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.

The thalassemias are the most common single gene disorder known to mankind. The phenotype of thalassemia depends upon the underlying gene defect in addition to many modulating factors. As the literature describes, inheritance of a β(0) genotype in the homozygous state results in the development of β-thalassemia (β-thal) major with key clinical features being transfusion dependency, physical abnormalities and iron overload. IVS-1-5 (G>C) is the severe β(+) allele whose homozygosity results in severe β-thal. We describe a patient who was asymptomatic until screened and was found to have mild anemia. Detailed analysis revealed the presence of the IVS-I-5 mutation in a homozygous state that was unlikely to present as a transfusion independent state. The study of such cases emphasizes the complexity of genetic interactions that underlie the phenotype of β-thal and highlight the importance of the regulation of Hb F production in β-thal syndromes. Simultaneous inheritance of some loci that modulate Hb F levels probably causes high levels of total hemoglobin (Hb) and to be transfusion independent.