A phase 2 trial of a "sandwich" strategy: Sequential CD22/CD19 chimeric antigen receptor T-cells therapy combined with autologous hematopoietic stem cell transplantation in patients with Philadelphia chromosome-negative B-cell acute lymphoblastic leukemia

Abstract

Background: The relapse after chimeric antigen receptor (CAR) T-cell therapy remains a critical challenge, and the optimal timing and treatment strategies for CAR T urgently need to be explored. Autologous hematopoietic stem cell transplantation (auto-HSCT) demonstrates comparable leukemia-free survival (LFS) and overall survival (OS) in patients who rapidly achieve MRD-negative complete remission (CR) compared with allogeneic HSCT (allo-HSCT). Thus, combining CAR T cells with auto-HSCT may represent a promising treatment strategy. The trial registration is ClinicalTrials.gov identifier NCT05470777.

Methods: This phase 2 trial evaluated the safety and efficacy of sequential CD22/CD19 CAR T cells combined with an auto-HSCT "sandwich" strategy in patients with Philadelphia chromosome-negative (Ph-negative) B-cell acute lymphoblastic leukemia (B-ALL), including adolescents and young adults (AYA) as well as adults who were unable or declined to allo-HSCT. The primary and secondary end points were OS and LFS, respectively. The trial registration is ClinicalTrials.gov identifier NCT05470777.

Results: At a median follow-up of 28 months, the median OS and LFS were not reached. The 2-year OS and LFS rates were 97% (95% confidence interval [CI], 90%-100%) and 72% (95% CI, 58%-90%), respectively. All 35 patients who completed the sandwich strategy survived. Continuous MRD-negative CR rates after the second CAR T-cell infusion were 80% by multiparameter flow cytometry and 70% by next-generation sequencing of immunoglobulin H rearrangements. OS and LFS did not differ between poor and standard genetic risk groups. Compared with the allo-HSCT external control group, the sandwich strategy showed improved OS and comparable LFS. No cases of immune effector cell-associated neurotoxicity syndrome or severe cytokine release syndrome were observed. The trial registration is ClinicalTrials.gov identifier NCT05470777.

Conclusion: The CD22/CD19 CAR T-cell and auto-HSCT sandwich strategy represents a promising approach for the treatment of Ph-negative B-ALL in AYA and adult patients, offering high efficacy and a favorable safety profile. The trial registration is ClinicalTrials.gov identifier NCT05470777.

Keywords: Philadelphia chromosome–negative B‐cell acute lymphoblastic leukemia; autologous hematopoietic stem cell transplantation; chimeric antigen receptor T cells; leukemia‐free survival; overall survival.