Non-transfusion-dependent β-thalassaemia (NTDβT) is a subset of inherited haemoglobin disorders characterised by reduced production of the β-
globin chain of haemoglobin leading to anaemia of varying severity. Although
blood transfusion is not a necessity for survival, it may be required to prevent complications of chronic anaemia, such as impaired growth and
hypercoagulability. People with NTDβT also experience
iron overload due to increased
iron absorption from food sources which becomes more pronounced in those requiring
blood transfusion. People with a higher foetal haemoglobin (HbF) level have been found to require fewer
blood transfusions, thus leading to the emergence of treatments that could increase its level. HbF inducers stimulate HbF production without altering any gene structures. Evidence for the possible benefits and harms of these inducers is important for making an informed decision on their use.
OBJECTIVES: We used standard, extensive Cochrane search methods. The latest search date was 21 August 2022.
SELECTION CRITERIA: We included randomised controlled trials (RCTs) or quasi-RCTs comparing single HbF inducer with placebo or usual care, with another single HbF inducer or with a combination of HbF inducers; or comparing different doses of the same HbF inducer.
DATA COLLECTION AND ANALYSIS: We included seven RCTs involving 291 people with NTDβT, aged two to 49 years, from five countries. We reported 10 comparisons using eight different HbF inducers (four pharmacological and four natural): three RCTs compared a single HbF inducer to placebo and seven to another HbF inducer. The duration of the intervention lasted from 56 days to six months. Most studies did not adequately report the randomisation procedures or whether and how blinding was achieved. HbF inducer against placebo or usual care Three HbF inducers,
HQK-1001,
Radix Astragali or a 3-in-1 combined natural preparation (CNP), were compared with a placebo. None of the comparisons reported the frequency of
blood transfusion. We are uncertain whether
Radix Astragali and CNP increase haemoglobin at three months (mean difference (MD) 1.33 g/dL, 95% confidence interval (CI) 0.54 to 2.11; 1 study, 2 interventions, 35 participants; very low-certainty evidence). We are uncertain whether
Radix Astragali and CNP have any effect on HbF (MD 12%, 95% CI -0.74% to 24.75%; 1 study, 2 interventions, 35 participants; very low-certainty evidence). Only medians on haemoglobin and HbF levels were reported for
HQK-1001. Adverse effects reported for
HQK-1001 were
nausea,
vomiting,
dizziness and suprapubic
pain. There were no prespecified adverse effects for
Radix Astragali and CNP. HbF inducer versus another HbF inducer Four studies compared a single inducer with another over three to six months. Comparisons included
hydroxyurea versus
resveratrol,
hydroxyurea versus
thalidomide,
hydroxyurea versus
decitabine and
Radix Astragali versus CNP. No study reported our prespecified outcomes on
blood transfusion. Haemoglobin and HbF were reported for the comparison
Radix Astragali versus CNP, but we are uncertain whether there were any differences (1 study, 24 participants; low-certainty evidence). Different doses of the same HbF inducer Two studies compared two different types of HbF inducers at different doses over two to six months. Comparisons included
hydroxyurea 20 mg/kg/day versus 10 mg/kg/day and
HQK-1001 10 mg/kg/day, 20 mg/kg/day, 30 mg/kg/day and 40 mg/kg/day.
Blood transfusion, as prespecified, was not reported. In one study (61 participants) we are uncertain whether the lower levels of both haemoglobin and HbF at 24 weeks were due to the higher dose of
hydroxyurea (haemoglobin: MD -2.39 g/dL, 95% CI -2.80 to -1.98; very low-certainty evidence; HbF: MD -10.20%, 95% CI -16.28% to -4.12%; very low-certainty evidence). The study of the four different doses of
HQK-1001 did not report results for either haemoglobin or HbF. We are not certain if major adverse effects may be more common with higher
hydroxyurea doses (
neutropenia: risk ratio (RR) 9.93, 95% CI 1.34 to 73.97;
thrombocytopenia: RR 3.68, 95% CI 1.12 to 12.07; very low-certainty evidence). Taking
HQK-1001 20 mg/kg/day may result in the fewest adverse effects. A combination of HbF inducers versus a single HbF inducer Two studies compared three combinations of two inducers with a single inducer over six months:
hydroxyurea plus
resveratrol versus
resveratrol or
hydroxyurea alone, and
hydroxyurea plus
l-carnitine versus
hydroxyurea alone.
Blood transfusion was not reported.
Hydroxyurea plus
resveratrol may reduce haemoglobin compared with either
resveratrol or
hydroxyurea alone (MD -0.74 g/dL, 95% CI -1.45 to -0.03; 1 study, 54 participants; low-certainty evidence). We are not certain whether the gastrointestinal disturbances,
headache and malaise more commonly reported with
hydroxyurea plus
resveratrol than
resveratrol alone were due to the interventions. We are uncertain whether
hydroxyurea plus
l-carnitine compared with
hydroxyurea alone may increase mean haemoglobin, and reduce
pulmonary hypertension (1 study, 60 participants; very low-certainty evidence). Adverse events were reported but not in the intervention group. None of the comparisons reported the outcome of HbF.
AUTHORS' CONCLUSIONS: We are uncertain whether any of the eight HbF inducers in this review have a beneficial effect on people with NTDβT. For each of these HbF inducers, we found only one or at the most two small studies. There is no information on whether any of these HbF inducers have an effect on our primary outcome,
blood transfusion. For the second primary outcome, haemoglobin, there may be small differences between intervention groups, but these may not be clinically meaningful and are of low- to very low-certainty evidence. Data on adverse effects and optimal doses are limited. Five studies are awaiting classification, but none are ongoing.