The Clinical Significance of the Spectrum of Interactions of the Rare IVS-II-5 G>C (HBB: c.315+5 G>C) Variation with Other ß-Thalassemia Mutations in Southern China.

Background: IVS-II-5 G>C (HBB: c.315+5 G>C) is a rare ß-thalassemia mutation. However, there is no clear evidence regarding the effect of this defect or co-inheritance of other ß-thalassemia mutations on phenotypes. Methods: The clinical phenotypes associated with compound heterozygosity for the IVS-II-5 G>C mutation and other ß-thalassemia mutations, together with the genetic modifiers' potential effect of the genetic modifiers α-thalassemia, were studied in 13 patients. In addition, analyses of red cell indices, hemoglobin component, iron status, and α-globin genes were carried out in 19 heterozygotes. Results: Next-generation sequencing of 24 undiagnosed patients with transfusion-dependent thalassemia (TDT) or non-transfusion-dependent thalassemia (NTDT) identified 13 carriers of the IVS-II-5 G>C mutation. There was a wide spectrum of phenotypic severity in compound heterozygotes and 6 (46.2%) of 13 were transfusion dependent. Analysis of 19 heterozygotes indicated that most were hematologically normal without appreciable microcytosis or hypochromia, and approximately half had normal hemoglobin A2 levels at the same time. Conclusion: Compound heterozygotes for IVS-II-5 G>C and other severe ß-thalassemia mutations are phenotypically severe enough to necessitate appropriate therapy and counselling. Co-inheritance of this nucleotide substitution with other ß-thalassemia mutations may account for a considerable portion of the incidence of undiagnosed patients with NTDT and TDT in Guangxi. Therefore, the IVS-II-5 G>C mutation can pose serious difficulties in screening and counselling.

Thalidomide for Patients with ß-Thalassemia: A Multicenter Experience.

OBJECTIVE: This study focused on the efficacy and safety of thalidomide for patients with ß-thalassemia in a multicenter trial. METHODS: Patients with non-transfusion-dependent thalassemia (NTDT) or transfusion-dependent thalassemia (TDT), who were unable to pursue conventional therapy with transfusion and chelation, were recruited over 3 years in three centers in southern China. We evaluated the efficacy and safety of thalidomide in the short-term (three months) and long-term follow-up (12 and 24 months). Response to thalidomide was defined as follows: Main Responder (MaR) showing an increase in hemoglobin (Hb) level of >2.0 g/dl or free from blood transfusion and Minor Responder (MiR) achieving elevated Hb level of 1.0-2.0 g/dl or ≥50% reduction in blood transfusion frequency. RESULTS: The overall response rate (ORR) was 93.5%, with MaR and MiR rates accounting for 62.9% and 30.6% in short-term follow-up. For patients with NTDT, the Hb level increased from a baseline mean of 6.8±1.1 g/dl to 9.7±1.9 g/dl (P<0.001). Elevated Hb was mainly attributable to increased fetal hemoglobin (HbF) levels. Among patients with TDT, while an increase in the average Hb concentration was observed, there was a significant drop in yearly transfusions from 20.7±7.7 to 5.8±6.8 blood units per year (P<0.001). The response of patients in both categories was sustained even after an average follow up of 14.6±9.6 months (3-37 months). Minimal side-effects were documented throughout, except peripheral neurotoxicity in one patient. Logistic regression analysis identified the ratio of HbF at baseline (P=0.038, OR=1.111, 95% CI: 1.006-1.226) as an independent risk factor for the primary response to thalidomide. CONCLUSION: Thalidomide had significant therapeutic effects on patients with ß-thalassemia with a sustained response. Peripheral neuropathy is one of the most feared complications. While these preliminary results support the potential long-term efficacy of thalidomide as a therapeutic agent for ß-thalassemia, several issues need to be addressed before its application in the clinic.