IDH1/IDH2 Mutation Frequency in Acute Myeloblastic Patients

June 28, 2017 updated by: ADOLFO MARTINEZ TOVAR, Hospital General de Mexico

STUDY TITLE IDH1/IDH2 Mutation Frequency in Acute Myeloblastic Patients and Myelodysplasticsyndromes, Clinical Response to Treatment

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.

Study Overview

Status

Unknown

Conditions

Intervention / Treatment

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 Type

Observational

Enrollment (Anticipated)

100

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

  • Mexico
      • Mexico City, Mexico, 06720
        • Recruiting
        • Ciudad de Mexico
        • Contact:
        • Contact:

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

18 years to 80 years (Adult, Older Adult)

Accepts Healthy Volunteers

No

Genders Eligible for Study

All

Sampling Method

Non-Probability Sample

Study Population

AML patients without treatment with morphological, genetic, immunophenotype classification.

Description

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

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Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Observational Models: Case-Only
  • Time Perspectives: Prospective

Cohorts and Interventions

Group / Cohort
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

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Identify the mutation frequency of IDH1/IDH2 genes in patients with AML entering Hematology service of the HGM and clinical impact in treatment respons
Time Frame: At two years from study entry
Number of patients with the IDH mutation in AML at initial diagnosis
At two years from study entry

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

Hospital General de Mexico

Investigators

  • Principal Investigator: ADOLFO A Martinez Tovar, phD, Hospital General de Mexico

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (Anticipated)

July 10, 2017

Primary Completion (Anticipated)

December 31, 2019

Study Completion (Anticipated)

May 5, 2020

Study Registration Dates

First Submitted

June 25, 2017

First Submitted That Met QC Criteria

June 28, 2017

First Posted (Actual)

July 2, 2017

Study Record Updates

Last Update Posted (Actual)

July 2, 2017

Last Update Submitted That Met QC Criteria

June 28, 2017

Last Verified

June 1, 2017

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • Hospital General de Mexico

Plan for Individual participant data (IPD)

Plan to Share Individual Participant Data (IPD)?

No

Drug and device information, study documents

Studies a U.S. FDA-regulated drug product

No

Studies a U.S. FDA-regulated device product

No

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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