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).
Highlights
Despite intensive treatment regimens, patients with high-risk neuroblastoma experienced poor survival outcomes [1]
As early as in the first clinical reports, the substantial toxicity burden caused by the ch14.18 antibody was recognized [4, 5], with patients suffering from intense, morphine-responsive pain, intermittent fever, allergic reactions, and changes in blood pressure
The aim of this study was to describe treatment-related toxicities from immunotherapy with dinutuximab, cytokines IL-2 and granulocyte-macrophage colony-stimulating factor (GM-CSF), and isotretinoin in a cohort of 26 high-risk neuroblastoma patients treated with induction and consolidation therapy according to the DCOG (Dutch Childhood Oncology Group) NBL2009 high-risk group protocol [10]
Summary
Patients with high-risk neuroblastoma experienced poor survival outcomes [1]. The introduction of immunotherapy using a chimeric anti-GD2 monoclonal antibody (dinutuximab, ch14.18) combined with immunostimulatory cytokines [interleukin-2 (IL-2) and granulocyte-macrophage colony-stimulating factor (GM-CSF)] has significantly improved survival rates for these patients [2]. As early as in the first clinical reports, the substantial toxicity burden caused by the ch14.18 antibody was recognized [4, 5], with patients suffering from intense, morphine-responsive pain, intermittent fever, allergic reactions (exanthema, urticaria), and changes in blood pressure. To increase antibody-dependent cellular cytotoxicity (ADCC) and the subsequent antitumor effect, the addition of immunostimulatory cytokines (IL-2, GM-CSF) was studied with encouraging results [6, 7]. Treatment-related toxic effects have resulted in treatment discontinuation and even deaths [2, 8, 9]
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