Phlebotomy and Hydroxyurea for Non-Transfusion Dependent Iron Overload in Beta-Thalassemia Intermedia

Background: Patients with beta-thalassemia intermedia are at increased risk of developing clinically relevant iron overload independent of blood transfusions, which can result in serious sequelae, including liver, myocardial and endocrine dysfunction. This is thought to be modulated by downregulation of hepcidin and upregulation of ferroportin¹. Standard of care in these patients has essentially consisted of iron-chelating agents such as deferasirox, presumably based on the hypothesis that phlebotomy would worsen clinical anemia and potentially exacerbate further ineffective erythropoeisis². We present the cases of two patients with non-transfusion dependent iron overload secondary to beta-thalassemia intermedia, who were treated with serial phlebotomies as well as hydroxyurea.

Case #1: Patient A was heterozygous for the Gln39X beta zero thalassemic allele as well as heterozygous for the H63D HFE-1 allele, and presented with a serum ferritin of 1928 ng/ml. T2* MRI of liver and myocardium demonstrated mild iron deposition in the liver and none in the heart. During a period of 18 months Patient A received serial phlebotomies and hydroxyurea 500 mg daily with decrease in serum ferritin to 770 ng/ml with no change in her baseline Hb and an increase in Hb F from 7% to 15%. Repeat T2*MRI of the liver and myocardium demonstrated no clinically significant iron deposition. Patient A continues to be phlebotomized every one to two months.

Case #2: Patient B was heterozygous for the Gln39X beta zero allele with no mutant HFE-1 alleles, and presented with a serum ferritin of 1230 ng/ml. T2* MRI of the liver and myocardium demonstrated iron deposition in the liver and none in the heart. Over a period of twelve months patient B received serial phlebotomies and hydroxyurea 500 mg daily with decrease in his serum ferritin to 450 ng/mL, with no change in baseline Hb and no increase in Hb F. Repeat T2* MRI demonstrated no cardiac iron overload and slight improvement in the liver T2* relaxation time. Patient B continues to be phlebotomized every one to two months.

Discussion: We presented two cases of non-transfusion dependent iron overload secondary to beta thalassemia intermedia managed with the combination of phlebotomy and low dose hydroxyurea, which resulted in clinically significant decrease in serum ferritin. In both patients the decrease in serum ferritin averaged ~65 ng/ml/month. As a reference, the higher dose regimen of deferasirox 10 mg/kg/d has a reported average decrease in serum ferritin of around 222 ng/mL/year, corresponding to an estimated 18.5 ng/mL/month². There was no change in either patient’s Hb/Hct or markers of ineffective erythropoiesis such as LDH, indirect bilirubin and reticulocyte count. This could be due to a somewhat protective effect from hydroxyurea, which may decrease unbound alpha-globin chains, thereby permitting phlebotomy while maintaining adequate counts.

Conclusion: These two cases suggest that in some non-transfusion dependent patients, the combination of phlebotomy and hydroxyurea may be an appropriate first-line treatment of iron overload due to beta-thalassemia. It appears to potentially offer enhanced efficacy with presumably less toxicity than standard iron-chelating agents in selected patients. Further investigation is needed to determine the specific population that would benefit most from this combination. The optimal treatment modality/combination in those patients has yet to be determined. Additional studies about treatment effect on iron-regulatory pathways are warranted.

References:

(1) Gardenghi S, et al. Ineffective erythropoiesis in beta-thalassemia is characterized by increased iron absorption mediated by down-regulation of hepcidin and up-regulation of ferroportin. Blood 2007: 109(11):5027-5035.

(2) Taher AT, et al. Deferasirox reduces iron overload significantly in nontransfusion-dependent thalassemia: 1-year results from a prospective, randomized, double-blind, placebo-controlled study. Blood 2012; 120(5): 970-977.