Inferior Survival in Double Refractory Large B-cell Lymphoma Eligible for third-line CD19 CAR T-cell Therapy Open Access

• In patients intended for third-line CAR T-cell therapy, DR-LBCL patients have an inferior OS compared to the NDR-LBCL counterparts.

• CAR T-cell eligible patients with DR-LBCL have a lower likelihood of proceeding with CAR T-cell infusion when compared to NDR-LBCL patients.

Outcomes following CD19 chimeric antigen receptor (CAR) T-cell therapy in third-line treatment and beyond for patients with large B-cell lymphoma (LBCL) refractory to both an anthracycline during initial and platinum-based salvage therapy, referred to as double refractory (DR), are not well described. It is also unclear if these patients may be less likely to proceed to CAR T-cell infusion. Our objectives were to assess third-line CAR T-cell survival outcomes in DR- and non-DR (NDR)-LBCL cohorts including the failure rates to proceed to cell infusion. Review of 199 LBCL patients referred for CAR T-cell treatment at our centre demonstrates that the DR-LBCL patients (n=68) have an inferior 12-month overall survival (OS; 47.1% [95%CI 36-61.7] versus 66.7% [95%CI 58.5-76.1], respectively, logrank p=0.0022) when compared to the non-double refractory (NDR-LBCL) patients (n=131). This OS difference is driven by a higher failure rate to proceed to CAR T-cell infusion (32% versus 18%, p=0.028). For patients unable to proceed to CAR T-cell infusion median OS was 2.56 months (95%CI 1.94-3.81); DR-LBCL 1.94 months (95%CI 1.61-3.35) versus NDR-LBCL 3.42 months (95%CI 2.56-not reached), logrank p=0.0027. 12-month OS (65% [95%CI 52.1-81.1] versus 72.3% [95%CI 63.8-81.9], logrank p=0.13) and 6-month progression free survival (46.5% [95%CI 22.8-94.7] versus 57.2% [95%CI 36.2-90.1], logrank p=0.40) of DR- and NDR-LBCL patients proceeding to CAR T-cell infusion appears similar. Our study highlights a high-risk subgroup characterised by inferior OS with challenges in getting to CAR T-cell infusion and could benefit from different management approaches such as novel bridging or “off the shelf” strategies.