IL-10 and TNFα are associated with decreased survival in low-risk pediatric acute myeloid leukemia; a children's oncology group report

Abstract

Pediatric acute myeloid leukemia (AML) is a devastating disease with a high risk of relapse. Current risk classification designates patients as high or low risk (LR) based on molecular features and therapy response. However, 30% of LR patients still suffer relapse, indicating a need for improvement in risk stratification. Cytokine levels, such as IL-6 and IL-10, have been shown to be prognostic in adult AML but have not been well studied in children. Previously, we reported elevated IL-6 levels in pediatric AML bone marrow to be associated with inferior prognosis. Here, we expanded our investigation to assess cytokine levels in diagnostic peripheral blood plasma (PBP) of pediatric AML patients and determined correlation with outcome. Diagnostic PBP was obtained from 80 patients with LR AML enrolled on the Children's Oncology Group AAML1031 study and normal PBP from 11 controls. Cytokine levels were measured and correlation with clinical outcome was assessed. IL-6, TNFα, MIP-3a, and IL-1β were significantly higher in AML patients versus controls when corrected by the Bonferroni method. Furthermore, elevated TNFα and IL-10 were significantly associated with inferior outcomes. Our data demonstrate that in diagnostic PBP of LR pediatric AML patients, certain cytokine levels are elevated as compared to healthy controls and that elevated TNFα and IL-10 are associated with inferior outcomes, supporting the idea that an abnormal inflammatory state may predict poor outcomes. Studies are needed to determine the mechanisms by which these cytokines impact survival, and to further evaluate their use as prognostic biomarkers in pediatric AML.

Keywords: Interluekin 6; cytokine; microenvironment; risk stratification; soluble factor.

Figure 1.. Cytokine levels in peripheral blood (PB) plasma are elevated at diagnosis in a subset of patients when compared to PB plasma of healthy children.

In this cohort of samples we found the following cytokines and growth factors to be significantly higher in AML patients v. controls: (A) IL-6, (B) IL-10, (C) TNFα, (D) MIP-3a, (E) IL-2, (F) IL-17A, (G) IL-1β, (H) IL-12(p70), and (I) Fractalkine. (J) IL-8 levels were not significantly different when compared to normal controls in this cohort. When corrected for multiple comparisons by the Bonferroni method, IL-6, TNFα, and IL-1β remained significantly different with p values <0.0012. For IL-6, the median in NPB was 2.8 pg/mL (25-75 Percentile 1.43-6.3) vs 12.31 pg/mL for AML (25-75 Percentile 7.29-21.09). For TNFα, the median in NPB was 12.1 pg/mL (25-75 Percentile 6.5-18.2) vs 21.7 pg/mL for AML (25-75 Percentile 14.9-34.9). For IL-10, the median in NPB was 23.9 pg/mL (25-75 Percentile 14.4-67.8) vs 64.0 pg/mL for AML (25-75 Percentile 38.9-90.9).

Figure 2.. Relationship between cytokine levels and clinical outcomes.

Among the cytokines that were found to be elevated in diagnostic samples, TNFα and IL-10 were associated with clinical outcome. Patients with high TNFα (n=40, A, B) had 3 year relapse free survival (RFS) of 49.6% compared to 76.6% for those with low TNFα (n=40, cut at the median 21.7 pg/mL. Patients with high IL-10 (n=11) had 3 year RFS of 36.4% compared to 67.3% for those with low IL-10 (n=69, cut-point of 112 pg/mL C, D). These differences in outcomes remained significant after Bonferroni correction. PB plasma IL-6 levels did not predict outcome at any cutpoint examined. The cutpoint that came closest to statistical significance is shown. (E, F).