Auto-HSCT combined with blinatumomab as an allo-HSCT-sparing strategy in newly diagnosed B-ALL: Phase II trial results

Abstract Background: Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is still the primary treatment for AYA and adult with Ph-negative B-ALL. However, allo-HSCT outcomes are compromised by relapse, infection, graft-versus-host disease (GVHD), and treatment-related mortality (TRM), impacting overall survival (OS) and quality of life. Recent clinical studies have demonstrated favorable efficacy and safety profiles for blinatumomab and inotuzumab ozogamicin in B-ALL patients. Despite incorporating immunotherapy, existing protocols largely retain intensive multi-course chemotherapy as a backbone, leading to cumulative toxicity and reduced quality of life. Evidence suggests that in patients achieving rapid deep remission, leukemia-free survival (LFS) and OS are comparable between autologous (auto-HSCT) and allo-HSCT, attributed to improved efficacy of auto-HSCT in early MRD-negative responders and the high TRM offsetting allo-HSCT benefits. Studies like BLAST (showing 78% MRD negativity after one blinatumomab cycle) and D-ALBA (increasing deep remission from 60% to 81% with two additional cycles) highlight blinatumomab's effectiveness in inducing deep remissions. We therefore initiated a phase II trial evaluating an allo-HSCT-sparing strategy combining blinatumomab with auto-HSCT (“sandwich” approach) in newly diagnosed CD19+ B-ALL patients. Methods:This multicenter, single-arm, open-label study (NCT06507514) enrolled newly diagnosed CD19+ B-ALL AYA/adult patients ineligible for or declining allo-HSCT. All patients or guardians have signed an informed consent form before the commencement of the study. Following standard induction and consolidation chemotherapy, patients receive blinatumomab. Upon achieving MRD-negativity (confirmed by multicolor flow cytometry, MFC) after the first cycle of blinatumomab, autologous stem cell mobilization and collection commence one week post-blinatumomab. Auto-HSCT follows successful stem cell harvest. After hematopoietic reconstitution (WBC ≥ 3×10⁹/L, PLT ≥ 50×10⁹/L), patients receive four cycles of blinatumomab maintenance. Patients undergo serial MRD monitoring by MFC and next-generation sequencing of IgH rearrangement (NGS-MRD). The primary end point was OS, and LFS was a secondary end point. Results Until the last follow-up on July 1, 2025, 14 patients were enrolled. All patients completed induction and consolidation chemotherapy, 1 patient discontinued study due to severe immune effector cell-associated neurotoxicity syndrome (ICANS) during the first cycle of blinatumomab. Thirteen patients received the first cycle of blinatumomab. Among the 13 evaluable patients, ten were diagnosed with Philadelphia chromosome-negative (Ph-) B-ALL and three were Philadelphia chromosome-positive (Ph+) B-ALL. Furthermore, ten had high-risk genetic features according to the NCCN guideline. After completion of induction and consolidation chemotherapy, 83.3% of the patients had a complete remission (CR), with 75% achieving MFC-MRD negativity and 40% achieving NGS-MRD negativity. Following the first cycle of blinatumomab, all 13 evaluable patients attained CR, with MFC-MRD negativity observed in 92.3% (12/13) and NGS-MRD negativity in 69.1% (9/13). including 1 patient withdrew from the trial because of molecular relpase. Subsequent to auto-HSCT (assessed in 12 patients), 100% achieved MFC-MRD negative CR, and 83.3% (10/12) attained NGS-MRD negative CR. No cases of severe cytokine release syndrome (CRS) occurred in the cohort. Only one patient experienced ICANS and chose to withdraw. With a median follow-up of 9 months, 12 (92.3%) patients still alive and 11 (84.6%) patients remain NGS-MRD negative CR. All three patients with KMT2A rearrangements exhibited CD19 antigen loss. One patient experienced molecular relapse after the first cycle of blinatumomab and withdrew from this trial. Two hematologic relapses occurred during maintenance therapy; one died of disease progression six months post-relapse. Conclusions:The blinatumomab plus auto-HSCT sandwich strategy demonstrates a promising allo-HSCT-sparing approach for newly diagnosed B-ALL in AYA and adult patients, achieving high efficacy with a favorable safety profile. Patients harboring KMT2A rearrangements showed susceptibility to CD19 antigen loss post-blinatumomab. Further validation through larger cohorts and extended follow-up will clarify this strategy's potential to replace allo-HSCT in selected populations.