Pituitary iron toxicity remains a critical problem in thalassemia and other transfusional iron overload syndromes because gonadotropic iron deposition occurs early and remains clinically silent until puberty. While MRI screening of heart and liver iron have improved overall survival in these disorders, the heart develops iron overload only after prolonged, unprotected exposure to transfusional iron. We previously demonstrated that overt, clinical hypogonadism is common (83%) in patients having detectable cardiac iron, and is independently associated with pituitary iron deposition and gland shrinkage. The US29T study was an investigator-initiated, industry-sponsored prospective observational trial examining trends in pituitary iron (by MRI R2) and pituitary volume over two years in children and young adults receiving deferasirox monotherapy for iron overload. We hypothesized that deferasiroxtherapy would prevent pituitary iron accumulation and gland shrinkage over the study interval.
31 chronically-transfused subjects with thalassemia major (N=28) and Blackfan-Diamond (N=3) syndrome, ages 2–25 years participated in this study. MRI assessment of pituitary R2 and volume was performed at baseline, 1 year, and 2 years; technical details are in (1) and (2).
Iron chelation was prescribed by the patient's referring hematologist based upon the patients LIC, cardiac R2*, and pancreas R2* according to local clinical practice; prescribing physicians were screened to the pituitary results. Hypogonadismwas defined clinically based upon inadequate progression of secondary sex characteristics during puberty, primary or secondary amenorrhea in women, or low testosterone in men.
All MRI measurements were transformed to Z-scores using age and sex matched norms from 100 nonthalassemic subjects (1). Analysis of variance was used with DunnettÕspost hoc correction.
26 patients completed two years. Reasons for discontinuation were a change to combination deferoxamine/deferasirox therapy (N=2), bone-marrow transplantation (N=1), loss to follow up (N=1), and inability to complete the baseline MRI examination. In the remaining patients, 10 were prepubertal, 12 had achieved normal puberty, and 4 were hypogonadalat baseline.
Figure 1 summarizes the change in pituitary R2 Z-score and volumes over the study interval. Pituitary R2 Z-score was elevated at baseline (2.9 ±0.6) but remained stable over two years. Changes in pituitary R2 correlated with mean cardiac and pancreatic R2* but not LIC.
Anterior and total pituitary volume were decreased at baseline (mean Z-score −1.1 and −1.4, respectively) but normalized over time; both Year 1 and Year 2 volumes were significantly improved (p<0.03) from baseline. Changes were most strongly correlated with average LIC; 24 out of 26 subjects increased their volume Z-scores over two years.
The single patient whose anterior pituitary shrank significantly (DZ = −0.8) during the study interval was openly noncompliant. Her liver iron rose from 10.4 mg/g to 21.4 mg/g, her cardiac R2* increased from 81 to 142 and her pituitary R2 Z-score climbed from 5.4 to 10.3 over two years. Although she had normal initiation of puberty at study entry, she developed pubertal arrest and has not begun her periods by the age of 16. The endocrine status of all of the other subjects in the study was clinically stable.
The most striking finding was the systematic restoration of pituitary volume toward the normal range, despite no net change in pituitary R2. We postulate that suppression of oxidative stress from labile plasma iron may represent the mechanism of improvement. Stabilization of pituitary R2 is also encouraging. Based upon the baseline cross-sectional relationship of R2 and age, one would have predicted a 0.4 increase in the average R2 Z-score over two years instead of the 0.1 decline observed. Deferasirox monotherapy, in clinical practice, appears to protect the pituitary gland for iron accumulation, shrinkage and dysfunction.
Wood:Ferrokin Biosciences: Consultancy; Shire: Consultancy; Apotex: Consultancy, Honoraria; Novartis: Honoraria, Research Funding. Paley:Novartis Pharmaceuticals: Employment. Berdoukas:Apopharma: Consultancy. Coates:Novartis: Speakers Bureau; Apopharma: Consultancy.
Asterisk with author names denotes non-ASH members.