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

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ClinicalTrials.gov Identifier: NCT04369287
Recruitment Status : Recruiting
First Posted : April 30, 2020
Last Update Posted : May 13, 2020
Sponsor:
Collaborator:
Celgene
Information provided by (Responsible Party):
Istituto Clinico Humanitas

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.


Condition or disease
Acute Myeloid Leukemia IDH1 Gene Mutation IDH2 Gene Mutation

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.

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Study Type : Observational
Estimated Enrollment : 654 participants
Observational Model: Cohort
Time Perspective: Prospective
Official Title: Prevalence, Correlation With Other Mutant Genes and Clinical Effect of IDH1/2 Mutations in Patients With Acute Myeloid Leukemia. The European IDH Research Alliance
Actual Study Start Date : January 1, 2016
Estimated Primary Completion Date : October 15, 2020
Estimated Study Completion Date : December 15, 2020


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



Primary Outcome Measures :
  1. 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

  2. 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)

  3. 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


Biospecimen Retention:   Samples With DNA
Peripheral blood (PB) and bone marrow (BM) samples


Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years to 90 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Sampling Method:   Non-Probability Sample
Study Population
IDH 1/2 mutated patients, IDH not mutaded patients
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)

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT04369287


Contacts
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Contact: Matteo Della Porta, MD +390282247668 ext +39 matteo.della_porta@hunimed.eu
Contact: Marilena Bicchieri, PhD +390282247668 ext +39 marilena.bicchieri@cancercenter.humanitas.it

Locations
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Italy
Istituto Clinico Humanitas Recruiting
Milano, Italy
Contact: Marilena Bicchieri, PhD    +390282247668 ext +39    marilena.bichieri@cancercenter.humanitas.it   
Sponsors and Collaborators
Istituto Clinico Humanitas
Celgene
Investigators
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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 of Results:
Cancer Genome Atlas Research Network, Ley TJ, Miller C, Ding L, Raphael BJ, Mungall AJ, Robertson A, Hoadley K, Triche TJ Jr, Laird PW, Baty JD, Fulton LL, Fulton R, Heath SE, Kalicki-Veizer J, Kandoth C, Klco JM, Koboldt DC, Kanchi KL, Kulkarni S, Lamprecht TL, Larson DE, Lin L, Lu C, McLellan MD, McMichael JF, Payton J, Schmidt H, Spencer DH, Tomasson MH, Wallis JW, Wartman LD, Watson MA, Welch J, Wendl MC, Ally A, Balasundaram M, Birol I, Butterfield Y, Chiu R, Chu A, Chuah E, Chun HJ, Corbett R, Dhalla N, Guin R, He A, Hirst C, Hirst M, Holt RA, Jones S, Karsan A, Lee D, Li HI, Marra MA, Mayo M, Moore RA, Mungall K, Parker J, Pleasance E, Plettner P, Schein J, Stoll D, Swanson L, Tam A, Thiessen N, Varhol R, Wye N, Zhao Y, Gabriel S, Getz G, Sougnez C, Zou L, Leiserson MD, Vandin F, Wu HT, Applebaum F, Baylin SB, Akbani R, Broom BM, Chen K, Motter TC, Nguyen K, Weinstein JN, Zhang N, Ferguson ML, Adams C, Black A, Bowen J, Gastier-Foster J, Grossman T, Lichtenberg T, Wise L, Davidsen T, Demchok JA, Shaw KR, Sheth M, Sofia HJ, Yang L, Downing JR, Eley G. Genomic and epigenomic landscapes of adult de novo acute myeloid leukemia. N Engl J Med. 2013 May 30;368(22):2059-74. doi: 10.1056/NEJMoa1301689. Epub 2013 May 1. Erratum in: N Engl J Med. 2013 Jul 4;369(1):98.

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Responsible Party: Istituto Clinico Humanitas
ClinicalTrials.gov Identifier: NCT04369287    
Other Study ID Numbers: ONC/OSS-04/2016
First Posted: April 30, 2020    Key Record Dates
Last Update Posted: May 13, 2020
Last Verified: May 2020

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Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by Istituto Clinico Humanitas:
AML, IDH1 gene, IDH2 gene, gene mutation
Additional relevant MeSH terms:
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Leukemia
Leukemia, Myeloid
Leukemia, Myeloid, Acute
Neoplasms by Histologic Type
Neoplasms