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Myelodysplastic syndrome

Dynamic changes in the clonal structure of MDS and AML in response to epigenetic therapy

Leukemia volume 31, pages 872–881 (2017)Cite this article

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Abstract

Traditional response criteria in myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML) are based on bone marrow morphology and may not accurately reflect clonal tumor burden in patients treated with non-cytotoxic chemotherapy. We used next-generation sequencing of serial bone marrow samples to monitor MDS and AML tumor burden during treatment with epigenetic therapy (decitabine and panobinostat). Serial bone marrow samples (and skin as a source of normal DNA) from 25 MDS and AML patients were sequenced (exome or 285 gene panel). We observed that responders, including those in complete remission (CR), can have persistent measurable tumor burden (that is, mutations) for at least 1 year without disease progression. Using an ultrasensitive sequencing approach, we detected extremely rare mutations (equivalent to 1 heterozygous mutant cell in 2000 non-mutant cells) months to years before their expansion at disease relapse. While patients can live with persistent clonal hematopoiesis in a CR or stable disease, ultimately we find evidence that expansion of a rare subclone occurs at relapse or progression. Here we demonstrate that sequencing of serial samples provides an alternative measure of tumor burden in MDS or AML patients and augments traditional response criteria that rely on bone marrow blast percentage.

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References

  1. Cashen AF, Schiller GJ, O'Donnell MR, DiPersio JF . Multicenter, phase II study of decitabine for the first-line treatment of older patients with acute myeloid leukemia. J Clin Oncol 2009; 28: 556–561.

    Article  PubMed  Google Scholar 

  2. Silverman LR, Demakos EP, Peterson BL, Kornblith AB, Holland JC, Odchimar-Reissig R et al. Randomized controlled trial of azacitidine in patients with the myelodysplastic syndrome: a study of the cancer and leukemia group B. J Clin Oncol 2002; 20: 2429–2440.

    Article  CAS  PubMed  Google Scholar 

  3. Kantarjian H, Issa JP, Rosenfeld CS, Bennett JM, Albitar M, DiPersio J et al. Decitabine improves patient outcomes in myelodysplastic syndromes: results of a phase III randomized study. Cancer 2006; 106: 1794–1803.

    Article  CAS  PubMed  Google Scholar 

  4. Dombret H, Seymour JF, Butrym A, Wierzbowska A, Selleslag D, Jang JH 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: 291–299.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Fenaux P, Mufti GJ, Hellstrom-Lindberg E, Santini V, Gattermann N, Germing U et al. Azacitidine prolongs overall survival compared with conventional care regimens in elderly patients with low bone marrow blast count acute myeloid leukemia. J Clin Oncol 2010; 28: 562–569.

    Article  CAS  PubMed  Google Scholar 

  6. Fenaux P, Mufti GJ, Hellstrom-Lindberg E, Santini V, Finelli C, Giagounidis A et al. Efficacy of azacitidine compared with that of conventional care regimens in the treatment of higher-risk myelodysplastic syndromes: a randomised, open-label, phase III study. Lancet Oncol 2009; 10: 223–232.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Silverman LR, Fenaux P, Mufti GJ, Santini V, Hellstrom-Lindberg E, Gattermann N et al. Continued azacitidine therapy beyond time of first response improves quality of response in patients with higher-risk myelodysplastic syndromes. Cancer 2011; 117: 2697–2702.

    Article  CAS  PubMed  Google Scholar 

  8. Gore SD, Fenaux P, Santini V, Bennett JM, Silverman LR, Seymour JF et al. A multivariate analysis of the relationship between response and survival among patients with higher-risk myelodysplastic syndromes treated within azacitidine or conventional care regimens in the randomized AZA-001 trial. Haematologica 2013; 98: 1067–1072.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Walter MJ, Shen D, Ding L, Shao J, Koboldt DC, Chen K et al. Clonal architecture of secondary acute myeloid leukemia. N Engl J Med 2012; 366: 1090–1098.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Cheson BD, Bennett JM, Kopecky KJ, Buchner T, Willman CL, Estey EH et al. Revised recommendations of the International Working Group for Diagnosis, Standardization of Response Criteria, Treatment Outcomes, and Reporting Standards for Therapeutic Trials in Acute Myeloid Leukemia. J Clin Oncol 2003; 21: 4642–4649.

    Article  PubMed  Google Scholar 

  11. Cheson BD, Greenberg PL, Bennett JM, Lowenberg B, Wijermans PW, Nimer SD et al. Clinical application and proposal for modification of the International Working Group (IWG) response criteria in myelodysplasia. Blood 2006; 108: 419–425.

    Article  CAS  PubMed  Google Scholar 

  12. Walter MJ, Shen D, Shao J, Ding L, White BS, Kandoth C et al. Clonal diversity of recurrently mutated genes in myelodysplastic syndromes. Leukemia 2013; 27: 1275–1282.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Welch JS, Ley TJ, Link DC, Miller CA, Larson DE, Koboldt DC et al. The origin and evolution of mutations in acute myeloid leukemia. Cell 2012; 150: 264–278.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Ding L, Ley TJ, Larson DE, Miller CA, Koboldt DC, Welch JS et al. Clonal evolution in relapsed acute myeloid leukaemia revealed by whole-genome sequencing. Nature 2012; 481: 506–510.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Atadja P . Development of the pan-DAC inhibitor panobinostat (LBH589): successes and challenges. Cancer Lett 2009; 280: 233–241.

    Article  CAS  PubMed  Google Scholar 

  16. Welch J, Petti A, Miller C, Fronick C, O'Laughlin M, Fulton R et al. TP53 and decitabine in acute myeloid leukemia and myelodysplastic syndromes. NEJM, in press.

  17. Klco JM, Miller CA, Griffith M, Petti A, Spencer DH, Ketkar-Kulkarni S et al. Association between mutation clearance after induction therapy and outcomes in acute myeloid leukemia. JAMA 2015; 314: 811–822.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Research TCGA. Genomic and epigenomic landscapes of adult de novo acute myeloid leukemia. N Engl J Med 2013; 368: 2059–2074.

    Article  Google Scholar 

  19. San-Miguel JF, Richardson PG, Gunther A, Sezer O, Siegel D, Blade J et al. Phase Ib study of panobinostat and bortezomib in relapsed or relapsed and refractory multiple myeloma. J Clin Oncol 2013; 31: 3696–3703.

    Article  CAS  PubMed  Google Scholar 

  20. Jackson-Grusby L, Laird PW, Magge SN, Moeller BJ, Jaenisch R . Mutagenicity of 5-aza-2'-deoxycytidine is mediated by the mammalian DNA methyltransferase. Proc Natl Acad Sci USA 1997; 94: 4681–4685.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Kantarjian HM, Thomas XG, Dmoszynska A, Wierzbowska A, Mazur G, Mayer J et al. Multicenter, randomized, open-label, phase III trial of decitabine versus patient choice, with physician advice, of either supportive care or low-dose cytarabine for the treatment of older patients with newly diagnosed acute myeloid leukemia. J Clin Oncol 2012; 30: 2670–2677.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Lubbert M, Suciu S, Baila L, Ruter BH, Platzbecker U, Giagounidis A et al. Low-dose decitabine versus best supportive care in elderly patients with intermediate- or high-risk myelodysplastic syndrome (MDS) ineligible for intensive chemotherapy: final results of the randomized phase III study of the European Organisation for Research and Treatment of Cancer Leukemia Group and the German MDS Study Group. J Clin Oncol 2011; 29: 1987–1996.

    Article  PubMed  Google Scholar 

  23. Haferlach T, Nagata Y, Grossmann V, Okuno Y, Bacher U, Nagae G et al. Landscape of genetic lesions in 944 patients with myelodysplastic syndromes. Leukemia 2014; 28: 241–247.

    Article  CAS  PubMed  Google Scholar 

  24. Papaemmanuil E, Gerstung M, Malcovati L, Tauro S, Gundem G, Van Loo P et al. Clinical and biological implications of driver mutations in myelodysplastic syndromes. Blood 2013; 122: 3616–3627.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Metzeler KH, Walker A, Geyer S, Garzon R, Klisovic RB, Bloomfield CD et al. DNMT3A mutations and response to the hypomethylating agent decitabine in acute myeloid leukemia. Leukemia 2012; 26: 1106–1107.

    Article  CAS  PubMed  Google Scholar 

  26. Itzykson R, Kosmider O, Cluzeau T, Mansat-De Mas V, Dreyfus F, Beyne-Rauzy O et al. Impact of TET2 mutations on response rate to azacitidine in myelodysplastic syndromes and low blast count acute myeloid leukemias. Leukemia 2011; 25: 1147–1152.

    Article  CAS  PubMed  Google Scholar 

  27. Bejar R, Lord A, Stevenson K, Bar-Natan M, Perez-Ladaga A, Zaneveld J et al. TET2 mutations predict response to hypomethylating agents in myelodysplastic syndrome patients. Blood 2014; 124: 2705–2712.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Traina F, Visconte V, Elson P, Tabarroki A, Jankowska AM, Hasrouni E et al. Impact of molecular mutations on treatment response to DNMT inhibitors in myelodysplasia and related neoplasms. Leukemia 2014; 28: 78–87.

    Article  CAS  PubMed  Google Scholar 

  29. Craddock C, Quek L, Goardon N, Freeman S, Siddique S, Raghavan M et al. Azacitidine fails to eradicate leukemic stem/progenitor cell populations in patients with acute myeloid leukemia and myelodysplasia. Leukemia 2013; 27: 1028–1036.

    Article  CAS  PubMed  Google Scholar 

  30. Will B, Zhou L, Vogler TO, Ben-Neriah S, Schinke C, Tamari R et al. Stem and progenitor cells in myelodysplastic syndromes show aberrant stage-specific expansion and harbor genetic and epigenetic alterations. Blood 2012; 120: 2076–2086.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Xie M, Lu C, Wang J, McLellan MD, Johnson KJ, Wendl MC et al. Age-related mutations associated with clonal hematopoietic expansion and malignancies. Nat Med 2014; 20: 1472–1478.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Jaiswal S, Fontanillas P, Flannick J, Manning A, Grauman PV, Mar BG et al. Age-related clonal hematopoiesis associated with adverse outcomes. N Engl J Med 2014; 371: 2488–2498.

    Article  PubMed  PubMed Central  Google Scholar 

  33. Genovese G, Kahler AK, Handsaker RE, Lindberg J, Rose SA, Bakhoum SF et al. Clonal hematopoiesis and blood-cancer risk inferred from blood DNA sequence. N Engl J Med 2014; 371: 2477–2487.

    Article  PubMed  PubMed Central  Google Scholar 

  34. McKerrell T, Park N, Moreno T, Grove CS, Ponstingl H, Stephens J et al. Leukemia-associated somatic mutations drive distinct patterns of age-related clonal hemopoiesis. Cell Rep 2015; 10: 1239–1245.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Merlevede J, Droin N, Qin T, Meldi K, Yoshida K, Morabito M et al. Mutation allele burden remains unchanged in chronic myelomonocytic leukaemia responding to hypomethylating agents. Nat Commun 2016; 7: 10767.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Boumber Y, Kantarjian H, Jorgensen J, Wen S, Faderl S, Castoro R et al. A randomized study of decitabine versus conventional care for maintenance therapy in patients with acute myeloid leukemia in complete remission. Leukemia 2012; 26: 2428–2431.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

This work was supported by Novartis, NIH/NCI K23CA140707 (GLU) and a SPORE in Leukemia (P50CA171963 to DCL, EJD, JFD, JSW, TJL, TAG, and MJW), ICTS-CTSA (to EJD), Gabrielle’s Angel Foundation (to MJW), a Leukemia and Lymphoma Society Scholar Award (to MJW), and the Lottie Caroline Hardy Trust (TAG, MJW). Support for procurement of human samples was provided by an NIH/NCI grant (P01 CA101937). Technical assistance was provided by the Alvin J Siteman Cancer Center Tissue Procurement Core supported by an NCI Cancer Center Support Grant (P30CA91842).

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Author notes

  1. G L Uy, E J Duncavage and G S Chang: These authors contributed equally to this work.

Authors and Affiliations

  1. Division of Oncology, Department of Medicine, Washington University School of Medicine, St Louis, MO, USA

    G L Uy, M A Jacoby, J Shao, S Heath, K Elliott, T Reineck, L Ganel, C N Abboud, A F Cashen, J F DiPersio, D C Link, J S Welch, T J Ley, P Westervelt & M J Walter

  2. Department of Pathology and Immunology, Washington University School of Medicine, St Louis, MO, USA

    E J Duncavage

  3. McDonnell Genome Institute, Washington University School of Medicine, St Louis, MO, USA

    G S Chang, C A Miller, R S Fulton, C C Fronick, M O'Laughlin & R K Wilson

  4. Division of Genomics and Bioinformatics, Department of Medicine, Washington University School of Medicine, St Louis, MO, USA

    C A Miller & R K Wilson

  5. Massachusetts General Hospital/Harvard Medical School, Boston, MA, USA

    T A Graubert

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Correspondence to G L Uy or M J Walter.

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GLU has received compensation as a consultant for Novartis. The other authors declare no conflict of interest.

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Uy, G., Duncavage, E., Chang, G. et al. Dynamic changes in the clonal structure of MDS and AML in response to epigenetic therapy. Leukemia 31, 872–881 (2017). https://doi.org/10.1038/leu.2016.282

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