Genetic Modifiers Of Beta-Thalassaemia Associated With Management Without Blood Transfusion: Ten Years Experience

Abstract

Background Long survival with improve quality life in treatment of thalassaemia patients can be procure by blood transfusion and sedulous chelation but, it is cumbrous. Therapeutic manoeuvers designed to stabilize or increase hemoglobin without transfusion and to reduce the blood transfusion. Efforts have been undertaken to find an alternative approach to transfusion in β-thalassaemia. Methods On the basis of our previous studies evaluating the safety & efficacy of Hydroxyurea (HU) in beta thalassemia patients which is an oral Hb-F augmentation agent, at 10-15 mg/kg/day was used on 473 patients for Mean duration of 3 years under the guidelines of Helsinki’s declaration. Response was measured by using transfusion requirement prior to 6 months period of enrollment in the study as control. Patients were finally divided into Complete Responders (CR), partial responders (PR) and non-responders(NR).Patients’ genetic profile was investigated. Chi square test was applied to check association between variables, p-value ≤0.05 considered significant. Results Complete responders were 176, PR were 194 while 103 were NR. Most common genetic mutations observed were IVS1-5 (46%) either homozygous or heterozygous, Fr 8-9 (14.3%), IVS1-1 (11%), Cd 30 (5.5%), Fr 41-42 (5.5%), Del-619 (5%) &Cap+1 (1.9%). Astounding results were found when association of these mutations with response of HU was observed. Response was found to be closely related with gene mutations Cd-30 (61.5 % Responders), IVS1-1 (58 % Responders), Cap+1 (44.4 % Responders), IVS1-5 (33.6 % Responders). Homozygous Xmn-I polymorphism was observed in 21% & heterozygous in 24% of the patients, while 55 % had no Xmn-I polymorphism. Xmn-I polymorphism was found to be significantly associated with Response 67 % (p-value 0.00). Conclusion Hydroxyurea showed promising results in this long term follow up of large cohort of patients. We suggest screening all newly diagnosed thalassaemic children for Genetic characteristic in order to offer Hb-F Augmenting agent as an alternative to blood transfusion. Disclosures: No relevant conflicts of interest to declare.

Evaluation of the combination therapy of hydroxyurea and thalidomide in β-thalassemia

“…Likewise, the presence of the XmnI polymorphism was also significantly associated with a higher response rate. 11 Other studies have also reported the presence of the XmnI polymorphism to be positively associated with the response to HU. 26 , 27 In the present study, to our surprise, the combination of HU and thalidomide success was not associated with any particular genetic mutation or the presence of the XmnI polymorphism.…”

“… 10 Since then, we have also published a series of papers describing the genetics, metabolomics, and proteomics associated with HU use in patients with thalassemia. 11 , 12 , 13 In our 15 years of experience with HU, 36% of our patients were complete responders and are entering the third decade of their lives with improved life quality as they maintain their Hb around or above 7 to 8 g/dL; for some, their phenotype has transformed from thalassemia major to intermedia. However, 20% demonstrated a partial response and 43.75% demonstrated no response to HU.…”

Unraveling Impact of Hemoglobin F and A2 Levels: Correlation With Disease Severity and Treatment Response in Transfusion-Dependent Beta-Thalassemia

“…Ansari et al in their prior research, explored the influence of HU and various mutations on response categories in individuals with TDT, revealing a positive correlation between genotypes and HU response [28]. Surprisingly, in their recent experiment of the combination therapy of HU and thalidomide for TDT patients, the success of this combination response was not linked to any specific genetic mutation [23].…”

Genetic Haemoglobin Disorders in Pakistan

“…Fortunately, the transmission of HIV is not a significant problem [27]. Hydroxyurea is also being successfully used to reduce the transfusion dependency in thalassaemia intermedia and selected patients of thalassaemia major [28,29].…”