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P. Kountouris et al.
Table 5. Univariate and multivariate analysis of risk factors for survival in the secondary analysis.
Number
Sex
Female 245 Male 244
Year of birth
<1974 215 ≥1974 274
Clinic
Larnaca 107 Limassol 128 Nicosia 209 Paphos 45
HBB genotype
Severe 81 Moderate 321 Mild 84
α-globin gene number
<4 108 ≥4 369
XmnI polymorphism
CC 452 CT 19
Iron chelation
DFO only 74 DFO switched to DFP-containing 332 DFO switched to DFX 83
Splenectomy
Childhood 130 Adulthood or not splenectomized 354
Univariate % survival at right
Multivariate
HR 2.34, 95% CI 1.26–4.34, P=0.007
HR 2.04, 95% CI 1.05–3.98, P=0.036
HR 0.10, 95% CI 0.05–0.19, P<0.001 HR 0.08, 95% CI 0.025–0.028, P<0.001
HR 7.92, 95% CI 2.03–30.75, P=0.003
censorship at
30 Sept. 2018 (95% CI)
93.0 (89.9-96.3) 86.7 (82.6-91.1)
86.0 (81.5-90.8) 93.0 (90.0-96.1)
90.3 (84.8-96.2) 89.0 (83.7-94.6) 89.0 (84.9-93.3) 95.6 (89.7-100)
93.8 (88.7-99.2) 90.9 (87.7-94.1) 82.1 (74.3-90.8)
92.5 (87.7-97.7) 89.1 (86.0-93.2)
89.5 (86.7-92.4) 100
64.5 (54.2-76.8) 93.7 (91.1-96.3) 96.4 (92.4-100)
82.2 (75.8-89.1)
93.7 (91.2-96.3)
Comparison of survival estimate (log rank)
χ2 =5.3, 1 d.f., P=0.021 χ2 =6.3, 1 d.f., P=0.012
χ2 =2.0, 3 d.f., P=0.578
χ2 =6.4, 1 d.f., P=0.011
χ2 =1.1, 1 d.f., P=0.287 χ2 =2.0, 1 d.f., P=0.158
χ2 =75.1, 2 d.f., P<0.001
χ2=14.7, 1 d.f., P<0.001
d.f.: degrees of freedom; 95% CI: 95% confidence interval, HR: hazard ratio: DFO: deferoxamine; DFP: deferiprone; DFX: deferasirox.
most severe category (β0/β0) is rare in the Cypriot TDT pop- ulation (0.8%), and this contrasts with some other TDT populations, such as in Sardinia where 92% of TDT patients have homozygous or compound heterozygous β0 mutations.16 Nevertheless, the two commonest variants in this cohort are common in the Mediterranean and the Middle East, and are also observed in many immigrant pop- ulations.18 For risk factor analysis, we introduced a genotyp- ic severity categorization, with the assumption that severi- ty increases linearly across the spectrum mild/ moderate/severe. This categorization could be explored in studies of severity, treatment and outcomes in other popu- lations, even if the specific variants are different.
The variability of risk factors during follow-up creates problems for the statistical modeling. We addressed this by evaluating two different models, the first of which incorpo- rated only non-modifiable factors and did not include treat- ment factors, but assumed that standard care was applied uniformly to all subjects. The worse survival associated with male sex had been previously reported1,2 and could be linked to worse adherence to the recommended chelation therapy and a higher prevalence of specific complications, such as heart disease, in male patients. Moreover, the signif- icantly worse survival associated with milder HBB geno- type would suggest that standard care is not sufficiently effective to cancel the pathological effects of milder geno- type. One recent confirmatory study has shown a conver- gence in mortality in a population of thalassemia major and thalassemia intermedia patients in Sicily with similar length
of follow-up.27 The definition of thalassemia intermedia in the study from Sicily was regular transfusion after the age of 2 years. Based on the transfusion data of the current study, the above definition of thalassemia intermedia encompasses 44.4% (122 out of 275) of patients with mod- erate or mild genotypes in the Cyprus TDT patient cohort.
The second model, which included treatment effects, confirmed that male sex and milder HBB genotype were significantly associated with mortality. Here, chelation ther- apy for each individual was categorized according to the predominant agent used. We confirmed that oral iron chela- tion therapy had a strong independent protective effect on survival compared to continuing with deferoxamine thera- py. The positive effect on survival of switching from defer- oxamine- to deferiprone-containing therapy has been previ- ously reported from this cohort and in other studies.3,32 The survival benefit of deferasirox compared to deferoxamine has not previously been reported, and may be related to improved adherence to an oral rather than injected agent and its once-daily administration. It is important to note that the categorization of chelation therapy is a simplifica- tion, and the assumptions of the Cox proportional-hazards model are not fully met with regard to chelation. Therefore, the significant protective effects observed in this study should be interpreted with caution.
We did not have comprehensive data on other genetic modifiers,33 while some genotype data were missing, par- ticularly α-globin genotype (44/537, 8.2%) and XmnI poly- morphism (57/537, 10.6%). However, the prevalence of
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