Efficacy and Safety of Adding Blinatumomab to First-Line Treatment for Chinese Children with B-Cell Acute Lymphoblastic Leukemia

Purpose: This study aimed to investigate the efficacy and safety of adding blinatumomab to first-line treatment in Chinese children with B-cell acute lymphoblastic leukemia (B-ALL) who were either chemotherapy-intolerant or classified as intermediate-risk/high-risk.

Methods: The clinical data of children with newly diagnosed B-ALL treated with blinatumomab plus chemotherapy as first-line treatment were retrospectively analyzed. Newly diagnosed B-ALL children who were chemotherapy-intolerant or classified as intermediate-risk/high-risk received one to two cycles of blinatumomab therapy (15µg/m², 14-28 days) in addition to the Chinese Children's Leukemia Group(CCLG)-B-ALL-2018 regimen. Following blinatumomab treatment, chemotherapy was continued, or allogeneic hematopoietic stem cell transplantation was performed for those with indications. Minimal residual disease (MRD) remission, as assessed by multiparameter flow cytometry (MFC-MRD), was defined as the presence of leukemic blasts with MRD <0.01% in bone marrow. MRD remission, measured by next-generation sequencing and flow cytometry, was defined as the presence of leukemic blasts with MRD <0.0001% in bone marrow.

Results: From March 2021 to September 2023, 90 children with newly diagnosed B-ALL were treated with blinatumomab. Among them, 49 (54.4%) with chemotherapy intolerance, 48 (53.3%) were in the intermediate-risk group, and 32 (35.6%) were in the high-risk group. The median time from diagnosis to the start of blinatumomab was 10.8 (range, 0.7-25.9) months. Of these patients, 19 (21.1%) received blinatumomab after induction chemotherapy, 11 (12.2%) during consolidation chemotherapy, and 60 (66.7%) after consolidation chemotherapy. Ninety children completed a total of 112 cycles of infusion, 68 (73.9%) in one cycle and 22 (24.1%) in two cycles, with a median duration of 28 days (range, 2-56 days).

The complete remission (CR)/complete remission with incomplete hematologic recovery (CRi) rate after one cycle of blinatumomab was 100.0%, MRD remission rate was 94.4%, and MFC-MRD remission rate was 98.9%. Seven patients were treated with allogeneic hematopoietic stem cell transplantation during consolidation therapy, specifically one infant with MLL-AF4, three with persistently positive BCR-ABL1 fusion genes, two with persistently positive NGS-MRD, and one with EBF1-PDGFRB that could not be tolerated chemotherapy and blinatumomab because of G4 ICANS. After a median follow-up of 26.8 months, 2-year event-free survival (EFS) rate was 97.8% ± 1.6%, 2-year overall survival (OS) rate was 100%, and 2-year cumulative incidence of relapse (CIR) was 2.2% ± 1.6%. Compared with 212 historical control patients treated under the CCLG-B-ALL-2018 protocol and matched for sex, age, and white blood cell count at onset of leukemia, the 2-year EFS was significantly higher in the blinatumomab group (97.8 ± 1.6% vs. 92.3 ± 1.9%, p=0.047).

Subgroup analysis showed that high-risk children in the blinatumomab group had significantly higher 2-year EFS and 2-year OS compared to those in the control group (2-year EFS: 93.6 ± 4.3% vs. 76.5 ± 6.9%, p=0.040; 2-year OS: 100% vs. 89.2 ± 5.1%, p=0.046). When stratified by genetic risk, high-risk children in the blinatumomab group had a higher 2-year EFS than those in the control group (97.3 ± 2.7% vs. 83.0 ± 4.7%, p=0.045). Additionally, children with MRD >0.1% at the end of induction (day 33) in the blinatumomab group had a higher 2-year EFS compared to those in the control group (94.4 ± 5.4% vs. 65.7 ± 11.5%, p=0.025).

Adverse events associated with blinatumomab were tolerable, with treatment discontinuation in 6 (6.7%) patients, including G3 infection-related events in 3 (3.3%) patients and G3/4 immune effector cell-associated neurotoxicity syndrome (ICANS)-related epilepsy in 3 (3.3%) patients.

Conclusion: In children with chemotherapy-intolerant or intermediate-risk/high-risk B-ALL, the addition of blinatumomab to first-line chemotherapy can enhance the deep remission rates and improve survival, particularly in high-risk patients and those with high MRD after induction regimen.