Hydroxyurea in thalassemia intermedia—a promising therapy

Abstract

Pharmacological agents such as hydroxyurea (HU) have been known to cause induction of fetal hemoglobin and possibly may alleviate the symptoms in thalassemia intermedia patients. Thirty-seven patients with beta-thalassemia intermedia were enrolled to assess response to HU therapy. Major response was defined as transfusion independence or hemoglobin rise of more than 20 g/l and minor response as rise in hemoglobin of 10-20 g/l or reduction in transfusion frequency by 50%. The median age was 10 years (range: 4-50 years) and median follow-up was 12 months (range: 4-36 months). Twenty-six patients (70.2%) showed response to HU therapy. Seventeen patients (45.9%) were major responders, and nine patients (24.3%) showed minor response. There was no correlation of response with beta-thalassemia mutation or XmnI polymorphism; however, the presence of alpha(3.7) deletion was associated with major response in three patients. Mean fetal hemoglobin (HbF) levels rose on HU therapy. Older age, low baseline F cell percent, and low baseline HbF levels (below 10%) were predictors of poor response. Response was evident within 1 month of starting HU therapy in the majority of responders. Thus, a short trial of HU therapy can predict durable response.

Resveratrol: Antioxidant activity and induction of fetal hemoglobin in erythroid cells from normal donors and β-thalassemia patients

“…HU is the most used HbF inducer in both moderate to severe forms of β-thalassaemia. More than 500 patients with β-thalassemia have been treated with HU worldwide and about 50% of them responded to the treatment, exhibiting a clear amelioration of the clinical parameters (22,29,(38)(39)(40). Other inducers of HbF synthesis, such as butyrate, 5-azacytidine and more recently, decitabine, have also been employed, however, these HbF inducers have shown only a modest response in the majority of β-thalassemia patients as well as some degree of toxicity (22).…”

“…HU and butyrate analogues are the most studied compound (22). For example, Dixit et al (38) reported the results of treatment with HU of 37 patients with β-thalassemia intermedia. After a median follow-up of 12 months, 26 patients (70.2%) responded: 45.9% were major responders (transfusion independence or >20 g/l increase in Hb) and 24.3% were minor responders (a 50% reduction in transfusion frequency or a 10-20 g/l increase in Hb) (22,29).…”

“…the expression of the γ-globin genes has been suggested as a very promising therapeutic approach, including the reduction of the patients requirement for blood transfusions (29,(38)(39)(40).…”

Hydroxyurea responsiveness in -thalassemic patients is determined by the stress response adaptation of erythroid progenitors and their differentiation propensity

“…7 Hydroxyurea (HU) is FDA approved for treatment of SCD patients and it is also widely used for β-thalassemia. [8][9][10][11][12] How HU induces HbF production is poorly understood. Mechanisms proposed for the induction of HbF by HU include rapid erythroid regeneration, increased erythropoietin (EPO) production, apoptosis, nitric oxide (NO) production, 13 increased guanylate cyclase activity 13 and activation of the p38 MAPK pathway.…”

Fetal hemoglobin chemical inducers for treatment of hemoglobinopathies

“…These findings have been confirmed in large studies carried out on Iranian, Indian, and Algerian β-thalassemic patients, showing good responses in a significant proportion (i.e., >50%) of β-thalassemic patients, without any major toxicity related to HU administration [194][195][196][197][198][199][200].…”