Chemoimmunotherapy for Pediatric Refractory or Relapsed Neuroblastoma

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In an expansion of a Children’s Oncology Group trial reported in the Journal of Clinical Oncology, Mody et al found that the combination of irinotecan, temozolomide, the anti–disialoganglioside GD2 antibody dinutuximab, and granulocyte-macrophage colony-stimulating factor (I/T/DIN/GM-CSF) showed marked antitumor activity in pediatric patients with refractory or relapsed neuroblastoma.

Study Details

In the Children’s Oncology Group ANBL1221 trial (initial enrollment from February 2013 to March 2015), 17 patients had been randomly assigned to receive I/T/DIN/GM-CSF. Subsequently, an expansion cohort of 36 additional patients were nonrandomly assigned to the regimen (from August 2016 to May 2017). Patients were eligible for treatment at first relapse or first diagnosis of refractory disease.

Age at enrollment ranged from 1.3 to 15.9 years (median = 5.1 years). Temozolomide at 100 mg/m2 and irinotecan at 50 mg/m2 were administered on days 1 to 5 of 21-day cycles, dinutuximab at 17.5 mg/m2 was given on days 2 to 5, and GM-CSF at 250 mg/m2 was given on days 6 to 12. The primary endpoint was objective response analyzed on an intent-to-treat basis using International Neuroblastoma Response Criteria.


  • Objective response was observed in 41.5% of patients.
  • Estimated 1-year progression-free and overall survival rates among all patients were 67.9% and 84.9%.

Response Rates

Objective response was observed in 9 (52.9%) of the 17 initially randomly assigned patients, including complete response in 5. Objective response was seen in 13 (36.1%) of 36 patients in the expansion cohort, including complete response in 6. Overall, objective responses were observed in 22 (41.5%) of 53 patients, with best responses of complete response in 11 (20.7%), partial response in 11 (20.7%), stable disease in 22 (41.5%), and progressive disease in 7 (13.2%), with 2 patients (3.7%) not being evaluable for response (neither received study treatment).

Assessment of plasma dinutuximab levels in 41 patients showed that median trough levels were significantly higher in patients with vs without objective response (P < .001). Estimated 1-year progression-free and overall survival rates among all patients were 67.9% and 84.9%.

Adverse Events

Among the 51 patients who received study treatment, the most common grade ≥ 3 adverse events were fever/infection (35.3%), neutropenia (33.3%), pain (29.4%), and diarrhea (19.6%). One patient met protocol-defined criteria for unacceptable toxicity (grade 4 hypoxia). Pain of any grade was more common in the initial group of 17 patients (43.8% vs 22.9%). Cases of hypoxia and motor neuropathy were reported in the initial group; two cases of grade 3 hypoxia and no cases of motor neuropathy were observed in the expansion cohort.

The investigators concluded, “I/T/DIN/GM-CSF has significant antitumor activity in patients with relapsed/refractory neuroblastoma. Study of chemoimmunotherapy in the frontline setting is indicated, as is further evaluation of predictive biomarkers.”

Rochelle Bagatell, MD, of Children’s Hospital of Philadelphia/Perelman School of Medicine, University of Pennsylvania, is the corresponding author for the Journal of Clinical Oncology article.

Disclosure: The study was supported by the National Cancer Institute, National Institutes of Health, and St. Baldrick’s Foundation. For full disclosures of the study authors, visit

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