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FLT3 gene mutation is the most common genetic alteration and poor prognostic factor in acute myeloid leukemia (AML), and it exists in about 30% of AML patients.
On February 4, 2021, Sigatan® (geritinib fumarate tablets) was approved by the National Medical Products Administration (NMPA) for the treatment of FLT3 mutation-positive relapsed or refractory AML, marking China FLT3 mutant AML patients usher in the first targeted therapy drug, opening a new era of targeted therapy.
In this regard, Yimaitong specially invited Professor Shen Zhixiang from Ruijin Hospital of Shanghai Jiaotong University School of Medicine to share the current status of AML treatment in my country and the impact of geritinib on the treatment model of AML.
Professor Shen Zhixiang Chief Physician, Professor, Doctoral Supervisor, Lifetime Professor, Ruijin Hospital, Shanghai Jiaotong University School of Medicine, Former Chairman of the Chinese Medical Association, National Society of Hematology, Deputy Chief Editor of "Chinese Journal of Hematology", "Chinese Medical Journal (English Edition)", etc.
Editors of various journals have published more than 100 papers and monographs in domestic and foreign journals, and edited eight books including "Malignant Hematology", "Lymphoma", "Concise Clinical Hematology", "Research Progress in Hematology", etc.
Monographs, and participated in the compilation of more than 10 monographs.
The treatment of AML is struggling, and there is an urgent need to explore new protocols.
Acute leukemia can be divided into two categories: AML and acute lymphoblastic leukemia (ALL).
Unlike ALL, the incidence of AML is higher in adults and is the most common subtype of leukemia in adults.
type.
However, compared with other hematological malignancies, the treatment effect of AML is not good, and the prognosis and survival rate of patients are very low.
Professor Shen Zhixiang said, “At present, the survival time of adult AML patients in China is generally 2-3 years, which is very cruel to the patients, especially for young patients aged 30-40, which will also cause a serious family burden.
"In addition, a study based on the 2017 Global Burden of Disease database shows that China has a heavy burden of AML disease, and the disability-adjusted life years is second only to India, ranking second in the world.
Professor Shen Zhixiang pointed out that in the past few decades The research on new drugs for the treatment of AML in China is progressing slowly.
Combined chemotherapy and hematopoietic stem cell transplantation are the main treatments for AML.
"However, the long-term survival rate of most AML patients undergoing chemotherapy is very low, and only a few patients can undergo bone marrow transplantation.
"FLT3 inhibitors have broken through the shackles, and dawning has begun.
Although the progress of AML in drug treatments has been relatively slow in the past ten years, the research in tumor cytology has been very rapid.
With the development of leukemia molecular biology, cytogenetics, and cell apoptosis, The research on mechanisms such as death has been in-depth, and people have found that AML patients have a variety of gene mutations, such as FLT3 (ITD and TKD), NPM1, IDH1, IDH2, etc.
Among them, FLT3 gene mutations are the most typical, and the incidence in AML patients is about 1 /3, is the most common genetic alteration and poor prognostic factors in AML patients.
Moreover, traditional chemotherapy cannot meet the treatment needs of AML patients with FLT3 mutations.
Professor Shen Zhixiang said that the appearance of FLT3 inhibitors is associated with FLT3 mutation-positive AML patients.
Lai Shuguang.
The
first generation of FLT3 inhibitors are pan-targeted multi-kinase inhibitors, which lack specificity for FLT3, which can easily lead to off-target and toxicity.
In contrast, geritinib is the second generation of FLT3 inhibitors, which has a negative effect on FLT3.
Mutation has high selectivity, stronger inhibitory effect, and less off-target effect.
Not only that, geritinib is a type I FLT3 inhibitor, acting on the activation loop of the kinase domain, and can simultaneously inhibit internal tandem repeats (FLT3-ITD) and Tyrosine kinase domain point mutation (FLT3-TKD).
It is
known that FLT3-ITD mutation and FLT3-TKD mutation are two common FLT3 mutations, both of which are involved in the occurrence of AML.
Geiritinib has excellent efficacy, and a number of remarkable clinical trials have confirmed its significant benefits in patients with relapsed or refractory AML.
The results of ADMIRAL Study 2 confirmed that, compared with salvage chemotherapy, geritinib alone increased the overall remission rate of FLT3-ITD mutation relapsed or refractory AML patients from 26% to 68%, and the median survival time from 5.
6 cases The month was extended to 9.
3 months.
In addition to single-agent therapy, the combined application of geritinib and other drugs has also achieved good results.
A phase 1b extended cohort study 3 released at the 2020 ASH conference showed that in patients with FLT3 mutation-positive AML who have received a large number of treatments (most of whom have previously received FLT3 TKI treatment), geritinib combined with venal Carat has achieved a very high elimination rate of bone marrow and blood blasts, and the modified compound complete remission rate is as high as 85.
4%.
Gerritinib can not only be combined with targeted drugs, but also with traditional standard chemotherapy regimens.
The final results of a phase 1 study of gerritinib combined with induction consolidation chemotherapy in the treatment of newly diagnosed AML4 showed that after receiving gerritinib and 3+7 induction chemotherapy, patients with FLT3 mutations had a composite complete remission rate of 81.
6%, which was moderate The bit OS has not been reached, and the gene mutation clearance rate is 70.
0%, which is well tolerated.
In addition, a phase 3 multi-center open study 5 showed that geritinib combined with azacitidine in the treatment of FLT3 mutant AML that is not suitable for intensive induction chemotherapy has a composite complete remission rate of 67% in the safety cohort.
Professor Shen Zhixiang said that whether it is geritinib alone or in combination with venexa, early chemotherapy, azacitidine and other drugs, it will bring significant survival benefits to AML patients.
Geiritinib, the beginning of the era of AML targeted therapy The burden of AML disease in my country is heavy, and the survival rate of patients is low.
Geiritinib came into being.
Its approval marks the entry of China's FLT3 mutation-positive relapse or refractory AML into a new targeted therapy era.
Professor Zhixiang Shen said that geritinib fills the gap in the treatment needs of Chinese FLT3 mutation-positive AML patients, and brings new treatment hope for these patients.
"I hope that more clinical studies can be carried out after geritinib is launched in China to understand the significant benefits that geritinib brings to AML patients in the real world, so that doctors and patients will have more confidence in the use of geritinib.
It will bring higher survival and quality of life to patients.
It is
expected that in the future, geritinib can be used not only in patients with relapsed or refractory AML, but also in newly-treated AML patients, benefiting more AML patients.
"References: 1.
Yi M, et al.
The global burden and attributable risk factor analysis of acute myeloid leukemia in 195 countries and territories from 1990 to 2017: estimates based on the global burden of disease study 2017.
J Hematol Oncol.
2020 Jun 8;13(1):72.
2.
Perl AE et al.
Gilteritinib or Chemotherapy for Relapsed or Refractory FLT3-Mutated AML.
N Engl J Med.
2019 Oct 31;381(18):1728-1740.
3.
Efficacy and Safety of Venetoclax in Combination with Gilteritinib for Relapsed/Refractory FLT3-Mutated Acute Myeloid Leukemia in the Expansion Cohort of a Phase 1b Study.
2020ASH: Oral 333.
4.
A Phase 1 Study of Gilteritinib in Combination with Induction and Consolidation Chemotherapy in Patients with Newly Diagnosed AML: Final Results.
2020ASH: Oral 24.
5.
Phase 3, Multicenter, Open-Label Study of Gilteritinib, Gilteritinib Plus Azacitidine,or Azacitidine Alone in Newly Diagnosed FLT3 Mutated (FLT3mut+) Acute Myeloid Leukemia (AML) Patients Ineligible for Intensive Induction Chemotherapy.
2020ASH: Oral 27.
RECOMMEND recommended reading 1.
Professor Ma Jun: The FLT3 inhibitor gerritinib fills the unsatisfactory AML treatment 2.
Professor Wu Depei: Precise diagnosis and precise treatment, gerritinib helps AML accurately benefit 3.
Professor Wang Jianxiang: More flowers, talk about the application of geritinib in FLT3 mutation-positive AML.
"Read the original text", We make progress together
On February 4, 2021, Sigatan® (geritinib fumarate tablets) was approved by the National Medical Products Administration (NMPA) for the treatment of FLT3 mutation-positive relapsed or refractory AML, marking China FLT3 mutant AML patients usher in the first targeted therapy drug, opening a new era of targeted therapy.
In this regard, Yimaitong specially invited Professor Shen Zhixiang from Ruijin Hospital of Shanghai Jiaotong University School of Medicine to share the current status of AML treatment in my country and the impact of geritinib on the treatment model of AML.
Professor Shen Zhixiang Chief Physician, Professor, Doctoral Supervisor, Lifetime Professor, Ruijin Hospital, Shanghai Jiaotong University School of Medicine, Former Chairman of the Chinese Medical Association, National Society of Hematology, Deputy Chief Editor of "Chinese Journal of Hematology", "Chinese Medical Journal (English Edition)", etc.
Editors of various journals have published more than 100 papers and monographs in domestic and foreign journals, and edited eight books including "Malignant Hematology", "Lymphoma", "Concise Clinical Hematology", "Research Progress in Hematology", etc.
Monographs, and participated in the compilation of more than 10 monographs.
The treatment of AML is struggling, and there is an urgent need to explore new protocols.
Acute leukemia can be divided into two categories: AML and acute lymphoblastic leukemia (ALL).
Unlike ALL, the incidence of AML is higher in adults and is the most common subtype of leukemia in adults.
type.
However, compared with other hematological malignancies, the treatment effect of AML is not good, and the prognosis and survival rate of patients are very low.
Professor Shen Zhixiang said, “At present, the survival time of adult AML patients in China is generally 2-3 years, which is very cruel to the patients, especially for young patients aged 30-40, which will also cause a serious family burden.
"In addition, a study based on the 2017 Global Burden of Disease database shows that China has a heavy burden of AML disease, and the disability-adjusted life years is second only to India, ranking second in the world.
Professor Shen Zhixiang pointed out that in the past few decades The research on new drugs for the treatment of AML in China is progressing slowly.
Combined chemotherapy and hematopoietic stem cell transplantation are the main treatments for AML.
"However, the long-term survival rate of most AML patients undergoing chemotherapy is very low, and only a few patients can undergo bone marrow transplantation.
"FLT3 inhibitors have broken through the shackles, and dawning has begun.
Although the progress of AML in drug treatments has been relatively slow in the past ten years, the research in tumor cytology has been very rapid.
With the development of leukemia molecular biology, cytogenetics, and cell apoptosis, The research on mechanisms such as death has been in-depth, and people have found that AML patients have a variety of gene mutations, such as FLT3 (ITD and TKD), NPM1, IDH1, IDH2, etc.
Among them, FLT3 gene mutations are the most typical, and the incidence in AML patients is about 1 /3, is the most common genetic alteration and poor prognostic factors in AML patients.
Moreover, traditional chemotherapy cannot meet the treatment needs of AML patients with FLT3 mutations.
Professor Shen Zhixiang said that the appearance of FLT3 inhibitors is associated with FLT3 mutation-positive AML patients.
Lai Shuguang.
The
first generation of FLT3 inhibitors are pan-targeted multi-kinase inhibitors, which lack specificity for FLT3, which can easily lead to off-target and toxicity.
In contrast, geritinib is the second generation of FLT3 inhibitors, which has a negative effect on FLT3.
Mutation has high selectivity, stronger inhibitory effect, and less off-target effect.
Not only that, geritinib is a type I FLT3 inhibitor, acting on the activation loop of the kinase domain, and can simultaneously inhibit internal tandem repeats (FLT3-ITD) and Tyrosine kinase domain point mutation (FLT3-TKD).
It is
known that FLT3-ITD mutation and FLT3-TKD mutation are two common FLT3 mutations, both of which are involved in the occurrence of AML.
Geiritinib has excellent efficacy, and a number of remarkable clinical trials have confirmed its significant benefits in patients with relapsed or refractory AML.
The results of ADMIRAL Study 2 confirmed that, compared with salvage chemotherapy, geritinib alone increased the overall remission rate of FLT3-ITD mutation relapsed or refractory AML patients from 26% to 68%, and the median survival time from 5.
6 cases The month was extended to 9.
3 months.
In addition to single-agent therapy, the combined application of geritinib and other drugs has also achieved good results.
A phase 1b extended cohort study 3 released at the 2020 ASH conference showed that in patients with FLT3 mutation-positive AML who have received a large number of treatments (most of whom have previously received FLT3 TKI treatment), geritinib combined with venal Carat has achieved a very high elimination rate of bone marrow and blood blasts, and the modified compound complete remission rate is as high as 85.
4%.
Gerritinib can not only be combined with targeted drugs, but also with traditional standard chemotherapy regimens.
The final results of a phase 1 study of gerritinib combined with induction consolidation chemotherapy in the treatment of newly diagnosed AML4 showed that after receiving gerritinib and 3+7 induction chemotherapy, patients with FLT3 mutations had a composite complete remission rate of 81.
6%, which was moderate The bit OS has not been reached, and the gene mutation clearance rate is 70.
0%, which is well tolerated.
In addition, a phase 3 multi-center open study 5 showed that geritinib combined with azacitidine in the treatment of FLT3 mutant AML that is not suitable for intensive induction chemotherapy has a composite complete remission rate of 67% in the safety cohort.
Professor Shen Zhixiang said that whether it is geritinib alone or in combination with venexa, early chemotherapy, azacitidine and other drugs, it will bring significant survival benefits to AML patients.
Geiritinib, the beginning of the era of AML targeted therapy The burden of AML disease in my country is heavy, and the survival rate of patients is low.
Geiritinib came into being.
Its approval marks the entry of China's FLT3 mutation-positive relapse or refractory AML into a new targeted therapy era.
Professor Zhixiang Shen said that geritinib fills the gap in the treatment needs of Chinese FLT3 mutation-positive AML patients, and brings new treatment hope for these patients.
"I hope that more clinical studies can be carried out after geritinib is launched in China to understand the significant benefits that geritinib brings to AML patients in the real world, so that doctors and patients will have more confidence in the use of geritinib.
It will bring higher survival and quality of life to patients.
It is
expected that in the future, geritinib can be used not only in patients with relapsed or refractory AML, but also in newly-treated AML patients, benefiting more AML patients.
"References: 1.
Yi M, et al.
The global burden and attributable risk factor analysis of acute myeloid leukemia in 195 countries and territories from 1990 to 2017: estimates based on the global burden of disease study 2017.
J Hematol Oncol.
2020 Jun 8;13(1):72.
2.
Perl AE et al.
Gilteritinib or Chemotherapy for Relapsed or Refractory FLT3-Mutated AML.
N Engl J Med.
2019 Oct 31;381(18):1728-1740.
3.
Efficacy and Safety of Venetoclax in Combination with Gilteritinib for Relapsed/Refractory FLT3-Mutated Acute Myeloid Leukemia in the Expansion Cohort of a Phase 1b Study.
2020ASH: Oral 333.
4.
A Phase 1 Study of Gilteritinib in Combination with Induction and Consolidation Chemotherapy in Patients with Newly Diagnosed AML: Final Results.
2020ASH: Oral 24.
5.
Phase 3, Multicenter, Open-Label Study of Gilteritinib, Gilteritinib Plus Azacitidine,or Azacitidine Alone in Newly Diagnosed FLT3 Mutated (FLT3mut+) Acute Myeloid Leukemia (AML) Patients Ineligible for Intensive Induction Chemotherapy.
2020ASH: Oral 27.
RECOMMEND recommended reading 1.
Professor Ma Jun: The FLT3 inhibitor gerritinib fills the unsatisfactory AML treatment 2.
Professor Wu Depei: Precise diagnosis and precise treatment, gerritinib helps AML accurately benefit 3.
Professor Wang Jianxiang: More flowers, talk about the application of geritinib in FLT3 mutation-positive AML.
"Read the original text", We make progress together
