CAR-T cell therapy has become a standard treatment option for patients with relapsed or refractory large B-cell lymphoma (r/r LBCL). Initially approved for patients who had received at least two prior lines of therapy, CAR-T cell therapy has demonstrated the ability to induce durable remission in a significant proportion of patients. However, hematologic toxicity remains one of the most common and clinically important adverse effects associated with CAR-T treatment.
A recent real-world multicenter study published in Blood Advances evaluated hematologic toxicity in patients receiving second-line commercial CD19 CAR-T therapy for r/r LBCL. The study focused particularly on immune effector cell-associated hematotoxicity (ICAHT), a condition characterized by prolonged or severe blood count suppression after CAR-T infusion.
In 2023, the European Hematology Association (EHA) and the European Society for Blood and Marrow Transplantation (EBMT) established a consensus grading system for ICAHT. According to this definition, severe early neutropenic ICAHT is defined as an absolute neutrophil count (ANC) ≤100/μL lasting at least 7 days, or ANC ≤500/μL lasting at least 14 days within the first 30 days after CAR-T infusion. Previous studies have shown that severe ICAHT is associated with higher risks of infection, non-relapse mortality (NRM), and poorer survival outcomes.
The study included 82 adult patients treated at nine medical centers in Germany between October 2022 and April 2025. Patients received either axi-cel or liso-cel as second-line CAR-T therapy following standard lymphodepletion with fludarabine and cyclophosphamide. Most patients had primary refractory disease, and more than 90% received bridging therapy before CAR-T infusion.
After a median follow-up of 15 months, the complete response rate reached 62.5%. One-year progression-free survival (PFS) was 54.0%, while one-year overall survival (OS) was 74.4%.
Importantly, the incidence of severe early neutropenic ICAHT was only 12.2%, significantly lower than the approximately 23% reported in patients receiving CAR-T in later treatment lines. No grade 3 or higher neutropenic ICAHT events were observed in patients treated with liso-cel.
Patients who developed severe early ICAHT were more likely to experience severe anemia, thrombocytopenia, late neutropenia, and increased use of G-CSF support. Although these patients showed a trend toward lower progression-free survival, overall survival differences were not statistically significant.
The study also evaluated the predictive value of the CAR-HEMATOTOX score, a tool developed to estimate hematologic toxicity risk before lymphodepletion chemotherapy based on inflammatory markers and bone marrow reserve. While the score successfully predicted severe anemia and thrombocytopenia, it did not significantly predict severe early neutropenic ICAHT in this second-line setting. Researchers suggested that the lower overall toxicity burden and limited sample size may explain the reduced predictive performance.
These findings provide important clinical insight into the timing of CAR-T therapy. Earlier use of CAR-T in second-line treatment may not only improve long-term disease control but also reduce hematologic toxicity burden, transfusion requirements, growth factor use, infection risk, and non-relapse mortality. Patients treated earlier in the disease course may retain better bone marrow reserve, allowing them to tolerate CAR-T therapy more safely.
The study highlights that the benefits of earlier CAR-T intervention extend beyond survival outcomes alone. Reduced toxicity burden and improved hematologic safety should also be considered important advantages when evaluating treatment strategies for relapsed or refractory LBCL.
Reference
Zeremski, Vanja, et al. “Early CAR T-Cell Therapy in Relapsed/Refractory Large B-Cell Lymphoma Is Associated with Lower Hematotoxicity Burden.” Blood Advances, 2026.
