Page 172 - 2021_09-Haematologica-web

P. Kountouris et al.
Table 1. Pathogenic HBB variations in the cohort of thalassemia-dependent thalassemia patients.
Allele 1
IVS I-110 G>A IVS I-110 G>A IVS I-1 G>A
IVS I-1 G>A
IVS I-1 G>A
IVS I-110 G>A IVS I-110 G>A IVS I-110 G>A IVS II-745 C>G IVS I-110 G>A IVS I-110 G>A IVS I-110 G>A IVS II-745 C>G IVS I-110 G>A IVS II-745 C>G IVS I-110 G>A IVS I-110 G>A IVS I-1 G>A
IVS I-6 T>C
CD 39 CAG>TAG
Total
Allele 2
IVS I-1 G>A
CD 39 CAG>TAG
IVS II-745 C>G
IVS I-1 G>A
CD44-C
IVS II-1 G>A CD44-C
CD5-CT
CD 39 CAG>TAG
IVS I-110 G>A
IVS II-745 C>G
IVS II-848 C>A
IVS II-745 C>G
IVS I-6 T>C
IVS I-6 T>C
Hb Knossos
-87 C>G
IVS I-6 T>C
CD 39 CAG>TAG
Hb Lepore Boston-Washington
Allele phenotypes
β+/ β0 β+/ β0 β0/ β+ β0/ β0 β0 β0 β+/β0 β+/ β0 β+/ β0 β+/ β0 β+/ β+ β+/β+ β+/ β+ β+/β+ β+/ β++ β+/ β++ β+/ β++ β+/ β++ β0/ β++ β++/ β0 β0/ β++
Genotype category
Severe Severe Severe Severe Severe Severe Severe Severe Severe Moderate Moderate Moderate Moderate Mild
Mild Mild Mild Mild Mild Mild
Number (%)
48 (9.4) 23 (4.5) 5 (1.0) 2 (0.4) 2 (0.4) 2 (0.4) 1 (0.2) 1 (0.2) 1 (0.2) 306 (59.8) 29 (5.7) 1 (0.2) 1 (0.2) 81 (15.8) 4 (0.8) 1 (0.2) 1 (0.2) 1 (0.2) 1 (0.2) 1 (0.2) 512
20,963. The majority of the patients were born between 1960 and 1979 (453 patients, 84.4%). Splenectomy status was significantly associated with clinic (P=0.02), with 21.8% of patients splenectomized during childhood in Nicosia, compared to 36.7%, 29.3% and 34.9% in, respec- tively, Larnaca, Limassol and Paphos, while there was no significant difference in choice of iron chelation therapy between clinics. Thirty-eight (7.1%) patients had evidence of hepatitis C infection (HCV antibody positive), of whom 9 (1.7%) were HCV RNA positive at the end of the study and 29 (7.3%) were HCV RNA negative. Three patients (0.6%) were positive for hepatitis B surface antigen.
A summary of the genotypes of the study patients is shown in Table 1. HBB genotype data were not available for 24 patients, who had died before genotyping was intro- duced in Cyprus. An additional patient was removed from the genotype analysis because thalassemia was caused by α-locus duplications co-inherited with β-thalassemia trait.23 Homozygous IVS I-110 G>A (β+) was the commonest genotype (59.8%) and there was a large proportion of patients with a combination of IVS I-110 G>A (β+) and IVS I-6 T>C (β++). There was a significant trend on performing splenectomy in childhood with decreasing severity of geno- type, specifically 19% in the severe genotype group, 27.8% in the moderate genotype group, and 38.1% in the mild genotype group (P=0.02). There was also a significant trend across the genotypic spectrum in chelation therapy, with increasing proportions of patients with a milder phenotype remaining on deferoxamine rather than switching to oral chelation, specifically 14.3% with severe genotype, 17.5% with moderate genotype; and 28.9% with mild genotype (P=0.02). Genotyping for the α-globin locus and the XmnI C/T polymorphism was almost complete for the study population (92.4% and 89.4%, respectively). The XmnI T allele, which is associated with increased Hb F production,
has a low prevalence and, thus, limited influence on clinical outcomes in the study population. In contrast, α+-tha- lassemia trait is present in about 19% of the population, whereas the prevalence of α0-thalassemia trait is lower (1.6%).24
Mortality rates and causes of death
By September 2018, 94 (17.5%) patients had died. Crude comparisons of proportions are shown in Table 2, indicat- ing that survival was significantly associated with sex, splenectomy in childhood, and receiving oral chelation compared to those chelated primarily with deferoxamine. However, 44 of 70 (57.1%) of the patients who received deferoxamine chelation died before the year 2000, and these patients would not have had the opportunity to receive prolonged oral chelation. Those with more severe HBB genotypes were also more likely to survive (P=0.03 for trend). The mean age of death in the severe genotype cate- gory was higher (39.2 years, 95% confidence interval [95% CI]: 28.4-50.1) than in the moderate (mean age 31.4, 95% CI: 28.3–34.4) and mild (35.0 years, 95% CI: 30.0-40.1) genotype categories. There were no significant differences in proportions surviving or not surviving with different α-globin gene numbers or with the XmnI polymorphism.
Causes of death are shown in Table 3. The ten deaths caused by liver disease included six cases of liver failure and four cases of hepatocellular carcinoma. Other malignancies comprised acute myeloid leukemia (n=2), T-cell lymphoma (n=1), metastatic melanoma (n=1), renal carcinoma (n=1), carcinoma of colon (n=1), carcinoma of skull (n=1). Other causes of death were categorized as not known (n=7), acci- dent (n=5), stroke (n=2), hypoglycemia (n=1), myasthenia (n=1), acute graft-versus-host disease (n=1), and pulmonary hypertension (n=1). Table 3 also shows mortality rates per 10,000 patient-years from different causes during sequential
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haematologica | 2021; 106(9)