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Ferrata Storti Foundation
Haematologica 2021 Volume 106(9):2458-2468
Effect of HBB genotype on survival in a cohort of transfusion-dependent thalassemia patients in Cyprus
Petros Kountouris,1,2 Kyriaki Michailidou,1,2 Soteroula Christou,3
Michael Hadjigavriel,4 Maria Sitarou,5 Anita Kolnagou,6 Marina Kleanthous1,2 and Paul Telfer7
1The Cyprus Institute of Neurology and Genetics, Nicosia, Cyprus; 2Cyprus School of Molecular Medicine, Nicosia, Cyprus; 3Thalassemia Center, Archbishop Makarios Hospital, Nicosia, Cyprus; 4Thalassemia Center, Limassol General Hospital, Limassol, Cyprus; 5Thalassemia Center, Larnaca General Hospital, Larnaca, Cyprus; 6Thalassemia Center, Paphos General Hospital, Paphos, Cyprus and 7Center for Genomics and Child Health, Blizard Institute, Queen Mary University of London, London, UK
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 centers 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 proportion- al-hazards regression. Of the 537 subjects who were followed for a total of 20,963 person-years, 80.4% (95% confidence interval [95% CI]: 76.4- 84.7) 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 associ- ated 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 geno- type was confirmed in a second model, which included treatment effects. Patients with a milder genotype initiated transfusion significant- ly later and had reduced blood requirements compared to those with moderate or severe genotypes, although pre-transfusion hemoglobin lev- els did not differ between genotypes. Our results suggest that early treat- ment decisions to delay transfusion and different long-term treatment strategies in individuals with milder genotypes have led to adverse long- term effects of under-treated thalassemia and worse survival. We pro- pose that HBB genotype determination and use of this information to aid in decision-making can improve long-term outcomes of thalassemia patients.
Introduction
Standard care of transfusion-dependent thalassemia (TDT) has improved dramati- cally over the past five decades with the introduction of regular transfusion, a variety of iron-chelating drugs, improved evaluation of transfusion iron overload with mag- netic resonance imaging modalities, and the development of specialist centers and regional networks.1-7 There has been a consensus on standard care disseminated in national and international guidelines, which are periodically updated,9-10 resulting in progressive improvement in survival in successive birth cohorts.2,5-11
One aspect of care that is not standardized concerns the decision to start regular transfusion. Individuals at the most severe end of the phenotypic spectrum require regular transfusion before the age of 2 years for survival. At the other end of the spec- trum are non-TDT patients who do not require regular transfusion to survive, are less anemic, and have less bone marrow expansion. Clinicians have traditionally avoided
Red Cell Biology & its Disorders
Correspondence:
PETROS KOUNTOURIS
petrosk@cing.ac.cy
Received: May 25, 2020. Accepted: July 21, 2020. Pre-published: July 30, 2020.
https://doi.org/10.3324/haematol.2020.260224 ©2021 Ferrata Storti Foundation
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