Efficacy and Safety of Deferasirox Estimated By Serum Ferritin and Labile Plasma Iron Levels in Patients with Aplastic Anemia, Myelodysplastic Syndrome, or Hematologic Malignancy with Transfusional Iron Overload

INTRODUCTION

Patients receiving red blood cell (RBC) transfusions are at risk of iron overload. Humans do not have a physiologic mechanism to excrete excess iron, and total body iron is regulated primarily by the rate of absorption. Transfusion induced Iron overload can cause significant organ damage and is an important cause of morbidity and mortality.

METHODS

This study was an open-label, single-arm, prospective, phase 4, multicenter clinical study to evaluate the efficacy and safety of deferasirox (DFX) in patients with aplastic anemia (AA), myelodysplastic syndrome (MDS), or hematologic malignancy (HM). Eligibility criteria were serum ferritin (SF) levels ≥1000 ng/mL and ongoing transfusion requirements. For evaluation of the iron overload, SF and transferrin saturation (TFST) were measured every 4 weeks, and labile plasma iron (LPI) levels were regularly followed once every 6 months. Patients received DFX at an initial dose of 20 mg/kg/day for up to 1 year.

RESULTS

A total of 109 patients were enrolled. SF levels decreased significantly following treatment (from 2000 to 1650 ng/mL, p=0.003). The median absolute reduction in SF levels was -389 ng/mL (range -5428 to 3788) in AA (p=0.029), -567 ng/mL (range -3040 to 4969) in MDS (p=0.136), and -552 ng/mL (range -2899 to 5451) in HM (p=0.057). Median TFST reduction was -14.9% (range -69.4 to 71.0) in all patients (n = 65, p = 0.064). In the MDS and HM groups, TFST decreased significantly from baseline: -14.9% (range -57.4 to 52.2) in the MDS group (p = 0.040) and -16.3% (range -69.2 to 20.8) in the HM group (p = 0.005), while TFST reduction in the AA group was -7.4% (range -58.3 to 71.0) (p = 0.790). Baseline LPI levels were within normal laboratory ranges in all groups. Mean LPI levels decreased from 0.24 μmol/L at baseline to 0.03 μmol/L at 1 year in all patients (p=0.035). The mean LPI reduction in each group was -0.23±0.41 μmol/L (p=0.220) in AA, -0.26±0.51 μmol/L (p=0.110) in MDS, and -0.19±0.70 μmol/L (p=0.336) in HM. All of the AEs related with DFX were grade 1 or 2, and there were no severe AEs (grade ≥3) reported during the study period. Gastrointestinal disorders were commonly observed among groups (n=32, 29.4%), including diarrhea in 8.3%, nausea in 7.4%, and abdominal discomfort in 5.5% of patients. Overall differences in end organ function, including heart, pancreas, thyroid, and gonad, between baseline and 1-year follow up were not statistically significant. No significant differences in LVEF at 1-year after DFX treatment were seen (p = 0.103). Pancreatic dysfunction measured by FBS (p = 0.480) and C-peptide (p = 0.096) levels did not appear to be affected by iron overload during DFX treatment. The results of thyroid function tests (TFT) were not significantly different between the pre- and post-treatment periods in terms of TSH (p = 0.207), free T3 (p = 0.259), or free T4 (p = 0.654) levels. Gonadal dysfunction was not observed during the DFX treatment.

DISCUSSION

ICT may be an appropriate option for patients with HM or higher risk MDS. In the current study, DFX successfully reduced serum ferritin and LPI levels in HM from baseline to 1 year of treatment. The roles of ICT or DFX during treatment for HM on infection risk and survival benefits need to be elucidated in prospective studies. In conclusion, DFX reduced serum ferritin and LPI levels in patients with transfusional iron overload. Despite the relatively high percentage of gastrointestinal side effects, DFX was tolerable in all patients.