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<p>CD19-directed chimeric antigen receptor-T cell (CAR-T) therapies have transformed treatment for relapsed/refractory large B-cell lymphoma (LBCL), yet heterogeneity in toxicity and efficacy persists. To address this, we developed a novel composite endpoint: severe toxicity-free and progression-free survival at 6 months (TPFS6), defined as absence of severe CRS, ICANS, progressive/stable disease (PD/SD), and non-relapse mortality (NRM) within 6 months of CAR-T therapy. In our cohort, 37% achieved TPFS6. Events contributing to TPFS6 failure included severe CRS (6.8%), ICANS (30.3%), NRM (1.7%), and PD/SD (61.2%). Multivariable analysis demonstrated female sex (<i>p</i> = 0.01), ECOG &lt; 2 (<i>p</i> = 0.05), and lower LDH and CRP (both <i>p</i> = 0.004) predicted TPFS6. With a median follow-up of 36.2 months, the estimated 2-year OS and PFS were 54.5% and 39.6%, respectively. Landmark analysis showed TPFS6 was associated with improved OS (HR = 0.19; 95% CI: 0.11–0.35; <i>p</i> &lt; 0.001) and PFS (HR = 0.33; 95% CI: 0.16–0.67; <i>p</i> = 0.002). CAR-T product type was not significantly associated with OS but was with PFS (HR = 3.09; 95% CI: 1.27–7.50; <i>p</i> = 0.013). TPFS6 remained prognostic for OS and PFS even after accounting for PD/SD, underscoring the impact of severe toxicity on subsequent survival. TPFS6 is a clinically meaningful endpoint integrating efficacy and safety and may predict long-term outcomes following CAR-T therapy.</p>

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A novel severe toxicity-free, and progression-free survival endpoint predicts outcomes after CD19 chimeric antigen receptor-T cell therapy in large B-cell lymphoma

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年7月17日

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  • Aditi Saha,
  • Junmin Whiting,
  • Razan Mohty,
  • Kristen Flores,
  • Jongphil Kim,
  • Taiga Nishihori,
  • Julio Chavez,
  • Sameh Gaballa,
  • Farhad Khimani,
  • Hien Liu,
  • Bijal Shah,
  • Marian Dam,
  • Muhammad Jaffer,
  • Sepideh Mokhtari,
  • Nima Ghalehsari,
  • Hany Elmariah,
  • Christina Bachmeier,
  • Jose Alejandro Guevara,
  • Heather Jim,
  • Sayeef Mirza,
  • Brahm H. Segal,
  • Doris K. Hansen,
  • Nelli Bejanyan,
  • Fabiana Perna,
  • Rawan Faramand,
  • Michael Jain,
  • Frederick Locke,
  • Aleksandr Lazaryan

摘要

CD19-directed chimeric antigen receptor-T cell (CAR-T) therapies have transformed treatment for relapsed/refractory large B-cell lymphoma (LBCL), yet heterogeneity in toxicity and efficacy persists. To address this, we developed a novel composite endpoint: severe toxicity-free and progression-free survival at 6 months (TPFS6), defined as absence of severe CRS, ICANS, progressive/stable disease (PD/SD), and non-relapse mortality (NRM) within 6 months of CAR-T therapy. In our cohort, 37% achieved TPFS6. Events contributing to TPFS6 failure included severe CRS (6.8%), ICANS (30.3%), NRM (1.7%), and PD/SD (61.2%). Multivariable analysis demonstrated female sex (p = 0.01), ECOG < 2 (p = 0.05), and lower LDH and CRP (both p = 0.004) predicted TPFS6. With a median follow-up of 36.2 months, the estimated 2-year OS and PFS were 54.5% and 39.6%, respectively. Landmark analysis showed TPFS6 was associated with improved OS (HR = 0.19; 95% CI: 0.11–0.35; p < 0.001) and PFS (HR = 0.33; 95% CI: 0.16–0.67; p = 0.002). CAR-T product type was not significantly associated with OS but was with PFS (HR = 3.09; 95% CI: 1.27–7.50; p = 0.013). TPFS6 remained prognostic for OS and PFS even after accounting for PD/SD, underscoring the impact of severe toxicity on subsequent survival. TPFS6 is a clinically meaningful endpoint integrating efficacy and safety and may predict long-term outcomes following CAR-T therapy.