment provides a clinically actionable checkpoint at which intensified bridging, alternative or consolidative therapies, or modified treatment planning may still be considered. The model showed promise in an independent cohort supporting its generalizability.