Analysis of anemia and iron supplementation among glioblastoma patients reveals sex-biased association between anemia and survival

Abstract

The association between anemia and outcomes in glioblastoma patients is unclear. We analyzed data from 1346 histologically confirmed adult glioblastoma patients in the TriNetX Research Network. Median hemoglobin and hematocrit levels were quantified for 6 months following diagnosis and used to classify patients as anemic or non-anemic. Associations of anemia and iron supplementation of anemic patients with median overall survival (median-OS) were then studied. Among 1346 glioblastoma patients, 35.9% of male and 40.5% of female patients were classified as anemic using hemoglobin-based WHO guidelines. Among males, anemia was associated with reduced median-OS compared to matched non-anemic males using hemoglobin (HR 1.24; 95% CI 1.00-1.53) or hematocrit-based cutoffs (HR 1.28; 95% CI 1.03-1.59). Among females, anemia was not associated with median-OS using hemoglobin (HR 1.00; 95% CI 0.78-1.27) or hematocrit-based cutoffs (HR: 1.10; 95% CI 0.85-1.41). Iron supplementation of anemic females trended toward increased median-OS (HR 0.61; 95% CI 0.32-1.19) although failing to reach statistical significance whereas no significant association was found in anemic males (HR 0.85; 95% CI 0.41-1.75). Functional transferrin-binding assays confirmed sexually dimorphic binding in resected patient samples indicating underlying differences in iron biology. Anemia among glioblastoma patients exhibits a sex-specific association with survival.

Figure 1

Anemia status and patient distribution. (A) Median hemoglobin and hematocrit levels within 6 months post glioblastoma diagnosis. (B) Distribution of the 1346 glioblastoma patients by sex, anemia status, and whether the anemic patients received an iron supplement. Created with help from biorender.com.

Figure 2

Sex-specific overall survival of patients stratified by anemic versus non-anemic using hemoglobin cutoffs. Sex-specific median overall survival was assessed for anemic versus non-anemic patients before (A, C) and after (B, D) propensity score matching. Anemia, as defined using World Health Organization cutoffs of < 12 g/dL for females and < 13 g/dL for males, was associated with reduced 5-year overall survival.

Figure 3

Sex-specific overall survival of patients stratified by anemic versus non-anemic using hematocrit cutoffs. Sex-specific median overall survival was assessed for anemic versus non-anemic patients before (A, C) and after (B, D) propensity score matching. Anemia, as defined using hematocrit cutoffs of < 36% for females and < 39% for males, was associated with reduced 5-year overall survival.

Figure 4

Overall survival of patients stratified by iron supplementation status and sex. Median overall survival was assessed for patients that received an iron supplement versus those that did not receive an iron supplement stratified by sex before (A, C) and after (B, D) propensity score matching. Iron supplementation was associated with prolonged overall survival in female patients but not in male patients.

Figure 5

Transferrin binding in human glioblastoma samples by sex. Binding of ¹²⁵I-tagged transferrin to extracted plasma membrane fractions from homogenized human glioblastoma tumors (n = 6 male, n = 6 female) was assessed by sex. Male tumors had significantly higher binding of radiolabeled transferrin compared to female tumors. P-value corresponds to unpaired two-sample Wilcoxon rank sum test.