A long-term follow-up study conducted by researchers at the First Affiliated Hospital, Zhejiang University School of Medicine has identified high Ki-67 expression as an important negative prognostic factor in patients with relapsed or refractory B-cell non-Hodgkin lymphoma (R/R B-NHL) treated with CD19 CAR-T cell therapy. The study also provides valuable insights into the long-term safety profile of CAR-T therapy, including immune recovery, infection risk, viral reactivation, and secondary malignancies.
Study Overview
The retrospective study included 79 patients with R/R B-NHL who received CD19-targeted CAR-T cell therapy between December 2017 and December 2024. Patients were treated with either CD19 single-target CAR-T or CD19/CD22 dual-target CAR-T products incorporating 4-1BB or CD28 co-stimulatory domains.
Researchers evaluated treatment efficacy, survival outcomes, CAR-T cell kinetics, and long-term safety events.
Durable Responses Achieved with CD19 CAR-T Therapy
The study demonstrated strong and durable clinical responses:
- Overall Response Rate (ORR): 89.7%
- Complete Response (CR) Rate: 65.4%
- 3-Year Duration of Response (DOR): 44.9%
- 3-Year Progression-Free Survival (PFS): 40.2%
- 3-Year Overall Survival (OS): 48.3%
Multivariate analysis showed that high Ki-67 expression (>60%) was significantly associated with lower complete response rates, shorter duration of response, and reduced progression-free survival. Bone marrow involvement was also linked to poorer duration of response, while refractory disease and more than four prior lines of therapy were associated with lower complete response rates.
Interestingly, long-term CAR-T cell persistence beyond 180 days did not correlate with improvements in DOR, PFS, or OS, suggesting that early CAR-T expansion and rapid tumor clearance may be more important determinants of long-term outcomes than prolonged persistence.
Ki-67 Identified as a Key Prognostic Biomarker
Patients with high Ki-67 expression (>60%) demonstrated significantly impaired CAR-T cell expansion, including:
- Lower peak CAR-T cell levels
- Reduced area under the curve (AUC) during the first 28 days after infusion
- Significantly impaired CD8-positive CAR-T cell expansion
Receiver operating characteristic (ROC) analysis suggested an optimal Ki-67 cutoff of approximately 70%, and validation analyses confirmed its prognostic significance. Sensitivity analyses excluding patients who received PD-1 maintenance therapy produced consistent results.
These findings indicate that Ki-67 may serve as a valuable biomarker for patient stratification and risk assessment before CAR-T therapy.
Long-Term Safety Findings
The study also highlighted several important long-term safety considerations:
Hypogammaglobulinemia
- 92.4% of patients developed hypogammaglobulinemia.
- 32.9% required intravenous immunoglobulin (IVIg) replacement therapy.
- IgM recovered earlier, while IgG and IgA often remained suppressed for prolonged periods.
Viral Reactivation
- Viral reactivation occurred in 5.1% of patients.
- Cases included cytomegalovirus (CMV) and hepatitis B virus (HBV) reactivation.
Secondary Malignancies
- Secondary cancers were reported in 5.1% of patients.
- Reported cases included renal cell carcinoma, parotid gland cancer, and hepatocellular carcinoma.
Mortality
- Overall mortality reached 50.6%.
- Disease progression accounted for 34.2% of deaths.
- Non-relapse mortality accounted for 10.1%, with infections being the most common cause.
Clinical Implications
The findings confirm that CD19 CAR-T cell therapy can produce durable remissions in patients with relapsed or refractory B-cell non-Hodgkin lymphoma while maintaining a manageable long-term safety profile.
Importantly, high Ki-67 expression emerged as a strong negative prognostic marker associated with impaired CAR-T expansion and inferior clinical outcomes. The study suggests that incorporating Ki-67 into pre-treatment risk stratification may help identify patients who require closer monitoring or alternative therapeutic strategies.
The researchers also recommend long-term monitoring of immunoglobulin levels, consideration of IVIg replacement when necessary, and ongoing surveillance for viral reactivation and secondary malignancies following CAR-T treatment.
Reference
Yu Y, Wang W, Mo Z, et al. Long-Term Follow-Up of CD19 CAR-T for R/R B-NHL: Ki-67 as a Prognostic Factor for Sustained Remission. Transplantation and Cellular Therapy. 2026. DOI: 10.1016/j.jtct.2026.05.010.
