Hydroxyurea for reducing blood transfusion in non-transfusion dependent beta thalassaemias

Foong, Kelvin Weng Chiong; Ho, Jacqueline J; Loh, C-Khai; Viprakasit, Vip

doi:10.1002/14651858.cd011579.pub2

Cited by 17 publications

(13 citation statements)

References 58 publications

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“…The relevance of these reports is due to the fact that no treatment has been so far approved concerning HbF inducers in thalassemia. While hydroxyurea (HU) is frequently used (despite the lack of formal approval), its use is limited by the potential adverse effects and reported efficacy in only a subset of patients [37][38][39]. Thus, a substantial percentage of thalassemia patients are not treated with HU and may benefit by other treatments.…”

Section: Introductionmentioning

confidence: 99%

Expression of γ-globin genes in β-thalassemia patients treated with sirolimus: results from a pilot clinical trial (Sirthalaclin)

Zuccato

Cosenza

Zurlo

et al. 2021

Preprint

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Introduction: The β-thalassemias are due to autosomal mutations of the β-globin gene, inducing absence or low-level synthesis of β-globin in erythroid cells. It is widely accepted that high production of fetal hemoglobin (HbF) is beneficial for β-thalassemia patients. Sirolimus, also known as rapamycin, is a lipophilic macrolide isolated from a strain of Streptomyces hygroscopicus found to be a strong HbF inducer in vitro and in vivo. In this study, we report biochemical, molecular and clinical results of the sirolimus-based NCT03877809 clinical trial (A Personalized Medicine Approach for β-thalassemia Transfusion Dependent Patients: Testing sirolimus in a First Pilot Clinical Trial: Sirthalaclin). Methods: Accumulation of γ-globin mRNA was analyzed by reverse-transcription-quantitative PCR and the hemoglobin pattern by HPLC. The immunophenotype was analyzed by FACS using antibodies against CD3, CD4, CD8, CD14, CD19, CD25. Results: The results were obtained in 8 patients with β+/β+ and β+/β0 genotypes, treated with a starting dosage of 1 mg/day sirolimus for 24-48 weeks. The first finding of the study was that expression of γ-globin mRNA was increased in blood and erythroid precursor cells isolated from β-thalassemia patients treated with low-dose sirolimus. A second important conclusion of our trial was that sirolimus influences erythropoiesis and reduces biochemical markers associated to ineffective erythropoiesis (I.E.) (excess of free α-globin chains, bilirubin, soluble transferrin receptor and ferritin). In most (7/8) of the patients a decrease of the transfusion index was observed. The drug was well tolerated with minor effects on immunophenotype, the only side effect being frequently occurring stomatitis. Conclusions: The data obtained indicate that sirolimus given at low doses modifies hematopoiesis and induces increased expression of γ-globin genes in a sub-set of β-thalassemia patients. Further clinical trials are warranted, considering the possibility to test the drug in patients with less severe forms of the disease and exploring combination therapies.

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Section: Introductionmentioning

confidence: 99%

Expression of γ-globin genes in β-thalassemia patients treated with sirolimus: results from a pilot clinical trial (Sirthalaclin)

Zuccato

Cosenza

Zurlo

et al. 2021

Preprint

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“…Inherited hemoglobin disorders (such as sickle-cell disease and thalassemias) are among the most frequent monogenic diseases, originally characteristic of the tropics and subtropics, but now commonly distributed worldwide, mainly due to migration [ 38 ]. Hydroxyurea (HU) is currently the only FDA-approved drug for the induction of HbF in SCD patients, but it is effective in only 70% of patients, and a solution is required for the 30% non-responders [ 39 ], while regarding β -thalassemia patients, in spite of its sustained benefits for some untransfused patients with β -thalassemia intermedia [ 24 , 25 ], specific approvals for β -thalassemia are lacking. Therefore, HbF induction might be of great interest for the development of therapeutic protocols for these hemoglobinopathies [ 13 , 23 , 38 ].…”

Section: Discussionmentioning

confidence: 99%

“…Currently, hydroxyurea (HU) is the only FDA-approved therapeutic treatment for the induction of HbF in SCD patients [ 13 , 23 ]. With respect to β -thalassemia, in spite of its verified benefits in certain cases, demonstrated by the reach of a transfusion-independent phenotype in patients with β -thalassemia intermedia [ 24 , 25 ], specific approvals for β -thalassemia are lacking. On the other hand, adverse effects and potential toxicity in the case of long-term treatment are expected, and have been described for HU [ 26 , 27 ].…”

Section: Introductionmentioning

confidence: 99%

Discovery of Novel Fetal Hemoglobin Inducers through Small Chemical Library Screening

Breveglieri

Pacifico

Zuccato

et al. 2020

IJMS

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The screening of chemical libraries based on cellular biosensors is a useful approach to identify new hits for novel therapeutic targets involved in rare genetic pathologies, such as β-thalassemia and sickle cell disease. In particular, pharmacologically mediated stimulation of human γ-globin gene expression, and increase of fetal hemoglobin (HbF) production, have been suggested as potential therapeutic strategies for these hemoglobinopathies. In this article, we screened a small chemical library, constituted of 150 compounds, using the cellular biosensor K562.GR, carrying enhanced green fluorescence protein (EGFP) and red fluorescence protein (RFP) genes under the control of the human γ-globin and β-globin gene promoters, respectively. Then the identified compounds were analyzed as HbF inducers on primary cell cultures, obtained from β-thalassemia patients, confirming their activity as HbF inducers, and suggesting these molecules as lead compounds for further chemical and biological investigations.

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“…It has shown to upregulate human γ-globin and fetal haemoglobin (HbF) synthesis in several in vitro and in vivo studies in patients with sickle cell disease 11 , 12 . Similarly, hydroxyurea induces HbF and reduces the blood transfusion requirement in some patients with non-transfusion-dependent β-thalassaemia 13 . In addition to its effect on HbF, hydroxyurea has been shown to improve haemorheology and inhibit ineffective erythropoiesis in patients with sickle cell disease and β-thalassaemia.…”

Section: Introductionmentioning

confidence: 99%

A randomised double-blind placebo-controlled clinical trial of oral hydroxyurea for transfusion-dependent β-thalassaemia

Yasara

Wickramarathne

Mettananda

et al. 2022

Sci Rep

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Hydroxyurea is an antimetabolite drug that induces fetal haemoglobin in sickle cell disease. However, its clinical usefulness in β-thalassaemia is unproven. We conducted a randomised, double-blind, placebo-controlled clinical trial to evaluate the efficacy and safety of hydroxyurea in transfusion-dependent β-thalassaemia. Sixty patients were assigned 1:1 to oral hydroxyurea 10–20 mg/kg/day or placebo for 6 months by stratified block randomisation. Hydroxyurea treatment did not alter the blood transfusion volume overall. However, a significantly higher proportion of patients on hydroxyurea showed increases in fetal haemoglobin percentage (89% vs. 59%; p < 0.05) and reductions in erythropoietic stress as measured by soluble transferrin receptor concentration (79% vs. 40%; p < 0.05). Based on fetal haemoglobin induction (> 1.5%), 44% of patients were identified as hydroxyurea-responders. Hydroxyurea-responders, required significantly lower blood volume (77 ± SD27ml/kg) compared to hydroxyurea-non-responders (108 ± SD24ml/kg; p < 0.01) and placebo-receivers (102 ± 28ml/kg; p < 0.05). Response to hydroxyurea was significantly higher in patients with HbE β-thalassaemia genotype (50% vs. 0%; p < 0.01) and Xmn1 polymorphism of the γ-globin gene (67% vs. 27%; p < 0.05). We conclude that oral hydroxyurea increased fetal haemoglobin percentage and reduced erythropoietic stress of ineffective erythropoiesis in patients with transfusion-dependent β-thalassaemia. Hydroxyurea reduced the transfusion burden in approximately 40% of patients. Response to hydroxyurea was higher in patients with HbE β-thalassaemia genotype and Xmn1 polymorphism of the γ-globin gene.

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Hydroxyurea for reducing blood transfusion in non-transfusion dependent beta thalassaemias

Cited by 17 publications

References 58 publications

Expression of γ-globin genes in β-thalassemia patients treated with sirolimus: results from a pilot clinical trial (Sirthalaclin)

Expression of γ-globin genes in β-thalassemia patients treated with sirolimus: results from a pilot clinical trial (Sirthalaclin)

Discovery of Novel Fetal Hemoglobin Inducers through Small Chemical Library Screening

A randomised double-blind placebo-controlled clinical trial of oral hydroxyurea for transfusion-dependent β-thalassaemia

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