Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Article
  • Published:

Clinical impact of clonal hematopoiesis in acute myeloid leukemia patients receiving allogeneic transplantation

Bone Marrow Transplantation volume 54, pages 1189–1197 (2019)Cite this article

Subjects

Abstract

Age-related somatic mutations linked to clonal hematopoiesis have been found in apparently healthy individuals and increase the risk of developing hematologic malignancies. In acute myeloid leukemia (AML) the clinical relevance of clonal hematopoiesis remains controversial and data on patients with detectable clonal hematopoiesis, consolidated with hematopoietic stem cell transplantation are limited. We analyzed samples from 113 AML patients in complete remission prior to hematopoietic stem cell transplantation for the presence of clonal hematopoiesis-associated mutations. The results were correlated with clinical and biological data. In complete remission we found 75 mutations previously linked to clonal hematopoiesis in 47 patients (41.6%). Twenty patients had ≥2 mutations linked to clonal hematopoiesis. DNMT3A, TET2, and ASXL1 were most frequently mutated. When compared to pre-treatment samples we found variable patterns of mutation persistence depending on the gene mutated. In AML patients after allogeneic hematopoietic stem cell transplantation the presence of clonal hematopoiesis-associated mutations in complete remission did not associate with inferior clinical outcome. This study demonstrates that clonal hematopoiesis is a frequent phenomenon in AML patients. Presence of clonal hematopoiesis has no negative prognostic impact in the context of an allogeneic hematopoietic stem cell transplantation and might be beneficial if certain genes are affected.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Fig. 1
Fig. 2
Fig. 3
Fig. 4

Similar content being viewed by others

References

  1. 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;20:1472–8. https://doi.org/10.1038/nm.3733

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. 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;371:2488–98. https://doi.org/10.1056/NEJMoa1408617

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. 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;10:1239–45. https://doi.org/10.1016/j.celrep.2015.02.005

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Young AL, Challen GA, Birmann BM, Druley TE. Clonal haematopoiesis harbouring AML-associated mutations is ubiquitous in healthy adults. Nat Commun. 2016;7:12484 https://doi.org/10.1038/ncomms12484

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Genovese G, Kähler 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;371:2477–87. https://doi.org/10.1056/NEJMoa1409405

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Buscarlet M, Provost S, Feroz Zada Y, Barhdadi A, Bourgoin V, Lépine G, et al. DNMT3A and TET2 dominate clonal hematopoiesis, demonstrate benign phenotypes and different genetic predisposition. Blood. 2017; https://doi.org/10.1182/blood-2017-04-777029

    Article  CAS  PubMed  Google Scholar 

  7. Steensma DP, Bejar R, Jaiswal S, Lindsley RC, Sekeres MA, Hasserjian RP, et al. Clonal hematopoiesis of indeterminate potential and its distinction from myelodysplastic syndromes. Blood. 2015;126:9–16. https://doi.org/10.1182/blood-2015-03-631747

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Jaiswal S, Natarajan P, Silver AJ, Gibson CJ, Bick AG, Shvartz E, et al. Clonal hematopoiesis and risk of atherosclerotic cardiovascular disease. N Engl J Med. 2017;377:111–21. https://doi.org/10.1056/NEJMoa1701719

    Article  PubMed  PubMed Central  Google Scholar 

  9. Shlush LI, Zandi S, Mitchell A, Chen WC, Brandwein JM, Gupta V, et al. Identification of pre-leukaemic haematopoietic stem cells in acute leukaemia. Nature. 2014;506:328–33. https://doi.org/10.1038/nature13038

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Corces-Zimmerman MR, Hong W-J, Weissman IL, Medeiros BC, Majeti R. Preleukemic mutations in human acute myeloid leukemia affect epigenetic regulators and persist in remission. Proc Natl Acad Sci USA. 2014;111:2548–53. https://doi.org/10.1073/pnas.1324297111

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Gibson CJ, Lindsley RC, Tchekmedyian V, Mar BG, Shi J, Jaiswal S, et al. Clonal hematopoiesis associated with adverse outcomes after autologous stem-cell transplantation for lymphoma. J Clin Oncol. 2017;35:1598–605. https://doi.org/10.1200/JCO.2016.71.6712

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Bhatnagar B, Eisfeld A-K, Nicolet D, Mrozek K, Blachly JS, Orwick S, et al. Persistence of DNMT3A R882 mutations during remission does not adversely affect outcomes of patients with acute myeloid leukaemia. Br J Haematol. 2016;175:226–36. https://doi.org/10.1111/bjh.14254

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Gaidzik VI, Weber D, Paschka P, Kaumanns A, Krieger S, Corbacioglu A, et al. DNMT3A mutant transcript levels persist in remission and do not predict outcome in patients with acute myeloid leukemia. Leukemia. 2017; https://doi.org/10.1038/leu.2017.200

    Article  PubMed  Google Scholar 

  14. Ploen GG, Nederby L, Guldberg P, Hansen M, Ebbesen LH, Jensen UB, et al. Persistence of DNMT3A mutations at long-term remission in adult patients with AML. Br J Haematol. 2014;167:478–86. https://doi.org/10.1111/bjh.13062

    Article  CAS  PubMed  Google Scholar 

  15. Rothenberg-Thurley M, Amler S, Goerlich D, Kohnke T, Konstandin NP, Schneider S, et al. Persistence of pre-leukemic clones during first remission and risk of relapse in acute myeloid leukemia. Leukemia. 2018;32:1598–608. https://doi.org/10.1038/s41375-018-0034-z

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Jongen-Lavrencic M, Grob T, Hanekamp D, Kavelaars FG, Al Hinai A, Zeilemaker A, et al. Molecular minimal residual disease in acute myeloid leukemia. N Engl J Med. 2018;378:1189–99. https://doi.org/10.1056/NEJMoa1716863

    Article  CAS  PubMed  Google Scholar 

  17. Morita K, Kantarjian HM, Wang F, Yan Y, Bueso-Ramos C, Sasaki K, et al. Clearance of somatic mutations at remission and the risk of relapse in acute myeloid leukemia. J Clin Oncol. 2018;36:1788–97. https://doi.org/10.1200/JCO.2017.77.6757

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Döhner H, Estey E, Grimwade D, Amadori S, Appelbaum FR, Büchner T, et al. Diagnosis and management of AML in adults: 2017 ELN recommendations from an international expert panel. Blood. 2017;129:424–47. https://doi.org/10.1182/blood-2016-08-733196

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Niederwieser D, Maris M, Shizuru JA, Petersdorf E, Hegenbart U, Sandmaier BM, et al. Low-dose total body irradiation (TBI) and fludarabine followed by hematopoietic cell transplantation (HCT) from HLA-matched or mismatched unrelated donors and postgrafting immunosuppression with cyclosporine and mycophenolate mofetil (MMF) can induce durable complete chimerism and sustained remissions in patients with hematological diseases. Blood. 2003;101:1620 https://doi.org/10.1182/blood-2002-05-1340

    Article  CAS  PubMed  Google Scholar 

  20. McSweeney PA, Niederwieser D, Shizuru JA, Sandmaier BM, Molina AJ, Maloney DG, et al. Hematopoietic cell transplantation in older patients with hematologic malignancies: replacing high-dose cytotoxic therapy with graft-versus-tumor effects. Blood. 2001;97:3390 https://doi.org/10.1182/blood.V97.11.3390

    Article  CAS  PubMed  Google Scholar 

  21. Gyurkocza B, Storb R, Storer BE, Chauncey TR, Lange T, Shizuru JA, et al. Nonmyeloablative allogeneic hematopoietic cell transplantation in patients with acute myeloid leukemia. J Clin Oncol. 2010;28:2859–67. https://doi.org/10.1200/JCO.2009.27.1460

    Article  PubMed  PubMed Central  Google Scholar 

  22. Hegenbart U, Niederwieser D, Sandmaier BM, Maris MB, Shizuru JA, Greinix H, et al. Treatment for acute myelogenous leukemia by low-dose, total-body, irradiation-based conditioning and hematopoietic cell transplantation from related and unrelated donors. J Clin Oncol. 2006;24:444–53. https://doi.org/10.1200/JCO.2005.03.1765

    Article  CAS  PubMed  Google Scholar 

  23. Metzeler KH, Becker H, Maharry K, Radmacher MD, Kohlschmidt J, Mrozek K, et al. ASXL1 mutations identify a high-risk subgroup of older patients with primary cytogenetically normal AML within the ELN favorable genetic category. Blood. 2011;118:6920–9. https://doi.org/10.1182/blood-2011-08-368225

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Lin J, Yang J, Wen X-M, Yang L, Deng Z-Q, Qian Z, et al. Detection of SRSF2-P95 mutation by high-resolution melting curve analysis and its effect on prognosis in myelodysplastic syndrome. PLoS ONE. 2014;9:e115693 https://doi.org/10.1371/journal.pone.0115693

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Bill M, Jentzsch M, Grimm J, Schubert K, Lange T, Cross M, et al. Prognostic impact of the European LeukemiaNet standardized reporting system in older AML patients receiving stem cell transplantation after non-myeloablative conditioning. Bone Marrow Transplant. 2017;52:932–5. https://doi.org/10.1038/bmt.2017.42

    Article  CAS  PubMed  Google Scholar 

  26. Jentzsch M, Bill M, Nicolet D, Leiblein S, Schubert K, Pless M, et al. Prognostic impact of the CD34+/CD38− cell burden in patients with acute myeloid leukemia receiving allogeneic stem cell transplantation. Am J Hematol. 2017;92:388–96. https://doi.org/10.1002/ajh.24663

    Article  CAS  PubMed  Google Scholar 

  27. Benthaus T, Schneider F, Mellert G, Zellmeier E, Schneider S, Kakadia PM, et al. Rapid and sensitive screening for CEBPA mutations in acute myeloid leukaemia. Br J Haematol. 2008;143:230–9. https://doi.org/10.1111/j.1365-2141.2008.07328.x

    Article  CAS  PubMed  Google Scholar 

  28. Muffly L, Pasquini MC, Martens M, Brazauskas R, Zhu X, Adekola K, et al. Increasing use of allogeneic hematopoietic cell transplantation in patients age 70 years and older in the United States. Blood. 2017; https://doi.org/10.1182/blood-2017-03-772368

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Hirsch P, Tang R, Abermil N, Flandrin P, Moatti H, Favale F, et al. Precision and prognostic value of clone-specific minimal residual disease in acute myeloid leukemia. Haematologica. 2017;102:1227–37. https://doi.org/10.3324/haematol.2016.159681

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. 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;314:811–22. https://doi.org/10.1001/jama.2015.9643

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Pardanani A, Gotlib JR, Jamieson C, Cortes JE, Talpaz M, Stone RM, et al. Safety and efficacy of TG101348, a selective JAK2 inhibitor, in myelofibrosis. J Clin Oncol. 2010;29:789–96. https://doi.org/10.1200/JCO.2010.32.8021

    Article  CAS  Google Scholar 

  32. Verstovsek S, Kantarjian H, Mesa RA, Pardanani AD, Cortes-Franco J, Thomas DA, et al. Safety and efficacy of INCB018424, a JAK1 and JAK2 Inhibitor, in myelofibrosis. N Engl J Med. 2010;363:1117–27. https://doi.org/10.1056/NEJMoa1002028

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Marcucci G, Maharry K, Wu Y-Z, Radmacher MD, Mrózek K, Margeson D, et al. IDH1 and IDH2 gene mutations identify novel molecular subsets within de novo cytogenetically normal acute myeloid leukemia: a Cancer and Leukemia Group B study. J Clin Oncol. 2010;28:2348–55. https://doi.org/10.1200/JCO.2009.27.3730

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Papaemmanuil E, Gerstung M, Bullinger L, Gaidzik VI, Paschka P, Roberts ND, et al. Genomic classification and prognosis in acute myeloid leukemia. N Engl J Med. 2016;374:2209–21. https://doi.org/10.1056/NEJMoa1516192

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Wong TN, Miller CA, Klco JM, Petti A, Demeter R, Helton NM, et al. Rapid expansion of preexisting nonleukemic hematopoietic clones frequently follows induction therapy for de novo AML. Blood. 2016;127:893–7. https://doi.org/10.1182/blood-2015-10-677021

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Rajasagi M, Shukla SA, Fritsch EF, Keskin DB, DeLuca D, Carmona E, et al. Systematic identification of personal tumor-specific neoantigens in chronic lymphocytic leukemia. Blood. 2014;124:453–62. https://doi.org/10.1182/blood-2014-04-567933

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Schumacher TN, Schreiber RD. Neoantigens in cancer immunotherapy. Science. 2015;348:69–74. https://doi.org/10.1126/science.aaa4971

    Article  CAS  PubMed  Google Scholar 

  38. Strønen E, Toebes M, Kelderman S, van Buuren MM, Yang W, van Rooij N, et al. Targeting of cancer neoantigens with donor-derived T cell receptor repertoires. Science. 2016;352:1337–41. https://doi.org/10.1126/science.aaf2288

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

This work was supported by the Deutsche José-Carreras-Stiftung (#04R/2016 and #PS15/05 J.G.), Verein zusammen gegen den Krebs e.V., and Ein Herz für Kinder e.V. The authors thank Janet Bogardt, Annette Jilo, Dagmar Cron, Ines Kovacs, Kathrin Wildenberger, Scarlett Schwabe, Christine Günther, Daniela Bretschneider, Evelin Hennig, and Christel Müller for their assistance. The authors like to acknowledge Prof. Ralf Burckhardt and Dr. Max Hubmann for support in data collection.

Author information

Authors and Affiliations

  1. Department of Hematology and Oncology, University of Leipzig, Leipzig, Germany

    Juliane Grimm, Marius Bill, Madlen Jentzsch, Stefanie Beinicke, Janine Häntschel, Karoline Goldmann, Julia Schulz, Michael Cross, Georg–Nikolaus Franke, Gerhard Behre, Vladan Vucinic, Wolfram Pönisch, Thoralf Lange, Dietger Niederwieser & Sebastian Schwind

Authors
  1. Juliane Grimm
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Marius Bill
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Madlen Jentzsch
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Stefanie Beinicke
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Janine Häntschel
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Karoline Goldmann
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Julia Schulz
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Michael Cross
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Georg–Nikolaus Franke
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Gerhard Behre
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Vladan Vucinic
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. Wolfram Pönisch
    View author publications

    You can also search for this author in PubMed Google Scholar

  13. Thoralf Lange
    View author publications

    You can also search for this author in PubMed Google Scholar

  14. Dietger Niederwieser
    View author publications

    You can also search for this author in PubMed Google Scholar

  15. Sebastian Schwind
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Sebastian Schwind.

Ethics declarations

Conflict of interest

The authors declare that they have no conflict of interest.

Electronic supplementary material

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Grimm, J., Bill, M., Jentzsch, M. et al. Clinical impact of clonal hematopoiesis in acute myeloid leukemia patients receiving allogeneic transplantation. Bone Marrow Transplant 54, 1189–1197 (2019). https://doi.org/10.1038/s41409-018-0413-0

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/s41409-018-0413-0

This article is cited by

Search

Advanced search

Quick links