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sis in 55 of 101 evaluable patients. The presence of mini- mal disseminated disease, an independent prognostic fac- tor in ALK-positive ALCL, was associated with elevated concentrations of IL-6 (20.7 pg/mL versus 0 pg/mL, P=0.001), IL-10 (37.4 pg/mL versus 0 pg/mL, P<0.001), IL- 17a (P=0.031), MCP-1 (588.8 pg/mL versus 383.8 pg/mL, P=0.008), HGF (3877.2 pg/mL versus 2101.1 pg/mL, P=0.002), IP-10 (272.94 pg/mL versus 108.3 pg/mL, P<0.001), sCD30 (137 449.9 pg/mL versus 51 781.1 pg/mL, P=0.001), and sIL-2R (159 428.4 pg/mL versus 30 087.6 pg/mL, P<0.001) (Figure 2). G-CSF (48.1 pg/mL versus 0 pg/mL, P=0.041) and MIP-1α concentrations (214.2 pg/mL versus 106.6 pg/mL, P=0.042) were significantly higher in patients without minimal disseminated disease.
Using quantitative polymerase chain reaction, 29 of 90 patients were found to have a normalized copy number >10, where the number of copies of NPM-ALK is normal- ized to 10 000 copies of ABL. Concentrations of sIL-2R (P<0.001), IL-6 (P=0.004), IL-10 (P<0.001), IFN-γ (P<0.001), MIG (P=0.041) and IP-10 (P=0.003) were higher among these patients than among patients with lower normal- ized copy numbers.
Anti-anaplastic lymphoma kinase-antibody titers
Anti-ALK antibody titers inversely correlate with the risk of relapse and may serve as a surrogate for the strength of the ALK-specific immune response.19,20 The
patients were grouped according to the strength of the antibody titer into those with low (≤1/750), intermediate (>1/750 – <1/60750) and high (≥1/60750) titers. There were 34, 53, and 32 patients in the low, intermediate and high titer groups, respectively.
Patients with a low titer had significantly higher median concentrations of sIL-2R (P=0.013), IL-6 (P<0.001), IFN-γ (P=0.022), and IP-10 (P=0.021), but lower concentrations of IL-23 (P=0.008) compared to patients with an interme- diate or high titer (Figure 3).
Correlation of cytokine levels with outcomes
In univariate analysis, patients with concentrations above the median of IL-6, IL-10, IL-17a, IFN-γ, MCP-1, HGF, IP-10 and sIL-2R had a significantly lower 3-year event-free survival rate compared to patients with levels below the median (Table 2). The greatest difference in event-free survival rates was found between patients with IL-6 concentrations above the detection threshold and patients with no detectable IL-6 [event-free survival: 85.7% (95% confidence interval: 77.5 - 94.8) versus 44.6% (95% confidence interval: 33.4 - 59.8), P(log-rank)<0.001]. In a stepwise Cox regression analysis, including known risk factors and all cytokines for which findings were sig- nificant in the univariate analysis, only IL-6 retained an independent prognostic value with a hazard ratio of 2.9 ± 0.4 (Table 2).
Figure 3. Cytokine levels correlated with anti- anaplastic lymphoma kinase antibody titer. Median cytokine levels are shown for patients with low (≤1/750, n=34), intermediate (>1/750 – <1/60750, n=53), and high (≥1/60750, n=32) anti-ALK antibody titers. Logarithmic representation, values in pg/mL. Only cytokines for which significant differ- ences were found are shown.
haematologica | 2018; 103(3)