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

Study Purpose

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.

Recruitment Criteria

Accepts Healthy Volunteers

Healthy volunteers are participants who do not have a disease or condition, or related conditions or symptoms

No
Study Type

An interventional clinical study is where participants are assigned to receive one or more interventions (or no intervention) so that researchers can evaluate the effects of the interventions on biomedical or health-related outcomes.


An observational clinical study is where participants identified as belonging to study groups are assessed for biomedical or health outcomes.


Searching Both is inclusive of interventional and observational studies.

Observational
Eligible Ages 18 Years - 90 Years
Gender All
More Inclusion & Exclusion Criteria

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)

Trial Details

Trial ID:

This trial id was obtained from ClinicalTrials.gov, a service of the U.S. National Institutes of Health, providing information on publicly and privately supported clinical studies of human participants with locations in all 50 States and in 196 countries.

NCT04369287
Phase

Phase 1: Studies that emphasize safety and how the drug is metabolized and excreted in humans.

Phase 2: Studies that gather preliminary data on effectiveness (whether the drug works in people who have a certain disease or condition) and additional safety data.

Phase 3: Studies that gather more information about safety and effectiveness by studying different populations and different dosages and by using the drug in combination with other drugs.

Phase 4: Studies occurring after FDA has approved a drug for marketing, efficacy, or optimal use.

Lead Sponsor

The sponsor is the organization or person who oversees the clinical study and is responsible for analyzing the study data.

Istituto Clinico Humanitas
Principal Investigator

The person who is responsible for the scientific and technical direction of the entire clinical study.

Francesc Sole, MDJoana DesterroKlaus MetzelerPau MontesinosJorge SierraMatteo Della Porta, MDMaria Teresa VosoChristoph RoelligLisa PleyerMoritz Middeke
Principal Investigator Affiliation Josep Carreras Leukaemia Research InstituteInstituto Português de Oncologia de LisboaLaboratory for Leukemia Diagnostics. University of MunichHematology Department. Hospital Universitari i Politècnic La FeHospital de la Santa Creu i Sant Pau Autonomous University of Barcelona, SpainHumanitas Research HospitalFondazione GIMEMATechnische Universität Dresden | TUD · Medical ClinicSalzburg Cancer Reasearch Institute (SCRI), Cancer Cluster Salzburg (CCS)Technische Universität Dresden | TUD · Medical Clinic
Agency Class

Category of organization(s) involved as sponsor (and collaborator) supporting the trial.

Other, Industry
Overall Status Unknown status
Countries Italy
Conditions

The disease, disorder, syndrome, illness, or injury that is being studied.

Acute Myeloid Leukemia, IDH1 Gene Mutation, IDH2 Gene Mutation
Additional Details

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.

Arms & Interventions

Arms

: 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

Interventions

Contact a Trial Team

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International Sites

Istituto Clinico Humanitas, Milano, Italy

Status

Recruiting

Address

Istituto Clinico Humanitas

Milano, ,

Site Contact

Marilena Bicchieri, PhD

[email protected]

+390282247668 #+39