Altered levels of interleukin-1β and interleukin-1 receptor antagonist in chronic myelogenous leukemia: Clinical and prognostic correlates

We have recently demonstrated that interleukin (IL)-1β levels are elevated in advanced chronic myelogenous leukemia (CML) and that IL-1 inhibitors can suppress CML clonogenic growth. To further assess the clinical implications of increased IL-1β expression in CML, we analyzed IL-1β and IL-1 receptor antagonist (IL-1RA) levels in leukocyte lysates from a series of CML patients and from normal volunteers. Both IL-1β and IL-1RA were measured by enzyme-linked immunosorbent assays (ELISAs), with the lower limits of sensitivity of the assays being 20 pg/mL and 6.5 pg/mL, respectively. The median IL-1β level in the 81 CML patients tested was higher (115.8 pg/2.4 x 10⁷ cells; range, 0 to 2,000 pg/2.4 x 10⁷ cells) than the median level in 25 control samples (10.8 pg/2.4 x 10⁷ cells; range, 0 to 95.5 pg/2.4 x 10⁷ cells) (P < .01). IL-1β was bioactive, as demonstrated with a bioassay based on cytotoxicity to a melanoma cell line (A375). For survival analysis, elevated IL-1β levels were defined as those exceeding the mean + 2 SD of normal levels (83 pg/2.4 x 10⁷ cells). The survival of the 44 patients with elevated IL-1β levels was significantly shorter than that of those who had low IL-1β levels (median, 44 v 58 months; P = .049 by Wilcoxon-Gehan method). An association between IL-1β and CML prognostic criteria shows that IL-1β levels were significantly higher in patients in accelerated/blastic crisis phases of the disease (364.0 pg/2.4 x 10⁷ cells) compared with patients in chronic phase (102.0 pg/2.4 x 10⁷ cells) (P < .01), and that high IL-1β levels correlated with increased blasts in the marrow and peripheral blood (P < .01). In contrast, while IL- 1RA levels did not differ between chronic phase CML patients (median, 471.7 pg/2.4 x 10⁵) and healthy volunteers (median, 454.4 pg/2.4 x 10⁵), patients with accelerated/blast crisis disease had significantly lower levels of IL- 1RA (median, 218.7 pg/2.4 x 10⁵; P = .03). Finally, although IL-1β has been previously shown to increase IL-1RA levels, there was no correlation between IL-1β and IL-1RA levels in our CML patients. In summary, our results suggest that (1) both IL-1β and IL-1RA may be dysregulated in CML, (2) high IL-1β and low IL-1RA protein levels are associated with advanced disease; and (3) IL-1β and IL-1RA are independently altered in CML.