Effect of HBB genotype on survival in a cohort of transfusion-dependent thalassemia patients in Cyprus

Abstract

Initiation of regular transfusion in transfusion-dependent thalassemia (TDT) is based on the assessment of clinical phenotype. Pathogenic HBB variants causing β-thalassemia are important determinants of phenotype and could be used to aid decision making. We investigated the association of HBB genotype with survival in a cohort study in the four thalassemia centres in Cyprus. HBB genotype was classified as severe (β0/β0 or β+/β0), moderate (β+/β+), or mild (β0/β++ or β+/β++). Risk factors for mortality were evaluated using multivariate Cox proportional-hazards regression. 537 subjects were followed for a total of 20,963 person years. 80.4% (95% CI 76.4-84.7) of individuals survived to 50 years of age with increasing rates of liver, infection and malignancy-related deaths observed during recent follow-up. We evaluated non-modifiable risk factors and found worse outcomes associated with male sex (Hazard ratio 1.9, 95% CI 1.1-3.0, p=0.01) and milder genotype (Hazard ratio 1.6, 95% CI 1.1-2.3, p=0.02). The effect of genotype was confirmed in a second model, which included treatment effects. Patients with a milder genotype initiated transfusion significantly later and had reduced blood requirements compared to those with moderate or severe genotypes, although pre-transfusion hemoglobin levels did not differ between genotypes. Our results suggest that early treatment decisions to delay transfusion and different long-term treatment strategies in milder genotypes have led to adverse long-term effects of under-treated thalassemia and worse survival. We propose that HBB genotype determination and use of this information to aid in decision making can improve long-term outcomes of thalassaemia patients.

Figure 1.

Kaplan-Meier curves for survival from birth. (A) Survival of the overall cohort, and categorized by (B) sex, (C) HBB genotype, and (D) year of birth.

Figure 2.

Kaplan- Meier curves for survival during follow-up 2000 to 2018 showing the effects of risk factors with statistically significant effects in univariate analysis. (A) Survival of the overall cohort, and categorized by (B) sex, (C) HBB genotype, (D) year of birth, (E) splenectomy during childhood, and (F) type of chelation therapy. DFO: deferoxamine; DFP: deferiprone; DFX: deferasirox.

Figure 3.

Boxplots illustrating the distribution of transfusion data among groups with HBB genotypes of different severity. Statistically significant associations, determined with the Wilcoxon rank-sum non-parametric test, are shown.