Background Background CAR-T cell therapy has changed the treatment of relapsed/refractory (R/R) Large B Cell Lymphoma (LBCL), yet nearly 60% of patients (pts) still relapse. While several therapeutic options exist following CAR-T failure, their optimal use and accessibility remain unclear. Aims Aims This study aims to evaluate the incidence, treatment strategies and outcomes for LBCL pts R/R after CAR-T therapy. Methods Methods We retrospectively analyzed R/R LBCL pts treated after CAR-T cell therapy across 15 centers of the Fondazione Italiana Linfomi. Pts received commercial CAR-T products (axicabtagene ciloleucel [axi-cel] or tisagenlecleucel [tisa-cel]) by December 31, 2023. All pts provided EBMT informed consent. Treatment strategies and pts outcomes were analyzed, along with potential prognostic markers. Results Results Among 241 CAR-T recipients, 119 (61 axi-cel [51.2%] and 58 tisa-cel [48.7%]) relapsed or were refractory. Most pts had Diffuse Large B-cell Lymphoma (72%), advanced stage (76%) and an International Prognostic Index (IPI) ≥3 (58.7%). CRS occurred in 83% (severe in 12%), while ICANS was observed in 23% (severe in 8%). Relapse/progression was histologically confirmed in 50% of pts, with nearly half (48%) exhibiting CD19 loss. At relapse, 77% of pts (n=92) received curative- intent treatment. Of these, 67% were intended for bispecific antibodies (BiAB), but only 19% accessed this therapy due to limited availability. Other therapies included Polatuzumab-based regimens (27%), chemotherapy (22%), immunomodulatory agents (15%), radiotherapy (6%) and experimental drugs (11%). Outcomes were poor, with a median overall survival (OS) of 6.5 months for treated pts and 0.7 months for those receiving palliative care (Fig1). OS was longest with BiAB (12.5 months) and polatuzumab-based regimens (8.7 months), significantly outperforming chemotherapy (3.4 months, p=0.003). Progression-free survival (PFS) was also superior with BiAB (6 months) compared to polatuzumab-regimens (3.9 months), immunomodulatory agents (2.1 months), or chemotherapy (1.2 months; p<0.001). The highest response rates were observed with BiAB (72.5% overall response rate [ORR], 50% complete response [CR]) and polatuzumab-regimens (37% ORR, 33% CR). At CAR-T infusion, bridging therapy response, IPI, CARHEMATOTOX score, stage, CRS, and ICANS were associated with post-CAR-T outcomes, though multivariate analysis confirmed only PET positivity at day 30. At CAR-T failure, ECOG >1, LDH >2× ULN, >2 extranodal sites, time to relapse <4 months, platelets <100×10^9/L, and high EASIX score were significant predictors for poor outcome. Multivariate analysis identified LDH, extranodal sites, and time to relapse as predictors for OS, while LDH and time to relapse were associated with PFS. Based on these findings, prognostic scores for OS and PFS were developed, stratifying pts into three risk categories (p<0.001, Fig1). Finally, pts achieving CR after salvage therapy had improved PFS when consolidated with allogeneic stem-cell transplantation (allo-SCT) (16.3 vs. 15.6 months, p=0.015), although no significant OS difference was observed. Summary/Conclusion Summary/Conclusion Relapse after CAR-T therapy in R/R LBCL is associated with poor outcomes, though BiAB have shown the most promising results despite past challenges in accessibility. Prognostic factors such as LDH levels, extranodal involvement, and early relapse can help in treatment decisions. While allo-SCT consolidation may improve PFS in selected pts, its impact on OS remains unclear and warrants further investigation.
A MULTI-CENTER REAL-LIFE ANALYSIS ON PATIENTS WITH LARGE B-CELL LYMPHOMA AFTER FAILURE OF CAR-T CELLS THERAPY
Francesca Maria Quaglia;
2025-01-01
Abstract
Background Background CAR-T cell therapy has changed the treatment of relapsed/refractory (R/R) Large B Cell Lymphoma (LBCL), yet nearly 60% of patients (pts) still relapse. While several therapeutic options exist following CAR-T failure, their optimal use and accessibility remain unclear. Aims Aims This study aims to evaluate the incidence, treatment strategies and outcomes for LBCL pts R/R after CAR-T therapy. Methods Methods We retrospectively analyzed R/R LBCL pts treated after CAR-T cell therapy across 15 centers of the Fondazione Italiana Linfomi. Pts received commercial CAR-T products (axicabtagene ciloleucel [axi-cel] or tisagenlecleucel [tisa-cel]) by December 31, 2023. All pts provided EBMT informed consent. Treatment strategies and pts outcomes were analyzed, along with potential prognostic markers. Results Results Among 241 CAR-T recipients, 119 (61 axi-cel [51.2%] and 58 tisa-cel [48.7%]) relapsed or were refractory. Most pts had Diffuse Large B-cell Lymphoma (72%), advanced stage (76%) and an International Prognostic Index (IPI) ≥3 (58.7%). CRS occurred in 83% (severe in 12%), while ICANS was observed in 23% (severe in 8%). Relapse/progression was histologically confirmed in 50% of pts, with nearly half (48%) exhibiting CD19 loss. At relapse, 77% of pts (n=92) received curative- intent treatment. Of these, 67% were intended for bispecific antibodies (BiAB), but only 19% accessed this therapy due to limited availability. Other therapies included Polatuzumab-based regimens (27%), chemotherapy (22%), immunomodulatory agents (15%), radiotherapy (6%) and experimental drugs (11%). Outcomes were poor, with a median overall survival (OS) of 6.5 months for treated pts and 0.7 months for those receiving palliative care (Fig1). OS was longest with BiAB (12.5 months) and polatuzumab-based regimens (8.7 months), significantly outperforming chemotherapy (3.4 months, p=0.003). Progression-free survival (PFS) was also superior with BiAB (6 months) compared to polatuzumab-regimens (3.9 months), immunomodulatory agents (2.1 months), or chemotherapy (1.2 months; p<0.001). The highest response rates were observed with BiAB (72.5% overall response rate [ORR], 50% complete response [CR]) and polatuzumab-regimens (37% ORR, 33% CR). At CAR-T infusion, bridging therapy response, IPI, CARHEMATOTOX score, stage, CRS, and ICANS were associated with post-CAR-T outcomes, though multivariate analysis confirmed only PET positivity at day 30. At CAR-T failure, ECOG >1, LDH >2× ULN, >2 extranodal sites, time to relapse <4 months, platelets <100×10^9/L, and high EASIX score were significant predictors for poor outcome. Multivariate analysis identified LDH, extranodal sites, and time to relapse as predictors for OS, while LDH and time to relapse were associated with PFS. Based on these findings, prognostic scores for OS and PFS were developed, stratifying pts into three risk categories (p<0.001, Fig1). Finally, pts achieving CR after salvage therapy had improved PFS when consolidated with allogeneic stem-cell transplantation (allo-SCT) (16.3 vs. 15.6 months, p=0.015), although no significant OS difference was observed. Summary/Conclusion Summary/Conclusion Relapse after CAR-T therapy in R/R LBCL is associated with poor outcomes, though BiAB have shown the most promising results despite past challenges in accessibility. Prognostic factors such as LDH levels, extranodal involvement, and early relapse can help in treatment decisions. While allo-SCT consolidation may improve PFS in selected pts, its impact on OS remains unclear and warrants further investigation.
I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.
