Reversal of Complications Following Intensive Combined Chelation in β-Thalassemia Major Patients.
Authors: Farmaki Kallistheni , Tzoumari Ioanna , Pappa Christina , Tompoukis Christos , Papagianni Aggeliki , Aggelopoulos Nikos , Mitas Demetrios , Berdoukas Vasilios 
Published: October 2019

Abstract
Life-threatening sequelae in β-thalassemia major patients (TM), result from transfusion iron overload (Fe load). Combined chelation with desferrioxamine (DFO) and deferiprone (DFP) is well tolerated and produces a synergistic effect superior to either drug alone. Combination can place all TMp in negative net iron balance and effect significant reduction in Fe load. 50 TM (24 males, 26 females) aged 8–48 yrs, were switched from monotherapy with DFO, to an individually tailored regimen (DFO 40–60 mg/kg/day- DFP 75–100 mg/kg/day) for 5–6yrs. Fe load was evaluated by mean ferritin levels (MEIA) and non-invasive heart &hepatic iron quantification, by annual Signa-MRI 1.5 Tesla, multi-echo T2 sequences. The heart was evaluated by Echo Doppler. Endocrine function was assessed by:- thyroid: FT4, FT3 &TSH in TRH-test, - Gonads: estradiol, progesterone, testosterone, Free-testosterone levels &LHRH stimulation- Glucose tolerance: OGGT with glucose &insulin measurements at each time and area under the curve (AUC). Insulin sensitivity and beta-cell function were assessed by indices of homeostasis model assessment (ISIHOMA &SCHOMA). Subsequently, all patients survived, even though with DFO alone in the previous decade, mortality ranged from 13.3–14.3%. In patients who accepted the treatment well, a trend analysis (PROC MIXED in SAS), revealed a negative trend of ferritin over time (p<0.0001) with a rate of decline equal to −95 ng/ml/month and a cumulative decrease in 5 years. The mean Ferritin value at baseline, 3.421μg/L, decreased dramatically to 87μg/L. MRI measurements led to significant reduction (p<0.0001) of Fe load to virtually Fe free organs (T2Heart from 28,2msec to 38,1msec &T2Liver from 22,7msec to37,2msec). In 12/50 with pre-existing cardiac dysfunction on medication, symptoms reversed and heart medications were stopped. Ventricular dimensions and function normalized in Echo tests. Mean LVEF increased significantly (p<0.0001) from 54% to 72% with no new dysfunction nor deterioration of heart function. In 17/50 with hypothyroidism on replacement therapy, 7/17 (41%) discontinued therapy and their TSH, FT4 normalised and 4/17 reduced their thyroxin dose. Free thyroxin (FT4) was significantly increased in euthyroid patients. In 14/24 males who were initially on testosterone replacement therapy, 4/14(28.5%) discontinued therapy, whereas 10/24 increased their testosterone levels. In 19/26 females with secondary amenorrhea, 2 had spontaneous ovulation with subsequent normal births and 2 gave birth following in vitro fertilization. In 6/50 with Insulin-dependent Diabetes, insulin dose was reduced. Initially, 14/50 TMp had non- Insulin dependent Diabetes (glucose 0>126 mg/dl, 2h>200mg/dl), 16/50 had Impaired Glucose Tolerance (IGT: glucose 2h>140<200 mg/dl) and 3/50 had Impaired Fasting Glucose (glucose 0>100<126 mg/dl). Following intensive combined chelation, 9/14 (64%), 10/16 (67%) and 3/3 (100%) respectively, normalised their glucose metabolism (p <0.001). An improvement in the glucose AUC was also noted (ANOVA-GENERAL LINEAR MODEL: p<0.002) despite BMI increase (p<0,001). Additionally, insulin secretion increased (SCHOMA: p<0,05 and Friedman/Wilcoxon p<0,004) and insulin sensitivity reduced, (ISIHOMA: p<0,742). These results indicate that in our patient cohort, intensive combination dramatically improved survival and led to reversal of secondary iron overload sequelae.