Deferasirox effectively decreases iron burden in patients with double heterozygous HbS/β-thalassemia

Abstract

Iron overload is present in several cases of double heterozygous HbS/beta-thalassemia (HbS/beta-thal). Deferasirox is an orally administered iron chelator which is effective on iron overloaded patients with transfusion-dependent anemia. The aim of this study was to investigate the efficacy and safety of deferasirox in HbS/beta-thal patients with iron overload. We evaluated 31 adult patients with HbS/beta-thal (14M/17F; median age 41 years) who had serum ferritin levels >1000 ng/mL and who were sporadically transfused. Total iron burden was monitored by measuring serum ferritin levels before and monthly after starting deferasirox, while liver iron concentration and cardiac iron burden were measured by magnetic resonance imaging (MRI) T2 and T2* parameters at baseline and 12 months after deferasirox treatment. Deferasirox managed to reduce the mean serum ferritin levels after 12 months of treatment from 1989±923 to 1008±776 ng/mL (P<0.001). This reduction was accompanied by a significant improvement on MRI T2* of the liver (from 3.9±3.2 to 5.8±3.1 ms; P<0.01) and by a comparable improvement of biochemical parameters of liver function. Mild nausea and diarrhoea of grade 1/2 were reported in 25% of patients within the first month of treatment, but did not re-occur. These data indicate that deferasirox provided effective control of iron levels (mainly of the liver) in minimally transfused patients with HbS/beta-thal, without significant adverse events, at similar doses to those studied widely for the treatment of patients with thalassemia syndromes.Response to Reviewers: I would like to thank the reviewer for the valuable comments about our paper entitled "Deferasirox effectively decreases iron burden in patients with double heterozygous HbS/beta-thalassemia". Please find below our answers to these comments. All changes have been bolded into the text.Reviewer #1: Comment 1. The manuscript was thoroughly revised and has remarkably improved. However, concerning two of the previous comments were incompletely answered. A more detailed answer will increase the comprehensibility of the corresponding parts of the paper. Certainly, it will be very easy for authors to add the missing information: As stated in the previous comment 5, for liver MRI, it would be helpful for the reader to know how the T2star values correspond to liver iron concentration given as mg/g or micromole/g dry or wet weight since at present the majority of institutions and colleagues are using these values and related cut-offs for the assessment of liver siderosis. Comment 2. (see previous comment 6): In "Methods" it is stated that: "The starting deferasirox dose was 10 or 20 mg/kg/day depending on baseline iron burden..." In "Results", it is written that "patients were treated with deferasirox at 10 and 20mg/kg/day? based on the number of transfusions?")? How was the "baseline iron burden defined" (according to "Results" by the number of transfusions) and what was the cut-off number of blood transfusions to decide for 20mg/kg/d? Answer: We tha...

Deferasirox effectively reduces iron overload in non-transfusion-dependent thalassemia (NTDT) patients: 1-year extension results from the THALASSA study

“…The THALASSA trial provides the largest dataset for iron chelation in NTDT to date, confirming preliminary findings of iron reduction in small studies/case reports [3–8, 10, 11, 15]. The 1-year study established a treatment paradigm for iron-overloaded NTDT patients whereby chelation with deferasirox can be initiated when LIC exceeds 5 mg Fe/g dw and continued with a treatment goal of reducing LIC below a threshold associated with complications [2].…”

“…A wealth of information on iron overload and its management is available from transfusion-dependent beta-thalassemia major. However, given the differences in iron metabolism, pathophysiology, and iron loading rate in patients with NTDT, a direct extrapolation cannot be made, making it important to investigate iron overload in NTDT [3–11]. …”

Deferasirox nephrotoxicity—the knowns and unknowns

“…In 22 published, randomized clinical trials that included a total of 2,119 deferasirox-treated patients, the overall incidence of nephrotoxicity defined as an increase in sCr levels was 22% (n = 471; Figure 2a and Supplementary Table 2 online). 2,9,12,[22][23][24]43,[45][46][47][48][49][50][51][52][53][54][55][56][57][58][59] Similarly, in 16 published clinical practice studies that included a total of 1,373 patients, sCr levels increased in 18% of participants (n = 242; Figure 2b and Supplementary Table 3 online). 37,38,40,60-72 However, in clinical trials and in clinical practice reports, the incidence of nephrotoxicity is higher when defined by a >33% increase in sCr levels over baseline (36% and 28.5%, respectively) than when defined by an increase in sCr levels above the ULN (7.2% and 6.3%, respectively; Figure 2).…”

“…42 This finding is expected because the liver metabolizes and secretes the drug. In published randomized clinical trials 2,9,12,[22][23][24]43,[45][46][47][48][49][50][51][52][53][54][55][56][57][58][59] and clinical practice studies, 37,38,40,60-72 incidence of increased sCr levels has been shown to vary by age (panels a-f) and dose of deferasirox (panels g-l). a,g | Data from randomized controlled trials that defined nephrotoxicity as sCr levels >ULN.…”

“…60 Serum cystatin C levels are a more sensitive indicator of changes in GFR than are sCr levels. Measurement of serum cystatin C levels disclosed 100% (P <0.001) of nephrotoxicity incidence in a clinical trial in 31 patients with double heterozygous sickle-cell β-thalassaemia, 58 whereas in a clinical practice study of 42 patients with β-thalassaemia, cystatin C levels increased in 36% of patients (n = 15; P = 0.001). 61 In 10 children aged >6 years with β-thalassaemia major who were treated with deferasirox, inulin clearance values disclosed a mean reduction in GFR of 19.7 ± 11.3%.…”