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

Yasara, Nirmani; Wickramarathne, Nethmi; Mettananda, Chamila; Silva, Ishari; Hameed, Nizri; Attanayaka, Kumari; Rodrigo, Rexan; Wickramasinghe, Nirmani; Perera, Lasantha B.; Manamperi, A.; Premawardhena, Anuja; Mettananda, Sachith

doi:10.1038/s41598-022-06774-8

Cited by 19 publications

(19 citation statements)

References 35 publications

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“…In a phase 3 trial, adverse events experienced by patients with TD β-thalassemia treated with hydroxyurea for 6 months included headache (2 of 30 patients), thrombocytopenia (1 of 30), leukopenia (1 of 30), hyperpigmentation (1 of 30), urinary tract infection (2 of 30), nausea (1 of 30), vomiting (1 of 30), and abdominal pain (1 of 30). 37 The short-term safety profile of hydroxyurea appears to be favorable to luspatercept; however, the increases in hemoglobin are generally less than those for luspatercept 38 ; likewise, hydroxyurea benefit is not as durable. Furthermore, long-term randomized trials of hydroxyurea in β-thalassemia are lacking.…”

Section: Discussionmentioning

confidence: 99%

Long-term safety and erythroid response with luspatercept treatment in patients with β-thalassemia

Piga

Longo

Gamberini

et al. 2022

Therapeutic Advances in Hematology

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Background: β-thalassemia is a hereditary blood disorder resulting in ineffective erythropoiesis and anemia. Management of anemia with regular blood transfusions is associated with complications including iron overload. Here, we report long-term safety and efficacy results of the first clinical study of luspatercept in β-thalassemia, initiated in 2013, enrolling adults with both nontransfusion-dependent (NTD) and transfusion-dependent (TD) β-thalassemia. Objectives: The objective was to report long-term safety data, for up to 5 years of treatment, for 64 patients with TD or NTD β-thalassemia, and long-term efficacy data for a subset of 63 patients with β-thalassemia who received high-dose luspatercept (0.6–1.25 mg/kg): 31 NTD and 32 TD patients. Design: The study was a phase 2, noncontrolled, open-label trial comprising a dose-finding base phase and a 5-year extension phase. Methods: Endpoints include safety; erythroid response over a continuous 12-week period [NTD: hemoglobin increase from baseline ⩾1.0 or ⩾1.5 g/dl; TD: red blood cell (RBC) transfusion burden reduction, ⩾20%, ⩾33%, or ⩾50%]; and changes in biomarkers of ineffective erythropoiesis, iron metabolism parameters, Functional Assessment of Chronic Illness Therapy – Fatigue (FACIT-F) scores, and 6-min walking distance. Results: Median duration of luspatercept exposure for NTD and TD patients was 910 days (range, 40–1850) and 433 days (range, 21–1790), respectively. Seventeen of 31 (54.8%) NTD patients achieved a mean hemoglobin increase of ⩾1.5 g/dl and 19 of 32 (59.4%) TD patients achieved ⩾50% reduction in RBC transfusion burden, during any continuous 12-week period. Median cumulative duration of response was 1126 days (range, 127–1790) for NTD patients and 909 days (range, 87–1734) for TD patients. The most common treatment-related adverse events of any grade were bone pain, headache, and myalgia. Conclusion: Long-term assessment of patients with β-thalassemia showed luspatercept was associated with sustained increases in hemoglobin levels in NTD patients and sustained transfusion burden reductions in TD patients. Trial registration: (ClinicalTrials.gov Identifiers: NCT01749540 and NCT02268409). Plain Language Summary Long-term safety and erythroid response with luspatercept treatment in patients with β-thalassemia Background: β-thalassemia is a genetic blood disorder caused by mutations in the β-globin gene, which encodes one of the proteins that comprise hemoglobin, a key constituent of red blood cells. Patients with β-thalassemia experience anemia, the main treatment for which is blood transfusions. Long-term repeated blood transfusions lower patients’ quality of life, use hospital resources, and the resulting accumulation of excess iron can cause organ failure and decrease life expectancy. The severity of the anemia experienced by patients with β-thalassemia varies; patients with transfusion-dependent β-thalassemia require regular blood transfusions, compared with those with nontransfusion-dependent β-thalassemia who require infrequent transfusions, or even none at all, to manage their symptoms. Luspatercept (Reblozyl®) is an agent that stimulates the production of red blood cells and is used to treat anemia caused by β-thalassemia. However, the long-term effects of luspatercept treatment on patients with β-thalassemia are not known. Objective: In this study, we report the long-term safety of luspatercept in 64 adult patients with either transfusion-dependent or nontransfusion-dependent β-thalassemia, and the long-term efficacy of high-dose luspatercept (0.6–1.25 mg/kg) in a subset of 63 patients. Results: The average time period that patients were treated with luspatercept was 910 days for nontransfusion-dependent β-thalassemia and 433 days for transfusion-dependent β-thalassemia. We report that in patients with nontransfusion-dependent β-thalassemia, luspatercept treatment was associated with sustained increases, just over 3 years, in hemoglobin levels. Likewise, in transfusion-dependent β-thalassemia, luspatercept treatment was associated with a sustained reduction, 2.5 years, in the amount of blood transfusion required to manage their anemia. Long-term treatment with luspatercept was not associated with any new side effects compared with previous short-term treatment studies. The most common side effects were headache (27 patients), bone pain (20 patients), and muscle pain (14 patients) with more than 90% of these patients experiencing these side effects as mild severity. Conclusion: The results of this study show that in patients with either transfusion-dependent or nontransfusion-dependent β-thalassemia, luspatercept provides lasting reduction in anemia with mostly mild and predictable side effects.

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Section: Discussionmentioning

confidence: 99%

Long-term safety and erythroid response with luspatercept treatment in patients with β-thalassemia

Piga

Longo

Gamberini

et al. 2022

Therapeutic Advances in Hematology

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“…It is important to mention that HU, despite the lack of specific approval for β-thalassemia and of robust clinical evidence 37 , is indeed used and provides sustained benefits in certain patients 38 . On the other hand, a substantial percentage of patients does not respond and some of the responding ones become insensitive after repeated administrations 39 , thus new interventions are eagerly needed.…”

Section: Drug Repositioning For Rare Diseases: β-Thalassemiamentioning

confidence: 99%

A Rational Approach to Drug Repositioning in β-thalassemia: Induction of Fetal Hemoglobin by Established Drugs

et al. 2022

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Drug repositioning and the relevance of orphan drug designation for β-thalassemia is reviewed. Drug repositioning and similar terms ('drug repurposing', 'drug reprofiling', 'drug redirecting', ‘drug rescue’, ‘drug re-tasking’ and/or 'drug rediscovery') have gained great attention, especially in the field or rare diseases (RDs), and represent relevant novel drug development strategies to be considered together with the “off-label” use of pharmaceutical products under clinical trial regimen. The most significant advantage of drug repositioning over traditional drug development is that the repositioned drug has already passed a significant number of short- and long-term toxicity tests, as well as it has already undergone pharmacokinetic and pharmacodynamic (PK/PD) studies. The established safety of repositioned drugs is known to significantly reduce the probability of project failure. Furthermore, development of repurposed drugs can shorten much of the time needed to bring a drug to market. Finally, patent filing of repurposed drugs is expected to catch the attention of pharmaceutical industries interested in the development of therapeutic protocols for RDs. Repurposed molecules that could be proposed as potential drugs for β-thalassemia, will be reported, with some of the most solid examples, including sirolimus (rapamycin) that recently has been tested in a pilot clinical trial.

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“…Supporting a caution in using multiplexed CRISPR-Cas9-based approaches, Samuelson et al recently reported that multiplex CRISPR-Cas9 genome editing in hematopoietic stem cells for fetal hemoglobin reinduction generates chromosomal translocations [ 40 ]. For these reasons, we therefore decided to use for HbF induction a repositioned drug, rapamycin [ 42 , 43 , 44 , 45 , 46 , 47 , 48 ], among those already validated and used in clinical trials [ 49 , 50 , 51 , 52 ]. To the best of our knowledge, this strategy is novel, as no study is available on the combination of pharmacological induction of HbF with gene editing procedures aimed at the de novo production of HbA following the CRISPR-Cas9-based correction of genetic mutations.…”

Section: Introductionmentioning

confidence: 99%

“…Rapamycin, also known as sirolimus, is a potent inducer of HbF in in vitro systems [ 42 , 43 , 44 , 45 , 46 , 47 , 52 ], in in vivo animal models [ 46 , 47 , 53 , 54 ], and in few but highly informative patients affected by sickle-cell disease (SCD) [ 55 , 56 ]. In conclusion, all the available in vitro data concurrently indicate that rapamycin can be repurposed for the treatment of β-thalassemia for the following reasons: (a) rapamycin increases HbF in cultures from β-thalassemia patients with different basal HbF levels; (b) rapamycin increases the overall Hb content per cell; (c) rapamycin selectively induces γ-globin mRNA accumulation, with only minor effects on β-globin protein and β-globin mRNAs; (d) there is a strong correlation between the HbF increase induced by rapamycin and the increase in γ-globin mRNA content.…”

Section: Introductionmentioning

confidence: 99%

Co-Treatment of Erythroid Cells from β-Thalassemia Patients with CRISPR-Cas9-Based β039-Globin Gene Editing and Induction of Fetal Hemoglobin

Cosenza

Zuccato

Zurlo

et al. 2022

Genes

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Gene editing (GE) is an efficient strategy for correcting genetic mutations in monogenic hereditary diseases, including β-thalassemia. We have elsewhere reported that CRISPR-Cas9-based gene editing can be employed for the efficient correction of the β039-thalassemia mutation. On the other hand, robust evidence demonstrates that the increased production of fetal hemoglobin (HbF) can be beneficial for patients with β-thalassemia. The aim of our study was to verify whether the de novo production of adult hemoglobin (HbA) using CRISPR-Cas9 gene editing can be combined with HbF induction protocols. The gene editing of the β039-globin mutation was obtained using a CRISPR-Cas9-based experimental strategy; the correction of the gene sequence and the transcription of the corrected gene were analyzed by allele-specific droplet digital PCR and RT-qPCR, respectively; the relative content of HbA and HbF was studied by high-performance liquid chromatography (HPLC) and Western blotting. For HbF induction, the repurposed drug rapamycin was used. The data obtained conclusively demonstrate that the maximal production of HbA and HbF is obtained in GE-corrected, rapamycin-induced erythroid progenitors isolated from β039-thalassemia patients. In conclusion, GE and HbF induction might be used in combination in order to achieve the de novo production of HbA together with an increase in induced HbF.

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

Cited by 19 publications

References 35 publications

Long-term safety and erythroid response with luspatercept treatment in patients with β-thalassemia

Long-term safety and erythroid response with luspatercept treatment in patients with β-thalassemia

A Rational Approach to Drug Repositioning in β-thalassemia: Induction of Fetal Hemoglobin by Established Drugs

Co-Treatment of Erythroid Cells from β-Thalassemia Patients with CRISPR-Cas9-Based β039-Globin Gene Editing and Induction of Fetal Hemoglobin

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