Minimal doses of hydroxyurea for sickle cell disease

Abstract

The use of hydroxyurea (HU) can improve the clinical course of sickle cell disease. However, several features of HU treatment remain unclear, including the predictability of drug response and determination of adequate doses, considering positive responses and minimal side effects. In order to identify adequate doses of HU for treatment of sickle cell disease, 10 patients, 8 with sickle cell anemia and 2 with Sß thalassemia (8SS, 2Sß), were studied for a period of 6 to 19 months in an open label dose escalation trial (10 to 20 mg kg -1 day -1 ). Hemoglobin (Hb), fetal hemoglobin (Hb F) and mean corpuscular volume (MCV) values and reticulocyte, neutrophil and platelet counts were performed every two weeks during the increase of the HU dose and every 4 weeks when the maximum HU dose was established. Reduction in the number of vasoocclusive episodes was also considered in order to evaluate the efficiency of the treatment. The final Hb and Hb F concentrations, and MCV values were significantly higher than the initial values, while the final reticulocyte and neutrophil counts were significantly lower. There was an improvement in the concentration of Hb (range: 0.7-2.0 g/dl) at 15 mg HU kg -1 day -1 , but this concentration did not increase significantly when the HU dose was raised to 20 mg kg -1 day -1 . The concentration of Hb F increased significantly (range: 1.0-18.1%) when 15 mg HU was used, and continued to increase when the dose was raised to 20 mg kg -1 day -1 . The final MCV values increased 11-28 fl (femtoliters). However, reticulocyte (range: 51-205 x 10 9 /l) and neutrophil counts (range: 9.5-1.3 x 10 9 /l) obtained at this dose were significantly lower than those obtained with 15 mg kg -1 day -1 . All patients reported a decrease in frequency or severity of vasoocclusive episodes. These results suggest that a hydroxyurea dose of 15 mg kg -1 day -1 seems to be adequate for treatment of sickle cell disease in view of the minimal side effects observed and the improvement in laboratory and clinical parameters.

Effect of hydroxyurea on G gamma chain fetal hemoglobin synthesis by sickle-cell disease patients

“…The present results, which are in agreement with other studies (2,3,5), demonstrate that treatment with HU increases HbF levels in patients with SCD. In addition, the predominant effect of HU on G γ synthesis was evident since the G γ/ A γ ratio was significantly higher in the group treated with HU than in the control group.…”

“…On this base, several agents such as 5-azacytidine and hydroxyurea (HU), which are known to stimulate HbF synthesis, have been used in SCD patients to decrease the frequency and severity of pain episodes (2,3).…”

Follow‐up of sickle cell disease patients with priapism treated by hydroxyurea

“…The use of hydroxyurea has been proposed by many authors aiming to prevent priapism attacks and has been successfully tested by Al Ja'ma and Al Dabbous [36]. In our study, the use of hydroxyurea for priapism prevention was successfully used in five SCD patients; however, it is important to point out that the dose that was required to stop priapism was higher than that normally used in our clinic for frequent painful crisis treatment, which is usually lower than 20 mg/kg [37]. It is important to observe that, in two patients, there was a strong relationship between appearance of priapism symptoms and discontinuation of hydroxyurea and vice-versa.…”

“…After the initial treatment of priapism, all five patients developed stuttering priapism. Following our hydroxyurea protocol [37], the initial dose of hydroxyurea was 10 mg/kg/day, given once a day, and was increased by 5 mg/kg/day every 8 weeks until the patient presented no priapism at all. Toxicity was defined by the presence of at least one of the following characteristics: neutrophils < 2 Â 10 9 /L, platelets < 100 Â 10 9 /L, reticulocytes < 50 Â 10 9 /L, a 20% decrease in hemoglobin concentration, a 50% increase in serum creatinine, or a 100% increase in hepatic transaminases (AST and ALT).…”

Reticulocyte parameters and hemoglobin F production in sickle cell disease patients undergoing hydroxyurea therapy

“…The increase in the synthesis of HbF is associated with hypomethylation of the g-globin gene promoter. Although the exact mechanism by which HU increases HbF is not completely understood, it is clear that HU has therapeutic value in sickle cell anemia (3,4). Immature and larger reticulocytes are released from bone marrow during erythroid expansion in response to hemolysis.…”