Treatment-Related Toxicities During Anti-GD2 Immunotherapy in High-Risk Neuroblastoma Patients

Abstract

The introduction of immunotherapy using an anti-GD2 antibody (dinutuximab, ch14.18) has significantly improved survival rates for high-risk neuroblastoma patients. However, this improvement in survival is accompanied by a substantial immunotherapy-related toxicity burden. The primary objective of this study was to describe treatment-related toxicities during immunotherapy with dinutuximab, IL-2, GM-CSF, and isotretinoin. A retrospective, single center analysis of immunotherapy-related toxicities was performed in twenty-six consecutive high-risk neuroblastoma patients who received immunotherapy as maintenance therapy in the Princess Máxima Center (Utrecht, Netherlands). Toxicities were recorded and graded according to the CTCAE. Particular attention was drawn to pain and fever management and toxicities leading to dose modifications of dinutuximab and IL-2. Twenty-three patients (88%) completed all six courses of immunotherapy. Disease progression, isotretinoin-associated liver toxicity, and catheter-related infection in combination with peripheral neuropathy were reasons for immunotherapy discontinuation. The most common grade ≥3 toxicities for courses 1–5, respectively, were pain, catheter-related infections, and fever. In total, 310 grade ≥3 toxicities were recorded in 124 courses. Thirty-three grade 4 toxicities in 19/26 patients and no grade 5 toxicities (death) were seen. Fifty-nine percent of grade ≥3 toxicities were recorded in the two courses with IL-2. Catheter-related bloodstream infections were identified in 81% of patients. Four of these episodes led to intensive care admission followed by full recovery (grade 4).

Immunotherapy by anti-GD2 antibodies in patients with primary high-risk neuroblastoma, primary resistant and relapsed disease: Raisa Gorbacheva Memorial Research Institute of Children Oncology, Hematology and Transplantation, First Pavlov State Medical University of St. Petersburg experience

“…Используемый нами режим терапии характеризовался сравнительно низкой токсичностью. Вероятно, меньшие, чем в сходных когортах [35], число и степень наиболее серьезных осложнений (гипотензия, синдром повышенной проницаемости капилляров, реакции гиперчувствительности) объяснялись особенностями режима введения препарата с применением 24-часовой инфузии [14,31], а также отсутствием в схеме лечения ИЛ-2 [15]. Препараты ИЛ-2 не применялись с учетом данных SIOPEN о сравнимой эффективности схемы лечения, не включающей в себя ИЛ-2 [36], при меньшей токсичности данной терапии [16].…”

Managing Adverse Events Associated with Dinutuximab Beta Treatment in Patients with High-Risk Neuroblastoma: Practical Guidance

“…There is very little information in the literature regarding visual disturbances in association with dinutuximab beta therapy [ 19 ], and this expert group believes that these events are under-reported in clinical studies. Ocular abnormalities, such as mydriasis and impaired accommodation, have also been reported with the humanised anti-GD2 antibody hu14.18K322A [ 20 ].…”

Mechanisms, Characteristics, and Treatment of Neuropathic Pain and Peripheral Neuropathy Associated with Dinutuximab in Neuroblastoma Patients

“…Neuropathic pain affects from 33% to 88% of pediatric patients undergoing dinutuximab infusion. Pain usually manifests as allodynia, which involves various regions of the body, especially the abdomen, extremities, back, and chest, and then spreads peripherally to the ankles and feet [ 18 , 32 , 37 , 42 , 43 , 44 ]. Anti-GD2 induced pain is characterized by mechanical allodynia without thermal hyperalgesia [ 23 ].…”

“…It usually begins within an hour from the start of dinutuximab beta infusion and is limited to the time of administration of this drug, ending shortly after the termination of the infusion; it usually occurs during the first infusion of the drug and decreases after each course [ 22 ]. A retrospective study on 26 patients affected by high-risk neuroblastoma who received dinutuximab based immunotherapy concluded that grade ≥3 (of a 1 to 5 scale) pain occurs in about 88% of patients during immunotherapy course 1, but in 42% of patients during course 5 [ 42 ].…”

“…Peripheral neuropathy is a rare side effect of dinutuximab beta administration; it can be severe with a prevalence of between 2 and 6% of patients [ 42 ]. Ladenstein et al reported seven patients with grade 3 and 4 toxicities, the most frequent being paresthesia or deficits in motor function; one patients with tetraparesis improved over time, but did not recover completely [ 21 ].…”