Absolute Neutrophil Count after the First Chemotherapy Cycle as a Surrogate Marker for Treatment Outcomes in Patients with Neuroblastoma

Abstract

Purpose: We performed this study to determine whether the degree of neutropenia after the first chemotherapy cycle can be used as a surrogate marker of individual susceptibility to chemotherapeutic agents affecting treatment outcome in patients with neuroblastoma.

Materials and methods: The study included 313 patients who received the first cycle chemotherapy with a CEDC (cisplatin+etoposide+doxorubicin+cyclophosphamide) regimen and had absolute neutrophil count (ANC) data available. The cumulative incidences of progression and treatment-related mortality (TRM) were estimated. To identify genetic variations associated with the ANC, a genome-wide association study (GWAS) was performed.

Results: An ANC of 32.5/μL was determined as the cutoff point to categorize patients into the good and poor prognosis subgroups in terms of progression. Patients with a high nadir ANC had a higher cumulative incidence of progression than those with a low nadir ANC (p < 0.001). In multivariate analysis, high nadir ANC, age, bone marrow involvement, and unfavorable histology were poor prognostic factors. With regard to the TRM, patients with a low nadir ANC (ANC < 51.0/μL) had a higher cumulative incidence of TRM than those with a high nadir ANC (p=0.010). In GWAS, single-nucleotide polymorphisms of LPHN2 and CRHR1 were significantly associated with the nadir ANC.

Conclusion: In neuroblastoma patients, the degree of neutropenia after the first chemotherapy cycle can be used as a surrogate marker to predict an individual's susceptibility to chemotherapeutic agents. Tailoring of treatment based on the degree of neutropenia needs to be considered.

Keywords: Genome-wide association study; Germline; Neuroblastoma; Neutropenia; Treatment outcome.

Fig. 1

Survival outcomes according to the absolute neutrophil count (ANC) group. Cumulative incidence of progression/treatment-related mortality, event-free survival, and overall survival based on an ANC cutoff value of 32.5/μL in all patients (A), in patients aged ≥ 2 years (B), and in high-risk patients (C).

Fig. 2

Tumor response according to the absolute neutrophil count (ANC) group. The percentage of residual tumor volume at the first response evaluation in all patients (A), in high-risk patients (B), and in patients with undifferentiated (UD) or poorly differentiated (PD) neuroblastoma (C).

Fig. 3

Cumulative incidence of treatment-related mortality (TRM) according to the absolute neutrophil count (ANC) group. An ANC of 51.0/μL was selected as an optimal cutoff point for the cumulative incidence of TRM, and patients in the ANC > 51.0/μL group showed a lower 5-year cumulative incidence of TRM than those in the ANC ≤ 51.0/μL group (1.3%±0.02% vs. 9.4%±0.04%, respectively) in all patients (A) and in high-risk patients (B).

Fig. 4

Manhattan plot of the genome-wide association study. (A) Results of the genome-wide association analyses of common single- nucleotide polymorphisms (SNPs) (minor allele frequency > 0.05) associated with the absolute neutrophil count represented as a Manhattan plot. The X-axis represents the SNP markers on each chromosome. (B) Regional association plots at the RPTN locus. Regional association plots, including both genotypes and SNPs of the LPHN2, were generated using LocusZoom within 400 kb.