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Acute myeloid leukemia (AML) has high heterogeneity, and many patients have various cytogenetic abnormalities and gene mutations.
Therefore, genetic testing is particularly important for the accurate diagnosis and treatment of AML.
With the discovery of various gene mutations, precision targeted therapy is gradually applied to AML.
On February 3, 2021, Segartan® (geritinib fumarate tablets) was approved by the National Medical Products Administration (NMPA) of China for the treatment of FLT3 mutation-positive relapsed or refractory AML.
As gerritinib welcomes China's approval, Yimaitong specially invited Professor Wu Depei from the First Affiliated Hospital of Soochow University to share on the precise treatment of AML and the prospects of gerritinib in the treatment of FLT3 mutation-positive AML.
Professor Wu Depei Chief Physician, Professor, and Doctoral Supervisor, Director of the Department of Hematology, First Affiliated Hospital of Soochow University, Executive Deputy Director, National Center for Clinical Research on Blood System Diseases, Deputy Director, Jiangsu Institute of Hematology, Deputy Director, Soochow University Institute of Clinical Medicine, Soochow University Hematopoiesis Director of the Stem Cell Transplant Institute, Member of the 13th National Committee of the Chinese People's Political Consultative Conference, Chairman of the Chinese Medical Association Hematology Branch, Standing Committee Member of the Chinese Medical Association Internal Medicine Branch, Vice Chairman, Chinese Medical Doctor Association Hematology Branch, Genetic Testing: a must for modern AML clinical diagnosis and treatment At present, precision medicine has become the forefront and most concerned hotspot of tumor research, and it is a new direction for the development of tumor treatment.
Professor Wu Depei said that accurate targeted therapy relies on accurate diagnosis.
There are a large number of recurring cytogenetic abnormalities and gene mutations in AML, which affect the disease phenotype, the efficacy of traditional treatments, the risk of recurrence and the prognosis of patients with AML.
Therefore, adequate stratification of risk is particularly important for the choice of treatment pathways.
.
As we all know, the diagnosis of AML in the past was based on MIC classification, that is, the diagnosis of leukemia was mainly based on the morphological, immunological and cytogenetic characteristics of leukemia cells.
However, up to 60% of AML patients have normal cytogenetics at the time of diagnosis, which greatly limits the role of karyotype analysis in assessing the prognosis of patients.
Subsequent with significant progress in the study of molecular characteristics of leukemia, MICM classification was then proposed.
After incorporating the characteristics of molecular biology to build the foundation of precision medicine, leukemia in the WHO classification has been successfully transformed from a morphological type to a molecular type and the definition is more refined.
Professor Wu Depei pointed out, “A number of current guidelines clearly recommend routine cytogenetic and molecular testing for AML patients.
The
latest version of the NCCN guidelines has included CBF, FLT3, NPM1, IDH1, IDH2 and other gene mutations into the routine testing of AML.
Version 2020 The CSCO guidelines also recommend the use of related molecular tests in the recommendation of level I experts to stratify the prognosis of AML based on FLT3-ITD, NPM1, TP53 and other mutations.
"A hundred flowers bloom: a variety of targeted new drugs have taken turns in recent years, the targeting of AML Great progress has been made in treatment.
Professor Wu Depei said that for some common mutated genes in AML, a variety of effective targeted therapy drugs have been successfully developed, such as FLT3 inhibitors, BCL-2 inhibitors and IDH1/2 inhibitors.
FLT3 mutation is the most common gene mutation in AML patients, and about 30% of patients tested positive for the mutation.
Studies have shown that FLT3 mutations are closely related to the prognosis of AML patients.
Geiritinib is a highly selective, second-generation, type I, oral FLT3 inhibitor.
It has high inhibitory activity on FLT3-ITD and FLT3-TKD.
It can also inhibit tyrosine related to FLT3 inhibitor resistance.
Kinase AXL.
In 2018, the US FDA approved geritinib for the treatment of FLT3 mutation-positive relapsed or refractory AML.
At present, geritinib has also been approved in China, heralding the first precision targeted drug for AML patients with FLT3 mutations in my country.
Professor Wu Depei pointed out that the approval of new drugs is inseparable from the support of numerous clinical studies.
ADMIRAL study 1 showed that geritinib was significantly better than salvage chemotherapy in prolonging OS in patients with FLT3-ITD and TKD mutations.
Moreover, the continued use of geritinib after hematopoietic stem cell transplantation can still prolong the survival of patients.
In addition, geritinib also has a good effect in the first line.
The data released by 2020 ASH show that 2, after geritinib is combined with 3+7 induction chemotherapy, in FLT3 mutation patients, the compound complete remission rate is 81.
6%, with a median OS has not yet reached and is well tolerated.
Therefore, patients with positive FLT3 mutations may be given geritinib as soon as possible.
At present, targeting the apoptotic pathway has become the main part of the treatment of AML.
Venecla is a selective BCL-2 inhibitor, which has been approved for use with azacitidine/decitabine/low-dose cytarabine in China.
Combination therapy is not suitable for intensive induction chemotherapy due to comorbidities, or newly diagnosed adult AML patients aged ≥75 years.
Regarding IDH1/2 inhibitors, the FDA approved Ivosidenib for the treatment of IDH1 mutations in patients with relapsed or refractory AML, as well as newly diagnosed AML patients who are ≥75 years old or cannot use strong induction chemotherapy due to comorbidities.
Ivosidenib combined with azacitidine in the treatment of newly diagnosed AML patients with IDH1 mutations who are not suitable for intensive chemotherapy is superior to single-agent historical data.
In addition, the FDA also approved Enasidenib for the treatment of AML patients with relapsed or refractory IDH2 mutations.
The future can be expected: dual target combination, collaborative fight against AML As more and more targeted drugs become available, researchers are also trying to adopt targeted drug combination therapy strategies to further improve the efficacy and benefit a wider range of AML patients.
Professor Wu Depei said that the 2020 ASH meeting reported a phase 1b expansion cohort 3 of gerritinib combined with venecla in the treatment of relapsed or refractory FLT3 mutation-positive AML.
The results show that in FLT3 mutation-positive AML patients who have received a large number of treatments (most of them have received FLT3 TKI treatment in the past), geritinib combined with Venecla achieved extremely high bone marrow and blood blast clearance rates , The modified compound complete remission rate is as high as 83.
8%, which may indicate that the anti-leukemia activity of geritinib combined with Venecla is significantly higher than that of geritinib alone.
In terms of safety, non-hematological toxicity is moderate, and the combination is well tolerated.
It can be seen that the combination of two targeted drugs to fight AML may bring more benefits to patients, and it is worthy of further research.
Summary In the era of AML precision medicine, genetic testing can be said to be the only way for modern clinical diagnosis and treatment.
At present, domestic and foreign guidelines clearly recommend routine genetic testing for AML patients.
The risk stratification of the prognosis of AML based on the results of genetic testing is helpful for the selection of precise targeted treatment strategies.
The FLT3 inhibitor geritinib was approved in China, bringing FLT3 mutation-positive relapsed or refractory AML patients the first targeted therapy option.
It is hoped that more and more AML patients will be able to obtain precise diagnosis, precise treatment, and ultimately obtain precise benefits.
References: 1.
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.
2.
A Phase 1 Study of Gilteritinib in Combination with Induction and Consolidation Chemotherapy in Patients with Newly Diagnosed AML: Final Results.
2020ASH: Oral 24.
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.
Poke "read the original text" and we will make progress together
Therefore, genetic testing is particularly important for the accurate diagnosis and treatment of AML.
With the discovery of various gene mutations, precision targeted therapy is gradually applied to AML.
On February 3, 2021, Segartan® (geritinib fumarate tablets) was approved by the National Medical Products Administration (NMPA) of China for the treatment of FLT3 mutation-positive relapsed or refractory AML.
As gerritinib welcomes China's approval, Yimaitong specially invited Professor Wu Depei from the First Affiliated Hospital of Soochow University to share on the precise treatment of AML and the prospects of gerritinib in the treatment of FLT3 mutation-positive AML.
Professor Wu Depei Chief Physician, Professor, and Doctoral Supervisor, Director of the Department of Hematology, First Affiliated Hospital of Soochow University, Executive Deputy Director, National Center for Clinical Research on Blood System Diseases, Deputy Director, Jiangsu Institute of Hematology, Deputy Director, Soochow University Institute of Clinical Medicine, Soochow University Hematopoiesis Director of the Stem Cell Transplant Institute, Member of the 13th National Committee of the Chinese People's Political Consultative Conference, Chairman of the Chinese Medical Association Hematology Branch, Standing Committee Member of the Chinese Medical Association Internal Medicine Branch, Vice Chairman, Chinese Medical Doctor Association Hematology Branch, Genetic Testing: a must for modern AML clinical diagnosis and treatment At present, precision medicine has become the forefront and most concerned hotspot of tumor research, and it is a new direction for the development of tumor treatment.
Professor Wu Depei said that accurate targeted therapy relies on accurate diagnosis.
There are a large number of recurring cytogenetic abnormalities and gene mutations in AML, which affect the disease phenotype, the efficacy of traditional treatments, the risk of recurrence and the prognosis of patients with AML.
Therefore, adequate stratification of risk is particularly important for the choice of treatment pathways.
.
As we all know, the diagnosis of AML in the past was based on MIC classification, that is, the diagnosis of leukemia was mainly based on the morphological, immunological and cytogenetic characteristics of leukemia cells.
However, up to 60% of AML patients have normal cytogenetics at the time of diagnosis, which greatly limits the role of karyotype analysis in assessing the prognosis of patients.
Subsequent with significant progress in the study of molecular characteristics of leukemia, MICM classification was then proposed.
After incorporating the characteristics of molecular biology to build the foundation of precision medicine, leukemia in the WHO classification has been successfully transformed from a morphological type to a molecular type and the definition is more refined.
Professor Wu Depei pointed out, “A number of current guidelines clearly recommend routine cytogenetic and molecular testing for AML patients.
The
latest version of the NCCN guidelines has included CBF, FLT3, NPM1, IDH1, IDH2 and other gene mutations into the routine testing of AML.
Version 2020 The CSCO guidelines also recommend the use of related molecular tests in the recommendation of level I experts to stratify the prognosis of AML based on FLT3-ITD, NPM1, TP53 and other mutations.
"A hundred flowers bloom: a variety of targeted new drugs have taken turns in recent years, the targeting of AML Great progress has been made in treatment.
Professor Wu Depei said that for some common mutated genes in AML, a variety of effective targeted therapy drugs have been successfully developed, such as FLT3 inhibitors, BCL-2 inhibitors and IDH1/2 inhibitors.
FLT3 mutation is the most common gene mutation in AML patients, and about 30% of patients tested positive for the mutation.
Studies have shown that FLT3 mutations are closely related to the prognosis of AML patients.
Geiritinib is a highly selective, second-generation, type I, oral FLT3 inhibitor.
It has high inhibitory activity on FLT3-ITD and FLT3-TKD.
It can also inhibit tyrosine related to FLT3 inhibitor resistance.
Kinase AXL.
In 2018, the US FDA approved geritinib for the treatment of FLT3 mutation-positive relapsed or refractory AML.
At present, geritinib has also been approved in China, heralding the first precision targeted drug for AML patients with FLT3 mutations in my country.
Professor Wu Depei pointed out that the approval of new drugs is inseparable from the support of numerous clinical studies.
ADMIRAL study 1 showed that geritinib was significantly better than salvage chemotherapy in prolonging OS in patients with FLT3-ITD and TKD mutations.
Moreover, the continued use of geritinib after hematopoietic stem cell transplantation can still prolong the survival of patients.
In addition, geritinib also has a good effect in the first line.
The data released by 2020 ASH show that 2, after geritinib is combined with 3+7 induction chemotherapy, in FLT3 mutation patients, the compound complete remission rate is 81.
6%, with a median OS has not yet reached and is well tolerated.
Therefore, patients with positive FLT3 mutations may be given geritinib as soon as possible.
At present, targeting the apoptotic pathway has become the main part of the treatment of AML.
Venecla is a selective BCL-2 inhibitor, which has been approved for use with azacitidine/decitabine/low-dose cytarabine in China.
Combination therapy is not suitable for intensive induction chemotherapy due to comorbidities, or newly diagnosed adult AML patients aged ≥75 years.
Regarding IDH1/2 inhibitors, the FDA approved Ivosidenib for the treatment of IDH1 mutations in patients with relapsed or refractory AML, as well as newly diagnosed AML patients who are ≥75 years old or cannot use strong induction chemotherapy due to comorbidities.
Ivosidenib combined with azacitidine in the treatment of newly diagnosed AML patients with IDH1 mutations who are not suitable for intensive chemotherapy is superior to single-agent historical data.
In addition, the FDA also approved Enasidenib for the treatment of AML patients with relapsed or refractory IDH2 mutations.
The future can be expected: dual target combination, collaborative fight against AML As more and more targeted drugs become available, researchers are also trying to adopt targeted drug combination therapy strategies to further improve the efficacy and benefit a wider range of AML patients.
Professor Wu Depei said that the 2020 ASH meeting reported a phase 1b expansion cohort 3 of gerritinib combined with venecla in the treatment of relapsed or refractory FLT3 mutation-positive AML.
The results show that in FLT3 mutation-positive AML patients who have received a large number of treatments (most of them have received FLT3 TKI treatment in the past), geritinib combined with Venecla achieved extremely high bone marrow and blood blast clearance rates , The modified compound complete remission rate is as high as 83.
8%, which may indicate that the anti-leukemia activity of geritinib combined with Venecla is significantly higher than that of geritinib alone.
In terms of safety, non-hematological toxicity is moderate, and the combination is well tolerated.
It can be seen that the combination of two targeted drugs to fight AML may bring more benefits to patients, and it is worthy of further research.
Summary In the era of AML precision medicine, genetic testing can be said to be the only way for modern clinical diagnosis and treatment.
At present, domestic and foreign guidelines clearly recommend routine genetic testing for AML patients.
The risk stratification of the prognosis of AML based on the results of genetic testing is helpful for the selection of precise targeted treatment strategies.
The FLT3 inhibitor geritinib was approved in China, bringing FLT3 mutation-positive relapsed or refractory AML patients the first targeted therapy option.
It is hoped that more and more AML patients will be able to obtain precise diagnosis, precise treatment, and ultimately obtain precise benefits.
References: 1.
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.
2.
A Phase 1 Study of Gilteritinib in Combination with Induction and Consolidation Chemotherapy in Patients with Newly Diagnosed AML: Final Results.
2020ASH: Oral 24.
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.
Poke "read the original text" and we will make progress together
