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.