Endocrine function and bone disease during long‐term chelation therapy with deferasirox in patients with β‐thalassemia major

Abstract

*Iron overload in b-thalassemia major (TM) typically results in iron-induced cardiomyopathy, liver disease, and endocrine complications. We examined the incidence and progression of endocrine disorders (hypothyroidism, diabetes, hypoparathyroidism, hypogonadism), growth and pubertal delay, and bone metabolism disease during long-term deferasirox chelation therapy in a real clinical practice setting. We report a multicenter retrospective cohort study of 86 transfusion-dependent patients with TM treated with once daily deferasirox for a median duration of 6.5 years, up to 10 years. No deaths or new cases of hypothyroidism or diabetes occurred. The incidence of new endocrine complications was 7% (P 5 0.338, for change of prevalence from baseline to end of study) and included hypogonadism (n 5 5) and hypoparathyroidism (n 5 1). Among patients with hypothyroidism or diabetes at baseline, no significant change in thyroid parameters or insulin requirements were observed, respectively. Mean lumbar spine bone mineral density increased significantly (P < 0.001) and the number of patients with lumbar spine osteoporosis significantly decreased (P 5 0.022) irrespective of bisphosphonate therapy, hormonal replacement therapy, and calcium or vitamin D supplementation. There were no significant differences in the number of pediatric patients below the 5th centile for height between baseline and study completion. Six pregnancies occurred successfully, and four of them were spontaneous without ovarian stimulation. This is the first study evaluating endocrine function during the newest oral chelation therapy with deferasirox. A low rate of new endocrine disorders and a stabilization of those pre-exisisting was observed in a real clinical practice setting.

Body Composition in Adult Patients with Thalassemia Major

“…Various studies have shown that children with thalassemia major suffer from growth retardation, impaired immune function, and low body mass index [8–10]. The above treatment-related complications disrupt the balance between osteoblasts and osteoclasts by interfering with various molecular mechanisms leading to osteoporosis and increased fracture risk during adulthood [11, 12]. Chelation treatment should be added routinely in order to prevent iron overload and its toxic effects [12, 13].…”

“…The above treatment-related complications disrupt the balance between osteoblasts and osteoclasts by interfering with various molecular mechanisms leading to osteoporosis and increased fracture risk during adulthood [11, 12]. Chelation treatment should be added routinely in order to prevent iron overload and its toxic effects [12, 13]. However, parenteral administration of chelate agents reduces patients' compliance and the longer survival rates lead to some degree of toxic systemic iron overload.…”

“…It is well established that all the above parameters are impaired in patients with thalassemia major in addition to hyperactivity of bone marrow, iron overload, and diminished bone mineral density [7, 12]. However, there is limited published data regarding the body composition status in this population, especially during adulthood.…”

Deferasirox and children: From clinical trials to the real world

“…Finally, deferasirox use was not associated with growth failure (Supporting Information Fig. 3) [1,5,6]. This was truer when it was started during childhood, likely because other factors such as early hypophyseal damage with abnormal release of sexual hormones may compromise normal growth during adolescence independent of the use of deferasirox.…”

“…Despite the fact that rituximab in combination with chemotherapy has proven to increase FL progression free and overall survival, there is considerable inter-individual variability in the clinical response to this anti-CD20 monoclonal antibody (MAb) [2]. Apoptosis induction seems to be a process involved in the mechanism of action of MAbs [2][3][4] and several studies have reported the association of polymorphisms in genes coding for apoptotic extrinsic pathway proteins, such as death receptors and their ligands, with susceptibility to lymphomas or immunotherapy response [5,6]. However, there are no studies analyzing the relationship between polymorphisms in genes coding for extrinsic apoptosis inducers and rituximab response.…”