Tolerability and toxicity of induction chemoimmunotherapy with dinutuximab beta in newly diagnosed patients with high-risk neuroblastoma

Monoclonal antibodies (mAbs) directed against GD2 are used as part of post-consolidation treatment for high-risk neuroblastoma (NB) patients with minimal residual tumor after induction therapy. It has been reported that a good end-of-induction response is associated with better event-free survival and overall survival rates. The use of mAbs in combination with chemotherapy has been shown to be effective in treating patients with relapsed NB in several international studies. Thus, the need to achieve a good end-of-induction response in high-risk NB and the feasibility of combining chemotherapy with mAbs serve as a rationale for employing immunotherapy during induction treatment of newly diagnosed patients with NB. Here, we present the results of the first Russian single-center study on the use of chemoimmunotherapy (CIT) during induction treatment in newly diagnosed patients with high-risk NB. In this prospective study carried out at the Dmitry Rogachev National Medical Research Center of Pediatric Hematology, Oncology and Immunology between January and August 2023, we enrolled 5 high-risk stage 4 NB patients aged 18 months. This study was approved by the Institutional Review Board and the Independent Ethics Committee of the Dmitry Rogachev National Medical Research Center of Pediatric Hematology, Oncology and Immunology of the Ministry of Healthcare of the Russian Federation (Protocol No. 10э/9-22 dated 10. 12. 2022). Therapy was carried out according to the modified GPOH NB2004 protocol. Starting from the 3rd course of induction, patients received 4 alternating courses of chemotherapy in combination with anti-G mAbs ch14.18/CHO (dinutuximab beta) at a dose of 10 mg/m2/day administered as a continuous infusion over 5 days. Toxicity was assessed as per the CTCAE 5.0 (Common Terminology Criteria for Adverse Events, version 5.0). A total of 20 courses of CIT were given. All patients completed induction therapy, with 3/5 (60%) achieving at least a partial response. There were no cases of unexpected severe toxicity or death. There were no pauses in the administration of mAb throughout all the CIT cycles, and all the patients received dinutuximab beta at full dose. Grade 3/4 toxicity was predominantly hematological. Non-hematological toxicity of grade ≥ III/IV included hypokalemia in 5/20 (25 %) courses, hypertension in 4/20 (20 %) courses and diarrhea in 3/20 (15 %) courses (due to viral infection). The need for opioid analgesics decreased with each successive course of treatment. The selected CIT regimen combining induction chemotherapy as per the GPOH NB2004 protocol and dinutuximab beta demonstrated safety and acceptable toxicity in newly diagnosed patients with high-risk stage 4 NB older than 18 months. Further multicenter cooperative studies will allow for the development of the optimal induction regimen consisting of chemotherapy and mAbs for improved survival in patients with high-risk NB.