Mehran Karimi MD, Hematology Research Center, Shiraz University of Medical Sciences, Shiraz, Iran.

Introduction

Thalassaemia is the most common single gene disorder worldwide. Asian and Mediterranean regions such as Iran have a higher prevalence of patients with thalassaemia. Hydroxyurea (HU) is an antimetabolite that also promotes fetal hemoglobin (HbF). It is available for oral use as a capsule.

It is also known as hydroxycarbamide and marked as Hydrea® and Droxia®. HU is a virtually tasteless, white crystalline powder with a chemical formula of CH4N2O2. (Figure 1) (1) HU is approved by FDA for treatment of patients with certain cancers such as chronic myelocytic leukemia (1). It is sometimes used to treat psoriasis and is also used as an anti HIV regimen (2,3).

Frequent reports on the successful use of HU in patients with sickle cell disease have been received, and also (4) in patients with β-thalassaemia major (TM), who have presented a reduction in blood transfusion dependency. However, there is some controversy regarding the effectiveness of HU in patients with TM. The suggested mechanism of neutralizing the excess α- chain through the production of γ chains resulted in partial correction of ineffective erythropoiesis. Due to the lesser α/β globin imbalance in β-thalassaemia intermedia (TI), compared with TM, better clinical responses are expected in patients with TI (5). Clinical benefits and hematological improvements have been reported in patients with TI in previous studies (6-7).

Blood transfusion dependency at regular intervals and iron overload are the main complications in b- thalassaemia major. As a result, reducing transfusions is valuable in increasing safety and quality of life in TM patients. Studies on the efficacy of HU in TM showed a modest increase in Hb levels that cause reduction in blood transfusion dependency, or even eliminate the need for transfusion. One study in 2004 showed a good response to HU in transfusion-dependent, b-thalassaemia patients in Iran, in whom the Hb level was kept above 9.5 g/dL without transfusion (8). Table 1 shows the results of two new studies regarding the efficacy of HU in beta TM patients. (6,9)

Some studies showed polymorphism for gG XmnI (gG − 158 C > T), homozygous for b-globin mutations [IVS-II 1 (G-A) or IVS-I 5 (G > C)], and indicated that a-thalassaemia deletions have a strong influence on the clinical response to HU therapy (6,8).

B-THALASSAEMIA INTERMEDIA (TI)

TI is a clinical definition applied to patients whose clinical phenotype is milder than that of thalassaemia major. The clinical course of TI is characterized by several complications that can be prevented by accurate follow-up. Despite chronic anemia, individuals with TI do not require transfusion, except in association with intercurrent illness (7). Clinical response to HU is expected to be greater in TI because the a/b globin imbalance is lesser. Many studies demonstrated this hypothesis. Although many of these studies included only a small number of patients, we reported the clinical significance responses of HU in a larger group of TI patients from Iran (7). In this report, we divided 163 TI patients in two groups according to blood transfusion dependency. Group I consisted of 120 TI patients who received regular blood transfusion, and group II consisted of 43 TI patients with long-interval blood transfusions or without any history of blood transfusions. All patients were treated with HU 8–12 mg/kg/d orally once a day. 149/163 (91.4%) showed response to HU. The mean Hb level in groups I and II during study was 9.5 and 9.6 g/dL, respectively. HU also associated with a marked increased in MCV and MCH. After HU treatment, 97% of patients described an increase in exercise tolerance and sense of well-being compared to before treatment. We observed no significant facial changes after therapy, indicating disappearance of these changes. Spleen size in none-splenectomized patients during treatment with HU showed no change in size in 83% of patients. Table 2 shows the results of some other studies in TI (10-12). In addition, we showed that HU therapy can decrease complications of cardiac functions and reduce pulmonary hypertension during HU therapy in TI patients (13).

In a recent study, we evaluate the adverse effects of low-dose HU (8–12 mg/kg/d) in TI patients who had been treated with HU for a period of 10 years. Most recorded adverse effects were dermatologic, neurologic, and gastrointestinal, and none of them cause to discontinuation of therapy. There were no reports of hematologic toxicity, bone marrow suppression, or any secondary malignancies during HU treatment.( 14) These results showed that low-dose HU therapy in thalassaemia may be well tolerated without serious side effects. Nevertheless, the question about the safety of HU treatment in thalassaemia patients should not be considered closed and further studies regarding the long-term adverse effects of HU should be undertaken.

CONCLUSION

The patients with TI have some complications such as organomegaly, osteoporosis, iron deposition and extramedullary hematopoiesis which decrease the quality of life in these patients. HU has good effects on increasing Hb levels in TI patients, thus freeing some patients from the need for transfusion and decreasing complications such as osteoporosis and extramedullary hematopoiesis, as well as skeletal deformities and splenomegaly, and increasing energy state. Some studies also showed benefits from using HU in TM patients. So it could be a useful alternative to blood transfusion for some patients because of the oral use, inexpensive cost, and the positive clinical and hematological responses.

References:

  1. Katzung B, Masters S, Trevor A. Basic and Clinical Pharmacology, 11th Edition. 2009.
  2. Kumar B, Saraswat A, Kaur I. Rediscovering hydroxyurea: its role in recalcitrant psoriasis. Int J Dermatol. 2001;40(8):530–534.
  3. Biron F, Ponceeau B, Bouhour D, Boibieux A, Verrier B, Peyramond D. Long-term safety and antiretroviralactivity of hydroxyurea and didanosine in HIV-infected patients. J Acquir Immune Defic Syndr. 2000;25(4):329–336.
  4. Charache S, Terrin ML, Moore RD, et al. Effect of hydroxyurea on the frequency of painful crises in sickle cell anemia. Investigators of the multicenter study of hydroxyurea in sickle cell anemia. N Engl J Med. 1995;332(20):1317–1322.
  5. Karimi M. Hydroxyurea in the management of thalassemia intermedia. Hemoglobin. 2009;33 Suppl 1:S177-82.
  6. Bradai M, Pissard S, Abad MT, Dechartres A, Ribeil JA, Landais P, et al. Decreased transfusion needs associated with hydroxyurea therapy in Algerian patients with thalassemia major or intermedia. Transfusion. 2007 Oct;47(10):1830-6.
  7. Karimi M, Darzi H, Yavarian M. Hematologic and clinical responses of thalassemia intermedia patients to hydroxyurea during 6 years of therapy in Iran. J Pediatr Hematol Oncol. 2005 Jul;27(7):380-5.
  8. Yavarian M, Karimi M, Bakker E, Harteveld CL, Giordano PC. Response to hydroxyurea treatment in Iranian transfusion-dependent beta-thalassemia patients. Haematologica. 2004;89(10):1172–1178.
  9. Koren A, Levin C, Dgany O, Kransnov T, Elhasid R, Zalman L, et al. Response to hydroxyurea therapy in beta-thalassemia. Am J Hematol. 2008; 83(5):366-70.
  10. Dixit A, Chatterjee TC, Mishra P, Choudhry DR, Mahapatra M, Tyagi S, et al. Hydroxyurea in thalassemia intermedia--a promising therapy. Ann Hematol. 2005;84(7):441–6.
  11. Mancuso A, Maggio A, Renda D, Di Marzo R, Rigano P. Treatment with hydroxycarbamide for intermedia thalassaemia: decrease of efficacy in some patients during long-term follow up. Br J Haematol. 2006;133(1):105–6.
  12. Gamberini MR, Fortini M, De Sanctis V. Healing of leg ulcers with hydroxyurea in thalassaemia intermedia patients with associated endocrine complications. Pediatr Endocrinol Rev. 2004;Suppl 2:319–22.
  13. Karimi M, Borzouee M, Mehrabani A, Cohan N. Echocardiographic finding in beta-thalassemia intermedia and major: absence of pulmonary hypertension following hydroxyurea treatment in beta-thalassemia intermedia. Eur J Haematol. 2009;82(3):213–218.
  14. Karimi M, Cohan N, Moosavizadeh K, Falahi MJ, Haghpanah S. Adverse effects of hydroxyurea in beta-thalassemia intermedia patients: 10 years' experience. Pediatr Hematol Oncol. 2010 Apr;27(3):205-11.

Table 1: Results of two newly studies in the efficacy of HU in β-thalassemia major patients.

References No of patients HU dose (mg/kg/d) Length of therapy Results
Bradi et al. 45 16.3±2.3 Raised to 17.4±2.4 1 year 20(44.5%) good response with ↑1.5 gr/dl in Hb level
Korean et al. 11 10.9±3 46±25 months 9 good response with Hb level of mean 8.2±0.7 gr/dl and transfusion free

Table 2: Some studies about the efficacy of HU treatment in β-thalassemia intermedia.

References No of patients HU dose Length of therapy Results
Dixit et al. 37 10-20 (mg/kg/d) 4-36 months 45.9% transfusion free or ↑Hb>2gr/dl 24.3%↓transfusion to 50% or ↑Hb1-2gr/dl
Mancuso et al. 18 splenectomozed untransfused 5-30 (mg/kg/d) 1 year Mean Hb ↑ 1.5 gr/dl
Gamberini et al. 6 1000 (mg/d) 3 months ↓ the size of extra medullarly hematopoiesis mass and cured leg ulcers


Figure 1: Chemical structure of HU

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