Safety and effectiveness of thalidomide and hydroxyurea combination in β-thalassaemia intermedia and major: a retrospective pilot study
Several new treatment modalities including fetal globin gene reactivation, allogeneic haematopoietic stem cell transplantation (alloHSCT) and gene therapy are being explored to correct the disparity in α/β globin chains in thalassaemia (de Dreuzy et al., 2016). Fetal haemoglobin (HbF) expression could decrease ineffective erythropoiesis by reducing the build-up and precipitation of α-globin chains (Soni, 2017). Thalidomide, a drug known for immunomodulating and anti-angiogenic properties, has been shown to induce γ-globin gene expression and increase the proliferation of erythroid cells (Gambari, 2010), which could be through the amplification of reactive oxygen species (ROS)-p38 mitogen-activated protein kinase (MAPK) signalling and histone H4 acetylation during adult erythropoiesis (Aerbajinai et al., 2007). Furthermore, hydroxyurea (HU) is known to increase haemoglobin (Hb) by HbF induction and reduction of inflammation and hypercoagulability (Keikhaei et al., 2015).
A combination of thalidomide with HU for thalassaemia management has not been studied in a clinical setting to the best of our knowledge. In this single-centre, retrospective observational study, we reviewed the medical records of transplant ineligible [according to International Consensus Criteria (Angelucci et al., 2014): no fully matched sibling donor or very high-risk of transplant-related morbidity and mortality] patients of either sex with a confirmed diagnosis of β-thalassaemia major (severe anaemia, requirement of blood transfusions within the first two years of life) or β-thalassaemia intermedia (moderate anaemia, never transfused or sporadically transfused during infections or surgery, and transfusion dependent after 2 years of life) (Taher et al., 2009; Galanello & Origa, 2010), who were treated with thalidomide [dose: 50 mg once daily (OD) for <30 kg body weight (BW); 100 mg OD for >30 kg BW] and HU (500 mg daily) combination from Jul 2017 to Sep 2018 at Hemato-oncology Clinic, Vedanta Institute of Medical Sciences, Ahmedabad, India. This retrospective study was reviewed and approved by the ethics committee. Deferasirox, folic acid (5 mg) and aspirin (75/150 mg) were also administered. Medical charts had recorded informed consent for treatment and counselling regarding teratogenic potential of thalidomide.
The study endpoints were: (i) increase in Hb levels from baseline at 1, 2 and 3 months; (ii) percentage of patients with major response (Hb increments >20 g/l) and minor response (Hb increments: 10–20 g/l) (Ren et al., 2018); and (iii) percentage of responders (transfusion independent after therapy) and non-responders (requiring transfusion after treatment) (Italia et al., 2009). The endpoints were also compared between thalassaemia intermedia and thalassaemia major subgroups.
Of 25 patients in this study, 60% (n = 15) had β-thalassaemia intermedia and 40% (n = 10) had β-thalassaemia major. The majority (68%) were males, mean age was 14·4 years (range: 3–36 years), mean age at diagnosis was 31·4 months and at first transfusion, 28·3 months. Splenomegaly was observed in 80% of patients and splenectomy was performed in 20% of patients. Patients had varying degrees of iron overload (serum ferritin: 138–9777 ng/ml) with average Hb levels between 41 and 110 g/l at baseline.
After thalidomide and HU combination treatment, Hb levels (g/l) significantly increased from baseline (76·4 ± 16·7) to 1 month (85·4 ± 17·3, P = 0·0106), 2 months (92·2 ± 19·4, P = 0·0002) and 3 months (94·6 ± 21·8 g/l, P = 0·0014), respectively; these changes were significant for the thalassaemia intermedia subgroup at all timepoints [baseline: 81·2 ± 16·7, 1 month: 94·6 ± 14·6 (P = 0·0107), 2 months: 102·6 ± 12·0 (P = 0·0004) and 3 months: 106·9 ± 11·9 (P = 0·0004)] but not significant for the thalassaemia major subgroup [baseline: 68·7 ± 16·0, 1 month: 72·0 ± 12·6 (P = 0·4352), 2 months: 78·6 ± 20·1 (P = 0·1387) and 3 months: 74·3 ± 20·7 (P = 0·4688)]. In the thalassaemia major subgroup, Hb levels were not available post-treatment in one patient at 1 month, and in two patients at 3 months, and in the thalassaemia intermedia subgroup in one patient each at 2 and 3 months (Table 1). Individual Hb values for patients with thalassaemia intermedia and thalassaemia major are presented in Figs 1A and 1B, respectively. Thalidomide was stopped in two patients in the thalassaemia major subgroup [one patient with Hb 105 g/l at 2 months underwent a bone marrow transplant (BMT), and another patient had a low Hb of 55 g/l after 3 months].
| Sr No | Thalassaemia type | Age (years) | Gender | Age at diagnosis (mos) | Transfusion frequency | Baseline Hb level | Hb levels | |||
|---|---|---|---|---|---|---|---|---|---|---|
| Pretreatment | 3 mos | 1 mo | 2 mos | 3 mos | ||||||
| 1 | Intermedia | 8 | F | 84 | 1 U/mo | None | 77 | 100 | 107 | 108 |
| 2 | Intermedia | 13 | M | 60 | 1 U/6 mos | None | 110 | 106 | 109 | 112 |
| 3 | Intermedia | 15 | F | 36 | 2 U/mo | 1 U/2 mos | 87 | 87 | 96 | 88 |
| 4 | Intermedia | 15 | M | 72 | 4 U/mo | None | 55 | 72 | 114 | 134 |
| 5 | Intermedia | 12 | F | 24 | 1 U/mo | None | 52 | 89 | 83 | 97 |
| 6 | Intermedia | 13 | M | 30 | 2 U/mo | None | 83 | 94 | 97 | 105 |
| 7 | Intermedia | 15 | M | 24 | 2 U/mo | None | 69 | 117 | 112 | 110 |
| 8 | Intermedia | 18 | M | 36 | 2 U/mo | None | 74 | 79 | 88 | 88 |
| 9 | Intermedia | 14 | M | 108 | 1 U/mo | None | 81 | 110 | 113 | 110 |
| 10 | Intermedia | 13 | M | 84 | 2 U/mo | None | 88 | 89 | 94 | 106 |
| 11 | Intermedia | 12 | M | 36 | NT | NT | 88 | 91 | LFU | LFU |
| 12 | Intermedia | 7 | F | 36 | NT | NT | 80 | 86 | 93 | 97 |
| 13 | Intermedia | 23 | M | 36 | 2 U/mo | 1 U/mo | 106 | 118 | 121 | 115 |
| 14 | Intermedia | 18 | F | 36 | 4 U/mo | None | 88 | 89 | 111 | 112 |
| 15 | Intermedia | 36 | F | 30 | 2 U/mo | 2 U/mo | 86 | 80 | 89 | 105 |
| 16 | Major | 3 | M | 6 | 1 U/mo | None | 60 | 93 | 104 | 111 |
| 17 | Major | 8 | M | 3 | 2 U/mo | NA | 69 | 58 | 63 | LFU |
| 18 | Major | 16 | M | 4 | 4 U/mo | 4 U/mo | 79 | 73 | 69 | 59 |
| 19 | Major | 15 | M | 12 | 2 U/mo | None | 62 | 76 | 89 | 81 |
| 20 | Major | 10 | M | 3 | 2 U/3 mos | None | 98 | 74 | 105 | 92 |
| 21 | Major | 14 | M | 5 | 1 U/mo | None | 80 | NA | 90 | LFU |
| 22 | Major | 13 | F | 7 | 1 U/mo | 1 U/mo | 65 | 78 | 62 | 61 |
| 23 | Major | 18 | M | 6 | 1 U/mo | NA | 79 | 82 | 71 | 53 |
| 24 | Major | 22 | M | 3 | 1–2 U/mo | 1 U/mo | 54 | 60 | 90 | 82 |
| 25 | Major | 16 | F | 4·5 | 2 U/mo | 2 U/mo | 41 | 54 | 43 | 55 |
- ‘Intermedia’ designates β-thalassaemia intermedia, and ‘Major’ designates β-thalassaemia major. LFU, lost to follow-up; mo(s): month(s); NA, not available; U, unit(s). Hb levels were not available in one patient with thalassaemia major at 1 month, one patient with thalassaemia intermedia at 2 months (LFU), and three patients [two patients with thalassaemia major (one patient LFU) and one patient with thalassaemia intermedia (LFU)] at 3 months respectively.
The overall response rates (major + minor response) were 47·8%, 58·3% and 68·2% at 1, 2 and 3 months, respectively (thalassaemia intermedia: 46·7%, 71·5% and 78·6%; thalassaemia major: 44·4%, 40% and 50%, respectively) (Fig 1C).
In the thalassaemia intermedia subgroup (n = 15), two patients did not receive transfusion before and after treatment; one patient had increased Hb at all timepoints; the other had increased Hb at 1 month and was lost to follow-up. Of remaining 13 patients, 76·9% (10/13) were ‘responders’ and 23·1% (3/13) were ‘non-responders’; in the three patients who required transfusion post-treatment, a decrease in transfusion frequency by 50% was seen in two whereas it remained same in the third patient. Transfusion details for two patients in the thalassaemia major (n = 10) group were not available post-treatment; of the remaining eight patients, 62·5% (5/8) were ‘responders’ whereas 37·5% (3/8) were ‘non-responders’ and continued blood transfusions with similar frequency. Overall, transfusion independence was reported in 71·4% (15/21) patients (Fig 1D).
Total red and white blood cells, haematocrit and absolute neutrophil counts significantly increased while there was a non-significant decrease in serum ferritin levels. These changes were statistically significant for the thalassaemia intermedia subgroup but not for the thalassaemia major subgroup. A total of 15 adverse events were reported in 11 patients; of which thrombocytopenia was the most common adverse event reported (60%). No new safety concerns were observed.
The study’s limitations include its retrospective nature and a short follow-up duration of 3 months. Furthermore, the HbF levels were not measured in this study due to financial constraints of the patients; and hence, could not be reported.
This is the largest such series of patients in which the combination of thalidomide and HU has been evaluated. We document maintenance of Hb levels, transfusion independence and reduction in iron overload and other haematological parameters in most of our patients. Our data suggests that thalidomide and HU combination therapy is effective in high-risk patients ineligible (no fully matched sibling donor/very high-risk of transplant-related morbidity and mortality) or not willing to undergo bone marrow transplant (poor disease characteristics/economic reasons) and could be used as a bridge to transplantation in ineligible thalassaemia patients who are awaiting identification of a donor or whose degree of iron overload predicts significant treatment-related toxicity. Prospective long-term efficacy and safety studies with thalidomide and HU combination may elicit better results to influence clinical practice.
Acknowledgements
The authors wish to thank Mr. Shreekant Sharma (ISMPP CMPP™), Mr. Harshil Modi and Dr Venugopal Madhusudhana (ISMPP CMPP™) (Lambda Therapeutic Research Ltd.) for providing writing assistance, statistical analysis, and editorial assistance, respectively. The authors also thank Drs Deepak Bunger and Mujtaba Khan (Intas Pharmaceuticals Ltd.) for medical review inputs.
Funding/support
The statistical analysis and manuscript development were supported by an unrestricted research grant by Intas Pharmaceuticals Limited.
Conflict of interest disclosure
None declared.
Author contributions
Sandip Shah had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis. All authors equally contributed to the concept and design, acquisition, analysis, or interpretation of data, and drafting/review of the manuscript.
