CAR T-cell therapy response varies by extranodal disease site in large B-cell lymphoma.

in Blood cancer journal by Alejandro Luna, Sean M Devlin, Kai Rejeski, Jessica R Flynn, Magdalena Corona, Efrat Luttwak, Alfredo Rivas-Delgado, Ivan Landego, Giulio Cassanello, Marina Gomez-Llobell, Sandeep S Raj, Parastoo B Dahi, Richard J Lin, Allison Parascondola, M Lia Palomba, Gunjan L Shah, Michael Scordo, Ana Alarcon Tomas, Doris Leithner, Akshay Bedmutha, Heiko Schöder, Brandon S Imber, Gilles Salles, Jae H Park, Miguel-Angel Perales, Roni Shouval

TLDR

  • The study finds that extranodal sites are common sanctuary regions resistant to CD19-directed CAR-T therapy in large B-cell lymphoma, with site-specific outcomes and relapse risk.
  • Patients with concomitant EN and ND disease had poorer outcomes and higher relapse rates.
  • The study underscores the need for organ-targeted strategies to enhance treatment efficacy in CAR-T therapy.

Abstract

The role of extranodal (EN) sites as potential sanctuary regions resistant to CD19-directed chimeric antigen receptor T-cell (CAR-T) therapy in large B-cell lymphoma (LBCL) remains unclear. To investigate this, we retrospectively analyzed 283 adults treated with commercial CD19 CAR-T therapy, assessing 958 PET-CT scans across four time points: pre-apheresis, pre-lymphodepletion, best response, and relapse. EN involvement prior to CAR-T therapy was common (76%). Outcomes for patients with exclusive EN disease were similar to those with nodal (ND) disease alone; however, patients with concomitant EN and ND disease (EN + ND) had lower complete response rates and shorter progression-free survival. Site-specific outcomes varied: lungs/pleura/pericardium and gastrointestinal/peritoneum involvement had the lowest local response rates (48% and 51%, respectively). Notably, the risk of same-site relapse was highest in the lungs/pleura/pericardium (hazard ratio [HR] 7.8) and gastrointestinal/peritoneum (HR 5.97). Among patients relapsing after CAR-T, two-year overall survival rates from time of relapse were significantly lower in those with EN relapse (23% for exclusive EN; 25% for EN + ND) compared to exclusive ND relapse (64%; p = 0.008). These findings underscore the high prevalence of EN disease in CAR-T recipients and its site-specific impact on outcomes, highlighting the need for organ-targeted strategies to enhance treatment efficacy. Differential site-specific response and relapse/progression risk according to pre-CAR-T therapy anatomical site involvement in Large B-cell Lymphoma. Risk of site-specific relapse or progression was not evaluable for CNS/orbital/cranial sinuses, adrenal/genitourinary, hepatobiliary/pancreas, and spleen due to insufficient number of events.

Overview

  • The study investigates the role of extranodal (EN) sites as potential sanctuary regions resistant to CD19-directed chimeric antigen receptor T-cell (CAR-T) therapy in large B-cell lymphoma (LBCL).
  • The study analyzed 283 adults treated with commercial CD19 CAR-T therapy, evaluating 958 PET-CT scans across four time points.
  • The primary objective is to understand the site-specific impact of EN involvement on outcomes after CAR-T therapy and identify strategies to enhance treatment efficacy.

Comparative Analysis & Findings

  • EN involvement prior to CAR-T therapy was common (76%), with outcomes for patients with exclusive EN disease similar to those with nodal (ND) disease alone.
  • However, patients with concomitant EN and ND disease (EN+ND) had lower complete response rates and shorter progression-free survival.
  • The risk of same-site relapse was highest in the lungs/pleura/pericardium and gastrointestinal/peritoneum, with lower local response rates in these sites.

Implications and Future Directions

  • The high prevalence of EN disease in CAR-T recipients highlights the need for organ-targeted strategies to enhance treatment efficacy.
  • Future studies should investigate site-specific optimization of CAR-T therapy and potential combination therapies to improve outcomes.
  • Understanding the site-specific resistance mechanisms and developing treatments that target these areas may improve treatment outcomes.
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