Efficacy and safety of thalidomide in β-thalassaemia: a systematic review and meta-analysis.

Introduction

β-Thalassaemia is recognized as a major global health burden by the World Health Organization (WHO), with approximately 150 million individuals carrying thalassemia genes worldwide. It is characterized by globin gene imbalance resulting in ineffective erythropoiesis and chronic haemolytic anaemia. Though the disease was once geographically restricted to the countries within the “thalassaemia belt”, due to population migration, it is prevalent in many regions of the world 1 , 2 .

Based on recent literature, more than 350 mutations of the β-globin gene contributing to the wide clinical heterogeneity of β-thalassaemia have been identified. However, due to the geographic clustering, approximately 20 mutations are responsible for more than 80% of cases globally 3 , 4 . The disease phenotype varies from transfusion-dependent thalassaemia (thalassaemia major) to asymptomatic carrier states (thalassemia minor), with thalassemia intermedia demonstrating an intermediate severity with pronounced phenotype variability. Clinically, based on the blood transfusion requirement, β-thalassaemia patients can be sub-classified into two main groups; transfusion-dependent β-thalassaemia (TDT) and non-transfusion dependent β-thalassaemia (NTDT) 5 .

The application of the hematopoietic stem cell transplant, the only curative treatment for β-thalassaemia, is constrained due to the high cost, difficulties in finding a compatible donor, and the high risk of serious complications 5 , 6 . Practicality of gene therapy, a recently emerged optimistic curative treatment, is also restricted due to high cost and lack of long-term evidence on its efficacy and safety 7 .

Hence, irrespective of the recent pharmacological advances, maintaining haemoglobin levels within the normal range remains the major challenge in β-thalassaemia patients. Management of thalassaemia primarily depends on supportive treatment, which includes regular blood transfusion and iron chelation 5 . γ-Globin inducers, which can increase fetal haemoglobin level, have grabbed the attention of clinicians based on the promising evidence supported by numerous studies 6 , 8 – 11 .

Thalidomide was introduced as a treatment for morning sickness in the late 1950s and early 1960s. Later, it was abandoned due to the discovery of its teratogenicity 12 . However, after several decades, it was reintroduced as an effective treatment modality for erythema nodosum leprosum and multiple myeloma attributed to its immunomodulatory, anti-inflammatory and antiangiogenic effects 13 . The use of thalidomide in β-thalassaemia was first reported in 2008, in which a dramatic rise in haemoglobin was observed in a thalassaemia major patient treated with thalidomide 14 . Subsequently, several studies, including randomized controlled trials (RCTs) discovered its potential as a γ-globin inducer, ameliorating clinical severity, in both NTDT and TDT patients 15 – 18 . However, the introduction of thalidomide to the standard management of β-thalassaemia is still challenged due to the ongoing risk vs benefit considerations. The aim of this systematic review and meta-analysis is to evaluate the efficacy and safety of thalidomide in β-thalassaemia to provide a robust pooled estimate based on studies conducted during the last decade.

Methodology

We performed a comprehensive systematic search of the literature to evaluate the clinical efficacy and safety of thalidomide in β-thalassaemia patients. Scopus, PubMed and Cochrane databases were searched using the following keywords: “thalassaemia,” “hemoglobinopathies”, “Cooley’s anaemia,” “thalidomide,” and “thalomid”. The search was limited to the studies published in English between 01 January 2015 and 31 December 2025.

The protocol of this study was registered at PROSPERO (Prospective Register of Systematic Reviews; registration number: CRD42024627095). This systematic review and meta-analysis were conducted following the recommendations of the PRISMA (Recommendations of the Preferred Reporting Items for Systematic Reviews and Meta-Analyses) and the MOOSE (Meta-analysis Of Observational Studies in Epidemiology) 19 , 20 .

Study selection

Two reviewers independently screened the citations, first by title and abstract, and then by a review of the complete article, adhering to the following inclusion and exclusion criteria. Discrepancies between reviewers were resolved by consensus or by a third researcher.

Eligibility criteria

Studies: RCTs and observational studies that evaluated the clinical efficacy and/or safety of thalidomide monotherapy Sample size: ≥ 10 patients Publication language: English Patients: β-thalassaemia and haemoglobin E β-thalassemia patients of any age (TDT and NTDT patients)

Exclusion criteria

Case series and case reports Studies published only as abstracts Articles published in languages other than English Studies with a sample size of less than 10 patients Studies using thalidomide in combination with hydroxyurea

If a study compared two or more treatment groups, only the thalidomide monotherapy group was included.

Based on the transfusion requirement, β-thalassaemia patients were divided into TDT and NTDT categories. Those who undergo at least eight transfusions per year were considered TDT patients, whereas those who undergo less than eight transfusions per year or never had a blood transfusion were considered NTDT 5 , 21 , 22 .

Primary outcomes

Response rate (RR) and good response rates (good RR) following thalidomide treatment were evaluated as primary outcome measures. In TDT patients, ‘response’ to treatment was defined as the decline of blood transfusion requirement by ≥ 50%, and the ‘good response’ was defined as the complete cessation of transfusion following thalidomide treatment. In NTDT patients, ‘response’ to treatment was defined as the increment of haemoglobin level by ≥ 1 g/dL, and the ‘good response’ was defined as a ≥ 2 g/dL increment of haemoglobin compared to the baseline levels following thalidomide treatment.

Secondary outcomes

Adverse effects of thalidomide treatment and the impact of thalidomide on serum ferritin and spleen size were evaluated as secondary outcome measures.

Data extraction

Two reviewers independently extracted key characteristics of each study using a data extraction form from studies that evaluated the efficacy and safety of thalidomide on β-thalassaemia patients and recorded in a customized electronic spreadsheet. The key characteristics included author, year and country of publication, study design, disease type, sample size, age and gender of study populations, blood transfusion history, thalidomide dose, RR, good RR, serum ferritin levels, spleen size, incidence of adverse events, and follow-up duration. The corresponding author was contacted if the required information was unavailable in the published record.

Assessment of bias risk and quality assessment

The quality of the included studies was assessed independently by two reviewers. Discrepancies between reviewers were resolved by consensus or by a third researcher. The risk of bias for RCTs was assessed according to criteria delineated in the Cochrane Handbook for Systematic Reviews of Interventions 23 . The revised Cochrane risk-of-bias tool for randomized trials (RoB2) evaluates five domains; the bias arising from the randomisation process, bias resulting from deviations from intended interventions, bias caused by incomplete outcome data, bias associated with measurement of the outcome, and selective reporting.

The National Institutes of Health (NIH) pre-post quality assessment tool was used for before-after (pre-post) studies with no control group 24 . It is composed of multiple questions assessing the potential risk for selection, sampling bias, measurement bias, detection bias, reporting bias, and confounding bias. Based on the evaluation of each domain, the quality of studies is finally defined as ‘‘good”, ‘‘fair,” or ‘‘poor”.

Heterogeneity and publication bias

Heterogeneity between studies was evaluated by forest plots, the Chi-squared test and I 2 statistics. Visual assessment of forest plots was done to identify the extent of overlap in 95% confidence intervals (CIs). The statistical significance of the heterogeneity was determined by the Chi-squared test ( p < 0.05) and I 2 statistic to quantify the percentage of variability across studies that could not be due to random chance. I 2 values < 25%, 25–50% and > 50% were considered low, moderate and high heterogeneity, respectively 23 , 25 . The sensitivity analysis was performed to determine whether removing low-quality studies influence the results.

Publication bias was assessed via visual inspection of funnel plots as well as using Egger’s test, which determined the degree of asymmetry in the plots. Egger’s test is based on the null hypothesis that the outcome of the smaller studies is consistent with the larger studies. A p < 0.05 was considered statistically significant 26 .

Statistical analysis

In this meta-analysis, the RR and good RR were the primary effect sizes (ES). Since the majority of the studies were single-arm, pre-post studies with no control groups, the pooled estimate of the treatment effect was calculated as a proportion (number of responders or good responders over the treated sample size with thalidomide), together with corresponding 95%CIs. The secondary ES was the incidence rates of adverse events associated with thalidomide in both TDT and NTDT, along with corresponding 95% CIs.

When the heterogeneity was lower (I 2 < 50%), the fixed effects/common model was used to calculate the pooled ES. In contrast, the random-effect model was applied when heterogeneity within and between studies was moderate or higher 23 . All analyses were conducted via the “metaphor” and “meta” packages in R 4.4.3. p < 0.05 was considered statistically significant.

Results

Study selection

A total of 198 records were retrieved via the initial database search. After removing 85 duplicates, titles and abstracts were screened in 113 records per the selection criteria, and 71 were excluded (Fig. 1 ). The remaining 42 were evaluated based on their full text per the selection criteria, and 23 were excluded. The most common reason was combination therapy with hydroxyurea 27 , 28 . Two papers 15 , 29 were removed because the patients in those publications had an overlap with the study published by Chen et al. 30 . Accordingly, 19 studies met the inclusion criteria and were included in the qualitative analysis. For the quantitative analysis, 18 studies were included. Fig. 1 PRISMA flow diagram of literature search. PRISMA-preferred reporting items for systematic reviews and meta-analyses.

Study characteristics

From the pool of selected 19 studies encompassing 1731 patients, two were RCTs 17 , 30 , and the others were pre/post studies 16 , 18 , 31 – 45 , which compared the efficacy and safety of thalidomide following the intervention. Eleven studies exclusively involved TDT patients 16 , 17 , 30 – 32 , 34 , 35 , 40 , 42 – 44 , and two were only focused on NTDT patients 33 , 36 . Six studies had both TDT and NTDT patient cohorts 18 , 37 – 39 , 41 , 45 . Among these 19 studies, eight were conducted in China 18 , 30 , 34 – 38 , 42 and seven were from India 16 , 17 , 32 , 33 , 41 , 43 , 45 . Two were retrospective studies 16 , 35 . Two studies only focused on haemoglobin E β-thalassaemia 16 , 33 , and two had haemoglobin E β-thalassaemia patients in addition to β-thalassaemia major patients 32 , 41 . When more than one treatment arm was present, only the thalidomide arm was considered 33 (Tables 1 , 2 ). Table 1 Study characteristics. No Study & year Country Design Genotype Blood transfusion history N Age (y) a (range) M:F Thalidomide dose (daily) F/U(m) 1 Ali 2023 Pakistan Pre/post TM Monthly 532 5.3 (1.5–26) 353:179 1–4 mg/kg 6 2 Bhattacharjee 2023 India RCT TM Monthly 14 c 26.1 (NR) 5:2 50 mg 6 3 Chandra 2021 India Pre/post TM, HbE/β 12.6 ml/kg/m 37 14.7 (12–18) 26:11 2–3.7 mg/kg 6 4 Chen 2021 China RCT TM 3.5 U/m 50 c 18.4 (NR) 5:4 100–150 mg 3 5 Jain 2021 India Pre/post HbE/β < 6 U/year 15 c 20.3 (NR) 1:2 50 mg 12 6 Jian 2023 China Pre/post TM 4.2 U/m 22 15 (14–18) 7:4 50–100 mg 3 7 Ju 2024 China Pre/post TM, TI Regular in TDT 42 18.65 (13–49) 28:19 75–150 mg 6 8 Li 2021 China Pre/post b TM Regular < 28d in 23.4% > 28d in 76.6% 77 10 (5–18) 45:32 2.5–4.0 mg/kg 6 9 Nag 2020 India Pre/post b HbE/β 1 U/m 21 NR NR < 12 years- 50 mg; > 12 years- 100 mg 24 10 Ren 2017 China Pre/post TI Interval > 3 m 14 25.6 (18–65) 4:3 50 mg 3 11 Yang 2020 China Pre/post TM, TI NR 45 27.37 (12–41) 27:35 50 mg 3 12 Yang 2024 China Pre/post TM, TI Regular in TDT No history of transfusion in NTDT 52 15 (12–41) 15:11 < 25 kg or < 14 y- 50 mg; > 25 kg or > 14 y-100 mg 6 13 Yassin 2019 Iraq Pre/post TM, TI NR 37 10 (3–43) 21:16 2–10 mg/kg 15 14 Bawazir 2025 Saudi Arabia Pre/post TM 2–7 weekly 20 5.45 ± 3.81 5.6:1 1–4 mg/kg 6 15 Dolai 2025 India Pre/post TM, HbE/β 1 U/m in 47% of TDT No history of transfusion in NTDT 404 8.4 (2–17) 54.5:45.5 2–5 mg/kg 2–12 y-max 50 mg 13-17y-max100mg 12 16 Li 2025 China Pre/post TM < 28d in 42% 170 10.3 (5–18) 103:67 2.5- 3.8 mg/kg 3 17 Mishra 2025 India Pre/post TM Regular 50 c 21 (12–34) 2.6:1 25 -100 mg 5 18 Rahman 2025 Pakistan Pre/post TM < 1 m in (87.5%) 72 c 5.25 (3.0–8.0) 37:35 1.5 mg/kg (1–2 mg/kg) 30 19 Singha 2025 India Pre/post TM, TI Regular in TDT No history of transfusion in NTDT 61 16.8(2–50) 5:9 2–3 mg/kg 6 F/U = follow up; d = day; HbE/β = haemoglobin E β-thalassaemia; m = months; M:F = Male:Female ratio; N = sample size; NR = not reported; TM = thalassaemia major; TI = thalassaemia intermedia; RCT = randomized clinical trial; U = Unit of packed red blood cells; m = month; wk = week; y = years. a Mean /median (range); b Retrospective; c Only thalidomide arm was included. Table 2 Response to thalidomide in NTDT and TDT patients. No Study & year Transfusion dependency Total number of patients (N) Number (%) of patients showing a response Number (%) of patients showing a good response 1 Ali 2023 TDT 532 302 (56.8) 302 (56.8) 2 Bhattacharjee 2023 TDT 14 NR 2 (14.3) 3 Chandra 2021 TDT 37 19 (51.4) 15 (40.5) 4 Chen 2021 TDT 50 NR 34 (68.0) 5 Jain 2021 NTDT 15 a 15 (100) 10 (66.7) 6 Jian 2023 TDT 22 17 (77.3) 14 (63.6) 7 Ju 2024 TDT 29 31 (73.8) b 19 (45.2) b NTDT 13 8 Li 2021 TDT 77 62 (80.5) 51 (66.2) 9 Nag 2020 TDT 21 16 (76.2) 15 (71.4) 10 Ren 2017 NTDT 14 12 (85.7) 10 (71.4) 11 Yang 2020 TDT 12 12 (100) 5 (41.7) NTDT 33 93.9 (93.9) 26 (78.8) 12 Yang 2024 TDT 34 21 (61.8) 21 (61.8) NTDT 14 14 (100) 14 (100) 13 Yassin 2019 TDT 14 9 (64.3) 4 (28.6) NTDT 23 17 (73.9) 12 (52.2) 14 Bawazir 2025 TDT 20 NR 14 (70) 15 Dolai 2025 TDT 371 NR 127 (33.4) NTDT 33 NR NR 16 Li 2025 TDT 170 141 (82.9) 102 (60.0%) 17 Mishra 2025 TDT 50 a 45 (90.0) 32 (64) 18 Rahman 2025 TDT 72 a 53(73.6) 53 (73.6) 19 Singha 2025 TDT 25 22 (88) 10 (40) NTDT 36 32(88.8) 29(80.5) N = sample size; NTDT = non-transfusion-dependent β-thalassemia; TDT = transfusion dependent β-thalassaemia. a Only the thalidomide arm was included. b combined value for NTDT and TDT.

The RR and the good RR were independently assessed for TDT and NTDT patients. The study conducted by Ju et al. 18 reported a combined RR for both TDT and NTDT; therefore, it was not included in the quantitative analysis. Consequently, the quantitative analysis of the response rates included 18 studies. The RR and good RR in TDT patients were reported in 12 studies involving 944 patients 16 , 31 , 32 , 34 , 35 , 37 – 39 , 42 – 45 and 16 studies involving 1399 patients 16 , 17 , 30 – 32 , 34 , 35 , 37 – 45 , respectively. The RR and good RR in NTDT were reported in six studies involving 135 patients 33 , 36 – 39 , 45 . Although Dolai et al. 41 reported transfusion independence in TDT patients, data for overall RR (≥ 50% transfusion reduction) in TDT and subgroup-specific response rates based on predefined haemoglobin increment thresholds in NTDT were not reported. Therefore, these outcomes were not included in the pooled categorical analysis. Seventeen studies involving 1124 patients were evaluated for safety/adverse events analysis. The assessment of the safety profile of thalidomide was not an outcome in studies of Yang et al. and Bawazir et al. 38 , 40 .

Study quality

Based on the NIH quality assessment tool for before-after (pre-post) studies with no control group, the included 17 studies were of either “good” or “fair” quality, with no major alarming bias (see additional file 1: Supplementary Table 1 ). However, it was challenging to determine whether all enrolled subjects met the entry criteria, as some studies did not include sociodemographic details or baseline clinical characteristics of the patients. Also, in some studies, it was unclear whether all eligible participants were enrolled, which could have led to a selection bias. Furthermore, the small sample size was a common drawback across many studies, limiting the statistical power of the outcome of individual studies. In all studies, the outcome assessors were not blind to the intervention, which could have led to potential bias in the final results of the studies.

The risk of bias of the RCTs was assessed using the Rob2 tool for randomised controlled trials. It revealed that two RCTs included in this meta-analysis demonstrated a low risk of bias in most of the key domains (See additional file 1: Supplementary Fig. 1 ).

Response to thalidomide

We evaluated the pooled response rates for TDT and NTDT separately (Fig. 2 ). Based on the random effects model, the pooled thalidomide RR in TDT (defined as a decline of blood transfusion requirement by ≥ 50%) was 0.76 [95%CI, 0.67–0.83], with high heterogeneity ( I 2 = 84.2%, p < 0.0001 ). Among patients with NTDT, the pooled thalidomide RR was 0.91 [95% CI: 0.81–0.96], indicating 91% of patients had shown a haemoglobin increment of > 1 g/dL compared to baseline following thalidomide treatment. There was no heterogeneity among the studies ( I 2 = 0.0%, p = 0.49). Fig. 2 Forest plots of thalidomide response in β-thalassaemia. Note: CI- confidence interval; TDT- transfusion-dependent β-thalassaemia; NTDT- Non-transfusion-dependent β-thalassaemia; ES- effect size.

Good response to thalidomide

The pooled good RR, defined as complete cessation of blood transfusions following thalidomide treatment, in TDT was 0.55 [95%CI, 0.47–0.63], with moderate heterogeneity ( I 2 = 85.1%, p < 0.0001) between studies (Fig. 3 ). The pooled good RR, defined as haemoglobin increment of > 2 g/dL compared to baseline following thalidomide treatment, in NTDT was 0.76 [95%CI, 0.63–0.85]. The heterogeneity among studies was considerably low ( I 2 = 22.0% and p = 0.27). Fig. 3 Forest plots of thalidomide good response in β-thalassaemia. Note: CI- confidence interval; TDT- transfusion-dependent β-thalassaemia; NTDT- Non-transfusion-dependent β-thalassaemia; ES- effect size.

Adverse events of thalidomide

All studies, excluding Yang et al. 37 and Li et al. 42 , reported the safety profile of thalidomide. A total of 1670 patients were considered in the safety analysis. The included 17 studies reported a total of 1004 incidents, comprising 36 types of adverse events developed during the intervention period while on thalidomide. These were grouped as general, muco-cutaneous, gastrointestinal, liver-related, haematological, neurological, rheumatological, psychological, immunity and infections, and other (Table 3 ). Table 3 Adverse events. Adverse event Study Total (n = 1620) Ali et al., (n=532) Bhattacharjee et al,. (n=14) Chandra et al., (n=37) Chen et al., (n=50) Jain et al., (n=15) Jian et al., (n=22) Ju et al., (n=42) Li et al., (n=77) Nag et al., (n=21) Ren et al., (n=14) Yang et al., (n=52) Yassin et al., (n=37) Dolai et al,.(n=404) Li et al,. (n=170) Rahman et al.,(n=72) Singha et,.(n=61)* General Somnolence 11 3 21 10 15 129 2 55 298 (18.40%) Dizziness 5 20 24 3 Lethargy/fatigue 15 4 49 68 (4.20%) Weight gain 6 6 (0.37%) Anorexia 4 4 (0.25%) Muco-cutaneous Skin rash 5 9 12 1 1 4 4 3 4 43 (2.65%) Eyelid/facial oedema 3 3 9 15 (0.93%) Xerostomia 1 1 (0.06%) Gastrointestinal Constipation 33 1 14 5 2 5 9 10 2 2 10 129 4 15 9 250 (15.43%) Nausea/vomiting/abdominal pain 15 15 9 9 13 61 (3.77%) Liver-related Hyperbilirubinemia 1 1 5 7 (0.43%) Portal vein thrombosis 2 2 (0.12%) Transaminitis 1 1 (0.06%) Neurological Limb numbness/paresthesia 4 3 7 3 17 (1.05%) Peripheral neuropathy 2 8 10 (0.62%) Syncope/presyncope 3 3 (0.19%) Headache 2 2 5 6 15 (0.93%) Cerebrovascular accident 2 2 (0.12%) Central vein thrombosis 1 1 (0.06%) Seizures 1 1 2 (0.12%) Haematological Neutropenia 6 10 10 28 26 (1.60%) Thrombocytosis 9 33 42 (2.59%) Leukocytopenia 1 7 22 30 (1.85%) D-dimer elevation 6 6 (0.37%) Nose bleed 3 3 (0.19%) AIHA 1 1 (0.06%) Extra medullary haematopoiesis 1 1 (0.06%) Immunity and Infections Infections 8 10 18 (1.11%) Pyrexia 12 12 (0.74%) Rheumatological Mild joint swelling, hand and foot pain 4 2 4 3 13 (0.80%) Arthralgia 4 8 12 (0.74% Ostealgia 2 2 (0.12%) Renal AKD 1 1 (0.06%) Psychological Distress/depression/ irritability 1 2 4 7 (0.43%) Other Chest tightness menstrual disorders 1 7 1 2 9 (0.5 6%) AIHA- Auto Immune Haemolytic Anaemia; AKD- Acute Kidney Disease; *only clearly mentioned adverse events were pooled.

The majority of the patients experienced constipation followed by somnolence and dizziness as adverse effects of thalidomide. The pooled incidence rates for peripheral neuropathy and limb numbness/paraesthesia were both 1.5%, indicating a similar occurrence among the included studies. Most of the adverse reactions were either mild or moderate in severity.

One patient was diagnosed with acute kidney injury, a serious adverse event during the treatment. However, the patient was on deferasirox, an iron chelator with an established link to renal complications. Extramedullary haematopoiesis was identified in one patient, and it was resolved after replacing thalidomide with hydroxyurea. Thalidomide was discontinued in five (4.5%) patients after the development of seizures (n = 1), cerebrovascular thrombosis (n = 1), cerebrovascular incidents (n = 2) and portal vein thrombosis (n = 2). A child with β-thalassaemia major developed acute autoimmune haemolytic anaemia, and all other potential aetiologies were ruled out. However, the child did not require transfusions after 3 months of discontinuing thalidomide.

Mishra et al. reported liver toxicity in 12% of β-thalassaemia patients, mainly manifesting as transaminitis and hyperbilirubinemia. Singha et al. observed mild adverse effects in 15 patients. The most common side effect was constipation (n = 9), and the remaining experienced rash, neutropenia, paresthesia, joint pain and headache. However, individual event frequencies were not reported in these studies. Therefore, these events could not be incorporated into the pooled adverse-event summary table.

Effects of thalidomide on spleen size

Nine studies comprising 1183 β-thalassaemia patients reported the impact of thalidomide on the spleen 16 , 28 , 31 , 33 , 36 , 41 , 43 – 45 . Among them, only Dolai et al. 41 , Rahman et al. 44 and Singha et al. 45 observed a statistically significant reduction in spleen size.

Effects of thalidomide on serum ferritin

Several studies reported serum ferritin as an indicator of iron overload in β-thalassaemia patients 16 , 17 , 30 – 33 , 37 , 38 , 41 , 44 , 45 . Although diverse reporting formats were used, a significant reduction in serum ferritin was noticed in all the patients. Nag et al. observed a decline in serum ferritin levels in both responders and non-responders; however, values remained higher in non-responders. Even though Chen et al. failed to identify a significant reduction in serum ferritin after 3 months of thalidomide therapy, the ferritin levels reduced after 6 months.

Overall, despite heterogeneity in study design, follow-up duration, and clinical characteristics of patients, all studies reported a statistically significant decrease in serum ferritin following thalidomide therapy. A detailed summary of ferritin outcomes of each study is provided in the Supplementary Table 3 (See additional file 1: Supplementary Table 2 ).

Sensitivity analysis and publication bias

To further assess the heterogeneity, sensitivity analysis of pooled outcomes, and the reliability of pooled outcomes were conducted for TDT. After removing individual studies, the pooled RR and good RR varied between 74–78% and 58–61%, respectively, indicating stable pooled results. Similarly, heterogeneity (I 2 ) did not change significantly. After removing Dolai 2025, the heterogeneity (I 2 ) reduced to 80%, increasing the good RR to 0.60. However, based on the sensitivity analysis, exclusion of any single study did not significantly alter the RR or good RR in TDT patients.

Egger’s regression test concluded that there is no significant publication bias for studies reporting RR ( p = 0.07) and good RR ( p = 0.29) in studies focused on the TDT patient cohort (Fig. 4 ). Since only five studies were included in the NTDT category, assessment of publication bias via Egger’s test was not feasible. The observed marginal asymmetry in the funnel plots might be due to random variation rather than publication bias. Fig. 4 Funnel plots of thalidomide responses in β-thalassaemia patients. ( a ) A response rate (RR) of transfusion-dependent β-thalassaemia patients, Egger’s test p = 0.07. ( b ) The good response rate (good RR) of transfusion-dependent β-thalassaemia patients, Egger’s test p = 0.29.

Discussion

β-Thalassaemia is one of the most extensively studied genetic disorders globally. Yet in many countries, disease management primarily relies on symptomatic management, including blood transfusions and iron chelation. Several pharmacological agents that could improve anaemia in β-thalassaemia have been identified recently. However, their efficacy and safety are yet to be evaluated fully.

Among the pharmacological agents with the potential to improve anaemia in β-thalassaemia, fetal haemoglobin inducers have shown significant promise. Hydroxyurea is the most commonly used fetal haemoglobin inducer due to its reported efficacy and safety. However, several studies have highlighted the limited benefit of hydroxyurea confined to a subset of patients (e.g., haemoglobin E β-thalassaemia) and a transient response 47 , 48 . The applicability of ruxolitinib, a recently introduced efficient pharmacological agent 11 , is restricted in the developing world due to financial constraints. ZYNTEGLO, a gene therapy recently approved by the U.S. Food and Drug Administration (FDA) for haemoglobin β-thalassaemia major, costs USD 2.8 million per patient. Thus, the development of a more affordable, yet potent pharmacologic option for β-thalassaemia remains an unmet need.

Numerous studies have been done to delineate the mechanism of upregulation of γ-globin expression with thalidomide. Thalidomide is known to stimulate intracellular reactive oxygen species (ROS) synthesis via induction of erythroid transcription factors, including GATA binding factor 1 (GATA-1), and exert anti-inflammatory properties via inhibition of tumour necrosis factor-α (TNF-α) 13 , 49 . The resulting high ROS levels have been identified to promote the p38 mitogen-activated protein kinase (MAPK) signalling pathway and histone H4 acetylation, increasing the γ-globin expression 50 . Erythroid Krupple-like factor (EKLF) and GATA-1, which are induced by thalidomide, play a vital role in erythroid differentiation and the expression of globin genes 49 .

Recent studies discovered that thalidomide promotes the proliferation of immature erythroid precursors and slows down erythroid differentiation, subsequently inducing γ-globin and fetal haemoglobin levels in β-thalassaemia patients 50 – 52 . Furthermore, a post hoc analysis of a randomised controlled trial including 100 patients revealed that thalidomide can increase red blood cell life span and prevent haemolysis in β-thalassaemia major patients, significantly improving quality of life 15 .

Among the studies included in this systematic review, only two were randomized controlled trials (RCTs). Findings of this meta-analysis concluded that thalidomide is efficient in reducing transfusion need and increasing haemoglobin levels in β-thalassaemia patients. Fifty-five percent (55%) of TDT patients became transfusion independent with thalidomide treatment, and 76% experienced more than 50% reduction in transfusion volumes. Significant haemoglobin increment was observed in 91% of the NTDT patients, which would improve their clinical phenotype, including transfusion requirement. Achieving transfusion independence is a significant medical gain. Similarly, reduced transfusion requirement and higher haemoglobin levels have numerous short- and long-term benefits, including reduced iron overload, lower risk of transfusion-associated complications, improved quality of life, and reduced healthcare cost. Findings of this meta-analysis confirm the findings of a previously conducted meta-analyses published in 2022 53 , 54 .

Blood transfusions can cause a significant burden to national healthcare budgets. The high cost of iron chelators worsens this. As the majority of the thalassaemia patients live in developing countries, more affordable adjuvant therapy, such as thalidomide, could have a substantial impact on countries’ health care systems 6 . This is supported by the observation that all studies included in this meta-analysis were conducted in the developing world.

Emerging evidence indicates the efficacy of thalidomide in β-thalassaemia patients even at relatively low doses. In TDT, response to thalidomide was not significantly different between patients who received low and standard doses 39 , 46 . This suggests that the higher efficacy could not be entirely dependent on dose intensification. While earlier case reports describe sustained haemoglobin improvement at higher doses (75–100 mg/day), several studies have demonstrated responses at substantially lower doses (1–2 mg/kg/day) , specifically in NTDT patients 55 , 56 .

Thalidomide was generally well tolerated. Almost half of the patients did not experience any adverse events. All the adverse events were transient and reversible. Most of the adverse events resolved spontaneously or with lowering of the dose. In patients who discontinued thalidomide, adverse events were reversed in about two weeks after drug cessation. Teratogenicity is the major drawback associated with thalidomide. Thalidomide is contraindicated during pregnancy despite the alterations made to its chemical structure to reduce embryotoxicity 57 . All studies using thalidomide excluded pregnant and lactating women, while some studies excluded sexually active women who were not willing to use birth control methods.

Iron overload is one of the main complications of β-thalassemia and is usually assessed by serum ferritin levels. Several studies reported a significant decline in serum ferritin following thalidomide therapy, which could be attributed to the improvements in ineffective erythropoiesis and reduction in transfusion requirements observed in many patients. However, the diverse formats of ferritin outcomes restricted the ability to directly compare the influence of thalidomide on serum ferritin levels across studies.

Recent studies have identified a few genetic predictors of thalidomide response in β-thalassaemia patients. Variants in HbF regulatory loci, especially single nucleotide polymorphisms (SNP) in the HBS1L–MYB intergenic region (e.g., rs9399137), have been associated with significant haematologic response to thalidomide, supporting the concept of HbF regulatory pathways modulation via the drug. The impact of SNPs in HBG2 (rs7482144) and BCL11A (rs4671393) on the response to the treatment remains inconsistent across studies 37 , 58 . Although there were no statistically significant differences in the responses among patients carrying β 0 /β 0 , β 0 /β + and β + /β + mutations 30 , 42 , the most common genetic mutation combinations among good responders were βCD41-42/βCD17 and βCD41-42/β-28 15 .

Moreover, additional polymorphisms outside the regulatory regions of HbF, such as CHI3L1, NPNT, and ZNF208, also influence the treatment response. The three commonest SNPs among excellent responders were in the exon region of CHI3L1 (rs880633), NPNT (rs35132891), and ZNF 208 (rs10425763) 40 suggesting the influence of additional molecular mechanisms determining thalidomide treatment responsiveness.

Graphical evaluation of the forest plots for good RR and RR for TDT revealed wide and partially overlapping 95%CIs, indicating heterogeneity among studies, evident by large I 2 values. The observed heterogeneity is not surprising considering the weak correlation between β-thalassaemia genotype and phenotype, and the variability among the study characteristics across the included studies. The random effect model considers within-study and between-study variations and was therefore considered when heterogeneity was higher to generate a more conservative analysis. The leave-one-out sensitivity analysis resulted in only minor changes in heterogeneity estimates as well as the response rates. For response rate in TDT patients, this indicates that the observed heterogeneity in the current meta-analysis is not driven by a single influential study but most likely attributed to the genuine clinical and methodological variability across studies.

Limitations of the study

The current meta-analysis has a few limitations. The imbalance between the study designs with only 2/18 studies representing 64/1689 (4%) participants being RCTs is the major limitation of this analysis. Most of the studies were single-arm studies with no control groups, and the follow-up durations were relatively short, which might lead to the omission of the long-term impact of thalidomide from the conclusion. Language and database restrictions were other limitations. Only articles published in English and indexed in Scopus, PubMed and Cochrane databases were included, which may have resulted in a probability of excluding relevant records indexed in other databases and published in other languages. Additionally, conference proceedings, abstracts, case reports, and case series were not included, which could result in the omission of related information. Finally, another limitation of this meta-analysis is that most of the included studies were conducted in a limited number of countries.

Conclusion

Thalidomide appears to be effective and tolerable in β-thalassaemia patients. It increased the haemoglobin levels in NTDT patients and reduced the transfusion requirement in TDT patients. Somnolence and constipation were the most common side effects, and the incidence rates of other adverse events were lower. However, further double-blind RCTs assessing the efficacy of thalidomide in β-thalassaemia patients with longer follow-up durations are important to confirm the findings of this meta-analysis and to evaluate the long-term adverse effects and sustained therapeutic effects of thalidomide.

Supplementary Information

Supplementary Information 1. Supplementary Information 2.

Abbreviations

Auto immune hemolytic anemia

Acute kidney disease

Confidence interval

Meta-analysis of observational studies in epidemiology

National institutes of health

Non-transfusion dependent β-thalassaemia

Recommendations of the preferred reporting items for systematic reviews and meta-analyses

Prospective register of systematic reviews

Randomized clinical trials

Revised cochrane risk-of-bias tool for randomized trials 2

Response rate

Transfusion-dependent β-thalassaemia

Publisher’s note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Acknowledgements

Not applicable.

Author contributions

NY: Conceptualization, literature search, article selection, Data extraction, formal analysis, Writing – review & editing. ST: Literature search, Data extraction, formal analysis KP: Article selection, Data extraction AP: Conceptualization, supervision, Validation, Review SM: Conceptualization, Supervision, Validation, Writing – review & editing.

Funding

The authors have not received any financial support.

Data availability

The dataset supporting the conclusions of this article is included within the article and its additional files. Further inquiries can be directed to the corresponding authors.

Declarations

Competing interests

The authors declare no competing interests.

Ethics approval and consent to participate

Not applicable.

Consent for publication

Not applicable.

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