Blinatumomab following reduced-intensity induction chemotherapy in Chinese children with intermediate- or high-risk B-cell precursor acute lymphoblastic leukemia

Abstract

Abstract Background Minimal residual disease (MRD) level after induction therapy is a key independent prognostic factor in pediatric B-cell precursor acute lymphoblastic leukemia (BCP-ALL), with lower MRD burden strongly associated with superior event-free and overall survival. Blinatumomab, a bispecific CD19/CD3 T-cell engager, has demonstrated potent MRD clearance and clinical benefit when integrated into frontline regimens. We hypothesized that administering blinatumomab after a reduced-intensity induction chemotherapy—replacing components of conventional induction—could enhance MRD eradication while reducing cumulative chemotherapy exposure in children with intermediate- or high-risk BCP-ALL. Methods Between April 2024 and May 2025, we conducted a multicenter, single-arm, prospective trial (ChiCTR2400083570) under the Chinese Children's Leukemia Group (CCLG), enrolling patients with newly diagnosed BCP-ALL. Eligibility criteria included: (1) intermediate-risk (MR) with MRD ≥1% by multiparametric flow cytometry (MFC) at day 15; or (2) high-risk (HR) per the Chinese Children's Leukemia Group 2018-ALL (CCLG-2018-ALL) criteria at day 15. All patients received a reduced-intensity induction chemotherapy: daunorubicin (2 doses), vincristine (2 doses), pegaspargase (1 dose), and prednisone about 2 weeks. This was followed by continuous intravenous blinatumomab (15 μg/m²/day) for 2 weeks in MR patients (replacing the subsequent 2-week phase of induction) or 4 weeks in HR patients (replacing the subsequent 2-week phase and the first course of early consolidation [CAML1]). Subsequent chemotherapy resumed 2 weeks after blinatumomab completion. The primary endpoint was MRD negativity at the end of induction in MR patients or at the end of consolidation in HR patients. MRD was assessed centrally using MFC (sensitivity 1×10⁻⁴) and next-generation sequencing (NGS) of immunoglobulin genes (sensitivity 1×10⁻⁶). Results A total of 202 patients were enrolled (median age: 5.8 years; range: 1.1–15.7; 51.5% female); 100 MR and 102 HR. Baseline genetic alterations included ETV6::RUNX1 (13.4%), KMT2A rearrangements (5.9%), and BCR::ABL1 fusion (6.9%). Mean MFC MRD at day 15 was 12.3% (range: 0–80.5%). Complete remission rate was 99.0% (200/202). MRD negativity was achieved in 95.0% (192/202) by MFC and 70.0% (112/160) by NGS at end of induction. In the MR group, MRD negativity rates were 97.0% (MFC, 97/100) and 73.1% (NGS, 57/78). In the HR group, MRD negativity was 93.1% (MFC, 95/102) and 67.1% (NGS, 55/82) at end of induction, improving to 95.1% (MFC, 97/102) and 81.7% (NGS, 67/82) at the end of consolidation. Among 76 HR patients with serial monitoring, MFC MRD negativity increased from 76.3% (58/76) at week 2 to 93.4% (71/76) at week 4 of blinatumomab. Grade ≥3 non-hematologic toxicities included infection (20.8%), sepsis (6.9%), hepatotoxicity (7.9%), cytokine release syndrome (CRS, 4.5%), pancreatitis (2.0%), hypofibrinogenemia (2.0%), and ICANS (0.5%). Treatment interruption occurred in 10 patients (5.0%), primarily due to CRS (n=4) or hepatotoxicity (n=2). With a median follow-up of 8.4 months, 10 patients (5.0%) proceeded to allogeneic hematopoietic stem cell transplantation (allo-HSCT): 2 from the MR group (due to rising MRD, including 1 with BCR::ABL1 fusion and 1 with ETV6:: RUNX1 fusion) and 8 from the HR group (due to MRD persistence, including 3 with KMT2A rearrangement, 1 with MEF2D rearrangement, 1 with DUX4 rearrangement, and 3 with no detectable fusion gene). Among the remaining 192 patients, 100% were MFC MRD-negative and 99.0% NGS MRD-negative at last assessment. Conclusion In Chinese children with intermediate- or high-risk BCP-ALL, integrating blinatumomab after a reduced-intensity induction chemotherapy achieves high rates of deep molecular remission with a favorable safety profile. These findings support the potential of immunotherapy-driven frontline strategies to improve early outcomes and reduce long-term toxicity in pediatric BCP-ALL.