Background
β-thalassemia is a rare hereditary hemoglobinopathy with a prevalence rate of 18 out of 100,000 [1]. Worldwide there are over 1 million people with β-thalassemia, with each year over 40,000 newborns diagnosed, nearly 62% (approximately 25,500) of whom have transfusion-dependent β-thalassemia (TDT) [1‐3]. TDT is a progressive and debilitating condition [4] characterized by reduced or absent functional hemoglobin in red blood cells. Individuals living with TDT experience a range of symptoms and complications, including anemia, iron overload, immune system disorders, heart and renal failure, and liver disease [5, 6]. Lifelong, regular red blood cell transfusions (RBCTs) are required to maintain hemoglobin levels, and iron chelation therapy (ICT) is needed to mitigate toxicities associated with RBCT-related iron overload [7]. However, patient adherence to these current management options is challenged by side effects and demanding regimens [7‐11]. As a result, TDT and its management substantially impair health-related quality of life (HRQoL) [8, 9, 12‐14] and are associated with high healthcare utilization and costs [9, 15‐18].
Despite advances in RBCTs and ICT during the last few decades, complications associated with TDT persist and both morbidity and mortality remain high for individuals with TDT in comparison to the general population [7]. We previously described in a qualitative analysis that individuals living with TDT in the US and the UK experience negative impacts on HRQoL that disrupt their daily lives, and these disruptions are intensified by inadequate healthcare interactions, demanding treatment schedules, and stigma [11].
Although some quantitative evidence of the effect of TDT on HRQoL exists [9, 12, 13, 19], few studies have evaluated the effect longitudinally using patient-reported outcome measures (PROMs) [19] in individuals with TDT. In addition, data on the indirect economic impacts of TDT including time spent managing TDT, time spent in the healthcare setting, out-of-pocket treatment costs, and financial burden are also limited [12]. To address these evidence gaps, this study aimed to quantitatively examine the symptomatic experience, HRQoL, and economic impacts associated with living with TDT.
Methods
Study design and data source
A two-phase approach was used to describe and quantify the impact of TDT on individuals living with the condition.
In Phase 1, a targeted literature review was conducted to support the development of a conceptual framework and moderation guide for qualitative interviews and focus groups. Semi-structured interviews and focus group discussions were conducted to better understand the experiences and humanistic burden associated with living with TDT. Phase 1 findings have been published elsewhere [11]. A gap assessment was conducted, and the subsequent gaps identified informed the development of the bespoke questions included in Phase 2 of this study.
In Phase 2, a multi-country prospective longitudinal observational study was conducted. An international scientific advisory team (including two clinical experts, an academic with expertise in patient-reported outcomes and two patient advocate representatives) collaborated to identify and evaluate relevant research questions and validated PROMs for inclusion. Bespoke questions were revised with feedback from the scientific advisory team, ensuring that concepts that mattered to patients were appropriately incorporated and assessed.
Survey responses were collected online over a six-month period (at month 0 [baseline], month 3, and month 6); data were obtained prospectively between May 2022 and November 2022. This study is reported in accordance with the guidelines for Strengthening the Reporting of Observational studies in Epidemiology (STROBE) checklist [20].
Study population
Individuals were eligible to participate if they were: (1) residents of the US or Europe (France, Germany, Italy, and the UK); (2) aged ≥ 18 years; and (3) living with TDT based on a self-reported clinical diagnosis of TDT and had ≥ 8 RBCTs per year in each of the 2 years before enrollment. Study invitations were sent through patient advocacy groups, which included Cooley’s Anemia Foundation (CAF) in the US [21], UK Thalassaemia Society (UKTS) in the UK [22], and Thalassaemia International Federation (TIF) [23] in France, Germany, and Italy. Individuals were excluded if they had received hematopoietic stem cell transplantation, gene therapy, and/or gene editing at any point in their medical history. In addition, individuals were excluded if they were unable to provide informed consent or were currently enrolled in a clinical trial to treat TDT. To facilitate study recruitment for Phase 2, a convenience sampling approach was adopted.
Study outcomes
The primary outcome was to describe HRQoL impacts among people with TDT over three time points (baseline (0), 3, 6 months). All study materials were developed in English, translated into the local language and culturally validated, as reviewed by a native speaker for the country-level data collection. For the PROMs, where there were relevant validated translations, these were used instead of translating the English version.
Participants completed a background questionnaire at enrollment. Demographics (i.e., age, sex, country of residence, race/ethnicity, marital status, employment, gross annual household income) and clinical characteristics, including medical history, the number of recent RBCTs (received in the 12 months before enrollment, between April 2021 and April 2022), and current treatments (received in the 1 month before enrollment) were collected.
Findings from the gap assessment highlighted concepts relevant to the TDT patient experience. These concepts, along with input from the scientific advisory team were used to identify the following PROMs: EuroQoL Five-Dimensions Five Level (EQ-5D-5 L) and associated Visual Analogue Scale (EQ-VAS) [24], Functional Assessment of Cancer Therapy - General (FACT-G), Functional Assessment of Chronic Illness Therapy– Fatigue (FACIT-F) [25], Transfusion-dependent Quality of Life questionnaire (TranQoL) [26], 11-point numerical rating scale (NRS) of pain [27], and Work Productivity and Activity Impairment Questionnaire (WPAI) [28].
Summary of PROMs are provided in Supplementary Table 1. Instruments were evaluated to ensure measurement of concepts of interest, content, and psychometric validity. Overlap of important concepts and relevance of measures were assessed and considered in the context of respondent burden [29].
Additionally, bespoke questions relating to financial burden and distress, including time spent managing TDT and out-of-pocket costs were incorporated. Bespoke questions were developed with input from the scientific advisory team. The bespoke questions were structured as follows “On average, how much do you spend every month out-of-pocket to manage your transfusion-dependent beta-thalassemia?”, “How much of a financial burden are out-of-pocket expenses to manage your TDT for you and/or your family?” and “How often do out-of-pocket expenses to manage your TDT cause you distress?”. Participants were invited to respond to every question, although “not applicable” and “do not know” were included as available response options, as appropriate.
Statistical analyses
Prior to analyses, all data were aggregated and pseudonymized. Participant demographics, symptoms, and treatment characteristics were assessed with descriptive statistics. Standard manuals were used to score the PROMs, and US general population normative data [30‐32] were presented alongside minimal clinically important differences (MCIDs) for changes in the EQ-VAS, FACT-G, and FACIT-F. Welch’s t-test was used to compare the mean values of PROMs between two independent groups (i.e., the study sample and the US general population). PROMs were also analyzed by age subgroups (18–35 years, 36–55 years and > 55 years), gender (male and female, to note non-binary was not presented due to < 5 individuals) and assessed for stability over time (at month 0, 3, and 6) using ANOVA and repeated measure ANOVA respectively. For all analyses, statistically significant differences were assessed at a 0.05 level, and p-values were two-sided. All analyses were performed using R (version 4.3.1) and R Studio (version 2023.06.1 + 524) software.
Ethics
This study was performed in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki Declaration and its later amendments or comparable ethical standards.
Exemption for this study was granted by WIRB-Copernicus Group Institutional Review Board. Informed consent was obtained from all participants included in this research. Recruitment was conducted through patient advocacy groups, with no interactions occurring within hospital settings or involving healthcare professionals. This research was deemed exempt from NHS Health Research Authority research ethic committee review. This research was conducted in accordance with the Association of the British Pharmaceutical Industry, British Healthcare Business Intelligence Association and European Pharmaceutical Market Research Association codes of conduct [33‐35].
Results
Demographics and clinical characteristics
A total of 155 adults with TDT were included in this study (Table 1). The mean age of participants was 38.5 (standard deviation [SD]: 10.8) years. The majority of participants were female (65.8%) and lived in the US (53.5%) or UK (22.6%). Of participants willing to disclose their income, most (59.1%) had a gross annual household income of < 50,000 USD (Table 1).
Table 1
Participant self-reported demographics (N = 155)
n (%) | |
|---|---|
Age (years) | |
Mean (SD) | 38.5 (10.8) |
Median (IQR) [range] | 37 (30–47) [18‒65] |
Age (years) | |
18–35 | 69 (44.5) |
36–55 | 77 (49.7) |
55+ | 9 (5.8) |
Gender | |
Female | 102 (65.8) |
Male | 52 (33.5) |
Non-binary | 1 (0.6) |
Country of Residence | |
US | 83 (53.5) |
UK | 35 (22.6) |
Italy | 20 (12.9) |
Germany | 12 (7.7) |
France | 5 (3.2) |
Race/ethnicity (n = 118)a | |
White or Caucasian | 50 (32.3) |
Asian or Pacific Islander | 49 (31.6) |
Black or African American | 4 (2.6) |
Other | 15 (9.7) |
Prefer not to say | 37 (23.9) |
Current marital status | |
Married/domestic partner | 62 (40.0) |
Single | 59 (38.1) |
In a committed relationship | 17 (11.0) |
Separated/divorced | 14 (9.0) |
Widowed | 1 (0.6) |
Prefer not to say | 2 (1.3) |
Employment | |
Full-time | 51 (32.9) |
Unemployed | 34 (21.9) |
Part-time | 28 (18.1) |
Other | 27 (17.4) |
Receiving/awaiting disability payments or on leave due to TDT | 12 (7.7) |
Prefer not to say | 2 (1.3) |
Gross annual household income (n = 135)b | |
Less than 10,000 USD per year | 20 (14.8) |
10,000 to 25,000 USD per year | 24 (17.8) |
25,000 to 50,000 USD per year | 24 (17.8) |
50,000 to 75,000 USD per year | 11 (8.1) |
75,000 to 100,000 USD per year | 12 (8.9) |
100,000 to 200,000 USD per year | 19 (14.1) |
200,000 USD per year and greater | 5 (3.7) |
Prefer not to say | 20 (14.8) |
Clinical characteristics are summarized in Table 2. Participants reported a mean (SD) of 18.7 (8.2) RBCTs in the past 12 months, with most either receiving RBCTs every 2 weeks (about 2 times per month; 18.1%), every 3 weeks (51.0%), or every 4 weeks (about 1 time per month; 27.1%). The mean (SD) number of days since their last RBCT was 11.0 (8.2) days (Table 2). 17.4% of participants reported experiencing complications associated with RBCTs in the three months prior to enrollment. During the past 3 months, tiredness (81.9%), fatigue (74.8%), overall weakness (61.3%), pain/discomfort (50.3%) and shortness of breath (49.0%) were widely reported. Most participants (92.3%) had received ICT within the past month (Table 2). Of those who had received ICT, 14% reported missing their treatment 3 to 5 times in the past 2 weeks, and 9.4% reported feeling sick after taking the chelation medication. Many of whom acknowledged that they often missed their scheduled doses (19.8%) and felt sick due to treatment (9.4%).
Table 2
Participant self-reported clinical characteristics (N = 155)
n (%) | |
|---|---|
RBCT frequency in past 12 months (April 2021-22)a | |
Mean (SD) | 18.7 (8.2) |
Median (IQR) [range] | 17 (13–22) [9–51] |
RBCT frequency in past 12 months (April 2021–2022)a | |
Every 2 weeks (about twice a month) | 28 (18.1) |
Every 3 weeks | 79 (51.0) |
Every 4 weeks (about once a month) | 42 (27.1) |
Every 5 weeks | 1 (0.6) |
Every 6 weeks | 2 (1.3) |
Every 8 weeks (about once every two months) | 2 (1.3) |
Not applicable | 1 (0.6) |
Days since last RBCT (April 2021-22) | |
Mean (SD) | 11.0 (8.2) |
Median (IQR) [range] | 10 (5–15) [0–63] |
RBCT-related complications experienced | |
RBCT reaction | 84 (54.2) |
RBCT-related infection | 43 (27.7) |
Alloimmunity | 31 (20.0) |
Other | 25 (16.1) |
None of the above | 28 (18.1) |
Any RBCT-related complications in the past 3 months | 27 (17.4) |
Medical history | |
Osteoporosis or osteopenia | 108 (69.7) |
Vitamin D deficiency | 91 (58.7) |
Splenectomy | 78 (50.3) |
Stress | 76 (49.0) |
Anxiety | 69 (44.5) |
Sleep problems | 63 (40.6) |
Chronic pain | 61 (39.4) |
Depression | 57 (36.8) |
Delayed puberty requiring hormone therapy | 56 (36.1) |
Splenomegaly | 55 (35.5) |
Gallstones | 54 (34.8) |
Cholecystectomy | 53 (34.2) |
Mood swings | 53 (34.2) |
Short stature | 45 (29.0) |
Irritability | 45 (29.0) |
Diabetes | 34 (21.9) |
Hypothyroidism | 32 (20.6) |
Arrythmia | 29 (18.7) |
Degenerative changes in the spine or discs | 26 (16.8) |
Fractures secondary to osteoporosis | 26 (16.8) |
Extramedullary hemopoiesis | 20 (12.9) |
Hepatic fibrosis/Hepatic cirrhosis | 20 (12.9) |
Skin pain/soreness/sensitivity (caused by repeated cannulation) | 19 (12.3) |
Eczema | 18 (11.6) |
PTSD | 16 (10.3) |
Asthma | 14 (9.0) |
Heart failure | 14 (9.0) |
Deafness | 13 (8.4) |
Other heart issues (such as embolism) | 10 (6.5) |
left ventricular dilatation/dysfunction | 10 (6.5) |
Eating disorders | 10 (6.5) |
Hepatosplenomegaly | 9 (5.8) |
Extramedullary hemopoiesis | 9 (5.8) |
Pulmonary hypertension | 8 (5.2) |
Hypoparathyroidism | 7 (4.5) |
Phobia (needle/hospital) | 7 (4.5) |
Hypersplenism | 7 (4.5) |
Other skeletal problems | 6 (3.9) |
Osteonecrosis of the jaw secondary to treatment for osteoporosis | 5 (3.2) |
Extramedullary hemopoiesis mass | 5 (3.2) |
Leg ulcers | 4 (2.6) |
Other vision and hearing disorder | 4 (2.6) |
Hip replacement | 1 (0.6) |
Knee replacement | 1 (0.6) |
Myocardial infarction | 1 (0.6) |
Blindness | 0 (0.0) |
Symptoms | |
Tiredness | 127 (81.9) |
Fatigue | 116 (74.8) |
Pain or discomfort | 78 (50.3) |
Shortness of breath | 76 (49.0) |
Headache | 72 (46.5) |
Tachycardia (fast heartbeat) | 55 (35.5) |
Dizziness | 52 (33.5) |
Low concentration | 47 (30.3) |
Brain fog | 45 (29.0) |
Insomnia | 43 (27.7) |
Vomiting/diarrhea | 20 (12.9) |
Weakness | 4 (2.6) |
Current treatments (received in the last month) | |
ICT | 143 (92.3) |
Nutritional supplements | 70 (45.2) |
Over-the-counter pain medicine | 49 (31.6) |
Prescription pain medication | 26 (16.8) |
Bisphosphonates | 19 (12.3) |
Luspatercept | 18 (11.6) |
Splenectomy | 14 (9.0) |
Estrogen HRT | 13 (8.4) |
Testosterone replacement therapy (HRT) | 12 (7.7) |
Impact of TDT on HRQoL
Participants had a significantly lower mean (SD) EQ-VAS score at month 0 (67.1 [20.4]) than the US general population (80.4 [15.6]; group difference: p < 0.001; MCID: 7–10) [36]. EQ-VAS scores were consistent throughout the study period; minor fluctuations over 6 months did not reach the MCID (7–10 points), which demonstrated the stability of the EQ-VAS score (Fig. 1A).
Fig. 1
EQ-VASa (A) and FACT-Gb (B) scores reported over time in patients with TDT (n = 91). EQ-VAS, EuroQol Visual Analogue Scale; FACT-G. Functional Assessment of Cancer Therapy– General; TDT, transfusion-dependent β-thalassemia.aThe change in EQ-VAS score over time did not reach the MCID (7–10 points) [36]. bThe largest fluctuation in FACT-G total score did not reach the MCID (3–7 points) [30, 37, 38]. The sample size includes patients who completed all 3 surveys
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The mean (SD) FACT-G total score at month 0 (70.1 [19.0]) was significantly lower than the US general population (77.0 [16.1]; group difference: p < 0.001), with a 3.7-point relative reduction in physical well-being domain score and 5.2-point relative reduction in emotional well-being domain score (MCID: 3–7 points (Table 3) [37, 38]. Among participants, 48% reported fatigue and 51% reported tiredness in the past 7 days (described as “quite a bit” or “very much”). Additionally, FACT-G total scores were consistent from month 0 to month 6; the largest fluctuation did not reach the MCID of 3–7 points, which demonstrated the stability of the FACT-G score (Fig. 1B) [30, 37, 38].
The mean (SD) FACIT-F subscale score at month 0 (27.9 [13.7]) was 15.7 points lower than the mean score in the US general population (p < 0.001; MCID: 3.0-8.3) (Table 3) and was broadly similar to the mean (SD) score reported in anemic patients with cancer (23.9 [12.6]) [31, 39, 40].
Table 3
Patient-reported EQ-VAS, FACT-G, FACIT-F, TranQoL, and WPAI scores collected at month 0 (N = 155)
Score range | Mean (SD) | US general population | p-value | |
|---|---|---|---|---|
EQ-VASa | ||||
EQ-VAS (n = 146) | 0-100 | 67.1 (20.4) | 80.4 (15.6) | < 0.001 |
FACT-G (n = 152)b | ||||
Physical well-being | 0–28 | 19.0 (6.8) | 22.7 (5.4) | < 0.001 |
Social and family well-being | 0–28 | 19.3 (6.2) | 19.1 (6.8) | 0.776 |
Emotional well-being | 0–24 | 14.7 (4.4) | 19.9 (4.8) | < 0.001 |
Functional well-being | 0–28 | 17.2 (6.5) | 18.5 (6.8) | 0.021 |
FACT-G Total | 0-108 | 70.1 (19.0) | 80.1 (18.1) | < 0.001 |
FACIT-F (n = 91)c | ||||
FACIT-F Subscale | 0–52 | 27.9 (13.7) | 43.6 (9.4) | < 0.001 |
TranQoL | ||||
Physical health (n = 115) | 0-100 | 53.8 (22.6) | - | - |
Emotional health (n = 115) | 0-100 | 57.1 (19.9) | - | - |
Sexual health (n = 95) | 0-100 | 51.4 (32.0) | - | - |
Family functioning (n = 115) | 0-100 | 53.6 (18.1) | - | - |
School and career functioning (n = 115) | 0-100 | 62.5 (28.5) | - | - |
Total score (n = 115) | 0-100 | 53.9 (18.5) | - | - |
WPAI | ||||
Absenteeism (n = 79) | 0-100 | 19.5 (25.5) | - | - |
Presenteeism (n = 78) | 0-100 | 34.4 (30.9) | - | - |
Work productivity loss (n = 76) | 0-100 | 41.7 (32.4) | - | - |
Overall activity impairment (n = 151) | 0-100 | 44.2 (31.0) | - | - |
The mean (SD) TranQoL total score at month 0 was 53.9 (18.5). Mean (SD) domain scores across physical, emotional, sexual, family, and school and career health and functioning ranged from 51.4 (32.0) to 62.5 (28.5).
Pain was assessed using the 11-point NRS. On a scale of 0 (no pain at all) to 10 (worst imaginable pain), participants described their current level of pain with a mean (SD) score of 3.5 (2.8). Even at its best, 21.8% of participants rated their pain as “moderate” or “severe” (NRS scale range: 4–10). At its worst, 90.6% of participants rated their pain as “moderate” or “severe” (NRS scale range: 4–10).
Employment and financial burden
Among all participants, 32.9% (n = 51) had full-time employment and 18.1% (n = 28) had part-time employment (Table 1). On the WPAI questionnaire, employed participants reported missing approximately 0.75 days (5.9 h) of work in the last 7 days due to TDT and had an overall work productivity loss (i.e. work impairment) of 41.7% and reductions in work effectiveness of 34.4% (Table 3). Regardless of employment status, there was activity impairment of 44% across all participants. Employed participants were unable to work an average of 19.5% of the time due to their disease (Table 3). The degree of non-work-related activity impairment was 44.2% (Table 3).
Respondents at month 3 (n = 121) were asked bespoke questions on financial burden and distress; 39.2% reported that they did not have sufficient funds to cover the costs associated with managing their condition, estimating that they would need an additional median (interquartile range) of 400 USD (158 to 720 USD) per month. Out-of-pocket expenses were reported to be a moderate-to-major burden for 54.6% of participants (Fig. 2A) and caused frequent or very frequent financial distress for 40.5% (Fig. 2B).
Fig. 2
Financial burden of out-of-pocket expenses (n = 121) (A) and frequency that out-of-pocket expenses cause distress (n = 121) (B) in patients with TDTa. TDT, transfusion-dependent β-thalassemia. aThe sample sizes include patients who had a complete response to the survey at month 3
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Age subgroup and stability analyses
In a subgroup analysis, EQ-VAS, FACT-G, FACIT-F, TranQoL, and WPAI scores at month 0 were consistent between age groups (18–35, 35–55 and 55 + years old) (Supplementary Table 2) and gender (male and female, to note non-binary was not presented due to < 5 individuals) (Supplementary Table 3). Results for these measures were also stable across the 6-month observation period (Supplementary Table 4).
Discussion
In this real-world study, we aimed to characterize the HRQoL, and economic impacts associated with living with TDT. Our findings highlight the unmet need and humanistic and economic burden that underscore the requirement for innovative alternative treatments to significantly reduce the negative HRQoL impacts associated with living with TDT. Further, these findings indicate that individuals with TDT are burdened by both their TDT and management-related financial difficulties, beyond costs to healthcare systems.
Broadly, participants reported negative impacts of TDT and its management across HRQoL domains. Participants had significantly lower mean (SD) baseline EQ-VAS scores compared to published information about the general US population (67.1 [20.4] versus 80.4 [15.6], respectively). Participants also had significantly lower mean total FACT-G scores than the general US population (70.1 [19.0] versus 80.1 [18.1]), with marked impairment in physical and emotional well-being. Mean TranQoL total and domain scores were in line with international TDT populations (53.9 [18.5] versus 51.0 [20.0]) [12], although lower than in other North American populations (71.0 [17]) [41], with lowest scores among physical, emotional, and sexual health.
Anemia, chronic pain, and other iron-overload complications have been widely reported to have meaningful impacts on TDT-related HRQoL [8, 10, 14, 41‐43]. Overall weakness (61.3%) and shortness of breath (49.0%) were also frequently reported by participants in the month prior to study enrollment, however, individuals with TDT were particularly affected by tiredness and fatigue, which were reported by 81.9% and 74.8%, respectively. Nearly all participants felt either fatigued or tired, as measured by FACT-G, in the week preceding enrollment. Accordingly, the mean baseline (SD) FACIT-F subscale score was not only significantly lower in the study population than the US general population (27.9 [13.7] versus 43.6 [9.4]), but also largely comparable to that of anemic patients with cancer in the US (23.9 [12.6]) [13, 22, 23]. Largely consistent with findings reported here, Paramore et al. previously noted moderate fatigue among individuals with TDT, as measured by mean (SD) “worst fatigue” scores ranging from 5.55 (2.95) to 4.29 (2.81) across the RBCT cycle on the Brief Fatigue Inventory scale (from 0 to 10, with 10 indicating maximum severity) [12]. In our prior qualitative study, fatigue was often mentioned as an obstacle to education, work, and social life [11] and its severity can vary across the treatment cycle. The fluctuating pattern of extreme fatigue pre-RBCT and improved energy post-RBCT is a major contributor of reduced HRQoL [12] and a significant barrier to daily activities [11]. The degree of fatigue reported here highlights the cyclical variability and the unpredictable day-to-day impacts associated with living with TDT.
In line with existing qualitative and quantitative findings in TDT populations [9, 11, 12], participants in the current study experienced considerable chronic pain. Specifically, the mean (SD) pain score for current pain level was 3.5 (2.8). Additionally, “worst” pain levels were ranked as “moderate” to “severe” by almost all participants (90.6%) based on the pain NRS. Paramore et al. likewise found mean (SD) “worst pain” scores ranging from 4.93 (3.09) to 3.85 (2.92) across the RBCT cycle on the Brief Pain Inventory Short Form scale (from 0 to 10, with 10 indicating maximum severity) and Shah et al. reported moderate to extreme problems with pain among most (57%) UK adults with TDT, as per the EQ-5D-3 L pain domain [9, 12]. Altogether, these quantitative data underscore the burden of TDT-associated chronic pain, which our Phase 1 participants emphasized as the most common disruptor to daily life alongside fatigue [11]. Given that a knowledge gap has been identified among healthcare professionals related to chronic pain [11], further research and education efforts to address chronic pain are needed.
Individuals with TDT spend considerable time managing their disease, including recurring healthcare visits [9, 11, 12],, which likely contributes to the functional impairments observed in this study. Employed participants disclosed high levels of both presenteeism and absenteeism via the WPAI, which may have been associated with managing chronic pain, anemia, and other treatment-related complications. Specifically, employed participants were unable to work an average of 19.5% of the time due to their disease, which is higher than the 10% previously reported for adults with TDT in the UK [9]. Nonetheless, both study participants described comparable mean reductions in work effectiveness (34.4% versus 34.0%, respectively) and overall productivity (41.7% versus 42.0%, respectively) [9]. The degree of non-work-related activity impairment was also similar for our study (44.2%) and Shah et al. (48.0%) [9].
In addition to indirect impacts on employment and income, many participants (39.2% of the 121 respondents) shared that they were unable to fund the cost of their care, with out-of-pocket expenses representing a direct source of financial burden and distress. Accordingly, we previously identified the effect of treatment costs on personal finances as a key patient concern, particularly in the US [11]. Moreover, substantial costs associated with TDT management have been previously reported in the US and UK [15, 17, 44]. For example, a recent US study found that patients with TDT, compared with matched controls, had higher total annual ($137,125 versus $4,183) and projected lifetime ($7.1 million versus $235,000) healthcare costs [15]. Importantly, these patient expenditures were primarily driven by the cost of RBCTs (23.6%) and ICT (52.1%) [15]. Thus, the development of more effective treatment options that minimize dependence on RBCTs and ICT could greatly reduce the economic burden of TDT for both patients and healthcare systems.
Beyond the financial impacts, concerns regarding the administration and clinical burden of current treatments, namely RBCTs and ICT, were expressed in this study. Notably, 17.4% of participants reported experiencing complications associated with RBCTs in the three months prior to enrollment. Almost all participants were currently receiving ICT, many of whom acknowledged that they often missed their scheduled doses (19.8%) and felt sick due to treatment (9.4%). These issues with treatment adherence and tolerability are aligned with results of existing reports among patients with TDT [10, 11], including non-compliance to ICT due to the aforementioned time burden and side effects [11].
Our results are broadly consistent with those of previous quantitative studies reporting low scores on various HRQoL measures [9, 12, 13, 19], and build upon our previous qualitative findings on the patient burden of TDT and its management [11]. Collectively, these findings highlight the high burden of illness and support one of the 5 recently identified steps to improve the global care of thalassemia by documenting impairment of quality of life, as an important aspect of effective healthcare [45]. Furthermore, these findings support the need for more effective, tolerable, and affordable TDT treatment options. While there have been some improvements in management approaches, further studies are required to comprehensively understand and address the humanistic and economic burden of TDT.
Our results are broadly consistent with those of previous quantitative studies reporting low scores on various HRQoL measures [9, 12, 13, 19], and build upon our previous qualitative findings on the patient burden of TDT and its management [11]. Collectively, these findings highlight the high burden of illness and support one of the 5 recently identified steps to improve the global care of thalassemia by documenting impairment of quality of life, as an important aspect of effective healthcare [45]. Furthermore, these findings support the need for more effective, tolerable, and affordable TDT treatment options. While there have been some improvements in management approaches, further studies are required to comprehensively understand and address the humanistic and economic burden of TDT.
Limitations
Several limitations of the study design must be considered when interpreting the results. First, study participants were self-selected and recruited via a patient advocacy group email list, which may impact the generalizability of these results. However, covariate demographic characteristics (e.g., age, sex, employment status, household income) were described to inform comparison with other studies in this patient population. Although the bespoke questions were not formally validated in individuals with TDT, they were reviewed by clinical, methodological, and patient advocacy experts during development. Additionally, all data were self-reported, and participant eligibility and data accuracy were not independently verified by a clinician, which could lead to potential bias or inaccuracy. Although extensive, the data on economic burden is not comprehensive, as some components of direct and indirect costs are not covered. Data from this study were also compared to published information from US general population norm scores, which may not entirely reflect normative population scores of the participants from other countries (for example, UK, Italy, Germany, and France). US population norm data were chosen as a reference as respondents from the US represented the largest proportion of our study sample. Finally, this study employed online surveys, which may have limited participation to people with internet access and potentially excluded some potential participants with low digital literacy.
Conclusions
Our quantitative study demonstrated that adults living with TDT experience significant symptom burden, as well as negative impacts on their HRQoL and financial well-being. Participants reported severe fatigue similar to those reported by anemic patients with cancer. Many participants were unable to cover the costs of managing TDT, with out-of-pocket expenses commonly contributing to financial burden and distress. Our findings further indicate that these humanistic and economic burdens were consistent and persisted over the 6-month observation. Taken together, these study results reinforce that despite increased life expectancy due to improvement in the standard of care, quality of life continues to be impaired and there is an unmet need for alternative curative treatments for TDT.
Acknowledgements
Medical writing was provided by Daniella Babu, PhD, Alice Xue, MSc, and Matthew Williams, PhD, and editing support was provided by Nicholas Strange of Complete HealthVizion, IPG Health Medical Communications, Chicago, IL, USA, funded by Vertex Pharmaceuticals Incorporated. This study would not have been possible without our patient advocacy group partners and survey participants living with transfusion-dependent β-thalassemia, who kindly provided their time and shared their experiences.
Declarations
Ethical approval
Ethical approval was not required for this study and exemption for this study was granted by WIRB-Copernicus Group Institutional Review Board.
Consent to publish
The authors affirm that human research participants provided informed consent for publication.
Competing interests
Jennifer Drahos, Adriana Boateng-Kuffour, and Nanxin Li are employees of Vertex Pharmaceuticals Incorporated and may hold stock or stock options in the company. Melanie Calvert is Director of Birmingham Health Partners Centre for Regulatory Science and Innovation and Centre for Patient Reported Outcomes Research and a National Institute for Health and Care Research (NIHR) senior investigator; has received funding from Anthony Nolan, European Regional Development Fund-Demand Hub and Health Data Research UK, Gilead, GlaxoSmithKline, Janssen, Macmillan Cancer Support, Merck, NIHR, NIHR ARC WM, NIHR Birmingham BRC, NIHR BTRU Precision and Cellular Therapeutics, UCB Pharma, UKRI, and UK SPINE; and has received consultancy fees from Aparito, Astellas, Boehringer Ingelheim, CIS Oncology, Daiichi Sankyo, Gilead, Glaukos, GlaxoSmithKline, HalfLoop, Merck, Patient-Centered Outcomes Research Institute, Pfizer, Takeda, and Vertex Pharmaceuticals Incorporated. Laurice Levine has received honoraria from Editas and Vertex Pharmaceuticals Incorporated; received consulting fees from Agios and bluebird bio; received support for congress participation from Agios; and has served as an advisory board member for Editas. Neelam Dongha has received consulting fees from Vertex Pharmaceuticals Incorporated. Zahra Pakbaz has received research grants from Amgen, Forma Therapeutics, Global Blood Therapeutics, Novartis, Novo Nordisk, and Pfizer; received consulting fees from Agio, Amgen, Dova, Global Blood Therapeutics, Guide point, Novartis, Sanofi, Sobi, and Vertex Pharmaceuticals Incorporated; received honoraria from Cayenne Wellness Center and Child Foundation, Dova, and Global Blood Therapeutics Inc; served as an advisory board or committee member for Alexion, Sanofi, and Sobi; and acted as a CME course director for the Cayenne Wellness Center and Child Foundation and planning committee member for their annual education symposium. Farrukh Shah has received research grants from IQVIA, Novartis Pharma AG, Pharmacosmos, and Vertex Pharmaceuticals Incorporated; received honoraria from Biologix FZ co, Bristol Myers Squibb, Chiesi Ltd, and Novartis Pharma AG; served as an advisory board or committee member for Agios, bluebird bio, Bristol Myers Squibb, Silence Therapeutics Plc, and Vertex Pharmaceuticals Incorporated; and acted as Chair for the UK Forum on Haemoglobin Disorders. Nick Ainsworth is an employee of QC Medica and Antony P. Martin is a partner of QC Medica who were funded by Vertex Pharmaceuticals Incorporated to perform this research.
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