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ACUTE MYELOID LEUKEMIA

Enasidenib-induced differentiation promotes sensitivity to venetoclax in IDH2-mutated acute myeloid leukemia

Leukemia volume 36, pages 869–872 (2022)Cite this article

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Mutations in isocitrate dehydrogenase 1 (IDH1) and IDH2 block acute myeloid leukemia (AML) differentiation through production of 2-hydroxyglutarate (2-HG) [1,2,3]. Enasidenib is a first-in-class mutant IDH2 inhibitor that induces differentiation of IDH2-mutated leukemic cells by lowering 2-HG levels [4, 5]. In a phase I/II clinical trial, enasidenib monotherapy resulted in an overall response rate of ~40% and a median response duration of ~6 months in patients with relapsed/refractory IDH2-mutated AML [6, 7].

We previously found that accumulation of 2-HG increases dependency on the anti-apoptotic protein, B-cell leukemia/lymphoma-2 (BCL-2), in AML cells [8]. Venetoclax, a potent and selective inhibitor of BCL-2, preferentially targets IDH1/2-mutated human AML cells [8, 9]. These experimental findings are supported by clinical trials demonstrating an association between IDH1/2 mutations and sensitivity to venetoclax either as monotherapy or in combination with hypomethylating agents or low-dose cytarabine [10,11,12,13]. These pre-clinical and clinical findings suggest that the combination of enasidenib and venetoclax may be an effective regimen for IDH2-mutated AML. However, our previous finding that 2-HG increases dependency on BCL-2 poses a potential caveat to this approach. Suppression of 2-HG production by enasidenib may instead antagonize venetoclax activity. On the other hand, enasidenib-induced differentiation may further sensitize AML cells to venetoclax by lowering the apoptotic threshold, as has been observed with other differentiation agents [14,15,16,17,18,19,20]. Thus, there is uncertainty over the net impact of enasidenib treatment on venetoclax sensitivity.

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Fig. 1: Enasidenib-induced differentiation sensitizes OCI-mIDH2/N cells to venetoclax by upregulating BIM.
Fig. 2: Combination treatment with enasidenib and venetoclax is superior to venetoclax monotherapy in IDH2-mutated AML responsive to enasidenib-induced differentiation.

References

  1. Ward PS, Patel J, Wise DR, Abdel-Wahab O, Bennett BD, Coller HA, et al. The common feature of leukemia-associated IDH1 and IDH2 mutations is a neomorphic enzyme activity converting alpha-ketoglutarate to 2-hydroxyglutarate. Cancer Cell. 2010;17:225–34.

    Article  CAS  Google Scholar 

  2. Losman JA, Looper RE, Koivunen P, Lee S, Schneider RK, McMahon C. et al. (R)-2-hydroxyglutarate is sufficient to promoteleukemogenesis and its effects are reversible. Science. 2013;339:1621–5.

    Article  CAS  Google Scholar 

  3. Gross S, Cairns RA, Minden MD, Driggers EM, Bittinger MA, Jang HG, et al. Cancer-associated metabolite 2-hydroxyglutarate accumulates in acute myelogenous leukemia with isocitrate dehydrogenase 1 and 2 mutations. J Exp Med. 2010;207:339–44.

    Article  CAS  Google Scholar 

  4. Yen K, Travins J, Wang F, David MD, Artin E, Straley K. et al. AG-221, a first-in-class therapy targeting acute myeloid leukemia harboring oncogenic IDH2 mutations. Cancer Disco. 2017;7:478–93.

    Article  CAS  Google Scholar 

  5. Amatangelo MD, Quek L, Shih A, Stein EM, Roshal M, David MD, et al. Enasidenib induces acute myeloid leukemia cell differentiation to promote clinical response. Blood. 2017;130:732–41.

    Article  CAS  Google Scholar 

  6. Stein EM, DiNardo CD, Pollyea DA, Fathi AT, Roboz GJ, Altman JK, et al. Enasidenib in mutant IDH2 relapsed or refractory acute myeloid leukemia. Blood. 2017;130:722–31.

    Article  CAS  Google Scholar 

  7. Stein EM, DiNardo CD, Fathi AT, Pollyea DA, Stone RM, Altman JK, et al. Molecular remission and response patterns in patients with mutant-IDH2 acute myeloid leukemia treated with enasidenib. Blood. 2019;133:676–87.

    Article  CAS  Google Scholar 

  8. Chan SM, Thomas D, Corces-Zimmerman MR, Xavy S, Rastogi S, Hong WJ, et al. Isocitrate dehydrogenase 1 and 2 mutations induce BCL-2 dependence in acute myeloid leukemia. Nat Med. 2015;21:178–84.

    Article  CAS  Google Scholar 

  9. Bisaillon R, Moison C, Thiollier C, Krosl J, Bordeleau ME, Lehnertz B, et al. Genetic characterization of ABT-199 sensitivity in human AML. Leukemia. 2020;34:63–74.

    Article  Google Scholar 

  10. Konopleva M, Pollyea DA, Potluri J, Chyla B, Hogdal L, Busman T. et al. Efficacy and biological correlates of response in a Phase II study of venetoclax monotherapy in patients with acute myelogenous leukemia. Cancer Disco. 2016;6:1106–17.

    Article  CAS  Google Scholar 

  11. Chyla B, Daver N, Doyle K, McKeegan E, Huang X, Ruvolo V, et al. Genetic biomarkers of sensitivity and resistance to venetoclax monotherapy in patients with relapsed acute myeloid leukemia. Am. J. Hematol. 2018;93:E202–E205.

  12. DiNardo CD, Tiong IS, Quaglieri A, MacRaild S, Loghavi S, Brown FC, et al. Molecular patterns of response and treatment failure after frontline venetoclax combinations in older patients with AML. Blood. 2020;135:791–803.

    Article  CAS  Google Scholar 

  13. Wei AH, Montesinos P, Ivanov V, DiNardo CD, Novak J, Laribi K, et al. Venetoclax plus LDAC for newly diagnosed AML ineligible for intensive chemotherapy: a phase 3 randomized placebo-controlled trial. Blood. 2020;135:2137–45.

    Article  CAS  Google Scholar 

  14. Bradbury DA, Aldington S, Zhu YM, Russell NH. Down-regulation of bcl-2 in AML blasts by all-trans retinoic acid and its relationship to CD34 antigen expression. Br J Haematol. 1996;94:671–5.

    Article  CAS  Google Scholar 

  15. Ketley NJ, Allen PD, Kelsey SM, Newland AC. Modulation of idarubicin-induced apoptosis in human acute myeloid leukemia blasts by all-trans retinoic acid, 1,25(OH)2 vitamin D3, and granulocyte-macrophage colony-stimulating factor. Blood. 1997;90:4578–87.

    Article  CAS  Google Scholar 

  16. Benito A, Grillot D, Nuñez G, Fernández-Luna JL. Regulation and function of Bcl-2 during differentiation-induced cell death in HL-60 promyelocytic cells. Am J Pathol. 1995;146:481–90.

    CAS  PubMed  PubMed Central  Google Scholar 

  17. Santos-Beneit AM, Mollinedo F. Expression of genes involved in initiation, regulation, and execution of apoptosis in human neutrophils and during neutrophil differentiation of HL-60 cells. J Leukoc Biol. 2000;67:712–24.

    Article  CAS  Google Scholar 

  18. Mengubas K, Riordan FA, Hoffbrand AV, Wickremasinghe RG. Co-ordinated downregulation of bcl-2 and bax expression during granulocytic and macrophage-like differentiation of the HL60 promyelocytic leukaemia cell line. FEBS Lett. 1996;394:356–60.

    Article  CAS  Google Scholar 

  19. Grillier I, Umiel T, Elstner E, Collins SJ, Koeffler HP. Alterations of differentiation, clonal proliferation, cell cycle progression and bcl-2 expression in RAR alpha-altered sublines of HL-60. Leukemia. 1997;11:393–400.

    Article  CAS  Google Scholar 

  20. Otake Y, Sengupta TK, Bandyopadhyay S, Spicer EK, Fernandes DJ. Retinoid-induced apoptosis in HL-60 cells is associated with nucleolin down-regulation and destabilization of Bcl-2 mRNA. Mol Pharmacol. 2005;67:319–26.

    Article  CAS  Google Scholar 

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Acknowledgements

We acknowledge Dr. Mark Minden who directs the Princess Margaret Leukemia Tissue Bank and patients for donating the samples used in this study.

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Authors and Affiliations

  1. Princess Margaret Cancer Centre, University Health Network, Toronto, ON, Canada

    Severine Cathelin, Amit Subedi & Steven M. Chan

  2. Oncology Discovery, AbbVie Inc., North Chicago, IL, USA

    David Sharon, Dan Cojocari & Darren C. Phillips

  3. Oncology Development, AbbVie Inc., North Chicago, IL, USA

    Joel D. Leverson

  4. Bristol Myers Squibb, Summit, NJ, USA

    Kyle J. MacBeth

  5. Agios Pharmaceuticals, Inc., Cambridge, MA, USA

    Brandon Nicolay, Rohini Narayanaswamy, Sebastien Ronseaux & Guowen Liu

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  1. Severine Cathelin
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Contributions

SC contributed to experimental design, execution of experiments, data interpretation, and manuscript preparation. DS and AS contributed to execution of experiments, and manuscript editing. DC contributed to experimental design, execution of experiments, data interpretation, and manuscript editing. DCP, JDL, KJM, and BN contributed to experimental design, data interpretation, and manuscript editing. RN, SR, & GL contributed to execution of experiments. SMC contributed to experimental design, data interpretation, and preparation of the manuscript.

Corresponding author

Correspondence to Steven M. Chan.

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Competing interests

SMC received research funding from Celgene and AbbVie to conduct this study. DCP, DC and JDL are employees of AbbVie Inc. and are stock holders. KJM is employed by and owns stock in Celgene Corporation. BN, RN, SR, and GL are employees of Agios Pharmaceuticals Inc. and are stock holders.

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Cathelin, S., Sharon, D., Subedi, A. et al. Enasidenib-induced differentiation promotes sensitivity to venetoclax in IDH2-mutated acute myeloid leukemia. Leukemia 36, 869–872 (2022). https://doi.org/10.1038/s41375-021-01468-y

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