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

NCT ID: NCT04369287

Last Updated: 2020-05-13

Basic Information

• Recruitment Status: UNKNOWN
• Total Enrollment: 654 participants
• Study Classification: OBSERVATIONAL
• Study Start Date: 2016-01-01
• Study Completion Date: 2020-12-15

Brief Summary

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.

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.

Conditions

Acute Myeloid Leukemia; IDH1 Gene Mutation; IDH2 Gene Mutation

Study Design

• Observational Model Type: COHORT
• Study Time Perspective: PROSPECTIVE

Study Groups

IDH1-mutated AML

Patients affected with AML and carryng IDH1 mutations

No interventions assigned to this group

IDH2-mutated AML

Patients affected with AML and carryng IDH2 mutations

No interventions assigned to this group

IDH1/2 unmutated AML

Patients affected with AML without IDH1/2 mutations

No interventions assigned to this group

Eligibility 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)

• Minimum Eligible Age: 18 Years
• Maximum Eligible Age: 90 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Celgene

INDUSTRY

Sponsor Role: collaborator

Istituto Clinico Humanitas

OTHER

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Francesc Sole, MD

Role: PRINCIPAL_INVESTIGATOR

Josep Carreras Leukaemia Research Institute

Joana Desterro

Role: PRINCIPAL_INVESTIGATOR

Instituto Português de Oncologia de Lisboa

Klaus Metzeler

Role: PRINCIPAL_INVESTIGATOR

Laboratory for Leukemia Diagnostics. University of Munich

Pau Montesinos

Role: PRINCIPAL_INVESTIGATOR

Hematology Department. Hospital Universitari i Politècnic La Fe

Jorge Sierra

Role: PRINCIPAL_INVESTIGATOR

Hospital de la Santa Creu i Sant Pau Autonomous University of Barcelona, Spain

Matteo Della Porta, MD

Role: STUDY_CHAIR

Humanitas Research Hospital IRCCS, Rozzano-Milan

Maria Teresa Voso

Role: PRINCIPAL_INVESTIGATOR

Fondazione GIMEMA

Christoph Roellig

Role: PRINCIPAL_INVESTIGATOR

Technische Universität Dresden | TUD · Medical Clinic

Lisa Pleyer

Role: PRINCIPAL_INVESTIGATOR

Salzburg Cancer Reasearch Institute (SCRI), Cancer Cluster Salzburg (CCS)

Moritz Middeke

Role: PRINCIPAL_INVESTIGATOR

Technische Universität Dresden | TUD · Medical Clinic

Locations

Istituto Clinico Humanitas

Milan, , Italy

Site Status: RECRUITING

Countries

Italy

Central Contacts

Matteo Della Porta, MD

Role: CONTACT

matteo.della_porta@hunimed.eu

+390282247668 ext. +39

Marilena Bicchieri, PhD

Role: CONTACT

marilena.bicchieri@cancercenter.humanitas.it

+390282247668 ext. +39

Facility Contacts

Marilena Bicchieri, PhD

Role: primary

marilena.bichieri@cancercenter.humanitas.it

+390282247668 ext. +39

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Other Identifiers

ONC/OSS-04/2016

Identifier Type: -

Identifier Source: org_study_id