The use of blinatumomab in children with de novo Ph-negative B-lineage acute lymphoblastic leukemia and slow clearance of minimal residual disease

Abstract

   Children with acute lymphoblastic leukemia (ALL) and slow clearance of minimal residual disease (MRD) demonstrate a significantly worse outcome as compared to those with fast response to chemotherapy. Bispecific monoclonal antibody blinatumomab is the key drug for CD19-directed immunotherapy which opens wide opportunities for the elimination of MRD in patients with B-cell precursor ALL (BCP-ALL).   Aim of the study – to evaluate the effectiveness of blinatumomab for MRD elimination in children with BCP-ALL and slow MRD clearance treated by the “ALL-MB 2015” protocol.   The study was approved by the Independent Ethics Committee and the Scientific Council of the Dmitry Rogachev National Medical Research Center of Pediatric Hematology, Oncology and Immunology. Patients from the “ALL-MB 2015” trial who demonstrated slow MRD clearance at the end of induction were included in the current study. MRD monitoring was performed by multicolor flow cytometry modified with respect to possible CD19 loss during targeted treatment. Threshold of 0.001% was used for MRD positivity definition. Between February 2020 and August 2023, 228 children with de novo Ph-negative KMT2A-negative BCP-ALL were defined as slow MRD responders according to the criteria of the “Moscow-Berlin” group. Fifty of them were treated with blinatumomab because of slow MRD clearance. Blinatumomab course was given immediately after induction in 23 children, after Consolidation I – in 14 patients, after Consolidation II – in 11 patients, while two children received immunotherapy prior to maintenance. After completion of blinatumomab course, 23 patients continued protocol treatment, 21 received maintenance only, two were treated with high-risk blocks and four received hematopoietic stem cell transplantation. Only 2 of 50 (4.0 %) patients remained MRD-positive after completion of blinatumomab course. By the end of December 2023, only two adverse events were registered: one relapse and one remission death. Two-year event-free survival was 94.7 % (standard error 3.6 %), while cumulative incidence of relapse was 2.6 % (standard error 2.7 %). Outcome in these 50 patients was much better in comparison with 178 children with a slow MRD response who did not receive blinatumomab. The use of blinatumomab in children with de novo Ph-negative BCP-ALL with slow MRD clearance allows achieving MRD-negative remission in nearly all cases. Although a longer follow-up is necessary for the reliable conclusion of CD19-directed therapy effectiveness, the promising results are obtained in the current study in this unfavorable patient group.