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Prognostic relevance of DNMT3A R882 mutations in AML patients undergoing non-myeloablative conditioning hematopoietic stem cell transplantation

Bone Marrow Transplantation volume 53, pages 640–643 (2018)Cite this article

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Mutations in the epigenetic modifying gene DNA methyltransferase 3A (DNMT3A) are found in 14–35% of acute myeloid leukemia (AML) patients [1,2,3,4,5,6]. The majority of DNMT3A mutations cluster at codon R882 in exon 23 [1,2,3,4,5,6]. Most of the studies that have investigated the prognostic impact of these alterations reported inferior outcomes associated with the presence of DNMT3A mutations—particularly in codon R882 [1,2,3,4, 6,7,8,9]. However, the negative impact on outcomes may be dependent on the clinical and biological context, such as the presence of concurrent gene mutations (i.e. NPM1 mutations and/or presence of FLT3-ITD) and the DNMT3A mutation type (i.e. R882 vs. non-R882) [1,2,3,4,5,6, 9]. In older AML patients, DNMT3A mutations are more prevalent [7] and have been associated with poor outcomes [1, 6, 8].

DNMT3A mutations are often found to persist during remission (possibly due to a preexisting clonal hematopoiesis) and at AML relapse, and might contribute to chemotherapy resistance [10]. This raises the issue of allogeneic hematopoietic stem cell transplantation (HSCT) as a therapeutic approach specifically for DNMT3A mutated AML. Studies that included HSCT treated patients—most of which focused on younger AML patients—observed no influence of an HSCT on the negative prognostic impact of DNMT3A mutations [3,4,5, 9, 11]. For example, Gaidzik et al. [5]. described a shorter relapse-free survival in younger DNMT3A R882 mutated AML patients independent of the use of HSCT. Similarly, Ahn et al. [9]. and Xu et al. [11]. reported a negative impact of DNMT3A R882 mutations after HSCT in mainly younger patients with normal karyotype (NK) AML.

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References

  1. Ley TJ, Ding L, Walter MJ, McLellan MD, Lamprecht T, Larson DE, et al. DNMT3A mutations in acute myeloid leukemia. N Engl J Med. 2010;363:2424–33.

    Article  CAS  Google Scholar 

  2. Gale R, Lamb K, Allen C, El-Sharkarwi D, Stowe C, Jenkinson S, et al. Simpson’s paradox and the impact of different DNMT3A mutations on outcome in younger adults with acute myeloid leukemia. J Clin Oncol. 2015;33:2072–83.

    Article  CAS  Google Scholar 

  3. Thol F, Damm F, Lüdeking A, Winschel C, Wagner K, Morgan M, et al. Incidence and prognostic influence of DNMT3Amutations in acute myeloid leukemia. J Clin Oncol. 2011;29:2889–96.

    Article  CAS  Google Scholar 

  4. Ribeiro AF, Pratcorona M, Erpelinck-Verschueren C, Rockova V, Sanders M, Abbas S, et al. Mutant DNMT3A: a marker of poor prognosis in acute myeloid leukemia. Blood. 2012;119:5824–31.

    Article  CAS  Google Scholar 

  5. Gaidzik VI, Schlenk RF, Paschka P, Stölzle A, Späth D, Kuendgen A, et al. Clinical impact of DNMT3A mutations in younger adult patients with acute myeloid leukemia: results of the AML Study Group (AMLSG). Blood. 2013;121:4769–77.

    Article  CAS  Google Scholar 

  6. Marcucci G, Metzeler KH, Schwind S, Becker H, Maharry K, Mrózek K, et al. Age-related prognostic impact of different types of DNMT3A mutations in adults with primary cytogenetically normal acute myeloid leukemia. J Clin Oncol. 2010;30:742–50.

    Article  Google Scholar 

  7. Tsai CH, Hou HA, Tang JL, Liu CY, Lin CC, Chou WC, et al. Genetic alterations and their clinical implications in older patients with acute myeloid leukemia. Leukemia. 2016;30:1485–92.

    Article  CAS  Google Scholar 

  8. Ostronoff F, Othus M, Ho PA, Kutny M, Geraghty DE, Petersdorf SH, et al. Mutations in the DNMT3A exon 23 independently predict poor outcome in older patients with acute myeloid leukemia: a SWOG report. Leukemia. 2013;27:238–41.

    Article  CAS  Google Scholar 

  9. Ahn JS, Kim HJ, Kim YK, Lee SS, Jung SH, Yang DH, et al. DNMT3A R882 mutation with FLT3-ITD positivity is an extremely poor prognostic factor in patients with normal-karyotype acute myeloid leukemia after allogeneic hematopoietic cell transplantation. Biol Blood Marrow Transplant. 2016;22:61–70.

    Article  CAS  Google Scholar 

  10. Thol F, Klesse S, Köhler L, Gabdoulline R, Kloos A, Liebich A, et al. Acute myeloid leukemia derived from lympho-myeloid clonal hematopoiesis. Leukemia. 2017. https://doi.org/10.1038/leu.2016.345

    Article  PubMed  PubMed Central  Google Scholar 

  11. Xu Y, Sun Y, Shen H, Ding L, Yang Z, Qiu H, et al. Allogeneic hematopoietic stem cell transplantation could improve survival of cytogenetically normal adult acute myeloid leukemia patients with DNMT3A mutations. Am J Hematol. 2015;90:992–7.

    Article  CAS  Google Scholar 

  12. 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;97:3390–3400.

    Article  CAS  Google Scholar 

  13. 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.

    Article  CAS  Google Scholar 

  14. 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. https://doi.org/10.1038/bmt.2017.42

    Article  PubMed  Google Scholar 

  15. Döhner H, Estey EH, Amadori S, Appelbaum FR, Büchner T, Burnett AK, et al. Diagnosis and management of acute myeloid leukemia in adults: recommendations from an international expert panel, on behalf of the European Leukemia-Net. Blood. 2010;115:453–74.

    Article  Google Scholar 

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Acknowledgements

L.B. was supported by the foundation “Zusammen gegen den Krebs”. M.B. was supported by an intramural scholarship of the medical faculty of the University of Leipzig (#990101-089). The authors would like to thank Sabine Leiblein, Janet Bogardt, Annette Jilo, Dagmar Cron, Christel Müller, Evelin Hennig, Daniela Bretschneider, Martina Pleß, Ulrike Bergmann, Ines Kovacs, Scarlett Schwabe, Kathrin Wildenberger, and Christine Günther for assisting with and collecting patient data and material.

Author contributions

L.K.S. and L.B. designed and performed experiments. M.B. and K.S. performed experiments. L.K.S., L.B., S.S., J.G., and M.J. analyzed and interpreted data. M.C., V.V., T.L., W.P., G.N.F., and G.B. provided administrative and technical support. L.K.S., L.B., and S.S. wrote and all authors reviewed and approved the manuscript. S.S. and D.N. supervised the study.

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  1. Laura K. Schmalbrock and Lynn Bonifacio contributed equally to this work.

Authors and Affiliations

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

    Laura K. Schmalbrock, Lynn Bonifacio, Marius Bill, Madlen Jentzsch, Karoline Schubert, Juliane Grimm, Michael Cross, Thoralf Lange, Vladan Vucinic, Wolfram Pönisch, Gerhard Behre, Georg-Nikolaus Franke, Dietger Niederwieser & Sebastian Schwind

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Correspondence to Sebastian Schwind.

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Presented in part at the 41st Annual Meeting of the European Society for Blood and Marrow Transplantation, Istanbul, Turkey, March 23rd, 2015 and published in abstract form.

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Schmalbrock, L.K., Bonifacio, L., Bill, M. et al. Prognostic relevance of DNMT3A R882 mutations in AML patients undergoing non-myeloablative conditioning hematopoietic stem cell transplantation. Bone Marrow Transplant 53, 640–643 (2018). https://doi.org/10.1038/s41409-017-0060-x

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