ABSTRACT

Corresponding Author:
Dr. Alka Yadav,
H. No. 48/11J, Medical Campus,
Rohtak-124001.
E-mail:alkadv9@gmail.com

ABSTRACT

BACKGROUND

Hydroxyurea (HU) is found to be effective in sickle cell anemia and thalassemia intermedia. Its usefulness in thalassemia major is not clearly defined. The aim of the study was to analyze effectiveness of hydroxyurea in children with beta thalassemia major.

PARTICIPANTS

Patients of thalassemia major aged 3 years to 18 years, on regular blood transfusion with proper chelation for at least two years and in spite of that they were not able to maintain their pre-transfusion hemoglobin level of at least 8.0 gm% were selected as cases. Parameters understudy of these patients observed six months prior to the beginning of the study were considered as controls.

Hydroxyurea (the study drug) was given at an average dose of 13.70±2.80mg/kg/d as single oral dose to all cases for one year.

RESULTS

Twenty five children were enrolled for present study. Fourteen (56%) and 23 (92%) patients out of 25 children showed response to HU therapy when change in hemoglobin (Hb) and mean fetal hemoglobin level (HbF) levels were taken as response criteria respectively. Out of those, 7 children (28%) showed more than 10% (good response) rise in mean hemoglobin level while 10 (40%), 6 (24%) and 2 (8%) patients showed moderate (5-10%), mild response (<5%) and no response (0%) respectively to HU. Hydroxyurea significantly increases fetal hemoglobin levels and total hemoglobin after a duration of 3 months and 6 months respectively. There was also a statistically significant increase in the interval between the transfusions from a mean of 19.8 (13-30)±4.038 days to 21.68±4.413 days at 6 months and 25.76 (18-42)±6.629 days at 12 months during the study. Over study period serum ferritin levels decreased though insignificant in all the cases from 3^rd month onwards. No significant side effects were noted at the dose used in study.

CONCLUSIONS

Hydroxyurea can be used for the treatment of transfusion dependent thalassemia patients as an effective adjunct to regular transfusion regimen and cost and side effects can be reduced significantly.

KEYWORDS

Fetal Hemoglobin Augmentation, Hydroxyurea, Pharmacotherapy Thalassemia Major.

INTRODUCTION

Beta thalassemia is the most common single gene disorder in the world. Worldwide prevalence of gene varies between1-18% (Mean 9.5%) while in India its between 1-7% (Mean 3.3%).¹ Nearly 8000 to 10,000 new thalassemics (Homozygous) are born every year in India.² Over the past three decades, regular blood transfusions and iron chelation has dramatically improved the quality of life and has transformed the thalassaemia from a rapidly fatal disease in early childhood to a chronic disease compatible with prolonged life. Today life expectancy varies between 25-55 years, depending on the compliance with medical treatment.

DISCUSSION

We described responses of 25 transfusion-dependent major beta thalassemic patients with the treatment of HU. The effects on total Hb, transfusion requirements, and the level of ferritin were the most significant observation of our study. The mainstay of treatment in major β-thalassemia is regular blood transfusion and the use of iron chelators. Pharmacologic reactivation of γ-globin genes using drugs, for example hydroxyurea holds great promise for the treatment of thalassemia syndromes as well as of sickle cell disease.^9-12

In present study dose of hydroxyurea chosen was 10-20mg/kg/d. Earlier studies on use of hydroxyurea favours this dose range.^13,14 Hoppe C. et al. found prolonged responses as determined by increases in total Hb and decreased transfusion needs were achieved with low doses of HU (3–10mg/kg/day) in thalassemia major patients. However, higher doses were associated with mild reversible hematologic or hepatic toxicity and no further increase in hemoglobin.¹⁵

We observed a significant decrease in blood transfusion requirement beginning in the first three to four months of HU therapy. Similar findings were reported by Bradi et al. and Zamani F et al. who evaluated the long-term efficacy and safety of hydroxyurea in major beta-thalassemic patients and observed substantial and persistent increase in total hemoglobin levels after first three and four months of hydroxyurea therapy respectively.^7,16 Fucharosen S. et al. observed hematologic effects of orally administered HU in 13 patients with beta thalassemia major/HbE. Almost all patients responded to oral dose of HU (10-20mg/kg/d) for 5 months with a slight (10%), but statistically significant increase in hemoglobin levels and an improved balance in α: non-α globin chain ratios.¹⁷ In the present study none of our patients became transfusion independent, though duration between transfusions was significantly increased (Over up to 42 days in one patient). The failure to make any of the patient transfusion free could be due to short span of therapy. Sachdeva A. et al. observed that 25/70 (36%) patients had a complete response as need for transfusion was obviated, 15/70 (21%) patients had a partial response as the interval between transfusions increased to HU therapy (Dose of 15-20mg/kg/day for a period of 4 months to 3 years).¹⁸ Bradai M. et al. reported a marked elevation of total Hb levels with HU that permitted regular transfusions to be stopped in 7 children with transfusion-dependent -thalassemia.¹⁹ The significant decrease of serum ferritin observed in our patients is clinically very important as iron overload is the main hazard to these patients. The serum ferritin decrement is due to decrease of blood transfusion and to a lesser extent due to increased iron utilization by increased Hb production and also suppression of ineffective erythropoiesis.

HU treatment was well-tolerated and it did not cause any significant toxicity except in three patients who developed transient thrombocytopenia which resolved after a short period of HU cessation.

Though, present study was done on a small number of patients within a short time period, our results indicate that hydroxyurea significantly increases fetal hemoglobin levels and total hemoglobin after a duration of 3 months and 6 months respectively. The drug also reduces the number of transfusions and increases the interval between two transfusions significantly. No significant adverse effects to the HU therapy were observed at the dose used, i.e. 13.70±2.28mg/kg/d over 1 year of study period. Further studies will be required to evaluate the long term toxicity and benefits to the patients. Although desirable but genetic profile of patients under present study could not be done due to non-availability of genetic diagnostic facilities in our institute,so analysis of prediction of effectiveness of HU therapy in relation to genotype could not be carried out.

In conclusion we can say from the present study that HU initially increases HbF levels followed by increase in Hb, thus leading to decreased number of transfusions which are to be given at less frequent intervals. Thus from present study we can conclude that HU therapy increases total hemoglobin levels sufficiently to decrease the need for transfusions in patients with thalassemia major. Hydroxyurea can be used for the treatment of transfusion dependent thalassemia patients as an effective adjunct to regular transfusion regimen and cost and side effects can be reduced significantly. Analysis of prediction of effectiveness of HU therapy in relation to genotype could not be carried out, may need further studies for the same.

ACKNOWLEDGEMENT

Mr. Jasbir Singh, lecturer in Department of Pharmacology for his help in dispensing the drug for the patients, all our patients and their guardians and the staff members of thalassemia day care center.

REFERENCES

1.    Lokeshwar MR, Shah N, Kanakia S, et al. Thalassemia. In: Parthasarathy A ed. IAP textbook of Pediatrics. New Delhi; JAYPEE Publication 4th ed. 2009. p.794-815.
2.    Marwah RK, Lal A. Present status of hemoglobinopathies in India. Indian Pediatrics 1994;31:267-71.
3.    Rund D, Rachmilenitz E. Beta-thalassemia. N Eng J Med 2005;353:1135-46.
4.    Thein SL, Wainscoat JS, Sampietro M. Association of thalassemia intermedia with beta globin gene haplotype. Br J Haematol 1987;65:367-371.
5.    Rodgers GP, Dover GJ, Noguchi CT, et al. Haematological responses of patients with sickle cell disease to treatment with hydroxyurea. N Engl J Med 1990;322:1037–1045.
6.    Zeng YT, Huang SZ, Ren ZR, et al. Hydroxyurea therapy in b-thalassaemia intermedia: improvement in haematological parameters due to enhanced b-globin synthesis. Br J Haematol 1995;90:557–563.
7.    Bradai M, Pissard S, Abad MT, et al. Decreased transfusion needs to be associated with hydroxyurea therapy in Algerian patients with thalassemia major or intermedia. Transfusion 2007;47(10):1830-36.
8.    US Pharmacopeial Convention. Ch. 905 Uniformity of dosage units. The National Formulary, 30th rev. 2007. Rockville, MD, p. 378.
9.    Charache S, Terrin ML, Moore RD, et al. Effects 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;332:1317-22.
10.    Zimmerman S, Schultz W, Davis J, et al. Sustained long-term hematological efficacy of hydroxyurea at maximum tolerated dose in children with sickle cell disease. Blood 2004;103:2039-45.
11.    Yavarian M, Karimi M, Bakker E, et al. Response to hydroxyurea treatment in Iranian transfusion-dependent beta-thalassemia patients. Haematologica. 2004;89(10):1172-8.
12.    Dixit A, Chatterjee TC, Mishra P, et al. Hydroxyurea in thalassemia intermedia—a promising therapy. Ann of Hematol 2005;12:441-6.
13.    Ansari SH, Shambi TS, Siddiqui FJ. Efficacy of hydroxyurea in reduction of packed red cell transfusion requirement among children having beta-thalassemia major: Karachi HU Trial. J Pediatrics Hemato Oncol 2007;29(11):729-30.
14.    Kosaryan M, Koorosh VK, Karami H, et al. Effect of hydroxyurea on thalassemia major and thalassemia intermedia in Iranian patients. Pak J Med Sci 2009;25(1):74-78.
15.    Hoppe C, Vichinsky E, Lewis B, et al. Hydroxyurea and sodium phenylbutyrate therapy in thalassemia intermedia. Am J Hematol 1999;62:221–7.
16.    Zamani F, Shakeri R, Eslami SM, et al. Hydroxyurea therapy in 49 patients with major beta-thalassemia. Arch Iranian Med 2009;12(3):295–97.
17.    Suthat F, Nappadol S, Pranee W, et al. Hydroxyurea increases hemoglobin F levels and improves the effectiveness of erythropoiesis in β-thalassemia/hemoglobin E Disease. Blood 1996;87(3):887-92.
18.    Sachdeva A, Khanna K, Verma CP, et al. Hydroxyurea and termination of transfusion therapy in transfusion dependent thalassemics. In: The American Society of Hematology Annual Meeting 2002, Detroit, USA.
19.    Bradai M, Lamraoui F, Skopinski L, et al. Hydroxyurea can eliminate transfusion requirements in children with transfusion dependent beta-thalassemia. Blood 2003;102:1529–30.