Effect of ALK Amplification and Mutation on Outcomes in High-Risk Neuroblastoma

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In an analysis from the European Neuroblastoma Study Group (SIOPEN) HR-NBL1 high-risk neuroblastoma trial reported in the Journal of Clinical Oncology, Bellini et al found that ALK amplification and clonal mutation were associated with poorer outcomes in pediatric patients with high-risk neuroblastoma.

Study Details

Among 3,334 patients enrolled in the HR-NBL1/SIOPEN trial between November 2002 and December 2019, 1,092 patients with a tumor sample obtained at diagnosis available for additional molecular analysis with available follow-up data were included in the ALK analysis cohort. Samples from the 1,092 patients were assessed to determine ALK amplification status (n = 330), ALK mutational profile (n = 191), or both (n = 571).

Key Findings

Genomic ALK amplification was detected in 41 of 901 cases (4.5%), with MYCN amplification present in all except one case. Overall survival at 5 years was 28% (95% confidence interval [CI] = 15%–42%) among patients with ALK amplification vs 51% (95% CI = 47%–54%) among 860 with no ALK amplification (P < .001).

ALK mutations were detected at a clonal level (> 20% mutated allele fraction) in 76 of 762 cases (10%) and at a subclonal level (0.1%–20% mutated allele fraction) in 30 (3.9%). Presence of ALK mutations and MYCN amplification was significantly correlated (P < .001), with an enrichment of ALK F1174 in MYCN-amplified tumors being observed (P = .0005).

Among the 571 cases with known ALK amplification and ALK mutation status, 5-year overall survival was 37% (95% CI = 29%–45%) among 106 patients with any ALK alteration vs 51% (95% CI = 46–55) among 465 patients with no ALK alteration (P = .005).

Overall survival was worse among patients with ALK amplification or clonal ALK mutations vs those with subclonal ALK mutations or no ALK alterations: 5-year rates were 26% (95% CI = 10%–47%) among 19 patients with ALK amplification, 33% (95% CI = 21%–44%) among 65 with clonal ALK mutations, 48% (95% CI = 26%–67%) among 22 with subclonal ALK mutation, and 51% (95% CI = 46%–55%) among 465 with no alterations (overall P = .001).

In multivariate analysis, involvement of more than one metastatic compartment (hazard ratio [HR] = 2.87, P < .001), ALK amplification (HR = 2.38, P = .004), and clonal ALK mutation (HR = 1.77, P = .001) were independent predictors of poor outcome.

The investigators concluded: “Genetic alterations of ALK (clonal mutations and amplifications) in [high-risk neuroblastoma] are independent predictors of poorer survival. These data provide a rationale for integration of ALK inhibitors in upfront treatment of [high-risk neuroblastoma] with ALK alterations.”

Gudrun Schleiermacher, MD, PhD, of Institut Curie, Paris, is the corresponding author of the Journal of Clinical Oncology article.

Disclosure: The study was supported by the Annenberg Foundation, Association Hubert Gouin Enfance et Cancer, SiRIC/INCa, Programme Hospitalier de Recherche Clinique, and others. For full disclosures of the study authors, visit

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