Professor Lai Yongrong: New Progress in Thalassemia Treatment The 2nd China Hematology Development Conference

From January 14th to 16th, 2022, the 2nd China Hematology Development Conference will be held online
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With the theme of "Strengthening the Foundation, Emphasizing Clinical Practice, and Promoting Transformation—Building a New Ecology of Hematology Innovation and Development", many experts and colleagues in the field of hematology gathered together to exchange the cutting-edge progress of hematology and discuss the future development direction
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At the meeting, Professor Lai Yongrong from the First Affiliated Hospital of Guangxi Medical University introduced the new progress in the treatment of thalassemia (thalassemia)
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Thalassaemia epidemiological research Thalassemia is referred to as thalassemia, also known as thalassemia, thalassemia, thalassemia and thalassemia.
It is named after it was first discovered in the Mediterranean countries
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Thalassemia is a group of hereditary hemolytic anemias, which are caused by the defect of the globin gene (thalassemia gene) that reduces or cannot synthesize one or several globin peptide chains in hemoglobin, resulting in changes in the composition of hemoglobin, followed by Cause chronic hemolysis and anemia
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Thalassaemia is widely prevalent in the Mediterranean basin, the Middle East, Southeast Asia and southern China.
The average thalassemia gene carrier rate in China is 8%.
At present, there are about 300,000 patients with intermediate and severe thalassemia in the country, and the thalassemia gene carrier rate in Guangxi Province.
About 20%, the highest in the country
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Gene therapy of thalassemia progresses Thalassaemia is a monogenic disease.
In the past ten years, researchers have actively explored the gene therapy of thalassemia, and it has now moved from the laboratory to the clinic
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In June 2019, betibeglogene autotemcel (beti-cel; autologous CD34+ cells containing the gene encoding βA-T87Q globin) was approved by the European Union, becoming the first gene therapy for the treatment of β-thalassaemia
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Gene therapy for β-thalassemia is a milestone in the history of human disease treatment, making nearly 70% of patients no longer dependent on transfusion therapy after gene therapy: a trial included 22 patients with transfusion-dependent β-thalassemia (treatment sites were distributed in The United States, Thailand and France) received beti-cel treatment, and the results showed that the effective rate was 100%, 68.
18% (15 cases) of patients were no longer dependent on blood transfusion after treatment, and no serious side effects were found in the 10-year follow-up
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Professor Lai Yongrong said that at present, increasing the level of hemoglobin HbF in the fetal period to replace adult HbA is a recognized strategy for the treatment of β-thalassaemia, because the higher the level of HbF in patients with β-thalassemia, the milder the symptoms, and the two main strategies to increase the level of HbF include destroying The expression of inhibitory factors that inhibit HBG transcription and the destruction of HBG promoter and transcriptional repression-related sequences have been carried out in China.
treatment
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The progress of hematopoietic stem cell transplantation in thalassemia At present, hematopoietic stem cell transplantation is the most mature and curable method for the treatment of thalassemia
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According to Professor Lai Yongrong, as of April 2021, the number of thalassemia transplants in China was 3,812, and the First Affiliated Hospital of Guangxi Medical University had completed a total of 871 thalassemia transplants, ranking first in the number of transplants with a cure rate of 94%.
HLA sibs were transplanted mainly (617 cases), 190 cases were transplanted from unrelated donors, and 64 cases were haploid transplants
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Later, Professor Lai Yongrong introduced that the First Affiliated Hospital of Guangxi Medical University has made rapid progress in the treatment of thalassemia in recent years, and the complications after transplantation are well controlled
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Compared with literature reports, the incidence of acute graft-versus-host disease (aGVHD), post-transplant rejection, and transplant-related death after transplantation in the First Affiliated Hospital of Guangxi Medical University is relatively low (as shown in the figure below), and there is no thalassemia for 3 years.
The survival rate was 94%
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The progress of unrelated donor and haploid transplantation is not as mature as that of haploid transplantation, and related research exploration is also underway
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The progress of drug treatment of thalassemia Prof.
Lai Yongrong said that in recent years, good progress has been made in drug treatment of thalassemia
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Luspatercept is a first-in-class erythrocyte maturation agent (EMA) that regulates the maturation of advanced erythrocytes
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It is a soluble fusion protein composed of the Fc domain of human IgG1 fused to the extracellular domain of activin type IIB receptor (ActRIIB), which acts as a ligand trap and regulates the transformation of late RBC maturation through targeted binding A specific ligand of the growth factor (TGF)-β superfamily, reduces activation of Smad2/3 signaling pathway, improves ineffective erythropoiesis, promotes maturation of advanced erythrocytes, and increases hemoglobin levels
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It is currently successfully used to treat thalassemia
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The BELIEVE study was a phase III randomized (2:1), placebo-controlled study of patients in 65 centers in 11 countries evaluating the use of rotercept (224 patients) in patients with transfusion-dependent beta-thalassaemia.
) and placebo (112 patients), the primary endpoint of the study was a ≥33% reduction in red blood cell transfusion load from baseline during weeks 13-24, and 21.
4% of patients in the rotercept group achieved the primary endpoint of the study , 4.
5% of the placebo group, rotercept can effectively reduce the burden of blood transfusion in patients with thalassaemia, and the overall safety is good
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In addition, in April 2019, the U.
S.
FDA approved rotacept for the treatment of adult patients with transfusion-dependent beta-thalassaemia
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In addition, a Phase II, double-blind, randomized (2:1), placebo-controlled study, presented at the 2021 EHA meeting, evaluated the efficacy of rotercept in patients with non-transfusion-dependent thalassaemia, rotercept There were 100 patients in the group and 50 in the placebo group.
The primary endpoint of the study was an increase in hemoglobin levels ≥1.
0 g/dL from baseline during weeks 13-24.
77.
1% of patients in the rotacept group achieved the primary endpoint, and no patients in the placebo group.
achieved the primary endpoint
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Professor Lai Yongrong said that Rottecept has a better effect on patients with non-transfusion-dependent thalassaemia, and its adverse reactions are mainly bone pain, and the overall safety is good
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Thalassaemia iron-removing therapy The patients with thalassemia have a higher risk of iron overload, so iron-removing therapy is an important means of thalassaemia treatment
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Relevant studies have shown that if iron overload patients (SF≥800μg/L) are not treated, most of them will develop complications within 10 years, and iron removal therapy can reduce the complications of thalassemia patients and prolong their survival
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Both the Chinese Expert Consensus on the Diagnosis and Treatment of Non-transfusion-dependent Thalassemia (2018 Edition) and the Guidelines for the Diagnosis and Treatment of β-Thalassemia Major (2017 Edition) indicate that iron removal is one of the key measures for the treatment of thalassemia
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Professor Lai Yongrong said that at present, there are three kinds of chelating agents used for iron-removing treatment of thalassemia in China, including deferoxamine, deferiprone and deferasirox
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The recommended recommendations of the International Thalassaemia Federation (TIF) for the treatment of thalassemia major and iron removal are as follows
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Subsequently, Professor Lai Yongrong introduced that the therapeutic goals of iron overload include removing toxic unbound labile iron, reducing serum ferritin to <500-1000 μg/L, and maintaining and removing excess iron accumulated in vital organs and tissues for a long time
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Due to poor compliance and/or poor availability of suitable chelators, most or no effective treatment is achieved.
To achieve the therapeutic goal of iron overload, long-term adherence to iron chelator therapy is required, which requires great cooperation and cooperation from patients and their families.
Persist
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Finally, Professor Lai Yongrong emphasized that thalassemia not only affects the lives of patients, but also affects many aspects of the lives of surviving patients, including social, emotional and psychological challenges.
As the lives of thalassemia patients are prolonged, the treatment of thalassemia should be comprehensive.
Life cycle management requires multidisciplinary collaboration to improve patient survival and quality of life
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Professor Lai Yongrong, MD, doctoral supervisor, Deputy Director of the Department of Internal Medicine and Director of the Department of Hematology, the First Affiliated Hospital of Guangxi Medical University, National Standing Committee Member of the Hematology Branch of the Chinese Medical Association, National Standing Committee Member of the Hematology Branch of the Chinese Medical Association, Chairman of the Guangxi Society of Hematology Responsible for the country 4 Natural Science Foundation projects and 1 Ministry of Education project won 5 Guangxi Science and Technology Progress Awards (1 first prize; 1 second prize; 3 third prizes) and published more than 100 scientific research papers.
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