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

Study Overview
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Brief Summary
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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
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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: To define the prevalence and type of IDH1/2 mutations in acute myeloid leukemias. To define genotype-phenotype relationship in IDH1/2 mutated patients. 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). To describe the clinical outcome of IDH1/2 mutated patients with AML treated with currently available treatments.

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

Conditions
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Acute Myeloid Leukemia, IDH1 Gene Mutation, IDH2 Gene Mutation

Participation Criteria
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Eligibility Criteria
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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)

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 90 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| IDH1-mutated AML<br>Patients affected with AML and carryng IDH1 mutations | |
| IDH2-mutated AML<br>Patients affected with AML and carryng IDH2 mutations | |
| IDH1/2 unmutated AML<br>Patients affected with AML without IDH1/2 mutations | |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Prevalence of IDH1/2 mutations in patients with AML | 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 | 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 | 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 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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AML, IDH1 gene, IDH2 gene, gene mutation