Short-Term Blinatumomab Prior to Allo-HSCT for High-Risk B-ALL

Introduction:

Advances in new agents and immunotherapies have improved overall survival (OS) rates for B-lineage acute lymphoblastic leukemia (B-ALL), however, high-risk patients continue to experience poor outcomes. Allogeneic hematopoietic stem cell transplantation (allo-HSCT) remains a potential curative treatment for these patients, though it is associated with transplant-related complications and relapse. Blinatumomab (BiTE) has shown efficacy in patients with lower tumor burdens and reduced immune-mediated toxicity. Therefore, we aimed to evaluate the impact of short-term BiTE treatment before allo-HSCT on OS in high-risk B-ALL patients in remission.

Methods:

This study enrolled 82 patients aged 14-65 years with high-risk B-ALL in complete hematologic remission (CR) who met at least one high-risk criterion: 1.Minimal residual disease (MRD) positive by flow cytometry (threshold> 0.01%) or molecular assays by PCR (sensitivity1/10000). 2. Poor cytogenetic or molecular characterization at diagnosis: including hypodiploidy, complex karyotype(5 or more chromosomal abnormalities), KMT2A rearranged, Philadelphia chromosome(Ph)-positive or Ph like B-ALL, TP53 mutation, IKZF1 alterations. 3. Primary refractory disease. 4. Beyond CR1 at HSCT. No prophylactic therapy except tyrosine kinase inhibitor(TKI) maintenance in Ph+ B-ALL post-HSCT.

Patients were randomly assigned in a 1:1 ratio to one of two treatment groups. BiTE Group: Received short-term BiTE therapy as a bridging treatment before allo-HSCT. BiTE was administered intravenously continuously for 24 hours a day, starting at 9 µg/day from day 1 to day 3, and the dose was increased to 28 µg/day from day 4 to day 14. Following BiTE treatment, patients underwent a busulfan/cyclophosphamide (BU/CY)-based myeloablative conditioning regimen starting on day 15. Control Group: Received the same BU/CY-based myeloablative conditioning regimen directly, without preceding BiTE therapy.The primary endpoint of the study was OS, which measures the length of time from the start of treatment until death from any cause. Kaplan-Meier analysis and log-rank tests were used to compare the outcomes across the cohorts.

Results:

Enrolled between February 1, 2022, and May 31, 2024, the study included 82 patients (41 in each group). Baseline characteristics, including age, gender, donor type, median neutrophil/platelet engraftment time et al, were similar across both groups. No pre-HSCT adverse events were reported in the BiTE group. Median OS has not been reached yet in both two groups.

With a median follow-up of 14 months, the BiTE group showed a significantly longer 2-year OS(86.5% vs 65.8%, Hazard ratio 0.25,95% confidence interval[CI] 0.07-0.92, P=0.024) and event-free survival(EFS) (85.5% vs 65.6%, HR 0.29, 95%CI 0.09-0.89, P=0.021) compared to the control group. The 2-year cumulative incidence of relapse(CIR) seemed to be improved in the BiTE group(4.8% vs 14.6%, HR 0.31,95%CI 0.06-1.56, P=0.131). Apart from competing events, the cumulative incidence of grade Il-IV acute graft-versus-host disease (aGVHD) decreased in the BiTE group compared to the control group(14.7% vs 29.5%, HR 0.40,95%CI 0.15-1.03, P=0.053). No significant differences were observed in the occurrence of chronic graft-versus-host disease (cGVHD) (69.9% vs 58.3%, HR 1.32, 95% CI 0.76-2.31, P=0.336) . In addition, short-term BiTE treatment pre-HSCT increase neither the risk of infections in the para-transplantation period(P=0.810), nor the incidences of cytomegalovirus (CMV)(P=0.823), Epstein-Barr virus (EBV)(P=0.800) infections post-HSCT.

Conclusions:

Short-term BiTE before BUCY conditioning regimen could improve the OS and EFS of high-risk B-ALL compared with BUCY regimen, and was likely to lower the incidence of aGVHD.