Cytokine profiling in 128 patients with transient abnormal myelopoiesis: a report from the JPLSG TAM-10 trial

Abstract

Transient abnormal myelopoiesis (TAM) occurs in 10% of neonates with Down syndrome (DS). Although most patients show spontaneous resolution of TAM, early death occurs in ∼20% of cases. Therefore, new biomarkers are needed to predict early death and determine therapeutic interventions. This study aimed to determine the association between clinical characteristics and cytokine levels in patients with TAM. A total of 128 patients with DS with TAM enrolled in the TAM-10 study conducted by the Japanese Pediatric Leukemia/Lymphoma Study Group were included in this study. Five cytokine levels (interleukin-1b [IL-1b], IL-1 receptor agonist, IL-6, IL-8, and IL-13) were significantly higher in patients with early death than in those with nonearly death. Cumulative incidence rates (CIRs) of early death were significantly associated with high levels of the 5 cytokines. Based on unsupervised consensus clustering, patients were classified into 3 cytokine groups: hot-1 (n = 37), hot-2 (n = 42), and cold (n = 49). The CIR of early death was significantly different between the cytokine groups (hot-1/2, n = 79; cold, n = 49; hot-1/2 CIR, 16.5% [95% confidence interval (CI), 7.9-24.2]; cold CIR, 2.0% [95% CI, 0.0-5.9]; P = .013). Furthermore, cytokine groups (hot-1/2 vs cold) were independent poor prognostic factors in the multivariable analysis for early death (hazard ratio, 15.53; 95% CI, 1.434-168.3; P = .024). These results provide valuable information that cytokine level measurement was useful in predicting early death in patients with TAM and might help to determine the need for therapeutic interventions. This trial was registered at UMIN Clinical Trials Registry as #UMIN000005418.

Graphical abstract

Figure 1.

Cytokine levels are valuable markers for predicting early death in patients with TAM. (A) CIR of early death between patients with TAM with high and low levels of IL-1b (high, n = 64; low, n = 64; CIR, 20.3% [95% CI, 9.8-29.6] vs 1.6% [95% CI, 0.0-4.6]; P < .001); (B) high and low levels of IL-1ra (high, n = 36; low, n = 90; CIR, 30.6% [95% CI, 13.8-44.1] vs 3.4% [95% CI, 0.0-7.0]; P < .001); (C) high and low levels of IL-6 (high, n = 28; low, n = 98; CIR, 32.1% [95% CI, 12.4-47.4] vs 4.1% [95% CI, 0.0-8.0]; P < .001); (D) high and low levels of IL-8 (high, n = 35; low, n = 90; CIR, 31.4% [95% CI, 14.2-45.2] vs 2.2% [95% CI, 0.0-5.3]; P < .001); and (E) high and low levels of IL-13 (high, n = 69; low, n = 59; CIR, 18.8% [95% CI, 9.1-27.6] vs 1.7% [95% CI, 0.0-4.9]; P < .001).

Figure 2.

Total of 128 patients with TAM are classified into 3 groups by an unsupervised consensus clustering analysis based on cytokine profiling. (A) Based on unsupervised clustering, patients were classified into 3 cytokine groups (hot-1 [n = 37], hot-2 [n = 42], and cold groups [n = 49]). Missing data (1.1%) in 22 cytokines were imputed using the missForest method. Black boxes indicate each clinical feature. Gray boxes indicate patients with no data. (B-D) The mean cytokine differences (x-axis) and the negative log10-transformed statistical P value (y-axis) between hot-1 group and other groups (B), hot-2 group and other groups (C), cold group and other groups (D) are shown in the volcano plot.

Figure 3.

Cytokine group is significantly associated with the early death rate in patients with TAM. The CIR of early death in patients with TAM between cytokine hot-1/2 and cold groups (hot-1/2, n = 79; cold, n = 49; hot-1/2 CIR, 16.5% [95% CI, 7.9-24.2]; cold CIR, 2.0% [95% CI, 0.0-5.9]; P = .013).