Postconsolidation phase

A randomized study compared high-dose therapy and purged autologous BMT with three cycles of intensive consolidation chemotherapy. In addition, after the completion of either chemotherapy or autologous BMT, patients were randomly assigned to stop therapy or to receive 6 months of isotretinoin. The EFS and OS results described below reflect outcome from the time of each randomization.[25]; [31][Level of evidence A1]

A randomized study compared high-dose therapy and purged autologous BMT with three cycles of intensive consolidation chemotherapy. In addition, after the completion of either chemotherapy or autologous BMT, patients were randomly assigned to stop therapy or to receive 6 months of isotretinoin. The EFS and OS results described below reflect outcome from the time of each randomization.[25]; [31][Level of evidence A1]

The 5-year EFS rate was significantly better in the autologous BMT arm (30%), than in the consolidation chemotherapy arm (19%; P = .04). There was no significant difference in 5-year OS rates between the two arms (39% vs. 30%; P = .08).

A randomized study compared high-dose therapy and purged autologous BMT with three cycles of intensive consolidation chemotherapy. In addition, after the completion of either chemotherapy or autologous BMT, patients were randomly assigned to stop therapy or to receive 6 months of isotretinoin. The EFS and OS results described below reflect outcome from the time of each randomization.[25]; [31][Level of evidence A1]

Patients who received isotretinoin had a higher 5-year EFS rate than patients who received no maintenance therapy (42% vs. 31%), although the difference was not significant (P = .12).

A randomized study compared high-dose therapy and purged autologous BMT with three cycles of intensive consolidation chemotherapy. In addition, after the completion of either chemotherapy or autologous BMT, patients were randomly assigned to stop therapy or to receive 6 months of isotretinoin. The EFS and OS results described below reflect outcome from the time of each randomization.[25]; [31][Level of evidence A1]

The OS rate was higher for patients randomly assigned to receive isotretinoin (50%) than for those who stopped therapy (39%), but this difference was not significant (P = .10).

A retrospective, single-institution, nonrandomized trial compared patients who received GM-CSF and 3F8 anti-GD2 antibody therapy after either autologous HSCT or conventional chemotherapy.[50] The patients were a mixture of those referred for initial treatment or further therapy, and included patients with refractory and relapsed disease, some of whom had received autologous HSCT at referring institutions. In the autologous HSCT group, there was a significantly longer time from first chemotherapy or from autologous HSCT to initiation of GM-CSF and 3F8 anti-GD2 antibody treatment. The autologous HSCT group also had significantly more ultra–high-risk patients.

A retrospective, single-institution, nonrandomized trial compared patients who received GM-CSF and 3F8 anti-GD2 antibody therapy after either autologous HSCT or conventional chemotherapy.[50] The patients were a mixture of those referred for initial treatment or further therapy, and included patients with refractory and relapsed disease, some of whom had received autologous HSCT at referring institutions. In the autologous HSCT group, there was a significantly longer time from first chemotherapy or from autologous HSCT to initiation of GM-CSF and 3F8 anti-GD2 antibody treatment. The autologous HSCT group also had significantly more ultra–high-risk patients.

A trend for better EFS with GM-CSF and 3F8 anti-GD2 antibody therapy and autologous HSCT was observed (65% vs. 51%, P = .128), but there was no statistically significant difference in OS between patients who were treated with chemotherapy alone and those who were treated with autologous HSCT.

In a COG phase III trial (ANBL0032 [NCT00026312]), participants who had previously undergone HSCT were randomly assigned to receive dinutuximab administered with GM-CSF and IL-2 in conjunction with isotretinoin, versus isotretinoin alone.[48]

In a COG phase III trial (ANBL0032 [NCT00026312]), participants who had previously undergone HSCT were randomly assigned to receive dinutuximab administered with GM-CSF and IL-2 in conjunction with isotretinoin, versus isotretinoin alone.[48]

Immunotherapy together with isotretinoin (EFS rate, 66%) was superior to standard isotretinoin maintenance therapy (EFS rate, 46%). As a result, immunotherapy post-HSCT is considered the standard of care in COG trials for high-risk disease.

In a COG phase III trial (ANBL0032 [NCT00026312]), participants who had previously undergone HSCT were randomly assigned to receive dinutuximab administered with GM-CSF and IL-2 in conjunction with isotretinoin, versus isotretinoin alone.[48]

As a result of the COG studies, the U.S. Food and Drug Administration (FDA) approved dinutuximab.

In a COG phase III trial (ANBL0032 [NCT00026312]), participants who had previously undergone HSCT were randomly assigned to receive dinutuximab administered with GM-CSF and IL-2 in conjunction with isotretinoin, versus isotretinoin alone.[48]

Long-term follow-up (median follow-up time, 9.97 years; range, 0.7–15.3 years) was available for 226 eligible patients. The 5-year EFS rate was 56.6% (± 4.7%) for patients randomly assigned to receive immunotherapy (n = 114) versus 46.1% (± 5.1%) for those randomly assigned to receive isotretinoin only (n = 112) (P = .042). The 5-year OS rate was 73.2% (± 4.2%) for patients who received immunotherapy, versus 56.6% (± 5.1%) for patients who received isotretinoin (P = .045). Thirteen of 122 patients who received dinutuximab developed human anti-chimeric antibodies (HACA). Plasma levels of dinutuximab, HACA, and soluble IL-2 receptor-alpha did not correlate with EFS, OS, or clinically significant toxicity.[51][Level of evidence B1]

In a COG phase III trial (ANBL0032 [NCT00026312]), participants who had previously undergone HSCT were randomly assigned to receive dinutuximab administered with GM-CSF and IL-2 in conjunction with isotretinoin, versus isotretinoin alone.[48]

After randomization was stopped for ANBL0032, all patients were assigned to receive immunotherapy. With longer follow-up data available for 1,183 patients, survival and toxicity results were similar to previous reports. For patients older than 18 months at diagnosis with International Neuroblastoma Staging System stage 4 disease (n = 662), the 5-year EFS rate was 57%, and the OS rate was 70.9%. Toxicities were similar to those reported for the randomized cohort. Among patients with available data, higher dinutuximab levels and Fc gamma receptor 3A (FCGR3A) genotype were associated with superior EFS.[52]

In a COG phase III trial (ANBL0032 [NCT00026312]), participants who had previously undergone HSCT were randomly assigned to receive dinutuximab administered with GM-CSF and IL-2 in conjunction with isotretinoin, versus isotretinoin alone.[48]

Anti-GD2 antibodies, along with modulation of the immune system to enhance the antibody's antineuroblastoma activity, are often used to help treat patients with neuroblastoma. The clinical effectiveness of one such antibody led to the FDA approval of dinutuximab. The patient's response to immunotherapy may be caused, in part, by variation in immune function among patients. One anti-GD2 antibody, termed 3F8, used for treating neuroblastoma exclusively at one institution, directs natural killer cells to kill the neuroblastoma cells. However, the natural killer cells can be inhibited by the interaction of HLA antigens and killer immunoglobulin receptor (KIR) subtypes.[53,54] This finding was confirmed and expanded by an analysis of outcomes for patients treated in the national randomized COG-ANBL0032 (NCT00026312) study with the anti-GD2 antibody dinutuximab combined with GM-CSF and IL-2. The study found that certain KIR/KIR-ligand genotypes were associated with better outcomes for patients who were treated with immunotherapy.[55][Level of evidence A2] The presence of inhibitory KIR/KIR ligands was associated with a decreased effect of immunotherapy. Thus, the patient's immune system genes help determine response to immunotherapy for neuroblastoma. Additional studies are needed to determine whether this immune system genotyping can guide patient selection for certain immunotherapies.

A European study compared dinutuximab-beta (dinutuximab manufactured in hamster cells instead of mouse cells) to dinutuximab-beta plus subcutaneous (SQ) IL-2 administered as maintenance therapy after high-dose chemotherapy with autologous HSCT. All patients additionally received isotretinoin.[56]

A European study compared dinutuximab-beta (dinutuximab manufactured in hamster cells instead of mouse cells) to dinutuximab-beta plus subcutaneous (SQ) IL-2 administered as maintenance therapy after high-dose chemotherapy with autologous HSCT. All patients additionally received isotretinoin.[56]

The addition of SQ IL-2 did not improve outcome. The 3-year EFS rate was 56% for patients treated with dinutuximab-beta and 60% for patients treated with dinutuximab-beta and SQ IL-2 (P = .76).

A European study compared dinutuximab-beta (dinutuximab manufactured in hamster cells instead of mouse cells) to dinutuximab-beta plus subcutaneous (SQ) IL-2 administered as maintenance therapy after high-dose chemotherapy with autologous HSCT. All patients additionally received isotretinoin.[56]

There was also no difference in incidence of relapse/progression or 5-year OS.

A European study compared dinutuximab-beta (dinutuximab manufactured in hamster cells instead of mouse cells) to dinutuximab-beta plus subcutaneous (SQ) IL-2 administered as maintenance therapy after high-dose chemotherapy with autologous HSCT. All patients additionally received isotretinoin.[56]

Patients treated with IL-2 had higher rates of fever, pain, allergic reaction, capillary leak syndrome, neurotoxicity, and gastrointestinal toxicity. In this study, only 62% of patients randomly assigned to the IL-2 arm received the planned therapy because of toxicity.

A second SIOPEN trial reported the following:[56]

A second SIOPEN trial reported the following:[56]

Response rates and 2-year EFS and OS rates did not differ for patients treated with IL-2 versus no IL-2.

A second SIOPEN trial reported the following:[56]

SIOPEN subsequently eliminated IL-2 from standard postconsolidation therapy.

A third randomized, phase II, SIOPEN trial compared treatment with IL-2 to treatment without IL-2.[57]

A third randomized, phase II, SIOPEN trial compared treatment with IL-2 to treatment without IL-2.[57]

Response, EFS, and OS rates were not significantly different with IL-2 versus without IL-2, but toxicity was higher in the IL-2 arm.