Anti‐CD19 chimeric antigen receptor‐modified T‐cell therapy bridging to allogeneic hematopoietic stem cell transplantation for relapsed/refractory B‐cell acute lymphoblastic leukemia: An open‐label pragmatic clinical trial

Abstract

Chimeric antigen receptor-modified T-cell (CAR-T) therapy is effective and safe for patients with relapsed/refractory B-cell acute lymphoblastic leukemia (r/r B-ALL), but its value has been limited in terms of long-term leukemia-free survival. New strategies that can help CAR-T therapy achieve lasting effect are urgently warranted. This nonrandomized interventional pragmatic clinical trial had a particular aim. It explored whether consolidative allogeneic hematopoietic stem cell transplantation (allo-HSCT) could improve the long-term prognosis of the minimal residual disease-negative complete remission (MRD − CR) patients after CAR-T therapy. In the first stage, 58 r/r B-ALL patients received split doses of CAR-T cells after lymphodepleting chemotherapy, and 51 (87.9%) achieved CR. In the second stage, 21/47 MRD − CR patients without previous allo-HSCT and contraindications or other restrictions, on their own accord, received consolidative allo-HSCT within three months after CAR-T therapy. There was no difference in overall survival (OS) between the MRD − CR patients who received allo-HSCT and those who did not. However, event-free survival (EFS) and relapse-free survival (RFS) were significantly prolonged by allo-HSCT in the subgroups. This was with either high (≥5%) pre-infusion bone marrow MRD assessed by flow cytometry (BM-FCM-MRD) or poor prognostic markers (P < .05). However, no difference was found in EFS and RFS for patients with pre-infusion BM-FCM-MRD <5% and without poor prognostic markers (P > .05). To conclude, CAR-T therapy bridging to allo-HSCT is a safe and effective therapeutic strategy for r/r B-ALL patients, and may prolong their EFS and RFS, especially when they have high pre-infusion BM-FCM-MRD or poor prognostic markers.

Biomarkers in individualized management of chimeric antigen receptor T cell therapy

“…They found that the primary driver of CAR-T cell expansion and that minimizes the risk of CD19 + relapse was the cumulative burden of CD19-expressing cells, as assessed in the bone marrow prior to lymphodepleting chemotherapy. In contrast to other reports, neither the cell dose [27] nor leukemia burden [43,72] alone was a predictor of the magnitude or duration of CD19 CAR-T engraftment in this trial. The authors also suggested that a high antigen burden does not induce exhaustion of CAR T-cellsthe therapeutic cells, and that the elimination of the target cells promotes the transition of the effector cells into functional memory CAR-T cells.…”

“…In patients determined as high-risk of relapse after CAR-T therapy, consolidation therapy after infusion will be imperative to prolong survival. A study conducted in our institute highlighted that CAR-T therapy following allogeneic hematopoietic stem cell transplantation (allo-HSCT) was a safe and effective therapeutic strategy for relapsed/refractory B-ALL patients, and might prolong EFS and RFS, especially in patients with high preinfusion tumor burden [72]. Hence, the identification of biomarkers is crucial for early identification, accurate intervention, and individualized management.…”

Successful treatment of acute B lymphoblastic leukemia relapse in the skin and testicle by anti-CD19 CAR-T with IL-6 knocking down: a case report

“…CAR-T therapy is a novel therapeutic strategy for r/r B-ALL patients [8][9][10]. CAR-T cells can migrate into the leukemia cell sanctuary, such as cerebrospinal fluid by overcoming the blood-brain barrier (BBB), which might be an important approach for solving the sanctuary leukemia problems with traditional chemical agents [11].…”

Cluster of differentiation 19 chimeric antigen receptor T‑cell therapy in pediatric acute lymphoblastic leukemia (Review)

“…Although CAR T-cell treatments lead to relatively controllable adverse events in R/R ALL patients, these patients still have a high risk of relapse ( 6 , 7 ). In such patients, CAR T-cell therapy could be a bridge for HSCT, providing temporary molecular remission for transplantation and improving the prognosis ( 76 ).…”