Blinatumomab before and after allogeneic hematopoietic stem cell transplantation in adult patients with B-cell acute lymphoblastic leukemia

Abstract

Abstract Background: Allogeneic hematopoietic stem cell transplantation (AHSCT) plays a crucial role in the curative strategy for acute B-cell lymphoblastic leukemia (B-ALL), though relapse remains the primary cause of treatment failure.To improve outcomes,we developed a fludarabine- melphalan (FM) regimen intensified with either low-dose TBI (FMT) or low-dose thiotepa (FMTT), along with blinatumomab maintenance. Prior studies suggest this approach may reduce relapse rates, and prevent central nervous system (CNS) relapse without increasing mortality. Methods: The study included 31 consecutively treated adult (>18-year-old) B-ALL patients, who underwent AHSCT between 5/2020-6/2025. Conditioning consisted of fludarabine 40 mg/m2/d on Days -5 to -2, melphalan 100-140 mg/m2 on Day -5 and either TBI 2-4 Gy on Day -1 for patients without CNS involvement, or thiotepa 5 mg/kg on Day -6 for patients with CNS involvement. All patients with CNS leukemia also received pre-AHSCT craniospinal irradiation (CSI) (18 Gy in 10 daily fractions) and 6 monthly doses of intrathecal (IT) methotrexate post-AHSCT. GVHD prophylaxis comprised of PTCy, tacrolimus, mycophenolate mofetil, and oral budesonide. Patients who were categorized as having high-risk features for relapse (remission beyond CR1, primary induction failure, MRD-positivity or high-risk molecular/cytogenetic profile) with no active acute GVHD received maintenance blinatumomab every 3 months for 4 cycles, starting after achieving stable graft function. Results: A total of 31 patients with a median age of 50 years (range, 22-72) were included. Among the cohort, 14 patients (45%) had Ph-positive B-ALL, 14 (45%) had Ph-like B-ALL, and 3 (10%) had Ph-negative B-ALL. Donor types were haploidentical (N=19, 61%), HLA match-sibling (N=9, 29%), and match-unrelated (N=3, 10%). Nine patients (29%) had CNS involvement prior to AHSCT. Twenty-two (71%) patients received melphalan 100 mg/m2. Twenty-seven patients (87%) were in complete remission (CR1), and 27 patients (87%) were MRD-negative before AHSCT. Thirteen patients (42%) received blinatumomab prior to AHSCT due to MRD-positivity following induction therapy and subsequently all achieved MRD-negativity before AHSCT. Median HCT-CI was 2 (range, 0-7). The median follow-up of survivors was 700 days. All patients achieved neutrophil and platelet engraftment after a median of 15 days (range, 12-21) and 19 days (range, 10-40), respectively. All patients demonstrated full donor chimerisms between day +30 and +365 post-AHSCT. The 1-year and 3-year overall survival (OS) rates were both 74.4% (95% CI, 53.5–86.9). Progression-free survival (PFS) was 70.5% (95% CI, 49.4–84.1) at 1 year and 65.0% (95% CI, 42.9–80.4) at 3 years. The cumulative incidence (CI) of relapse and non-relapse mortality (NRM) at 1 year were 3.9% (95%CI, 0.3-16.7) and 25.6% (95%CI, 11.3- 42.8), respectively. CI of grade II-IV and III-IV acute GVHD was 0% at 100 days, and 7.8% and 3.9% at 1 year, respectively. CI of chronic GVHD was 3.7% (95%CI, 0.3-16.0) at 1 year. None of the 9 CNS leukemia patients who received FMTT conditioning with our pre-/post-AHSCT regimen experienced CNS relapse. Seventeen patients (55%) with high-risk features received maintenance blinatumomab. Median time to starting blinatumomab maintenance was 159.5 days (range, 69-533). The landmark analysis at 6 months showed that post-transplant blinatumomab maintenance was associated with significantly improved OS compared to no maintenance with 1 year OS of 100% vs 66.7%, p = 0.0193. PFS among the 17 high-risk patients who received blinatumomab maintenance at 1 year and 3 years from landmark analysis was 93.3% (95%CI, 61.3-99.0) and 83.0% (95%CI, 45.7-95.6), respectively. One-year OS was 100% in patients who received blinatumomab both before and after AHSCT, compared to 87.5% in those who did not receive blinatumomab (p = 0.4216). Nine patients (64% of Ph+ B-cell ALL) with Ph+ B-cell ALL received maintenance with both blinatumomab and a tyrosine kinase inhibitor, achieving a 100% DFS at 1-year post-AHSCT. Conclusion: An intensified FM regimen by the addition of low-dose TBI or thiotepa, followed by blinatumomab maintenance, is effective in improving post-AHSCT outcomes in adult B-ALL, particularly in patients with high-risk features showing low relapse rates and favorable OS, regardless of donor type. Extended follow-up and prospective studies are warranted to validate these findings.