Abstract
A phase 3 randomized study (COG ANBL0032) demonstrated significantly improved outcome by adding immunotherapy with ch14.18 antibody to isotretinoin as post-consolidation therapy for high-risk neuroblastoma (NB). This study, ANBL0931, was designed to collect FDA-required safety/toxicity data to support FDA registration of ch14.18. Newly diagnosed high-risk NB patients who achieved at least a partial response to induction therapy and received myeloablative consolidation with stem cell rescue were enrolled to receive six courses of isotretinoin with five concomitant cycles of ch14.18 combined with GM-CSF or IL2. Ch14.18 infusion time was 10-20 h per dose. Blood was collected for cytokine analysis and its association with toxicities and outcome. Of 105 patients enrolled, five patients developed protocol-defined unacceptable toxicities. The most common grade ≥ 3 non-hematologic toxicities of immunotherapy for cycles 1-5, respectively, were neuropathic pain (41, 28, 22, 31, 24%), hypotension (10, 17, 4, 14, 8%), allergic reactions (ARs) (3, 10, 5, 7, 2%), capillary leak syndrome (1, 4, 0, 2, 0%), and fever (21, 59, 6, 32, 5%). The 3-year event-free survival and overall survival were 67.6 ± 4.8% and 79.1 ± 4.2%, respectively. AR during course 1 was associated with elevated serum levels of IL-1Ra and IFNγ, while severe hypotension during this course was associated with low IL5 and nitrate. Higher pretreatment CXCL9 level was associated with poorer event-free survival (EFS). This study has confirmed the significant, but manageable treatment-related toxicities of this immunotherapy and identified possible cytokine biomarkers associated with select toxicities and outcome. EFS and OS appear similar to that previously reported on ANBL0032.
Highlights
Immunotherapy using anti-glycolipid disialoganglioside (GD2) antibody combined with cytokines has become the standard treatment in North America for patients with high-risk neuroblastoma (NB) who have achieved at least a partial remission following intensive induction and consolidation [1]
Ninety-three percent of the patients were less than 12 years old
As IL-5 levels were dramatically elevated on both courses inves tigated, we explored a possible relationship of this cytokine and the other analytes implicated with vascular disorders for associations with clinically significant (≥grade 3) hypotension (Table 7), or any grade capillary leak (Table 8)
Summary
Immunotherapy using anti-glycolipid disialoganglioside (GD2) antibody combined with cytokines has become the standard treatment in North America for patients with high-risk neuroblastoma (NB) who have achieved at least a partial remission following intensive induction and consolidation [1]. The primary objective of this study was to comprehensively define the safety profile of ch14.18 when administered with cytokines and isotretinoin in high-risk NB patients after completing standard induction chemotherapy and autologous stem cell transplant (ASCT) and generate data required to support the Biological License Application (BLA) for ch14.18 with the Food and Drug Administration (FDA). Therapeutic IL-2 induces immune cell stimulation but may induce hypotension and capillary leak syndrome This is believed to be mediated by nitric oxide (NO) directly or indirectly via induction of tumor necrosis factor alpha (TNFα) and interferon gamma (IFNγ) or other proinflammatory cytokines such as IL-6 [7,8,9]. Serum cytokine profiles during ch14.18 immunotherapy may be able to predict toxicities and/or outcome of the immunotherapy and were investigated as part of this study
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