Anti-GD2 and IL-2 in Neuroblastoma: Active Regimen With High Toxicity

Anti-GD2 and IL-2 in Neuroblastoma: Active Regimen With High Toxicity

Dr. Barbara Hero and Dr. Ruth Ladenstein
Patients with neuroblastoma showed encouraging response to immunotherapy with an anti-GD2 antibody, but addition of subcutaneous interleukin-2 (IL-2) resulted in increased toxicity with no apparent benefit. These results, from a phase III study by the International Society for Paediatric Oncology Europe Neuroblastoma (SIOPEN) Group (Abstract 10500), were presented by Ruth Ladenstein, MD, MBA, cPM, of St. Anna Children’s Hospital and Research Institute, Austria, at the Pediatric Oncology I Oral Abstract Session on June 3.

Dr. Ladenstein discussed results with the anti-GD2 antibody ch14.18/CHO in high-risk patients with neuroblastoma in the HR-NBL1/SIOPEN trial. Dinutuximab (formerly ch14.18) is a human/mouse chimeric antibody that contains murine retroviruses and is unavailable in Europe. Ch14.18/CHO, produced using good manufacturing practices from Chinese hamster ovary cells, has been evaluated as an anti-GD2 antibody by European investigators.1

Dr. Ladenstein explained that dinutuximab in combination with the cytokines IL-2 and granulocyte-macrophage colony-stimulating factor (GM-CSF) has demonstrated a survival benefit in high-risk patients with neuroblastoma. The role of the cytokines, however, is unclear. This prospective, randomized phase III trial investigated the use of subcutaneous IL-2 in combination with ch14.18/CHO.

In an earlier phase of the HR-NBL1/SIOPEN trial, two forms of myeloablative therapy were compared. In that phase, a regimen of busulfan/melphalan was superior to carboplatin/etoposide/melphalan in patients with high-risk neuroblastoma. For this final phase of the trial, 406 high-risk patients with neuroblastoma underwent a second random assignment. “High risk” was defined as stage 4 disease in patients aged 1 and older, stage 4 disease in patients younger than age 1 with MYCN amplification, or stage 2 or 3 disease in patients aged 0 to 21 with MYCN amplification. Patients underwent high-intensity induction therapy followed by autologous stem cell transplantation and local therapy including resection and radiation in earlier phases of the trial.

In the second randomization, patients were assigned to receive immunotherapy with the anti-GD2 antibody either alone or with the addition of IL-2. The anti-GD2 therapy was given as five daily 8-hour infusions with a cumulative dose of 100 mg/m2. The IL-2 was given subcutaneously at a dose of 6x106 IU/m2 for a total of five cycles. All patients also received six cycles of 160 mg/m2 of oral 13-cis-retinoic acid.

Endpoints of the study were 3-year event-free survival (EFS) and overall survival (OS). At 3 years, EFS was seen in 57% ± 4% of those receiving anti-GD2 alone and 60% ± 4% of those receiving the anti-GD2 plus IL-2. OS at 3 years was 66% ± 4% in those receiving anti-GD2 alone and 67% ± 4% in those receiving the combination. The differences between the two arms were not statistically significant.

Toxicity analysis showed a higher rate of early termination in patients receiving the combination (39%) compared with anti-GD2 alone (15%; p < 0.001). Lansky performance status of 30% or less was seen in 17% of those receiving anti-GD2 and 41% of those receiving the combination (p < 0.001). Common toxicology criteria (CTC) grades 3 and 4 allergic reactions were seen in 9% in the anti-GD2 arm and 20% in the combination arm (p = 0.03), and CTC grades 3 and 4 fever were seen in 14% and 41% of the two groups, respectively (p < 0.001). Incidence of capillary leak was lower in the anti-GD2 arm (4%) than in the combination arm (15%; p = 0.028).

In her conclusion, Dr. Ladenstein noted that there was a 51% overall response rate to immunotherapy and that patients with residual disease benefitted from treatment with ch14.18/CHO. However, major toxicities in the IL-2 arm, as noted above, prevented full delivery of the immunotherapy due to higher rates of interruptions and/or early terminations of ch14.18/CHO cycles. The outcomes measured showed no benefit of IL-2 cotreatment but a highly relevant toxicity burden.

Discussant Barbara Hero, MD, PhD, of University Children’s Hospital, Germany, noted that although anti-GD2 immunotherapy has improved outcomes in neuroblastoma in the post-transplant setting, it is not yet known whether the addition of cytokines is necessary. Regarding the current study, she wondered whether possible benefits of the addition of IL-2 were obscured by the high rate of interruptions. Another question raised was whether results might be different in patients with higher tumor burden after myeloablative therapy.