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Clonal heterogeneity of acute myeloid leukemia treated with the IDH2 inhibitor enasidenib

Nature Medicine volume 24, pages 1167–1177 (2018)Cite this article

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Abstract

Mutations in the gene encoding isocitrate dehydrogenase 2 (IDH2) occur in several types of cancer, including acute myeloid leukemia (AML). In model systems, mutant IDH2 causes hematopoietic differentiation arrest. Enasidenib, a selective small-molecule inhibitor of mutant IDH2, produces a clinical response in 40% of treated patients with relapsed/refractory AML by promoting leukemic cell differentiation. Here, we studied the clonal basis of response and acquired resistance to enasidenib treatment. Using sequential patient samples, we determined the clonal structure of hematopoietic cell populations at different stages of differentiation. Before therapy, IDH2-mutant clones showed variable differentiation arrest. Enasidenib treatment promoted hematopoietic differentiation from either terminal or ancestral mutant clones; less frequently, treatment promoted differentiation of nonmutant cells. Analysis of paired diagnosis/relapse samples did not identify second-site mutations in IDH2 at relapse. Instead, relapse arose by clonal evolution or selection of terminal or ancestral clones, thus highlighting multiple bypass pathways that could potentially be targeted to restore differentiation arrest. These results show how mapping of clonal structure in cell populations at different stages of differentiation can reveal the response and evolution of clones during treatment response and relapse.

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Fig. 1: Enasidenib treatment induces differentiation of AML progenitor and precursor cell populations and restores progenitor function.
Fig. 2: Differentiation response arising from wild-type cells in patients treated with enasidenib.
Fig. 3: Enasidenib induces differentiation from an ancestral IDH2-mutant clone.
Fig. 4: Enasidenib induces differentiation from a terminal IDH2-mutant clone.
Fig. 5: Mechanisms leading to relapse in enasidenib-treated patients.
Fig. 6: Relapse after enasidenib treatment occurs through clonal evolution/selection.

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Acknowledgements

We thank the patients and clinical staff for the samples studied. L.Q. was supported by an Oxford-Celgene Fellowship; P.V. acknowledges funding from the MRC Disease Team Awards (G1000729/94931 and MR/L008963/1), MRC Molecular Haematology Unit and the Oxford Partnership Comprehensive Biomedical Research Centre (NIHR BRC Funding scheme. oxfbrc-2012-1). V.P.-L. and S.D.B. acknowledge funding from the French National Institute of Health (INSERM-AVIESAN), the National Cancer Institute (INCa-DGOS-Inserm_6043 and INCa 2012-1-RT-09), SIRIC-SOCRATE 2.0 and the Fondation Association pour la Recherche sur le Cancer (ARC, Programme). M.D.D. is funded by a fellowship from the Institut National du Cancer (INCa-DGOS_5733). M.H. is supported as a fellow of the Fondation Philanthropia, Ecole des Sciences du Cancer, Gustave Roussy, Villejuif, France. We acknowledge the Core Flow Cytometry and Next Generation Sequencing Facilities at the WIMM; the Imaging, Cytometry and Integrated Biology platforms at Gustave Roussy (P. Rameau, Y. Lecluse, N. Droin, M. K. Diop and UMS AMMICa); the clinical departments at Gustave Roussy (J.-B. Micol for clinical specimens; N. Auger for cytogenetic analyses; and C. Marzac and E. Leclercq for FLT3 genotyping) and Memorial Sloan Kettering. R.L.L. is supported by grants from the NIH, including R35 CA197594-01A1 and a Memorial Sloan Kettering Cancer Center Support Grant (NIH P30 CA008748, including a supplement to R.L.L.). The views expressed are those of the authors and not necessarily those of the NHS, the NIHR or the Department of Health.

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Author notes

  1. These authors contributed equally: Lynn Quek, Muriel D. David.

  2. These authors jointly supervised this work: Stephane De Botton, Anjan Thakurta, Virginie Penard-Lacronique, Paresh Vyas

Authors and Affiliations

  1. MRC Molecular Hematology Unit, WIMM, University of Oxford, Oxford, UK

    Lynn Quek, Alison Kennedy, Marlen Metzner, Bilyana Stoilova & Paresh Vyas

  2. Haematology Theme, Oxford Biomedical Research Centre, Oxford University Hospitals NHS Foundation Trust, Oxford, UK

    Lynn Quek, Alison Kennedy, Marlen Metzner, Bilyana Stoilova & Paresh Vyas

  3. Department of Hematology, Oxford University Hospitals NHS Foundation Trust, Oxford, UK

    Lynn Quek, Andy Peniket & Paresh Vyas

  4. INSERM U1170, Gustave Roussy, Université Paris-Saclay, Equipe Labellisée Ligue Nationale Contre le Cancer, Villejuif, France

    Muriel D. David, Cyril Quivoron, Maël Heiblig, Christophe Willekens, Véronique Saada, Oliver A. Bernard, Stephane De Botton & Virginie Penard-Lacronique

  5. Celgene Corporation, Summit, NJ, USA

    Michael Amatangelo, Kyle MacBeth & Anjan Thakurta

  6. Department of Medicine, Leukemia Service, Memorial Sloan Kettering Cancer Center, New York, NY, USA

    Alan Shih, Eytan Stein & Ross Levine

  7. Département d’Hématologie, Gustave Roussy, Université Paris-Saclay, Villejuif, France

    Christophe Willekens, Véronique Saada & Stephane De Botton

  8. Département de Recherche Translationnelle/INSERM U830, Institut Curie, Université Paris Sciences et Lettres, Paris, France

    Samar Alsafadi

  9. Haematological Cancer Genetics, Wellcome Trust Sanger Institute, Hinxton, Cambridge, UK

    M. S. Vijayabaskar & George S. Vassiliou

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

    Sam Agresta & Katharine Yen

  11. Department of Haematology, University of Cambridge, Cambridge, UK

    George S. Vassiliou

  12. Department of Haematology, Cambridge University Hospitals NHS Trust, Cambridge, UK

    George S. Vassiliou

  13. Cancer Research UK Cambridge Institute, University of Cambridge, Robinson Way, Cambridge, UK

    George S. Vassiliou

  14. Center for Hematologic Malignancies, Memorial Sloan Kettering Cancer Center, New York, NY, USA

    Ross Levine

  15. Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY, USA

    Ross Levine

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  1. Lynn Quek
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Contributions

L.Q. and M.D.D. designed and performed experiments, and analyzed data; A.K., M.M., M.A., B.S., C.Q., M.H., C.W., V.S. and S. Alsafadi performed experiments and analyzed data; M.S.V. and G.S.V. analyzed data; M.A., A.S., A.P., K.Y., S. Agresta, S.D.B., R.L., E.S., K.M. and A.T. provided reagents/samples/clinical data; O.A.B., S.D.B., A.T., R.L., V.P.-L. and P.V. designed the experiments and analyzed the data. L.Q. and P.V. wrote the manuscript. All authors edited the manuscript.

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Correspondence to Lynn Quek, Stephane De Botton, Anjan Thakurta, Virginie Penard-Lacronique or Paresh Vyas.

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P.V. has received research grant support from Celgene and is on its speaker bureau. L.Q. has received research grant support from Celgene.

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Quek, L., David, M.D., Kennedy, A. et al. Clonal heterogeneity of acute myeloid leukemia treated with the IDH2 inhibitor enasidenib. Nat Med 24, 1167–1177 (2018). https://doi.org/10.1038/s41591-018-0115-6

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