Control of Oxidant-Stress and Inflammation by Iron Chelators Deferasirox (ICL670) or Deferoxamine in β-Thalassemia: An Ancillary Study of the Novartis CICL670A0107 Trial.
Authors: Walter Patrick , Macklin Eric , Porter John , Evans Patricia , Coates Tom , Olivieri Nancy F. , Giardina Patricia , Kwiatkowski Janet , Neufeld Ellis , Ames Bruce , Holland Jaymes , Marks Peter , Vichinsky Elliott , Harmatz Paul 
Published: April 2020

Objective: We examined whether oxidant-stress and inflammation in β-thalassemia can be controlled by deferasirox as effectively as by deferoxamine (DFO) through analysis of body iron burden and biomarkers of lipid peroxidation and inflammation.

Methods: Thalassemia Clinical Research Network patients participating in the Novartis CICL670A0107 trial (a randomized comparison of deferasirox, an oral iron chelator, vs. DFO) were eligible and 44 (25 male, 21.8±11.1 yrs) were enrolled in the study. Blood samples were obtained

fasting after a 5-day washout of DFO prior to commencing treatment with study drug, and 24 hours post-chelator and antioxidant supplementation at 1, 6, and 12 months on study. Thirty healthy untreated controls matched for age, sex, and race (15 male, 24.5±9 yrs) were also studied.

Plasma levels of malondialdehyde (MDA), a marker of lipid peroxidation, were determined by GC-MS; vitamin C by spectrophotometry; α-tocopherol by HPLC; and high-sensitivity C-reactive protein (hsCRP), a marker of inflammation, by nephelometry. In patients with thal, liver iron concentration (LIC) was analyzed by atomic absorption spectrometry and ferritin by immuno-assay. MDA, α-tocopherol, and hsCRP were log-transformed prior to analysis. Back-transformed means are reported.

Results: Mean MDA concentrations (nmol/L) at 0, 1, 6, and 12 months were as follows: deferasirox: 78, 77, 46, 48; DFO: 40, 44, 37, 33. Mean MDA concentration in control subjects was 19 nmol/L (range 2–76 nmol/L). MDA was elevated in both treatment groups as compared to controls (p&lt;.05). Mean MDA was highest prior to commencing study treatment and after 1 mo of study treatment with a significant decrease noted in both treatment groups over the course of treatment (deferasirox −27 nmol/L, DFO −12 nmol/L, p&lt;.001 for average decline, p=.34 for difference in rate of decline). This parallels significant declines in both groups in LIC (mean 2.0 mg/g dry/yr, p=.01) and ferritin (mean 444 ng/mL/yr, p&lt;.001). In cross-sectional analysis, MDA was positively correlated with ferritin (r2=.21, p=.06) and LIC (r2=.42, p&lt;.001) and negatively correlated with Vitamin C (r2= −.37, p&lt;.001) and α-tocopherol (r2= −.38, p&lt;.001). Mean hsCRP (mg/L) at months 0, 1, 6, and 12 were as follows: deferasirox: 1.4, 2.1, 0.9, 0.6; DFO: 0.8, 1.1, 0.9, 1.2. Mean hsCRP concentration in control subjects was 0.66 mg/L (range 0.2–5.1 mg/L). In contrast with MDA trajectories, hsCRP showed significant decrease only in the group receiving deferasirox (deferasirox −1.0 mg/L, DFO +0.37 mg/L, p&lt;.001).

Conclusions: These results demonstrated a correlation of iron burden with elevated biomarkers of oxidant-stress and inflammation. Iron chelation therapy with DFO or with deferasirox showed equal effectiveness in decreasing MDA. In contrast, only therapy with deferasirox produced a significant decline in hsCRP.