Thalassemia is a chronic, inherited blood disorder, which, in its most severe form, causes life-threatening anemia. Advances in treatment have led to increased life expectancy however the need for chronic blood transfusions and chelation therapy remains a significant burden for patients. Our study compared health related quality of life (HRQOL) from the Thalassemia Clinical Research Network's (TCRNs) Thalassemia Longitudinal Cohort (TLC) study to US norms and assessed association with clinical variables. There were 264 patients over age 14 who completed the Medical Outcomes Study 36-Item Short Form Health Survey version 2 (SF36v2) baseline assessment. When compared to US norms, TLC patients had statistically significant (P < 0.05) worse HRQOL on five of the eight subscales (physical functioning, role-physical, general health, social functioning, and role-emotional) and on both summary scales (physical component summary and mental component summary). Women, older patients, and those with more disease complications and side effects from chelation reported lower HRQOL. In general, adolescents and adults with thalassemia report worse HRQOL than the US population, despite contemporary therapy. The SF-36 should become a standard instrument for assessing HRQOL in thalassemia to determine predictors of low HRQOL which may be better addressed by a multidisciplinary team.
Although medical advances in the treatment of thalassemia have led to increased survival patients still suffer disease complications. These, along with the significant burden from chronic treatment with transfusions and chelation, can adversely impact patient's quality of life [1, 2]. Health Related Quality of Life (HRQOL) refers to the patient's perception of their physical and mental health. Measuring HRQOL is important to assess the impact that a chronic disease has on a patient's everyday life, to compare different groups of patients, and to measure the effect of an intervention .
There are several main gaps in the literature of HRQOL in thalassemia which our study will help fill. Most HRQOL studies have focused on children, whereas adult studies have been relatively small and included non-thalassemia patients [4, 5]. While lower HRQOL has been described in thalassemia patients, it is not known what clinical factors have a significant impact on HRQOL, nor have there been prior studies which follow patients over time. Our study will fill some of these gaps in the literature by focusing on the baseline data in a large adult population of thalassemia patients with robust clinical data as well as HRQOL evaluations.
The goal of our study is to define the HRQOL in adolescents and adults with thalassemia by describing the quality of life in a cohort of North American and UK patients with thalassemia, comparing those results with US norms, and evaluating the association between HRQOL and clinical factors. We hypothesized that patients with thalassemia will report lower HRQOL than the standard US population. Furthermore we hypothesized that HRQOL will be lower in (1) patients with more severe disease since those patients will require more regular transfusion, and are more likely to suffer from disease and transfusion related complications, (2) patients on non-oral chelation, since there is some literature to suggest that oral chelation is associated with greater patient satisfaction , and (3) patients who report problems with chelation adherence.
Our study included 264 patients over age 14 with self-reported SF-36 scores. Basic patient demographics are shown in Table I. As expected TLC patients reported significantly lower HRQOL compared with the US norm in seven domains; physical functioning, role-physical, general health, social functioning, role-emotional and both the physical and mental summary scores (see Table II). Effect size calculations demonstrated a clinically significant but small effect in role-physical, social functioning, role-emotional, and the physical summary score, and a large effect on general health. When limited to US patients HRQOL remained significantly lower in five domains; role-physical, general health, social functioning, role-emotional and the physical summary score with a clinically significant effect size in general health (large), and the physical summary score (small).
|Variable||TLC n = 264|
|Age (years)||Mean = 29 (14-58)|
|Deferoxamine (DFO, Desferal)||57 (22%)|
|Deferasirox (DFX, Exjade)||136 (52%)|
|Deferiprone (L1)||9 (3.4%)|
|B-thal regularly transfuseda||204 (78%)|
|B-thal intermittently transfusedb||24 (9%)|
|B-thal non-transfusedc||2 (0.8%)|
|EB-thal regularly transfuseda||20 (7.6%)|
|EB-thal intermittently transfusedb||6 (2.3%)|
|EB-thal non-transfusedc||1 (0.4%)|
|Ferritin||Median 1371 (range 67–23,712)|
|Number of secondary complications||Mean 1.7 (range 0–8)|
|SF-36 measure||US norm||TLC (n = 264)||P-value||Effect sizeb||US patients only||P-value||Effect size#|
|General health||50||41.5a||<0.0001||0.85 (large)c||41.27a||<0.0001||0.87 (large)c|
|Social functioning||50||46.79a||<0.0001||0.32 (small)c||48.01a||0.006||0.20|
|Physical summary||50||46.8a||<0.0001||0.32 (small)c||47.57a||<0.0001||0.24 (small)c|
In univariate analysis lower HRQOL was associated with female gender, older age, receiving treatment in the UK, having a higher number of complications, and having a higher number of chelation side effects (for patients on oral chelator). Higher HRQOL was associated with being transfused (general health domain only) and being on an oral chelator. There was no association between any measure of compliance and HRQOL for patients on DFO alone. Race and ferritin were not associated with differences in SF-36 scores. In multivariate analysis (controlling for gender, race, chelator choice, frequency of side effects from chelation, country, number of complications, ferritin and transfusion status), older age, greater number of side effects, country (UK), and number of complications were the major factors associated with lower HRQOL, with race and gender showing a more limited effect, and chelator choice and ferritin showing no association with HRQOL in any SF-36 domain (Table III).
|Age (decade)||Asian||Side effects||Country (US ref)||Complications||Female||Transfused|
|Physical Functioning||−2.28||−2.64||Canada −1.69 UK −9.42||−2.63|
|Role−Physical||−1.93||−1.63||Canada −2.14 UK −9.45|
|Bodily Pain||−2.97||Canada 0.79 UK −8.96||−1.16|
|Vitality||−1.57||−3.29||−2.37||Canada 0.87 UK −6.86||−0.98|
|Social Functioning||−2.25||−2.37||Canada −1.99 UK −6.58|
|Role-Emotional||−1.92||Canada −2.05 UK −10.20||−3.13|
|Mental Health||−1.67||Canada 0.59 UK −4.83||−1.10|
|Physical Summary||−2.12||−1.80||Canada −0.09 UK −8.03||−0.87|
|Mental Summary||−1.79||Canada −0.41 UK −5.91|
This is one of only a few published reports of HRQOL in thalassemia patients, and the first to look at clinical associations with HRQOL. As expected, we found that adolescent and adult patients with thalassemia had impaired HRQOL compared with US norms. After controlling for demographic and clinical variables, we found that older age, greater number of side effects, country (UK), greater number of complications, and to a lesser extent female gender, Asian race, and not being transfused were associated with lower HRQOL.
Older age and female gender were associated with lower HRQOL in the TLC patients, but are known to be associated with lower HRQOL in the general population as well. After controlling for population differences in HRQOL we found no effect of gender over and above that of the general population; however HRQOL is lower in the older TLC patients than would be expected in the general population. This difference was primarily seen in areas of patient reported physical health rather then mental health and remained even after removing UK patients from the analysis.
This conclusion, that HRQOL is lower than expected in older TLC patients, must be interpreted with caution. Since this initial evaluation is a cross-sectional analysis, older TLC patients were diagnosed in an earlier era and may have been receiving transfusion and chelation therapy for longer. Also oral chelation is a relatively new therapeutic option in the US, which may give a generational effect on HRQOL. It will be enlightening to follow TLC patients over time and see if this age effect on HRQOL persists.
Our multivariate results are quite striking, especially since chelator choice was not associated with HRQOL in any domain after adjusting for other variables. This is in contrast with some literature which suggests oral chelation is associated with higher patient satisfaction. This may be due to the fact that patients are free to choose their own chelation, or may reflect the importance of adding clinical variables to the analysis.
Country remained a significant factor across domains, even after controlling for multiple variables, with UK patients reporting lower HRQOL compared with US or Canadian patients; however, the number of UK patients is too small to make conclusions about this finding.
We have attempted to demonstrate which HRQOL differences are clinically relevant to the population. There is a growing literature on minimal clinically important difference (MCID) which can be loosely defined as the smallest change that is important, or seen by the patient as an improvement. A difference in two to five points on the normalized (mean of 50) SF-36 scores is often used as an approximation of the MCID [7, 8]. By that measure we can see that many factors (such as age, gender, side effects, and country) have a large effect which is likely to be clinically relevant.
Our findings show some differences from other published literature, although interestingly two Italian thalassemia studies showed contrasting results as well. Messina et al. showed striking impairments in social functioning, role-emotional and the mental component summary . However Scalone et al. showed SF-36 scores for thalassemia patients which were close to country norms, and in some cases even higher . By contrast our results show HRQOL lower than US norms with the greatest effect in general health and the physical domains. It is unclear why the Messina study showed such extremely low scores for social functioning, role-emotional, and the mental summary score, although this may be in part because of the higher average age of the patients in that study. Our findings are however similar to two studies by Payne et al. In a UK study they report SF-36 scores that were lower than age- and gender-matched country-specific norms for all domains and both summary scores, with much lower scores for physical functioning and general health . In a US study they found that patient reported lower HRQOL than US norms with general health showing the most impact .
It is important to keep in mind that HRQOL is in many ways a social construct, since it relies on a person's expectation of health. Thus SF-36 norms vary by country with Italian norms being lower than US. For a disease such as thalassemia, which occurs in different populations, and is seen increasingly in immigrants in the US, these cultural differences are an important area for further study.
As we continue to make medical advances and improve life expectancy in thalassemia, HRQOL become an even more important marker of treatment success. The fact that the SF36 is widely validated and accepted in many countries makes it a good choice to be a standard assessment in thalassemia. Poor HRQOL in TLC patients is due to a complex combination of living with a chronic disease, medical complications, and side effects from chelation therapy. By identifying specific factors associated with lower HRQOL, we can help patients and health care providers focus on those areas likely to have the largest impact. As we follow our patient cohort over time we will also be able to examine associations between clinical changes and changes in HRQOL, which will add valuable information to how we can maximize HRQOL while striving to reduce the clinical burden of disease.