High transferrin saturation predicts inferior clinical outcomes in patients with myelodysplastic syndromes

Abstract

Iron overload (IO) reflected by elevated ferritin is associated with increased mortality in myelodysplastic syndromes (MDS), however, ferritin is an imperfect metric. Elevated labile plasma iron correlates with clinical outcomes and transferrin saturation (TSAT) >80%, but is not readily measurable. The trajectory of TSAT, and its association with clinical outcomes remain undefined. Canadian MDS registry patients were evaluated. Mean TSAT, mean ferritin and transfusion dose density (TDD) were determined. Survival was evaluated by TSAT and ferritin (<50%, 50-80%, >80%), (≤500 μg/L, 501-800 μg/L, >800 μg/L). In 718 patients, median age was 74 years; 12%, 31%, 29%, 15% and 13% were IPSS-R very low, low, intermediate, high and very high. TSAT and ferritin were moderately correlated (r=0.63, P<0.0001). TSAT increased over time in transfusion- dependent patients (P=0.006). Higher TSAT and ferritin were associated with inferior 5-year overall (OS), progression- free (PFS), and leukemia-free survival (LFS) (P≤0.008) and higher TDD with inferior 5-year OS. TSAT >80% trended with inferior cardiac death-free survival (P=0.053). In univariate analysis, age, IPSS-R, blast percentage by Eastern Cooperative Oncology Group Performance Status, frailty, Charlson Comorbidity Index, iron chelation (Y/N), TDD, TSAT and ferritin were significantly associated with inferior OS. By multivariable analysis, TSAT >80% (P=0.007) remained significant for OS (R2 30.3%). In MDS, TSAT >80% and ferritin >800 μg/L portended inferior OS, PFS and LFS. TSAT may indicate the presence of oxidative stress, and is readily measurable in a clinical setting. The relationship between TSAT and cardiac death-free survival warrants further study.

Figure 1.

Correlations between transferrin saturation and ferritin across all patients regardless of transfusion status, collected from enrolment up to 42 months. (A) Mean transferrin saturation (TSAT) increased with incremental ferritin category (B) TSAT stratified by by ferritin category. Only 39% of all ferritins >1,000 µg/L were associated with a TSAT of >80%.

Figure 2.

Temporal trends in transferrin saturation and ferritin among 718 patients with myelodysplastic syndromes. The stacked bar plots are showing the proportions of patients with ferritin ≤500, 501-800 and >800µg/L, and the proportions of patients with transferrin saturation (TSAT) <50%, 50-80%, and >80% at 6-month intervals from enrolment up to 42 months in all patients, in time-varying transfusion-dependent and in time-varying transfusion-independent patients, where transfusion dependence was determined at sequential 6-month intervals.

Figure 3.

Overall survival of myelodysplastic syndrome patients. Higher transfusion dose density (TDD) at landmark year 1 is associated with inferior overall survival among all myelodysplastic syndrome patients.

Figure 4.

Higher mean transferrin saturation and ferritin are associated with inferior overall survival, progression-free survival and leukemia-free survival. Among those with a mean ferritin >800 µg/L, stratifying by transferrin saturation (TSAT) category further discriminated differences in overall survival (OS) (P=0.014) (dotted inlay). Total numbers of patients at time zero in the black, red and blue groups, respectively, were as follows: 302, 188 and 55 for OS analyses by TSAT category; 248, 100 and 197 for OS by ferritin category; 391, 237 and 90 for progression-free survival and leukemia-free survival by TSAT category; 309, 119, and 290 for progression-free survival and leukemia-free survival by ferritin category.

Figure 5.

The effect of iron chelation therapy (ever vs. never). Iron chelating therapy has an attenuating effect on the adverse prognostic impact of a higher transferrin saturation (TSAT) in both intermediate (TSAT 50-80%) and high (TSAT >80%) groups, although sample sizes were limited in the tails of the Kaplan Meier survival curves.

Figure 6.

Cardiac death-free survival. Among patients who were transfusion-dependent at enrollment, higher mean transferrin saturation (TSAT) was associated with inferior cardiac death-free survival (A), but higher mean ferritin was not (B). Total numbers of patients at time zero in the black, red and blue groups were 75, 107 and 36 for the analysis by TSAT, and 48, 31 and 139 for the ferritin analysis, respectively.