Hydroxyurea in the treatment of major �-thalassemia and importance of genetic screening

Abstract

Efforts have been undertaken to find an alternative approach to packed red cell transfusion (PRCT) in major beta-thalassemia. Augmentation of fetal hemoglobin (HbF) by hydroxyurea (HU) has been reported to be less effective in this condition as compared to sickle cell anemia due to molecular heterogeneity of the former disease. HU efficacy and its relation to Xmn1 polymorphism and IVSII-1 mutation was evaluated in major beta-thalassemics. Forty-five patients, M/F ratio 0.8, aged 6-33 years, received oral HU, 20 mg/kg per day, 4 days per week and daily1 mg folic acid. Thirty-six patients were PRCT dependent (group A) and nine independent (group B). The aim was to stabilize or increase pre-PRCT Hb over 10.0+/-0.5 g/dl and to reduce the need or cease the PRCT in group A and to increase Hb level and curb the ineffective erythropoesis, e.g., splenomegaly, facial bone deformity, in group B. HU was administered for at least 6 months (mean: 9 months) and discontinued in case of response failure. Screening for Xmn1 polymorphism and IVSII-1 mutation was carried out in most patients. In group A, 25 patients have become PRCT independent for a period of 2.5-7.3 years (mean: 4 years). The mean Hb, pre-HU 10.0 and post-HU 10.7 g/dl (range: 8.8-13.7 g/dl), mean serum ferritin pre- and post-HU was1877 and 525 ng/ml. The PRCT requirement was reduced in one patient, and ten patients did not respond. In group B HU has been given over 3.3 years (range: 2.8-4.8 years), Hb increased from 9.3 to 10.4/dl, and there was no tangible progression of ineffective erythropoesis. Responders in both groups expressed more comfort with this regimen. Xmn1 and IVSII-1 (homo- and/or heterozygosis) are relevant markers in most responding patients. Molecular determination of genetic markers in early childhood will help to identify candidates for pharmacological HbF switching by HU.

Hydroxyurea Treatment in Transfusion-Dependent β-Thalassemia Patients

“…The rest of the patients either did not respond or showed a poor response. In other words, about two-thirds of our patients were more or less responsive to HU, which is similar to most previous studies (15, 17, 18, 20, 22, 23, 25, 26). Although the definition of response varies in different studies, we showed (like many other investigators) that HU may bring about a state of transfusion independence in those known as responders.…”

“…The therapeutic response was obvious after a mean of 65 days of the drug consumption. Alebouyeh (17) found similar response, and his patients exhibited a rise in post-HU treatment Hb, as well as a decrease in serum ferritin. Another study conducted by Italia (22) showed a very good responsiveness in thalassemia intermedia patients, (74% good response).…”

“…We administered HU with a mean dose of about 10 mg/kg/day, similar to Karimi’s, Yavarian’s and Zamani’s studies (15, 25, 26), but much lower than some other investigators (17-20, 22, 29). We concluded that although increasing the dose of HU was positively correlated with fewer transfusion needs (r = 0.2, P = 0.03), it had no impact on the therapeutic response.…”

“…However, the experiences regarding the efficacy of HU in patients with β-thalassemia major are limited with controversial responses (17-25). …”

A validated cellular biobank for β-thalassemia

“…HU was chosen among the different available HbF inducers, since (a) it is already used in experimental therapy of patients affected by β-thalassemia and sickle-cell anemia and (b) it is the only drug approved by US Food and Drug Administration for Sickle-cell disease (SCD) patients [16, 17]. …”