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Frontiers in Hematology ·

Volume 5 - 2026 | https://doi.org/10.3389/frhem.2026.1770034

Complications and treatment patterns in patients with non-transfusion-dependent α- and β-thalassemia compared with matched controls: a retrospective observational study using administrative claims data in the United States

  • Arielle L. Langer1
  • Amey Rane2
  • Keely S. Gilroy2
  • Jing Zhao2
  • Louise Lombard2
  • Carolyn R. Lew3
  • Sujit Sheth4*corresponding author
  1. 1Division of Hematology, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA, United States
  2. 2Agios Pharmaceuticals, Inc., Cambridge, MA, United States
  3. 3Merative, Ann Arbor, MI, United States
  4. 4Division of Pediatric Hematology and Oncology, Department of Pediatrics, Weill Cornell Medical College, New York, NY, United States
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Abstract

Non-transfusion-dependent thalassemia (NTDT) can result in a range of clinical complications that can substantially reduce patient quality of life. To date, real-world studies on the clinical burden of the disease have focused on Europe and Asia and have been limited to β-NTDT. To assess the complications and treatment patterns in patients with α- or β-NTDT vs. matched controls in the United States (US). This retrospective observational study used data from US claims databases (January 1, 2013–June 30, 2021). Adult patients (≥18 years) with ≥1 inpatient or ≥2 outpatient claims for α- or β-thalassemia were included from Merative ™ MarketScan ® Commercial/Medicare and Multi-State Medicaid databases. Patients were classified as NTDT if they had <8 blood transfusions or ≥6 weeks between any two adjacent transfusions during the 12 months post-index date (date of first observed α- or β-thalassemia diagnosis code). Patients were matched with controls (1:5 ratio). Primary analysis focused on patients from the Commercial/Medicare database with mean hemoglobin <10 g/dL during follow-up, to minimize inclusion of patients with thalassemia trait. Complications and treatment patterns were assessed during ≥12 months post-index. Comparisons between patients with NTDT vs. controls were performed using Chi-square tests (categorical variables) and t-tests (continuous variables) (two-sided significance level of 0.05). Analyses for the α- and β-NTDT subgroups were also performed. In the Commercial/Medicare database, 149 patients with NTDT and hemoglobin <10 g/dL were matched with 745 controls (mean follow-up approximately 3 years). A significantly higher percentage of patients with NTDT had complications vs. controls, including malignancy (17.4% vs. 7.1%; p < 0.001), cardiovascular disease (15.4% vs. 7.8%; p = 0.003), liver disease (6.7% vs. 0.5%; p < 0.001), and gallstones (6.7% vs. 2.1%; p = 0.002). Overall, 18.8% of patients with NTDT had ≥1 transfusion; 4.0% received oral chelators. Similar trends across outcomes were observed for NTD α- and β-thalassemia subgroups vs. controls. Patients with NTDT had a high disease burden and experienced a range of serious complications, with significantly higher rates compared with controls. Additional effective and well-tolerated treatments are needed to address the underlying causes of NTDT and prevent complications.

Keywords

Introduction

Thalassemia is a group of inherited blood disorders characterized by reduced production of normal hemoglobin (Hgb), leading to anemia and other complications (1–4). It is caused by mutations in one or more of the globin genes (α-globin or β-globin), leading to α-thalassemia or β-thalassemia, respectively (1, 3, 5). Thalassemia is classified as a rare disease and prevalence estimates vary both across and within countries (6, 7). Although thalassemia has historically been more prevalent around the Mediterranean basin, the Middle East, Southeast Asia, and sub-Saharan Africa, it has become increasingly more common in the United States (US) and Northern Europe due to migration (7, 8).

Patients with α- or β-thalassemia present with variable red blood cell (RBC) transfusion requirements to manage the anemia and disease complications. The disease is phenotypically classified as either transfusion-dependent thalassemia (TDT), when patients require regular transfusion therapy for survival, or non-transfusion-dependent thalassemia (NTDT), when patients may require occasional or intermittent transfusions (3, 5). It should be noted, however, that a patient’s transfusion status may change over time during the course of the disease (5); in one study in the US, 41% of adult patients with a diagnosis of NTDT met the criteria for initiating chronic transfusions per established guidelines (9). Individuals who are heterozygous for thalassemia mutations exhibit borderline asymptomatic anemia and are classed as having thalassemia trait, which is not typically considered clinically significant and therefore not included among NTDT in the medical literature (5).

Thalassemia is the result of chronic ineffective erythropoiesis (premature death of RBC precursors in the bone marrow) and hemolysis (premature breakdown of RBCs), which together lead to serious complications with a substantial impact on patients’ quality of life and life expectancy (3, 5, 10). These can include chronic anemia, hypercoagulability, and primary iron overload (due to increased intestinal iron absorption), which can, in turn, result in downstream complications such as osteopenia and osteoporosis, pulmonary hypertension, leg ulcers, gallstones, hepatic disease, cardiovascular disease, and endocrinopathies (11–14). Furthermore, in patients with TDT, and some patients with NTDT receiving RBC transfusions, there is a high rate of morbidity due to secondary iron overload arising from transfusion management that necessitates treatment with iron chelators (15, 16). Chelation treatments have their own set of complications, including kidney, visual, and hearing toxicity (1, 17, 18).

Recent studies in Europe and Asia have suggested that NTDT may be associated with greater morbidity than previously recognized (11–14, 19). Although these studies provide some insight into the burden of NTDT, most were in non-transfusion-dependent (NTD) β-thalassemia, and limited data exist for α-thalassemia (19). A systematic literature review of the clinical impact and burden on patient quality of life associated with α-thalassemia has highlighted substantial gaps in knowledge for this type of thalassemia, with most studies limited to small sample sizes and retrospective analyses (20). In addition, few studies to date have examined the clinical burden of thalassemia in US-based real-world populations, with existing data primarily limited to patients with TDT (21), and there is a lack of studies comparing NTDT with matched controls, which is important for contextualizing the results. Therefore, there is a need for US-based real-world studies to assess the disease burden of patients with clinically significant NTDT, including both α- and β-thalassemia, compared with an appropriate control population.

In order to address these knowledge gaps and provide more insight into the disease burden of NTDT in the United States, the aim of this retrospective observational study was to assess the complications and treatment patterns in patients with NTDT, including subgroups with NTD α- and β-thalassemia, compared with matched control patients in a US real-world setting.

Methods

Study design and data sources

This was a retrospective observational study. Administrative claims data were obtained from the US Merative™ MarketScan® Commercial/Medicare, Multi-State Medicaid, and Lab Results claim databases. The Merative™ MarketScan® Commercial database contains information from the inpatient, outpatient, and outpatient prescription drug experience of employees and their dependents, covered under a variety of fee-for-service and managed-care health plans; the Merative™ MarketScan® Medicare database contains the healthcare experience (both medical and pharmacy) of retirees with Medicare Advantage or Medicare Supplemental insurance plans paid for by employers (a subset of the entire Medicare population). Inpatient and outpatient medical claims were linked to outpatient prescription drug claims and person-level enrollment data through unique enrollee identifiers. In addition, the Merative™ MarketScan® Lab Results database provides laboratory results, including Hgb levels, linked to the data elements contained in the Commercial and Medicare Supplemental databases. The Merative™ MarketScan® Multi-State Medicaid database was included in this study to ensure that patients with NTDT with a lower socio-economic status compared with those in the Commercial/Medicare database were also assessed. This database contains the pooled healthcare experience of Medicaid enrollees with fee-for-service or managed plans from multiple states, such as inpatient admission, outpatient services, and prescription drug claims, as well as information on long-term care and other medical care. Laboratory data were not available from the Merative™ MarketScan® Medicaid database; for this reason, and due to the differences between this database and the Commercial/Medicare database (including variations in population, level of healthcare resource use, and availability of variables), the Medicaid population was analyzed separately.

Study population

Inclusion criteria

All patients in the databases between January 1, 2013 and June 30, 2021 who met the eligibility requirements were included in the study. This study included patients aged ≥18 years with NTD α- or β-thalassemia. We identified patients with ≥1 inpatient or ≥2 outpatient claims for either α-thalassemia (International Classification of Diseases [ICD]-9-Clinical Modification [CM] 282.43 or ICD-10-CM D56.0) or β−thalassemia (ICD-9-CM 282.44, 282.45, 282.47 or ICD-10-CM D56.1, D56.2, D56.5). To be eligible for inclusion in the study, patients were also required to have ≥12 months of continuous enrollment in the health insurance program after and inclusive of the index date (defined as the date of first observed α- or β-thalassemia diagnosis code). Patients were followed from the index date to the end of continuous enrollment (i.e. if their continuous enrollment in the health insurance program ceased before the study end date), end of study (June 30, 2021), or death, whichever occurred first (minimum of 12 months).

Patients with NTDT were defined as those having <8 transfusions or ≥6 weeks between any two adjacent transfusions in the 12-month period post-index date. This definition was based on the definition of TDT used in prior studies of claims data (21, 22).

Exclusion criteria

Patients with evidence of other hemolytic anemias due to enzyme disorders, sickle cell disease or trait, hereditary spherocytosis, hereditary elliptocytosis, other hemoglobinopathies, other hemolytic anemias, or paroxysmal nocturnal hemoglobinuria were excluded. A list of the specific disorders and the corresponding ICD codes included in the study is shown in Supplementary Table S1. Patients with <12 months of enrollment, including those who lost enrollment or died within 12 months of identification, were also excluded from the study.

Patients with α- or β−thalassemia trait could not be definitively excluded from this analysis, because identification of patients relied on accurate coding of administrative claims data rather than confirmation of medical records. To minimize the risk of patients with thalassemia trait being erroneously included, the primary analysis focused on patients from the Commercial/Medicare database with mean Hgb levels <10 g/dL during the variable-length (≥12 months) follow-up period (from here onward referred to as the “NTDT population”), based on at least one Hgb reading during the follow-up period. Because laboratory data were not available for the Medicaid population, we were unable to analyze these patients by Hgb level.

Matched controls

The patients selected for study inclusion were matched with controls (1:5 ratio) who met the following criteria: ≥12 months of continuous enrollment from the index date, and no evidence of any thalassemia or other hemolytic anemia at any time during the patient’s history or follow-up. Index dates for controls were randomly assigned, based on the distribution of the index dates of patients with α- or β-thalassemia. Exact matching was performed with matching factors, including age category (18–24 years, then at 5-yearly intervals up to 70–74 years, and then 75 years and older), sex, length of follow-up, availability of lab data (Commercial/Medicare analysis only), payer type (Commercial/Medicare analysis only), and race/ethnicity (Medicaid analysis only).

Outcomes

Patient characteristics

Patient characteristics included age, sex, geographic region, payer type, and mean Hgb level. The clinical characteristic assessed over the follow-up period was the Charlson Comorbidity Index (assessed during the 12 months post-index date) (23). Data for geographic region and payer information at index date were only available from the Commercial/Medicare databases, and data for race were only available from the Medicaid database.

Complications

The number and percentage of patients with the following complications were assessed over the follow-up period: abnormal growth, stroke (cerebrovascular disease), diabetes (with/without chronic complications), gallstones (cholelithiasis), cardiovascular disease (congestive heart failure, myocardial infarction, arrhythmia), hypothyroidism, hypertension, leg ulcer, malignancy (any malignancy, metastatic solid tumor), osteoporosis/osteopenia, pulmonary hypertension, splenomegaly/hepatomegaly, hypogonadism, jaundice (including hyperbilirubinemia), and liver disease (including mild liver disease, moderate or severe liver disease). The number of unique comorbid conditions throughout the follow-up period was also assessed.

Treatment patterns

The following thalassemia-related procedures and medications were assessed during the follow-up period: transfusions (including the number and percentage of patients with 0, >0–<1, 1–3, 4–7, 8–11, 12–15, and ≥16 transfusions per year) and the number and percentage of patients receiving iron chelation therapy (deferoxamine, deferiprone, deferasirox), other procedures of interest (including hematopoietic stem cell therapy, splenectomy, and cholecystectomy), and medications of interest (including folic acid supplements, epoetin alfa, luspatercept, and hydroxyurea). The number of claims for iron chelators per patient per year (PPPY) in patients receiving chelation therapy was also calculated.

Statistical analyses

Data from the Commercial/Medicare and Medicaid databases were analyzed separately. Mean Hgb levels during the follow-up period (≥12 months) were assessed in the Commercial/Medicare database. Patients with mean Hgb levels <10 g/dL from this database were the primary NTDT population analyzed in the study. Hgb levels for all Commercial/Medicare-insured patients, thalassemia subgroup (NTD α- or β-thalassemia), and for matched controls in the 12-month follow-up period were reported for patients who had Hgb level values available in the Lab Results database. Patients’ average Hgb value over the follow-up and the number of Hgb values captured per patient were reported. The number and percentage of patients with complications were assessed as binary variables and identified by diagnosis codes on medical claims. The total number of complications (mean and standard deviation [SD]) was reported for the NTDT population and NTD α- or β-thalassemia subgroups vs. respective matched controls. Complications and treatment pattern outcomes were compared between the NTDT population and the NTD α- and β−thalassemia subgroups vs. their respective matched control groups, using Chi-square tests for categorical variables and t-tests for continuous variables, with a two-sided significance level of 0.05. Data for the overall Commercial/Medicare population (including all patients regardless of Hgb level) and the Medicaid population were also analyzed, with full data tables available in the Supplementary Appendix.

Results

Patient characteristics

A total of 3,999 patients with NTDT were originally identified from the Commercial/Medicare database (referred to as the “overall Commercial/Medicare population”) and were matched with 19,995 controls. Of the patients with NTDT, 892 had at least one Hgb reading during the follow-up period, of whom 149 (16.7%) had mean Hgb levels <10 g/dL (56 patients with NTD α-thalassemia and 93 patients with NTD β-thalassemia). These patients were matched with 745 controls. A total of 1,289 patients were identified from the Medicaid database (559 [43.4%] with NTD α-thalassemia and 730 [56.6%] with NTD β-thalassemia) and were matched with 6,445 controls.

Patient characteristics for the Commercial/Medicare NTDT population (Hgb levels <10 g/dL) are shown in Table 1. Most demographics were similar between the NTDT and matched control groups, with a mean (SD) age at index of 45.5 (15.8) years and 45.5 (15.6) years, respectively, and 87.9% of the NTDT population and matched controls were female (Table 1). Mean follow-up period was approximately 3 years in the NTDT (overall and by α- and β-thalassemia subgroup) and matched control groups (Table 1). The NTDT group had a significantly higher comorbidity burden based on mean (SD) Charlson Comorbidity Index (1.6 [2.3] vs. 0.8 [1.6]; p < 0.001), and significantly lower mean (SD) levels of Hgb (9.2 [0.8] vs. 13.2 [1.5] g/dL; p < 0.001) compared with matched controls. Similar results were seen in the NTD α- and β-thalassemia subgroups vs. their respective matched controls (Table 1), as well as the overall Commercial/Medicare population (Supplementary Table S2) and the overall Medicaid population (Supplementary Table S3).

Table 1. Patient characteristics among patients with NTDT in the Commercial/Medicare database.

CharacteristicsAll NTDTAll NTDTcontrol cohortP-valueNTD α-thalassemiaNTD α-thalassemiacontrol cohortP-valueNTD β-thalassemiaNTD β-thalassemiacontrol cohortP-value
N = 149N = 745N = 56N = 280N = 93N = 465
Age, years, mean (SD)45.5 (15.8)45.5 (15.6)0.97741.2 (13.9)41.4 (13.9)0.91648.2 (16.4)48.0 (16.4)0.916
Sex, n (%)1.0001.0001.000
Male18 (12.1)90 (12.1)4 (7.1)20 (7.1)14 (15.1)70 (15.1)
Female131 (87.9)655 (87.9)52 (92.9)260 (92.9)79 (84.9)395 (84.9)
Geographic region, n (%)*0.0940.4420.235
Northeast41 (27.5)138 (18.5)17 (30.4)60 (21.4)24 (25.8)78 (16.8)
North Central25 (16.8)147 (19.7)6 (10.7)44 (15.7)19 (20.4)103 (22.2)
South69 (46.3)388 (52.1)28 (50.0)154 (55.0)41 (44.1)234 (50.3)
West14 (9.4)72 (9.7)5 (8.9)22 (7.9)9 (9.7)50 (10.8)
Unknown0 (0.0)0 (0.0)0 (0.0)0 (0.0)0 (0.0)0 (0.0)
Payer, n (%)*1.0001.0001.000
Commercial132 (88.6)660 (88.6)54 (96.4)270 (96.4)78 (83.9)390 (83.9)
Medicare17 (11.4)85 (11.4)2 (3.6)10 (3.6)15 (16.1)75 (16.1)
Length of follow-up, days, mean (SD)1073.5 (654.9)1073.5 (653.2)1.0001123.3 (678.9)1123.3 (674.0)1.0001043.6 (641.9)1043.6 (639.1)1.000
Average Hgb reading per patient, g/dL, mean (SD)†9.2 (0.8)13.2 (1.5)< 0.0019.1 (0.8)13.1 (1.5)< 0.0019.2 (0.7)13.2 (1.5)< 0.001
Median [min, max]9.4 [6.1, 10.0]13.3 [5.2, 17.4]9.2 [6.1, 10.0]13.3 [5.2, 16.4]9.4 [6.1, 10.0]13.3 [7.7, 17.4]
Charlson Comorbidity Index, mean (SD)‡1.6 (2.3)0.8 (1.6)< 0.0011.1 (1.7)0.7 (1.6)0.1231.8 (2.6)0.9 (1.6)< 0.001

Hgb, hemoglobin; NTD, non-transfusion-dependent; NTDT, non-transfusion-dependent thalassemia; SD, standard deviation.

*Available for Commercial/Medicare only. †Measured during follow-up period (at least 12 months). ‡Reported during 12 months post-index.

Higher proportion of the NTDT group experienced complications vs. matched controls

Overall, the NTDT population had a significantly higher number of unique comorbid conditions compared with their matched controls during the follow-up period (mean [SD]: 2.9 [2.2] vs. 1.6 [1.6]; p < 0.001), with similar results observed for the NTD α-thalassemia (2.2 [1.5] vs. 1.4 [1.5]; p < 0.001) and NTD β-thalassemia (3.4 [2.5] vs. 1.8 [1.6]; p < 0.001) subgroups vs. their respective controls (Table 2).

Table 2. Complications among patients with NTDT in the Commercial/Medicare database during the follow-up period.

ComplicationsAll NTDTAll NTDT control cohortP-valueNTD α-thalassemiaNTD α-thalassemia control cohortP-valueNTD β-thalassemiaNTD β-thalassemiacontrol cohortP-value
N = 149N = 745N = 56N = 280N = 93N = 465
Complications, n (%)
Abnormal growth40 (26.8)183 (24.6)0.55713 (23.2)59 (21.1)0.72127 (29.0)124 (26.7)0.639
Cardiovascular disease23 (15.4)58 (7.8)0.0036 (10.7)16 (5.7)0.16717 (18.3)42 (9.0)0.008
Cerebrovascular disease7 (4.7)27 (3.6)0.5321 (1.8)5 (1.8)1.0006 (6.5)22 (4.7)0.488
Diabetes23 (15.4)88 (11.8)0.2218 (14.3)30 (10.7)0.44115 (16.1)58 (12.5)0.340
Gallstones (cholelithiasis)10 (6.7)16 (2.1)0.0022 (3.6)9 (3.2)0.8918 (8.6)7 (1.5)< 0.001
Hypertension57 (38.3)257 (34.5)0.38018 (32.1)73 (26.1)0.35139 (41.9)184 (39.6)0.671
Hypogonadism3 (2.0)12 (1.6)0.7271 (1.8)4 (1.4)0.8402 (2.2)8 (1.7)0.775
Hypothyroidism30 (20.1)108 (14.5)0.08210 (17.9)41 (14.6)0.54120 (21.5)67 (14.4)0.085
Jaundice8 (5.4)3 (0.4)< 0.0011 (1.8)0 (0.0)0.0257 (7.5)3 (0.6)< 0.001
Leg ulcers2 (1.3)6 (0.8)0.5250 (0.0)1 (0.4)0.6542 (2.2)5 (1.1)0.395
Liver disease10 (6.7)4 (0.5)< 0.0011 (1.8)1 (0.4)0.2059 (9.7)3 (0.6)< 0.001
Malignancy26 (17.4)53 (7.1)< 0.0015 (8.9)17 (6.1)0.43021 (22.6)36 (7.7)< 0.001
Osteoporosis/osteopenia11 (7.4)37 (5.0)0.2322 (3.6)9 (3.2)0.8919 (9.7)28 (6.0)0.196
Pulmonary hypertension4 (2.7)4 (0.5)0.0111 (1.8)0 (0.0)0.0253 (3.2)4 (0.9)0.061
Splenomegaly/Hepatomegaly8 (5.4)1 (0.1)< 0.0010 (0.0)0 (0.0)NA8 (8.6)1 (0.2)< 0.001
Number of unique comorbid conditions
Mean (SD)2.9 (2.2)1.6 (1.6)< 0.0012.2 (1.5)1.4 (1.5)< 0.0013.4 (2.5)1.8 (1.6)< 0.001
Median3.01.02.01.03.02.0

NA, not available due to lack of data; NTD, non-transfusion-dependent; NTDT, non-transfusion-dependent thalassemia; SD, standard deviation.

A significantly higher proportion of the NTDT group had complications compared with matched controls during the follow-up period (Table 2), including malignancy (17.4% vs. 7.1%; p < 0.001), cardiovascular disease (15.4% vs. 7.8%; p = 0.003), liver disease (6.7% vs. 0.5%; p < 0.001), gallstones (6.7% vs. 2.1%; p = 0.002), jaundice (5.4% vs. 0.4%; p < 0.001), splenomegaly/hepatomegaly (5.4% vs. 0.1%; p < 0.001), and pulmonary hypertension (2.7% vs. 0.5%; p = 0.011). Similar findings were observed in patients with NTD β-thalassemia compared with their respective matched controls, while in those with NTD α-thalassemia, only jaundice and pulmonary hypertension were significantly higher vs. the control cohort, likely due to the smaller sample size (Table 2).

Complications experienced by the overall Commercial/Medicare population are shown in Supplementary Table S4. A similar proportion of patients with complications was observed in the Medicaid and overall Commercial/Medicare databases, although in the Medicaid database significantly higher proportions of patients in the NTD α-thalassemia subgroup had hypothyroidism and gallstones vs. matched controls (Supplementary Table S5).

Overall, these data indicate that complications were significantly more common in patients with NTDT vs. matched controls, including in the NTD α-thalassemia and NTD β-thalassemia subgroups.

Use of medical procedures was significantly higher with NTDT vs. matched controls, while use of transfusions and medications was low

Transfusions

During the follow-up period, 18.8% of the NTDT population had received ≥1 transfusion, with 10.1% of patients having >0–<1 transfusions per year, 7.4% having 1–<4 transfusions per year, and 1.3% having ≥4 transfusions per year. Similar trends were seen in the NTD α- and β-thalassemia subgroups (Table 3).

Table 3. Treatment patterns among patients with NTDT in the Commercial/Medicare database during the follow-up period.

Treatment patternsAll NTDT Hgb <10 g/dLAll NTDT Hgb <10 g/dL control cohortP-valueNTD α-thalassemia Hgb <10 g/dLNTD α-thalassemia Hgb <10 g/dLcontrol cohortP-valueNTD β-thalassemia Hgb <10 g/dLNTD β-thalassemiaHgb <10 g/dL control cohortP-value
N = 149N = 745N = 56N = 280N = 93N = 465
Transfusion encounters*
Patients with ≥1 transfusion encounter, n (%)28 (18.8)8 (1.1)< 0.00111 (19.6)3 (1.1)< 0.00117 (18.3)5 (1.1)< 0.001
Distribution of transfusion encounters per year, n (%)
0121 (81.2)730 (98.0)< 0.00145 (80.4)274 (97.9)< 0.00176 (81.7)456 (98.1)< 0.001
>0–<1†15 (10.1)7 (0.9)< 0.0018 (14.3)3 (1.1)< 0.0017 (7.5)4 (0.9)< 0.001
1–<411 (7.4)1 (0.1)< 0.0013 (5.4)0 (0.0)< 0.0018 (8.6)1 (0.2)< 0.001
4–<82 (1.3)0 (0.0)0.0020 (0.0)0 (0.0)NA2 (2.2)0 (0.0)0.002
≥80 (0.0)0 (0.0)NA0 (0.0)0 (0.0)NA0 (0.0)0 (0.0)NA
Iron chelation therapy
Patients receiving oralchelators, n (%)6 (4.0)0 (0.0)< 0.0013 (5.4)0 (0.0)< 0.0013 (3.2)0 (0.0)< 0.001
Number of pharmacyclaims for oral chelatorsPPPY, mean (SD)‡3.8 (3.8)NANA1.4 (1.3)NANA6.2 (4.1)NANA
Patients receivinginjectable chelators, n (%)0 (0.0)0 (0.0)NA0 (0.0)0 (0.0)NA0 (0.0)0 (0.0)NA
Other medications, n (%)
Anti-thrombotics34 (22.8)58 (7.8)< 0.0016 (10.7)16 (5.7)0.16728 (30.1)42 (9.0)< 0.001
Anxiolytics19 (12.8)74 (9.9)0.3046 (10.7)24 (8.6)0.60813 (14.0)50 (10.8)0.370
Folic acid (prescribed only)33 (22.1)22 (3.0)< 0.00115 (26.8)12 (4.3)< 0.00118 (19.4)10 (2.2)< 0.001
Hydroxyurea4 (2.7)1 (0.1)< 0.0010 (0.0)0 (0.0)NA4 (4.3)1 (0.2)< 0.001
Luspatercept0 (0.0)0 (0.0)NA0 (0.0)0 (0.0)NA0 (0.0)0 (0.0)NA
Epoetin alfa9 (6.0)0 (0.0)< 0.0013 (5.4)0 (0.0)< 0.0016 (6.5)0 (0.0)< 0.001
Prescription supplements§61 (40.9)150 (20.1)< 0.00122 (39.3)56 (20.0)0.00239 (41.9)94 (20.2)< 0.001
Procedures, n (%)
Cholecystectomy4 (2.7)13 (1.7)0.4431 (1.8)6 (2.1)0.8643 (3.2)7 (1.5)0.254
Colonoscopy31 (20.8)126 (16.9)0.25411 (19.6)38 (13.6)0.24020 (21.5)88 (18.9)0.565
Echocardiogram46 (30.9)111 (14.9)< 0.00117 (30.4)33 (11.8)< 0.00129 (31.2)78 (16.8)0.001
Electrocardiogram93 (62.4)283 (38.0)< 0.00132 (57.1)87 (31.1)< 0.00161 (65.6)196 (42.2)< 0.001
Gallbladder ultrasound41 (27.5)67 (9.0)< 0.00119 (33.9)25 (8.9)< 0.00122 (23.7)42 (9.0)< 0.001
Hematopoietic stem celltransplantation2 (1.3)3 (0.4)0.1600 (0.0)0 (0.0)NA2 (2.2)3 (0.6)0.160
Liver biopsy0 (0.0)0 (0.0)NA0 (0.0)0 (0.0)NA0 (0.0)0 (0.0)NA
Liver MRI16 (10.7)9 (1.2)< 0.0014 (7.1)2 (0.7)< 0.00112 (12.9)7 (1.5)< 0.001
Osteoporosis screen21 (14.1)72 (9.7)0.1067 (12.5)27 (9.6)0.51814 (15.1)45 (9.7)0.124
Splenectomy1 (0.7)0 (0.0)0.0250 (0.0)0 (0.0)NA1 (1.1)0 (0.0)0.025
T2 cardiac MRI0 (0.0)2 (0.3)0.5270 (0.0)0 (0.0)NA0 (0.0)2 (0.4)0.526

Hgb, hemoglobin; MRI, magnetic resonance imaging; NA, not available due to lack of data; NTD, non-transfusion-dependent; NTDT, non-transfusion-dependent thalassemia; PPPY, per patient per year; SD, standard deviation.

*Data for patients in the control group with no medical visits during the observation period (N = 7; n=3 for NTD α-thalassemia and n=4 for NTD β) were not reported. †A patient may average <1 transfusion per year if they had one transfusion event during a follow-up of more than 1 year in length. ‡Among patients with chelator use. §Prescription supplements include iron, bisphosphonates, calcifediol, calcium, levothyroxine, vitamin C, vitamin E, and zinc.

Medications

In the NTDT group, 4.0% of patients received oral chelators, and the mean (SD) PPPY number of claims for oral chelators was 3.8 (3.8) (Table 3). Similar levels of chelation therapy use were observed in the NTD α- and NTD β-thalassemia subgroups (Table 3).

Overall, hydroxyurea was used by 2.7% of patients in the NTDT population vs. 0.1% in matched controls (p < 0.001) (Table 3). A total of 22.8% of patients with NTDT were using anti-thrombotics vs. 7.8% of the control group. Other treatments that were used significantly more commonly with NTDT vs. controls included folic acid (22.1% vs. 3.0%), epoetin alfa (6.0% vs. 0.0%), and prescription supplements (40.9% vs. 20.1%) (all p < 0.001). No patients were receiving off-label treatment with luspatercept. Similar treatment patterns were observed in the NTD α- and NTD β-thalassemia subgroups vs. their respective matched controls (Table 3).

Procedures

Several procedures were significantly more common in the NTDT population vs. matched controls, including electrocardiogram (62.4% vs. 38.0%), echocardiogram (30.9% vs. 14.9%), gallbladder ultrasound (27.5% vs. 9.0%), and liver magnetic resonance imaging (10.7% vs. 1.2%) (all p < 0.001) (Table 3). One patient (0.7%) in the NTDT population underwent splenectomy (Table 3). Similar trends were observed in patients with NTD α- and β-thalassemia vs. their respective matched controls (Table 3), as well as in the overall Commercial/Medicare population and the overall Medicaid population (Supplementary Tables S6, S7).

Treatment patterns for the overall Commercial/Medicare population and the overall Medicaid population are shown in Supplementary Tables S6, S7, with similar trends in treatment and monitoring procedures observed in these populations as for the main NTDT population.

Overall, these data suggest that patients with NTDT were significantly more likely to undergo a number of investigational and diagnostic procedures vs. matched controls, which is in keeping with the higher rates of complications observed in this population.

Discussion

This study provides insights into the rates of complications and treatment patterns in adult patients with NTDT compared with matched controls using claims databases in the US. We found that patients with NTDT have a high disease burden, with more patients having a wide range of complications, including malignancy, cardiovascular disease, liver disease, gallstones, and jaundice, compared with matched controls. Such complications are associated with considerable morbidity and mortality, requiring chronic treatment and further adding to the disease burden and impact on patients’ quality of life (24, 25). This high clinical burden highlights the significant unmet need for effective treatment interventions and disease-modifying therapies for all clinically significant forms of thalassemia, including NTD α- and β-thalassemia, targeting the pathophysiology underlying the disease (5).

Our data added to those from previous studies conducted in Europe and Asia, which indicated that NTDT is associated with a substantial clinical burden (11–14). The landmark retrospective medical chart study OPTIMAL CARE assessed the frequency of complications in 584 patients with thalassemia intermedia (mean Hgb 8.9 g/dL) at six comprehensive care centers in Lebanon, Italy, Iran, Egypt, United Arab Emirates, and Oman. This study found high prevalence rates in key complications in patients with NTDT with no transfusions and occasional transfusions, including osteoporosis, extramedullary hematopoiesis, hypogonadism, and cholelithiasis (14). In our study, a significantly higher proportion of patients with both NTD α- and β-thalassemia had complications than the matched controls, further supporting the extensive disease burden previously reported (14). However, in contrast to the OPTIMAL CARE study, a lower proportion of patients in our study were reported to have had osteoporosis (7.4.%), hypogonadism (2.0%), and cholelithiasis (6.7%), whereas a higher proportion of patients had hypothyroidism (20.1% vs. 0% in OPTIMAL CARE in patients with NTDT and no transfusions and 9.8% in those with occasional transfusions) and diabetes (15.4% vs. 0.7% and 1.4%, respectively) (14). The higher rate of hypothyroidism may have been due to the greater proportion of female patients in our study compared with OPTIMAL CARE (87.9% vs. 50.2%), although rates of hypothyroidism in our study were numerically higher in patients with NTDT vs. sex-matched controls. Overall, these differences between the current analysis and previous studies may be due to their inclusion of registry data from centers of excellence that typically include more severe patients, more routine monitoring procedures in patients with thalassemia in countries with a higher prevalence and awareness of the disease, or the interplay of thalassemia with the social and cultural determinants of health in the US. The differences in design between the two studies (analysis of claims databases in the current study vs. medical chart review in OPTIMAL CARE) may also have impacted the results due to the limitations of administrative claims data collected for reimbursement purposes.

Interestingly, our study showed that the serious complications of malignancy and cardiovascular disease, which are often reported in TDT, were significantly more common with NTDT vs. controls (15.4% vs. 7.8% for cardiovascular disease; 17.4% vs. 7.1% for malignancy). Indeed, the OPTIMAL CARE study did not report these complications in patients with NTDT (14). It is possible that the higher rates of malignancy in patients with NTDT may be due in part to surveillance bias (i.e. patients with NTDT having more frequent healthcare interactions than controls), or that some patients were diagnosed with NTDT during their cancer care. The rate of cardiovascular disease was higher in patients with NTD β-thalassemia vs. NTD α-thalassemia, which may have been due to the lower mean age in the NTD α-thalassemia group (41.2 vs. 48.2 years for NTD β-thalassemia). Complications known to be associated with NTDT, including leg ulcers, osteoporosis, diabetes mellitus, and hypothyroidism (2, 26) were reported by a higher number of patients with NTDT compared with matched controls but did not reach statistical significance. A longer follow-up period may be warranted to more accurately report these chronic complications.

Patients in both NTD α- and β-thalassemia subgroups experienced a similar trend in the rates and range of complications compared to their respective matched controls. Of note, patients in the NTD α-thalassemia subgroup, often assumed to be a less severe disease than NTD β-thalassemia, experienced a statistically significantly higher number of unique comorbid conditions compared with the matched control group. This emphasizes the clinical burden of NTD α-thalassemia and the need for careful monitoring and treatment of this disease subtype, as well as those with NTD β-thalassemia. In support of this, a recent study by Blunt et al. also reported a relatively high rate of complications in patients with deletional HbH α-thalassemia, including cardiac issues and osteoporosis (27). The Thalassemia International Federation recently introduced specific management guidelines for α-thalassemia, consistent with the increased awareness of the disease burden among this patient population (10).

Another key finding of our study was the relatively low use of treatment and monitoring procedures despite the large proportion of patients with NTDT with complications. Transfusions were reported in a relatively small proportion of patients, with 10.1% of patients observed to have had >0–<1 transfusions per year. Moreover, relatively few patients received iron chelators, even though they are considered best supportive care for the treatment of patients with NTDT with evidence of iron overload (5). In contrast, the OPTIMAL CARE study reported that 47.5% of patients received chelation therapy (although OPTIMAL CARE enrolled a mix of occasionally transfused and regularly transfused patients), and other studies have also reported higher use of chelators in patients with NTDT (11–14). Again, this may reflect a selection bias in the OPTIMAL CARE study because patients from centers of excellence, who are typically more severely ill, were included (11–14). Alternatively, the relatively low level of chelation therapy and monitoring procedures observed in our study may suggest that a greater awareness of the NTDT burden of disease, as well as the introduction of novel treatments, are needed in the US. Indeed, findings from an observational study, evaluating patients with NTDT referred to an adult thalassemia treatment center, outlined a critical need for thalassemia education for adult healthcare providers to emphasize the importance of monitoring for early complications of NTDT, as well as criteria for initiating a chronic transfusion program to mitigate disease complications (9). Our findings support the need for education of NTDT healthcare providers in order to increase the monitoring and effective treatment of patients, and prevent the development of complications (9).

The Medicaid database was included in this study to ensure that patients with NTDT with a lower socio-economic status compared with those in the Commercial/Medicare database were represented, although because Hgb data were not available in the Medicaid database, we were not able to limit the analysis to patients with Hgb levels <10 g/dL. The trends in complications were generally consistent across databases, although significantly higher proportions of patients had hypothyroidism and gallstones in the NTD α-thalassemia subgroup compared with matched controls in the Medicaid database, a difference that was not observed in the Commercial/Medicare database.

A related analysis from the Merative Marketscan databases suggests that patients with α- or β-NTDT have significantly higher all-cause healthcare resource utilization (HCRU) and costs compared with matched controls in the US (28). These findings include increased inpatient admissions, outpatient office visits, and emergency room visits, underscoring the need for effective and well-tolerated treatments across all clinically significant forms of thalassemia.

This study has several limitations. First, with regard to the study design, a limitation of using administrative claims data rather than patient medical records is the potential for misclassification of thalassemia and inaccurate data coding entry, though we minimized the risk of patients with thalassemia trait being erroneously included by excluding patients with Hgb ≥10 g/dL from the primary Commercial/Medicare analysis. The sample size was also relatively small because Hgb data were not available for all patients, and only patients with Hgb levels <10 g/dL were included in the NTDT population. In particular, the small sample sizes of the α- and β-thalassemia subgroups may have limited the ability to detect significant differences between these NTDT subgroups and controls. Additionally, there may have been systematic differences between the study cohorts that account for differences found in complications and treatment use. Despite demographic matching being performed, other imbalances may have existed that may have introduced bias. Furthermore, because only adult patients from the US with health coverage through commercial, Medicare, or Medicaid health insurance were included, the findings may not be generalizable to patients with thalassemia with other health insurance (such as TRICARE), those without healthcare coverage, or those from other regions. As the Medicaid database was not included in the primary analysis (because it did not include Hgb data), patients of lower socio-economic status may have been under-represented in the study. Also, by selecting patients with an Hgb level <10 g/dL, patients with a higher burden of morbidity may have been selected, although the Hgb threshold of 10 g/dL has been used in several prior NTDT studies as well as current management guidelines (5, 29–31). We also cannot rule out that the Hgb level of <10 g/dL was a transient event in some patients, since Hgb levels could be based on a single reading during follow-up. The relatively short follow-up time of around 3 years in this study is also a drawback, because thalassemia is a chronic disease and patients typically develop complications over long time periods. Studies of a longer duration may be needed to accurately assess the incidence of rarer complications. There is also the possibility that some patients with NTDT transitioned to TDT during the follow-up period, which may have led to an increased rate of complications and medication use. Finally, because only medications that incur an insurance claim are captured in the MarketScan databases, this may have under-represented over-the-counter medications.

Conclusions

This real-world study in the US showed that patients with NTDT, including NTD α- and β-thalassemia, have a large clinical burden including serious complications. A variety of thalassemia-related medications and procedures were reported in this study, but overall use of treatments and monitoring procedures was low despite the large disease burden. The burden of NTDT described in this study shows there is a significant unmet need for treatments and disease-modifying therapies that are effective and safe across NTD α- and β-thalassemia to prevent the serious and wide-ranging complications associated with the disease. Furthermore, effective education of healthcare providers who manage the care of patients with NTDT may be needed to highlight the clinical burden and enable well-structured monitoring and treatment regimens for patients to prevent the development of serious complications.

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Supplementary material

The Supplementary Material for this article can be found online at: https://www.frontiersin.org/articles/10.3389/frhem.2026.1770034/full#supplementary-material

Supplementary material Supplementary material at the source

Footnotes

Edited by: John Strouboulis, King’s College London, United Kingdom

Reviewed by: Ikeu Nurhidayah, Padjadjaran University, Indonesia

Arne De Kreuk, King’s College Hospital NHS Foundation Trust, United Kingdom

Margherita Di Mauro, Hospital Santa Maria Goretti, Italy

Statements

Conflict of interest

AL has been or is a consultant for Agios Pharmaceuticals, Inc., Anthos, and Takeda. AR is a former employee of Agios Pharmaceuticals, Inc. KG, JZ, and LL are employees of and own stock in Agios Pharmaceuticals, Inc. CL is an employee of Merative Inc. SS has been or is a consultant for Agios Pharmaceuticals, Inc., Bristol Myers Squibb (Celgene), Chiesi, and Novo Nordisk; has received research funding from Agios Pharmaceuticals, Inc., Bristol Myers Squibb (Celgene), and Forma (Novo Nordisk); and has participated on a data safety monitoring board/steering committee at Vertex Pharmaceuticals.

The authors declare that this study received funding from Agios Pharmaceuticals, Inc. The funder had the following involvement in the study: Study design, analysis, and interpretation of data.

Funding

The author(s) declared that financial support was received for this work and/or its publication. This study was funded by Agios Pharmaceuticals, Inc.

Data availability

The datasets presented in this article are not readily available because qualified researchers may request access to related clinical study documents. Please send your data-sharing requests to datasharing@agios.com. The following considerations will be taken into account as part of the review: 1. the ability for external researchers to reidentify trial participants such as in small, rare disease trials or single-center trials 2. the language used in data and requested documents (e.g. English or other) 3. the informed consent language with respect to allowance for data sharing 4. the plan to re-evaluate safety or efficacy data summarized in the approved product labeling 5. potential conflicts of interest or competitive risks. Requests to access the datasets should be directed to datasharing@agios.com.

Ethics approval

This study used de-identified data from the US Merative™ MarketScan® Commercial/Medicare, Multi-State Medicaid, and Lab Results claim databases. Given that de-identified secondary data were used, ethical committee review and patient consent were not required.

Author contributions

AL: Writing – original draft, Formal analysis, Conceptualization, Methodology, Writing – review & editing. AR: Formal analysis, Writing – original draft, Writing – review & editing. KG: Writing – review & editing, Writing – original draft, Formal analysis. JZ: Formal analysis, Writing – review & editing, Writing – original draft. LL: Formal analysis, Writing – review & editing, Writing – original draft. CL: Data curation, Formal analysis, Writing – review & editing, Writing – original draft, Data curation. SS: Conceptualization, Writing – review & editing, Writing – original draft, Formal analysis, Methodology.

Acknowledgements

Medical writing support was provided by Julie Gray of Adelphi Group, Macclesfield, UK, funded by Agios Pharmaceuticals, Inc., in accordance with Good Publication Practice guidance.

References

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Citation

Langer, A. L., et al. (2026). Complications and treatment patterns in patients with non-transfusion-dependent α- and β-thalassemia compared with matched controls: a retrospective observational study using administrative claims data in the United States. Frontiers in Hematology, Volume 5. https://doi.org/
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5 - 2026

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Copyright © 2026 Langer, Rane, Gilroy, Zhao, Lombard, Lew and Sheth.

License: https://creativecommons.org/licenses/by/4.0/

*Correspondence: Sujit Sheth

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