IDH1/IDH2 Mutation Frequency in Acute Myeloblastic Patients
Study Details
Study Description
Brief Summary
This leukemia is characterized by a poor prognosis for most patients, as they have a high relapse rate despite aggressive treatment with chemotherapy agents and allogeneic bone marrow transplantation. It has been proposed that relapse can be attributed to a leukemic cells population with quiescence properties that are resistant to chemotherapy, known as leukemic stem cells (LSCs). Clinical trials shown a major LSCs percentage than diagnosis correlated with worst prognosis or minimal residual disease with AML.
AML is most common in adults and represents about 40% of all leukemia types in American Continent. In Mexican patients with AML age median is 32 years, lower than other international series. Genomic and functional studies have identified two classes of mutations, which cooperate during AML development.
Somatic mutations have been identified recently that codify for isocitrate dehydrogenase (IDH). These genes codify key metabolic enzymes, which convert isocitrate into α-ketoglutarate (α-KG).15-16From which IDH1 and IDH2 genes presenta high frequency of mutations in AML and other types of tumors. IDH mutations affect mainly active site residues (for example, IDH1 R132, IDH2 R140 or IDH2 R172), resulting in the normal enzymatic function loss abnormally converting α-KG to 2-hydroxiglutarate (2-HG).
"Oncometabolyte" 2-HG may competitively inhibit multiple α-KG depending dioxygenases, including key epigenetic regulators as histones demethylases and TET proteins. Consequently, IDH mutations are associated with chromatin alterations including global alteration of histones and NDA methylation. This is the reason of the need to identify such mutations of genes (IDH1/IDH2) in patients with SMD and AML entering Hematology service of the Hospital General de Mexico from 2017 to 2019, and determine clinical impact in prognosis and monitoring the response to therapy, as well as prognosis and survival.
| Condition or Disease | Intervention/Treatment | Phase |
|---|---|---|
|
Detailed Description
Acute myeloid leukemia (AML) is a heterogeneous cancer implying accumulation of mature cells. This leukemia is characterized by a poor prognosis for most patients, as they have a high relapse rate despite aggressive treatment with chemotherapy agents and allogeneic bone marrow transplantation. It has been proposed that relapse can be attributed to a leukemic cells population with quiescence properties that are resistant to chemotherapy, known as leukemic stem cells (LSCs). Clinical trials shown a major LSCs percentage than diagnosis correlated with worst prognosis or minimal residual disease with AML.
AML is most common in adults and represents about 40% of all leukemia types in American Continent. In Mexican patients with AML age median is 32 years, lower than other international series.
AML may be classified in 8 sub-types based on FAB Classification (French-American-British Classification). FAB Classification is based on morphology and cytogenetic. Sub-types are M0 to M7, based on the type of leukemia cells and their maturity. Other classification system used is the one of the World Health Organization (WHO) that classifies the types of leukemia based on genetic/molecular alteration or existence of other potential factors impacting clinical prognosis. The Hospital General de Mexico classifies the leukemia types based on morphologic, immunophenotype, genetic and sometimes in molecular criteria.
Genomic and functional studies have identified two classes of mutations, which cooperate during AML development. Class I mutations, which confer proliferative and survival advantage to hematopoietic stem cells, an example is the occurrence of mutations in NRAS or KRAS genes, or mutations affecting receptor tyrosine kinase FLT3.Class II mutations characterize for promoting self-renewal and blocking differentiation of hematopoietic stem cells. These mutations include certain translocation, an example of this type of mutations is gene MLL1 derived from t(8;21) (AML1-ETO).Major mutations in AML are commonly detected in cytogenetically Normal (CN) cases representing 40% to 50% of all AML.
Such aberrations have demonstrated impacting prognosis of patients with AML. These genes include: FLT3, NPM1, CEBPA, MLL, NRAS, KIT, WT1, RUNX1, TET2, IDH1/2, DNMT3A, ASXL1, PHF6. For example, mutations in FLT3 (37%-46% of patients) indicate poor prognosis. On the contrary, mutations in NPM1 (48%-53% of patients) and CEBPA (13% to 15% of patients) indicate a better prognosis. AMLis a neoplastic clonal disease that originates from progressive accumulation of genetic and epigenetic aberrations affecting mechanisms regulating proliferation and differentiation of hematopoietic trunk cells (HTC). However, impact of these mutations in survival and chemo resistance to new therapeutic agents in LSCs, including emergent therapies against LSCs, which have not been described. In the Hospital General de Mexico, the prognosis of LAM at 5 years is only 30%. For this, it is necessary to detect mutation pattern of genes that may contribute to AML development or prognosis in Mexican patients of the Hospital General de México.
Somatic mutations have been identified recently that codify for isocitrate dehydrogenase (IDH). These genes codify key metabolic enzymes, which convert isocitrate into α-ketoglutarate (α-KG).15-16From which IDH1 and IDH2 genes presenta high frequency of mutations in AML and other types of tumors. IDH mutations affect mainly active site residues (for example, IDH1 R132, IDH2 R140 or IDH2 R172), resulting in the normal enzymatic function loss abnormally converting α-KG to 2-hydroxiglutarate (2-HG).
"Oncometabolyte" 2-HG may competitively inhibit multiple α-KG depending dioxygenases, including key epigenetic regulators as histones demethylases and TET proteins. Consequently, IDH mutations are associated with chromatin alterations including global alteration of histones and NDA methylation. This is the reason of the need to identify such mutations of genes (IDH1/IDH2) in patients with SMD and AML entering Hematology service of the Hospital General de Mexico from 2017 to 2019, and determine clinical impact in prognosis and monitoring the response to therapy, as well as prognosis and survival..
Study Design
Arms and Interventions
| Arm | Intervention/Treatment |
|---|---|
| AML patients Adult AML patients with the IDH mutation test performed at diagnosis. |
Genetic: IDH mutation test performed at diagnosis
Observation of the test result
|
Outcome Measures
Primary Outcome Measures
- Identify the mutation frequency of IDH1/IDH2 genes in patients with AML entering Hematology service of the HGM and clinical impact in treatment respons [At two years from study entry]
Number of patients with the IDH mutation in AML at initial diagnosis
Eligibility Criteria
Criteria
Inclusion Criteria:
Signed written informed consent according to ICH/GCP and national local laws
AML patients; >18 years IDH mutation test perfomed at diagnosis
Exclusion Criteria:
Patients whom don't continue treatment. AML-M3 subtype according to the FAB
-
Contacts and Locations
Locations
| Site | City | State | Country | Postal Code | |
|---|---|---|---|---|---|
| 1 | Ciudad de Mexico | Mexico City | Mexico | 06720 |
Sponsors and Collaborators
- Hospital General de Mexico
Investigators
- Principal Investigator: ADOLFO A Martinez Tovar, phD, Hospital General de Mexico
Study Documents (Full-Text)
None provided.More Information
Publications
- Hospital General de Mexico