Page 259 - 2021_02-Haematologica-web

Synergy between IDH1 inhibitor and hypomethylating agent
drugs in ongoing and future clinical trials. A phase I clinical study combining the IDH1 inhibitor ivosidenib with azac- itidine is ongoing and initial data showed promising results.27 It may be worth investigating the effect of pro- longed administration of azacitidine at a lower dose or with the oral formulation CC-486 concurrently with a mIDH1/2-inhibitor to further enhance its efficacy in IDH mutated AML patients.
In conclusion, the combination of BAY1436032 and azacitidine shows a strong reduction of LSC by suppress- ing cell proliferation, self renewal and by inducing differen- tiation.
Disclosures
AC and MH received research support to their University from Bayer AG; SK and MJ are employees of Bayer AG. MW, OP, and AH are employees and equity owners of Bayer AG. All other authors have no conflict of interest to disclose.
Contributions
AC and MH conceived and designed the study; AC, CG, NB, RGo, KG, RS, BO, JW, and RGe collected the data; AC, CG,
RGa., and MH analyzed and assembled the data; SK, OP, MW, MJ, and AH provided critical reagents; FT, AG and MH collected patient samples and provided the patient data, AC and MH wrote the manuscript. All authors reviewed the data and edited and approved the final version of the manuscript.
Acknowledgments
We acknowledge the assistance of the Cell Sorting Core Facility of Hannover Medical School supported in part by the Braukmann-Wittenberg-Herz-Stiftung and the Deutsche Forschungsgemeinschaft. We would like to thank all participating patients and contributing doctors, the staff of the Central Animal Facility of Hannover Medical School, and Silke Glowotz, Martin Wichmann, Annett Reinsch and Nadine Kattre for their support.
Funding
This work was supported by funding from Bayer AG, an ERC grant under the European Union’s Horizon 2020 research and innovation programme (No. 638035), by grant 70112697 from Deutsche Krebshilfe; the German Federal Ministry of Education and Research grant 01EO0802 (IFB-Tx); and DFG grants HE 5240/5-1, HE 5240/6-1 and HE5240/6-2.
References
1. Papaemmanuil E, Gerstung M, Bullinger L, et al. Genomic Classification and prognosis in acute Myeloid Leukemia. N Engl J Med. 2016;374(23):2209-2221.
2. Wagner K, Damm F, Gohring G, et al. Impact of IDH1 R132 mutations and an IDH1 single nucleotide polymorphism in cytogenetically normal acute myeloid leukemia: SNP rs11554137 is an adverse prognostic factor. J Clin Oncol. 2010; 28(14):2356-2364.
3. Dang L, White DW, Gross S, et al. Cancer- associated IDH1 mutations produce 2- hydroxyglutarate. Nature. 2009; 462(7274):739-744.
4. Lu C, Ward PS, Kapoor GS, et al. IDH muta- tion impairs histone demethylation and results in a block to cell differentiation. Nature. 2012;483(7390):474-478.
5. Chaturvedi A, Araujo Cruz MM, Jyotsana N, et al. Mutant IDH1 promotes leukemogene- sis in vivo and can be specifically targeted in human AML. Blood. 2013;122(16):2877- 2887.
6. Chaturvedi A, Araujo Cruz MM, Jyotsana N, et al. Enantiomer-specific and paracrine leukemogenicity of mutant IDH metabolite 2-hydroxyglutarate. Leukemia. 2016;30(8): 1708-1715.
7. DiNardo CD, Stein EM, de Botton S, et al. Durable remissions with ivosidenib in IDH1- mutated relapsed or refractory AML. N Engl J Med. 2018;378(25):2386-2398.
8. Hollenbach PW, Nguyen AN, Brady H, et al. A comparison of azacitidine and decitabine activities in acute myeloid leukemia cell lines. PLoS One. 2010;5(2):e9001.
9.Dombret H, Seymour JF, Butrym A, et al. International phase 3 study of azacitidine vs conventional care regimens in older patients with newly diagnosed AML with >30%
blasts. Blood. 2015;126(3):291-299.
10. Chaturvedi A, Herbst L, Pusch S, et al. Pan- mutant-IDH1 inhibitor BAY1436032 is highly effective against human IDH1 mutant acute myeloid leukemia in vivo. Leukemia.
2017;31(10):2020-2028.
11. Chou TC. Drug combination studies and
their synergy quantification using the Chou- Talalay method. Cancer Res. 2010; 70(2):440- 446.
12. Chou TC. Theoretical basis, experimental design, and computerized simulation of syn- ergism and antagonism in drug combination studies. Pharmacol Rev. 2006;58(3):621-681.
13. Heuser M, Argiropoulos B, Kuchenbauer F, et al. MN1 overexpression induces acute myeloid leukemia in mice and predicts ATRA resistance in patients with AML. Blood. 2007;110(5):1639-1647.
14. Ng SW, Mitchell A, Kennedy JA, et al. A 17- gene stemness score for rapid determination of risk in acute leukaemia. Nature. 2016;540(7633):433-437.
15. Jones PA. Altering gene expression with 5- azacytidine. Cell. 1985;40(3):485-486.
16. Jones PA. Effects of 5-azacytidine and its 2'- deoxyderivative on cell differentiation and DNA methylation. Pharmacol Ther. 1985; 28(1):17-27.
17. Shibata T, Kokubu A, Miyamoto M, Sasajima Y, Yamazaki N. Mutant IDH1 confers an in vivo growth in a melanoma cell line with BRAF mutation. Am J Pathol. 2011; 178(3):1395-1402.
18. Xu S, Furukawa T, Kanai N, Sunamura M, Horii A. Abrogation of DUSP6 by hyperme- thylation in human pancreatic cancer. J Hum Genet. 2005;50(4):159-167.
19. Furukawa T, Tanji E, Xu S, Horii A. Feedback regulation of DUSP6 transcription responding to MAPK1 via ETS2 in human cells. Biochem Biophys Res Commun. 2008; 377(1):317-320.
20. Rubin SM, Gall AL, Zheng N, Pavletich NP.
21.
Structure of the Rb C-terminal domain bound to E2F1-DP1: a mechanism for phosphoryla- tion-induced E2F release. Cell. 2005;123(6): 1093-1106.
Driscoll B, T'Ang A, Hu YH, et al. Discovery of a regulatory motif that controls the expo- sure of specific upstream cyclin-dependent kinase sites that determine both conforma- tion and growth suppressing activity of pRb. J Biol Chem. 1999;274(14):9463-9471.
22. Stein EM, DiNardo CD, Pollyea DA, et al. Enasidenib in mutant IDH2 relapsed or refractory acute myeloid leukemia. Blood. 2017;130(6):722-731.
23. Amatangelo MD, Quek L, Shih A, et al. Enasidenib induces acute myeloid leukemia cell differentiation to promote clinical response. Blood. 2017;130(6):732-741.
24. Figueroa ME, Abdel-Wahab O, Lu C, et al. Leukemic IDH1 and IDH2 mutations result in a hypermethylation phenotype, disrupt TET2 function, and impair hematopoietic differentiation. Cancer Cell. 2010;18(6):553- 567.
25. Sekeres MA, Othus M, List AF, et al. Randomized phase II study of azacitidine alone or in combination with lenalidomide or with vorinostat in higher-risk myelodysplas- tic syndromes and chronic myelomonocytic leukemia: North American Intergroup Study SWOG S1117. J Clin Oncol. 2017; 35(24):2745-2753.
26. Dohner H, Dolnik A, Tang L, et al. Cytogenetics and gene mutations influence survival in older patients with acute myeloid leukemia treated with azacitidine or conven- tional care. Leukemia. 2018;32(12):2546- 2557.
27.Dinardo CD, Stein AS, Stein EM, et al. Mutant IDH (mIDH) inhibitors, ivosidenib or enasidenib, with azacitidine (AZA) in patients with acute myeloid leukemia (AML). J Clin Oncol. 2018;36(15):7042-7042.
haematologica | 2021; 106(2)
573