IMMUNOTHERAPY FOR HIGH RISK NEUROBLASTOMA

September 30, 2010 — An immunotherapy combination improved cure rates by 20%, compared with standard treatment, in children with high-risk neuroblastoma, according to a new multicenter study published in the September 30 issue of the New England Journal of Medicine.

The study was stopped early because of the effectiveness of the experimental regimen.

"We expect these findings will change clinical practice, setting a new gold standard of treatment for this often-deadly disease," said John M. Maris, MD, a coauthor of the study, in a press statement. He is from the Children's Hospital of Philadelphia, Pennsylvania, and is chair of the neuroblastoma committee of the Children's Oncology Group, the cooperative multicenter research organization that sponsored the study.

The newly published data were first presented at the American Society of Clinical Oncology annual meeting in 2009, and were reviewed in detail by Medscape Medical News at the time.

In the 226-patient study, the rate of event-free survival at 2 years was 46% ± 5% for patients randomized to isotretinoin, the standard therapy, and 66% ± 5% for the patients randomized to immunotherapy — 3 biologic agents in combination with isotretinoin (P = .01).

The immunotherapy consisted of the monoclonal antibody ch14.18, plus 2 cytokines, granulocyte-macrophage colony-stimulating factor (GM-CSF), and interleukin (IL)-2.

Event-free survival is the key outcome in this setting because, as the authors note, "children with recurrent or progressive disease are rarely cured."

The rate of overall survival at 2 years was 75% ± 5% for standard therapy and 86% ± 4% for immunotherapy (P = .02). The median duration of follow-up was 2.1 years.

The need for an alternative treatment in this setting is pressing, according to the authors. "More than half the patients receiving standard therapy have a relapse and ultimately die from the tumor," they write.

More Details

The case for using immunotherapy in this setting partially stems from preclinical and preliminary clinical data that indicate that ch14.18, a monoclonal antibody against the tumor-associated disialoganglioside GD2, has activity against neuroblastoma and that such activity is enhanced when the antibody is combined with either GM-CSF or IL-2, explain the study authors, who were led by Alice L. Yu, MD, PhD, from the University of California, San Diego.

In the study, the randomization, in a 1:1 ratio, took place only in patients with high-risk neuroblastoma who responsed to induction therapy and stem-cell transplantation.

The standard therapy consisted of 6 cycles of isotretinoin, and the experimental immunotherapy consisted of 6 cycles of isotretinoin and 5 concomitant cycles of ch14.18 in combination with alternating GM-CSF and IL-2.

A total of 52% of patients had pain of grade 3, 4, or 5, and 23% and 25% of patients had capillary leak syndrome and hypersensitivity reactions, respectively.

When 61% of the number of expected events was observed, the study was stopped because it met the efficacy criteria, the authors report.

The immunotherapy regimen produced more treatment-related clinical toxic effects.

The effects in the immunotherapy group included, most importantly, pain, hypotension, capillary leak syndrome, and hypersensitivity reactions; there were relatively few toxic effects with standard therapy. Pain of grade 3 or 4 was observed in 52% of patients (during 25% of 598 cycles of immunotherapy).

The National Cancer Institute (NCI) was the sponsor of the study and provided the ch14.18 monoclonal antibody. Bayer provided the GM-CSF. Neither the NCI nor Bayer had a role in the study design or analysis.

N Engl J Med. 2010;363:1324-1334.