High efficacy and safety of low-dose CD19-directed CAR-T cell therapy in 51 refractory or relapsed B acute lymphoblastic leukemia patients

Abstract

Refractory or relapsed B lymphoblastic leukemia (B-ALL) patients have a dismal outcome with current therapy. We treated 42 primary refractory/hematological relapsed (R/R) and 9 refractory minimal residual disease by flow cytometry (FCM-MRD) B-ALL patients with optimized second generation CD19-directed CAR-T cells. The CAR-T-cell infusion dosages were initially ranged from 0.05 to 14 × 10/kg and were eventually settled at 1 × 10/kg for the most recent 20 cases. 36/40 (90%) evaluated R/R patients achieved complete remission (CR) or CR with incomplete count recovery (CRi), and 9/9 (100%) FCM-MRD patients achieved MRD. All of the most recent 20 patients achieved CR/CRi. Most cases only experienced mild to moderate CRS. 8/51 cases had seizures that were relieved by early intervention. Twenty three of twenty seven CR/CRi patients bridged to allogeneic hematopoietic stem cell transplantation (allo-HCT) remained in MRD with a median follow-up time of 206 (45-427) days, whereas 9 of 18 CR/CRi patients without allo-HCT relapsed. Our results indicate that a low CAR-T-cell dosage of 1 × 10/kg, is effective and safe for treating refractory or relapsed B-ALL, and subsequent allo-HCT could further reduce the relapse rate.

Chimeric antigen receptor T‐cell therapy as a bridge to haematopoietic stem cell transplantation for refractory/relapsed B‐cell acute lymphoblastic leukemia

“…Previous reports demonstrated persistence for 19‐28z CAR‐T cells was about three months. Pan et al () observed 93·3% patients with undetectable CAR‐T19 cells in the peripheral blood on day 30 and a median 64 days for relapse after CAR‐T19 without HSCT. Therefore, we recommended bridging to allo‐HSCT after CR with CAR‐T to have more patients remaining in durable remission and the interval from CAR‐T to allo‐HSCT within two months if possible.…”

“…For refractory/relapsed B-ALL, unprecedentedly high CR rates have been reported by different centres despite differences in CAR construct and transfection methods (Davila et al, 2014;Maude et al, 2014;Lee et al, 2015;Pan et al, 2017;Pan et al, 2019), but half of the patients will relapse within one year after CAR-T therapy if not bridged to allo-HSCT (Lee et al, 2015;Gardner et al, 2018). Following CAR-T therapy, more cases could be successfully transitioned to allo-HSCT than the low frequency of about 5% for refractory/relapsed B-ALL transitioned to transplantation after salvage chemotherapy (Thomas et al, 1999).…”

Use of Chimeric Antigen Receptor T Cells in Allogeneic Hematopoietic Stem Cell Transplantation

“…Zhang et al had showed that the patients with relapsed/refractory Bcell malignancies showed no sign of relapse if they received CAR-T cells treatment followed by allo-HSCT at the last follow-up [23]. In personal communication, Tong also showed that the survival is better for patients with refractory/relapsed B-cells ALL who received allo-HSCT after CD19-CAR-T cells treatment compared with the patients only received CAR-T cells [24].…”

The one-two punch (of CAR T cells)

“…Even so, 17 (85%) of 20 were in an ongoing remission with a 1-year leukemia-free survival (LFS) of 79.5% and overall survival of 92.3%, which represents an improvement in remission durability over that seen with their single-antigen targeting treatments. 9,10 These data support the safety and feasibility of sequential CAR T-cell infusion strategies, while demonstrating evidence for dual CAR T-cell expansion and the potential for clinical benefit, leading to an improved LFS without the necessity of a consolidative HSCT.…”