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P. Kountouris et al.
Table 4. Univariate and multivariate analysis of risk factors for survival in the primary analysis. Univariate
Multivariate
HR 1.9, 95% CI 1.2–3.0, P=0.011
HR 1.6, 95% CI 1.1–2.3, P=0.023
Sex Female Male
Year of birth <1974
≥1974
Clinic Larnaca Limassol Nicosia Paphos
HBB genotypea Severe Moderate Mild
α-globin gene numberb <4
≥4
Xmn polymorphismb CC
CT
% survival at age 50 (95% CI)
87.3 (82.9-91.8) 73.6 (66.9-81.0)
75.4 (70.1-81.1) Not yet reached
79.4 (71.6-88.0) 82.0 (75.1-89.5) 78.7 (72.0-86.0) 84.5 (68.9-100.0)
85.7 (75.4-97.5) 85.3 (80.6-90.2) 77.9 (68.7-88.3)
90.9 (84.5-97.7) 83.6 (78.8-88.8)
86.2 (82.1-90.5) 100
Comparison of survival estimate
χ2 =13.62, 1 d.f., P<0.001 χ2 =10.2, 1 d.f., P=0.001
χ2 =2.7, 3 d.f., P=0.437
χ2 =4.4, 1 d.f., P=0.037
χ2 =2.01, 1 d.f., P=0.157 χ2 =2.8, 1 d.f., P=0.097
aThe vector of trend weight for the three categories was 0, 1 and 2 for severe, moderate and mild genotype, respectively. bThe analysis was based on cases for which data were available (see Table 2 for missing data). d.f.: degrees of freedom; 95% CI: 95% confidence interval, HR: hazard ratio.
1980-2000, when the only option available was deferox- amine, follow-up was restricted to the period 2000-2018, when at least one option for oral chelation was available, and data were left-truncated at January 1, 2000.
The results of the survival analysis are shown in Table 4 and Figure 1. Survival by age 50 was estimated at 80.4% (95% CI: 76.4-84.7). In the first model of survival, univari- ate analysis showed that male sex, milder HBB genotype and birth before 1974 were significantly associated with worse survival, while there was no significant effect of treatment clinic, α-globin gene number or XmnI polymor- phism. When the survival analysis was applied separately to cardiac and non-cardiac deaths, the genotype had no significant effect on cardiac deaths, but a significant effect on non-cardiac deaths (P=0.02). In the multivariate model, independent predictors of survival were male sex (hazard ratio [HR] 1.9, 95% CI: 1.2-3.0, P=0.01) and geno- type, with each decrement in severity being associated with a 1.6-fold increased risk of mortality (HR 1.6, 95% CI: 1.1-2.3, P=0.02).
In the second model, 489 evaluable patients were fol- lowed for a total of 8,644 person-years. The estimated survival rate was 89.9% (95% CI: 87.3–92.6) as of September 30, 2018. Univariate and multivariate analyses of risk factors for survival over this time period are shown in Table 5 and Figure 2. In the univariate analysis, male sex, birth before 1974, milder genotype, splenectomy in childhood and deferoxamine-only chelation treatment were significantly associated with worse survival, with iron chelation treatment being the most significant factor. In multivariate analysis, the best-fit model included chelation, sex, splenectomy in childhood and HBB geno- type. Importantly, the significant effects of male sex and milder genotype on survival were confirmed in the sec- ond multivariate model, while deferoxamine-only treat- ment and splenectomy in childhood were also associated with worse survival.
Association of genotype with transfusion parameters
Transfusion data were available for 336 patients of the cohort (62.6%) and were used to evaluate possible associa- tions between HBB genotype and the transfusion regimens. The mean age of first regular transfusion was 29.4 months, the mean transfusion frequency per year was 28.7 times, the mean blood volume transfused was 179 mL/kg/year and the mean pre-transfusion hemoglobin level was 9.9 g/dL.
The HBB genotype was significantly associated with age at first regular transfusion (P=0.001), annual transfusion fre- quency (P=0.04) and blood volume transfused (P=0.01), whereas no association was found for pre-transfusion hemoglobin levels (P=0.8).
Post-hoc statistical analysis was subsequently performed to demonstrate differences in transfusion between different genotypic severity groups, shown in Figure 3. Statistically significant differences were identified between the severe and mild groups for age at first transfusion (P=0.004) and annual transfusion frequency (P=0.024). In addition, statis- tically significant differences were found between the mod- erate and mild groups for age at first regular transfusion (P=0.0006), annual transfusion frequency (P=0.025) and blood volume transfused (P=0.003). The was not a signifi- cant association between the severe and moderate groups for any of the transfusion parameters studied.
Discussion
The first report on this cohort was right-censored at December 31, 2004.1 The current data cut-off allows a fur- ther 14 years of follow-up, and more robust estimates of overall survival, trends in mortality and risk factors for mor- tality.
In a study of health outcomes and healthcare costs in the UK,11 survival of thalassemia patients treated according to
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