Bispecific monoclonal antibody blinatumomab in the first-line therapy of B-lineage acute lymphoblastic leukemia in children and adolescents: interim results of the Russian Ministry of Health approbation protocol

   The bispecific monoclonal antibody blinatumomab (CD19/CD3) is widely and successfully used to treat children with relapsed/refractory B-cell precursor acute lymphoblastic leukemia (BCP-ALL). Advances have also led to the use of immunotherapy in children with primary BCP-ALL. This paper presents the effectiveness of a single blinatumomab course instead of consolidation chemotherapy and with short maintenance therapy in primary BCP-ALL patients. 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. Between February 2020 and November 2022, 165 children with non-high-risk BCP-ALL (according to clinical stratification criteria defined in the study) were enrolled in the ALL-MB 2019 pilot study (NCT04723342). Patients received conventional risk-adapted induction therapy according to the ALL-MB 2015 protocol. Those who achieved complete morphological remission at the end of induction received 15 µg/m2/day of blinatumomab immediately after induction for 4 weeks, followed by 12 months of maintenance therapy. Minimal residual disease (MRD) was measured using multicolor flow cytometryat the end of induction, then immediately after blinatumomab course, and then four times during maintenance therapy at threemonth intervals. All 165 patients successfully completed induction therapy and achieved complete hematological remission. All had their MRD measured at the end of induction. One hundred thirty-six (82.2%) patients were MRD-negative, and the remaining 29 patients showed various levels of MRD positivity. MRD was assessed in all 164 patients who completed the blinatumomab course. One patient had blinatumomab discontinued due to acute neurotoxicity and was subsequently treated according to the intermediate-risk ALL-MB 2015 protocol. All but one patient achieved MRD negativity after blinatumomab course, regardless of MRD value at the end of induction. One adolescent girl with a high MRD level after induction remained MRD positive after blinatumomab course and further received high-risk therapy with allogeneic hematopoietic stem cell transplantation. At the time of analysis, 162 children had completed all therapy, including 12 months of maintenance. MRD was examined in 151 of them, and all were MRD negative. Over a 4-year study period with a median follow-up of 2.5 years, 10 relapses were registered: 4 in the standard-risk group and 6 in the intermediate-risk group. The 4-year event-free survival was 89.1 ± 3.7 % for all patients, 92.0 ± 4.2 % and 82.8 ± 8.1 % for the standard and intermediate risk groups, respectively. At the time of analysis, all patients were alive; no deaths were registered. Although the presented results are preliminary and more time is needed for definitive conclusions, a 4-week 15 µg/m2/day blinatumomab course immediately after induction followed by 12 months of maintenance therapy is effective in achieving and maintaining MRD negativity in children with non-high risk BCP-ALL. This study showed the fundamental possibility of treating ALL by combining immunotherapy with the bispecific monoclonal antibody blinatumomab with a significant chemotherapy reduction.