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

Acute Myeloid Leukemia Clinical Trial

— Euro_IDH_AML  

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

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT04369287
• Other study ID #: ONC/OSS-04/2016
• Status: Recruiting
• Start date: January 1, 2016
• Est. completion date: December 15, 2020

Study information

• Verified date: May 2020
• Source: Istituto Clinico Humanitas
• Contact: Matteo Della Porta, MD
• Phone: +390282247668
• Email: matteo.della_porta[@]hunimed.eu
• Is FDA regulated: No
• Study type: Observational

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 654
• Est. completion date: December 15, 2020
• Est. primary completion date: October 15, 2020
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years to 90 Years

Eligibility

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)

Related Conditions & MeSH terms

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

Locations

Country	Name	City	State
Italy	Istituto Clinico Humanitas	Milano

Sponsors (2)

Lead Sponsor	Collaborator
Istituto Clinico Humanitas	Celgene

Country where clinical trial is conducted

Italy, 

References & Publications (14)

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, Lampre — View Citation

Chou WC, Lei WC, Ko BS, Hou HA, Chen CY, Tang JL, Yao M, Tsay W, Wu SJ, Huang SY, Hsu SC, Chen YC, Chang YC, Kuo KT, Lee FY, Liu MC, Liu CW, Tseng MH, Huang CF, Tien HF. The prognostic impact and stability of Isocitrate dehydrogenase 2 mutation in adult p — View Citation

Della Porta MG, Travaglino E, Boveri E, Ponzoni M, Malcovati L, Papaemmanuil E, Rigolin GM, Pascutto C, Croci G, Gianelli U, Milani R, Ambaglio I, Elena C, Ubezio M, Da Via' MC, Bono E, Pietra D, Quaglia F, Bastia R, Ferretti V, Cuneo A, Morra E, Campbell — View Citation

DiNardo CD, Propert KJ, Loren AW, Paietta E, Sun Z, Levine RL, Straley KS, Yen K, Patel JP, Agresta S, Abdel-Wahab O, Perl AE, Litzow MR, Rowe JM, Lazarus HM, Fernandez HF, Margolis DJ, Tallman MS, Luger SM, Carroll M. Serum 2-hydroxyglutarate levels pred — View Citation

DiNardo CD, Ravandi F, Agresta S, Konopleva M, Takahashi K, Kadia T, Routbort M, Patel KP, Mark Brandt, Pierce S, Garcia-Manero G, Cortes J, Kantarjian H. Characteristics, clinical outcome, and prognostic significance of IDH mutations in AML. Am J Hematol — View Citation

Figueroa ME, Abdel-Wahab O, Lu C, Ward PS, Patel J, Shih A, Li Y, Bhagwat N, Vasanthakumar A, Fernandez HF, Tallman MS, Sun Z, Wolniak K, Peeters JK, Liu W, Choe SE, Fantin VR, Paietta E, Löwenberg B, Licht JD, Godley LA, Delwel R, Valk PJ, Thompson CB, L — View Citation

Gross S, Cairns RA, Minden MD, Driggers EM, Bittinger MA, Jang HG, Sasaki M, Jin S, Schenkein DP, Su SM, Dang L, Fantin VR, Mak TW. Cancer-associated metabolite 2-hydroxyglutarate accumulates in acute myelogenous leukemia with isocitrate dehydrogenase 1 a — View Citation

Larsson CA, Cote G, Quintás-Cardama A. The changing mutational landscape of acute myeloid leukemia and myelodysplastic syndrome. Mol Cancer Res. 2013 Aug;11(8):815-27. doi: 10.1158/1541-7786.MCR-12-0695. Epub 2013 May 3. Review. — View Citation

Losman JA, Looper RE, Koivunen P, Lee S, Schneider RK, McMahon C, Cowley GS, Root DE, Ebert BL, Kaelin WG Jr. (R)-2-hydroxyglutarate is sufficient to promote leukemogenesis and its effects are reversible. Science. 2013 Mar 29;339(6127):1621-5. doi: 10.112 — View Citation

Papaemmanuil E, Gerstung M, Malcovati L, Tauro S, Gundem G, Van Loo P, Yoon CJ, Ellis P, Wedge DC, Pellagatti A, Shlien A, Groves MJ, Forbes SA, Raine K, Hinton J, Mudie LJ, McLaren S, Hardy C, Latimer C, Della Porta MG, O'Meara S, Ambaglio I, Galli A, Bu — View Citation

Thol F, Damm F, Wagner K, Göhring G, Schlegelberger B, Hoelzer D, Lübbert M, Heit W, Kanz L, Schlimok G, Raghavachar A, Fiedler W, Kirchner H, Heil G, Heuser M, Krauter J, Ganser A. Prognostic impact of IDH2 mutations in cytogenetically normal acute myelo — View Citation

Wang F, Travins J, DeLaBarre B, Penard-Lacronique V, Schalm S, Hansen E, Straley K, Kernytsky A, Liu W, Gliser C, Yang H, Gross S, Artin E, Saada V, Mylonas E, Quivoron C, Popovici-Muller J, Saunders JO, Salituro FG, Yan S, Murray S, Wei W, Gao Y, Dang L, — View Citation

Ward PS, Patel J, Wise DR, Abdel-Wahab O, Bennett BD, Coller HA, Cross JR, Fantin VR, Hedvat CV, Perl AE, Rabinowitz JD, Carroll M, Su SM, Sharp KA, Levine RL, Thompson CB. The common feature of leukemia-associated IDH1 and IDH2 mutations is a neomorphic — View Citation

Ye D, Xiong Y, Guan KL. The mechanisms of IDH mutations in tumorigenesis. Cell Res. 2012 Jul;22(7):1102-4. doi: 10.1038/cr.2012.51. Epub 2012 Mar 27. — View Citation

* Note: There are 14 references in all — Click here to view all references

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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
Primary	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
Primary	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