Prevalence and Clinical Effect of IDH1/2 Mutations in Patients With Acute Myeloid Leukemia (Euro_IDH_AML)

May 11, 2020 updated by: Istituto Clinico Humanitas

Prevalence, Correlation With Other Mutant Genes and Clinical Effect of IDH1/2 Mutations in Patients With Acute Myeloid Leukemia. The European IDH Research Alliance

Among the most notable cancer genome-wide sequencing discoveries in recent years was the finding of mutation hot-spots in the isocitrate dehydrogenase (IDH) genes in grade II/III astrocytomas and oligodendrogliomas and in secondary glioblastomas. This was rapidly followed by identification of recurrent IDH1/2 mutations in myeloid neoplasms (MN), including acute myeloid leukemia (AML). Mutant IDH is now a therapeutic target of great interest in cancer research, especially in AML, given the limitations of current approved therapies and the encouraging early clinical data demonstrating proof of concept for investigational mutant IDH1/2 inhibitors.

The origin of mutations in AML was explored by investigating the clonal evolution of genomes sequenced from patients with M1- or M3-AML and comparing them with hematopoietic stem/progenitor cells (HSPCs) from healthy volunteers. Six genes were found to have statistically higher mutation frequencies in M1 versus M3 genomes (NPM1, DNMT3A, IDH1, IDH2, TET2 and ASXL1), suggesting they are initiating rather than cooperating events. Prospective evaluation of serial 2- HG levels during treatment of newly diagnosed AML treated with standard chemotherapy revealed that both 2-HG level and mutated IDH allele burden decreased with response to treatment but began to rise again as therapy failed.

The prognostic impact of IDH mutations in AML is under continued investigation and varies across studies. In this research project authors aim a) to define the prevalence and type of IDH1/2 mutations in AML patients; b) to define relationships between IDH1/2 mutations and other oncogenic mutations in AML, as well as to describe clonal evolution of the disease and c) to describe the clinical outcome of IDH1/2 mutated patients with AML treated with currently available treatments.

Study Overview

Status

Unknown

Conditions

Detailed Description

Among the most notable cancer genome-wide sequencing discoveries in recent years was the finding of mutation hot-spots in the isocitrate dehydrogenase (IDH) genes in grade II/III astrocytomas and oligodendrogliomas and in secondary glioblastomas. This was rapidly followed by identification of recurrent IDH1/2 mutations in myeloid neoplasms (MN), including acute myeloid leukemia (AML), myelodysplastic syndromes (MDS) and myeloproliferative neoplasms (MPN).

Mutant IDH is now a therapeutic target of great interest in cancer research, especially in AML, given the limitations of current approved therapies and the encouraging early clinical data demonstrating proof of concept for investigational mutant IDH1/2 inhibitors.

There is evidence to suggest that IDH mutations may cooperate with other mutations to initiate and drive oncogenesis in myeloid malignancies. High levels of 2-hydroxyglutarate (2-HG, as a result of gene mutation) have been shown to inhibit αKG-dependent dioxygenases including histone and DNA demethylases, proteins that regulate cellular epigenetic status. Consistent with 2-HG promoting cancer via an effect on chromatin structure, tumors harboring IDH mutations display a CpG island methylator phenotype. More recent studies have shown that overexpression of mutant IDH enzymes can induce histone and DNA hypermethylation, as well as block cellular differentiation. Together, these data suggest that cancer-associated IDH mutations can induce a block in cellular differentiation through epigenetic modifications, which contributes to tumor initiation and progression, and thus support the clinical evaluation of agents targeted to mutant IDH

The origin of mutations in AML was explored by investigating the clonal evolution of genomes sequenced from patients with M1- or M3-AML and comparing them with hematopoietic stem/progenitor cells (HSPCs) from healthy volunteers. Six genes were found to have statistically higher mutation frequencies in M1 versus M3 genomes (NPM1, DNMT3A, IDH1, IDH2, TET2 and ASXL1), suggesting they are initiating rather than cooperating events. Furthermore, all of these genes have been shown to play a role in chromatin modification, suggesting that epigenetic alterations may function to initiate tumorigenesis.

Prospective evaluation of serial 2-HG levels during treatment of newly diagnosed AML treated with standard chemotherapy revealed that both 2-HG level and mutated IDH allele burden decreased with response to treatment but began to rise again as therapy failed.

The prognostic impact of IDH mutations in AML is under continued investigation and varies across studies

In this research project, the authors aim:

  1. To define the prevalence and type of IDH1/2 mutations in acute myeloid leukemias.
  2. To define genotype-phenotype relationship in IDH1/2 mutated patients.
  3. To define relationships between IDH1/2 mutations and other oncogenic mutations in AML, as well as to describe clonal evolution of the disease (including the evaluation of genotype at disease relapse).
  4. To describe the clinical outcome of IDH1/2 mutated patients with AML treated with currently available treatments.

Study Type

Observational

Enrollment (Anticipated)

654

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

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 90 years (Adult, Older Adult)

Accepts Healthy Volunteers

No

Genders Eligible for Study

All

Sampling Method

Non-Probability Sample

Study Population

IDH 1/2 mutated patients, IDH not mutaded patients

Description

Inclusion Criteria:

  • Age ≥ 18 years
  • Diagnosis of AML According to 2016 WHO classification criteria
  • Ability to give informed consent according to ICH/EU GCP, and national/local regulations.

Exclusion Criteria:

  • Lack of written informed consent
  • Lack of biological samples (blood, bone marrow aspirate)

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: Cohort
  • Time Perspectives: Prospective

Cohorts and Interventions

Group / Cohort
IDH1-mutated AML
Patients affected with AML and carryng IDH1 mutations
IDH2-mutated AML
Patients affected with AML and carryng IDH2 mutations
IDH1/2 unmutated AML
Patients affected with AML without IDH1/2 mutations

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Prevalence of IDH1/2 mutations in patients with AML
Time Frame: 2016-2020
IDH1/2 mutational status will be analyzed in all centers by NGS or sanger sequencing on samples obtained from patients affected with AML enrolled in the study with the aim to provide information on the prevalence and type of IDH1/2 mutations
2016-2020
genotype-phenotype correlations in AML patients carryng IDH1/2 mutations
Time Frame: 2016-2020
Data obtained from targeted gene sequencing will be correlated with clinical and hematological variables of interest (i.e., demographic factors, WHO 2016 category, cytogenetics, presence of recurrent molecular abnormalities, response to treatment, overall survival, disease-free survival) to identify specific associations between genotype and disease phenotype)
2016-2020
Overall survival in patients with AML carryng IDH1/2 mutations
Time Frame: 2016-2020
Specific analyses will be carried out to describe overall survival of AML with IDH1/2 mutations with currently available treatments. Moreover, A comparison between survival of IDH-mutated vs. IDH-unmutated patients will be performed
2016-2020

Collaborators and Investigators

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

Sponsor

Istituto Clinico Humanitas

Collaborators

Celgene

Investigators

  • Principal Investigator: Francesc Sole, MD, Josep Carreras Leukaemia Research Institute
  • Principal Investigator: Joana Desterro, Instituto Português de Oncologia de Lisboa
  • Principal Investigator: Klaus Metzeler, Laboratory for Leukemia Diagnostics. University of Munich
  • Principal Investigator: Pau Montesinos, Hematology Department. Hospital Universitari i Politècnic La Fe
  • Principal Investigator: Jorge Sierra, Hospital de la Santa Creu i Sant Pau Autonomous University of Barcelona, Spain
  • Study Chair: Matteo Della Porta, MD, Humanitas Research Hospital
  • Principal Investigator: Maria Teresa Voso, Fondazione GIMEMA - Franco Mandelli Onlus
  • Principal Investigator: Christoph Roellig, Technische Universität Dresden | TUD · Medical Clinic
  • Principal Investigator: Lisa Pleyer, Salzburg Cancer Reasearch Institute (SCRI), Cancer Cluster Salzburg (CCS)
  • Principal Investigator: Moritz Middeke, Technische Universität Dresden | TUD · Medical Clinic

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 (Actual)

January 1, 2016

Primary Completion (Anticipated)

October 15, 2020

Study Completion (Anticipated)

December 15, 2020

Study Registration Dates

First Submitted

April 27, 2020

First Submitted That Met QC Criteria

April 27, 2020

First Posted (Actual)

April 30, 2020

Study Record Updates

Last Update Posted (Actual)

May 13, 2020

Last Update Submitted That Met QC Criteria

May 11, 2020

Last Verified

May 1, 2020

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • ONC/OSS-04/2016

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.

Clinical Trials on Acute Myeloid Leukemia

Search Similar Trials

Sponsors and Collaborators

Medical Conditions

Drug Interventions

CROs by country

CROs in Argentina

Conditions

Rare Diseases

Drug Interventions

Dietary Supplements

Sponsor/Collaborators

Locations

Subscribe