Frontiers in immunology · 2025
Impact of inotuzumab ozogamicin as bridging therapy and tumor burden in CAR-T therapy for B-acute lymphoblastic leukemia.
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Alcalde-Mellado Patricia, Ruiz-Maldonado Victoria, Delgado-Serrano Javier, Sanoja-Flores Luzalba, Reinoso-Segura Marta, Pérez-Ortega Laura, Sierro-Martínez Belén, García-Guerrero Estefanía, Pérez de Soto Concepción, Pérez-Hurtado José María, González-Campos José, Pérez-Simón José Antonio, Molinos-Quintana Águeda, Caballero-Velázquez Teresa
Аннотация
INTRODUCTION: Inotuzumab ozogamicin is increasingly being used as bridging therapy (BT) prior to chimeric antigen receptor T-cell (CAR-T) in relapsed/refractory B-cell acute lymphoblastic leukemia (R/R ALL), but its impact on CAR-T expansion and clinical outcomes remains controversial.
METHODS: This study analyzed 24 R/R ALL patients receiving tisagenlecleucel after BT (Inotuzumab [n=10] vs. chemotherapy/steroids [n=14]). CAR-T expansion was monitored via multiparametric flow cytometry at different time-points after infusion, with outcomes assessed by event-free survival (EFS), overall survival, and immunophenotypic profiling.
RESULTS: Results indicate that despite lower CAR-T expansion with inotuzumab (median 58.3 vs. 337.7 CAR-T/μL; p=0.011), no difference at 12-month EFS was observed (66.7% vs. 64.3%; p=0.648). However, low tumor burden (LTB) at the time of infusion correlated with improved EFS (81.8% vs. 25% high tumor burden (HTB); p=0.019). Remarkably, inotuzumab achieved superior tumor reduction: 80% of HTB patients achieved LTB vs. 28.6% with chemotherapy (p=0.032). Achieving or maintaining LTB significantly improved EFS in 12 months (81.8% and 100% respectively) vs 25% for patients who maintained HTB. Immunophenotyping revealed a higher proportion of CD8+ stem cell memory (SCM) CAR-T cells at peak of expansion in the inotuzumab group (p=0.036). Interestingly, shorter EFS was observed among those patients who presented a lower percentage of SCM CD8+ CAR-T and lower SCM CD8+CARneg/μL on 28 days and on 90 days after CAR-T therapy.
DISCUSSION: Overall, inotuzumab as BT effectively reduces tumor burden but attenuates CAR-T expansion without compromising survival outcomes. As high tumor burden is a dominant driver of relapse and toxicity, the net effect of inotuzumab may be favorable in selected patients.
METHODS: This study analyzed 24 R/R ALL patients receiving tisagenlecleucel after BT (Inotuzumab [n=10] vs. chemotherapy/steroids [n=14]). CAR-T expansion was monitored via multiparametric flow cytometry at different time-points after infusion, with outcomes assessed by event-free survival (EFS), overall survival, and immunophenotypic profiling.
RESULTS: Results indicate that despite lower CAR-T expansion with inotuzumab (median 58.3 vs. 337.7 CAR-T/μL; p=0.011), no difference at 12-month EFS was observed (66.7% vs. 64.3%; p=0.648). However, low tumor burden (LTB) at the time of infusion correlated with improved EFS (81.8% vs. 25% high tumor burden (HTB); p=0.019). Remarkably, inotuzumab achieved superior tumor reduction: 80% of HTB patients achieved LTB vs. 28.6% with chemotherapy (p=0.032). Achieving or maintaining LTB significantly improved EFS in 12 months (81.8% and 100% respectively) vs 25% for patients who maintained HTB. Immunophenotyping revealed a higher proportion of CD8+ stem cell memory (SCM) CAR-T cells at peak of expansion in the inotuzumab group (p=0.036). Interestingly, shorter EFS was observed among those patients who presented a lower percentage of SCM CD8+ CAR-T and lower SCM CD8+CARneg/μL on 28 days and on 90 days after CAR-T therapy.
DISCUSSION: Overall, inotuzumab as BT effectively reduces tumor burden but attenuates CAR-T expansion without compromising survival outcomes. As high tumor burden is a dominant driver of relapse and toxicity, the net effect of inotuzumab may be favorable in selected patients.