Optimizing the Dose of Hydroxyurea Therapy for Patients with β-Thalassemia Intermedia (Hb E-β-thalassemia): A Single Center Study from Eastern India

Abstract

Over the past 20 years, hydroxyurea (HU) has emerged as an important therapeutic agent to augment Hb F and thus total hemoglobin (Hb) in Hb E [β26(B8)Glu→Lys; HBB: c.79G > A]-β-thalassemia (Hb E-β-thal), albeit used in varying doses with little consensus on its optimal dose. We report the interim analysis findings of a broader study to assess the impact of Comprehensive Thalassemia Care, of which the present report was a part. Sixty-one Hb E-β-thal patients who were transfusion independent or requiring occasional transfusions [β-thal intermedia (β-TI)] were randomized to one of two groups; A (n = 32) and B (n = 29) to receive 10 and 20 mg/kg/day HU, respectively. The primary objective of the study was to assess the differences in responses to different doses of HU. Secondary end points were to see the tolerability and safety of HU in different doses. Good response (GR) was defined as a rise of Hb by > 1.0 g/dL; intermediate response (IR) as a rise in Hb by 0.6-1.0 g/dL anytime during the study period. No response (NR): rise in Hb by < 0.5 g/dL in 12 weeks or drop in Hb level from the previous value. Over a follow-up period of 24 weeks, we had 18 (56.2%) GRs, nine (28.2%) IRs and five (15.6%) NRs, while the number of GRs, IRs and NRs in group B were five (17.2%) 12 (41.4%) and 12 (41.4%), respectively. Adverse effects were more common in group B, making this dose (20 mg/kg/day) of HU more myelo-suppressive than Hb F inducing.

Challenges in chronic transfusion for patients with thalassemia

“…22,25 On the contrary, splenectomy increases the risk of infections and a number of serious long-term complications such as thromboembolism, pulmonary hypertension, and iron-induced endocrinopathies. 25 Other avenues to improve anemia include hydroxyurea, which produces an ∼1 g/dL rise in total Hb in 50% of patients, [26][27][28] however, the response in HbE β thalassemia is variable and insufficient to eliminate the need for transfusions. 18 Luspatercept is an approved therapy to reduce the transfusion requirements in patients with TDT including HbE β thalassemia.…”

Hydroxyurea for reducing blood transfusion in non-transfusion dependent beta thalassaemias

“…After title and abstract screening, we retrieved the full-text of 53 records. Among them were six randomised controlled trials (seven records), but only one trial could be included in this review (Bohara 2014) (Figure 1).…”

“…We also attempted to establish whether the primary study used an intention-to-treat analysis, such as the participants were analysed in the groups to which they were randomised. We have contacted the trial investigator (Bohara 2014) for more information on the number of participants in each group at each time point. We have tried twice and have to date not received a response.…”

“…We did not find any randomised controlled trials comparing hydroxyurea with a placebo or standard care. The only included trial was a randomised controlled trial comparing x10 mg/kg/day with 20 mg/kg/day of hydroxyurea at a single centre in India (Bohara 2014). Treatment was stopped if participants developed adverse effects or if they failed to respond to the allocated treatment, but they remained in the trial until trial completion at 24 weeks.…”

“…The Bohara trial generated a random sequence by using a random number table (Bohara 2014). We judged this trial to have a low risk of bias for this criterion.…”