International Journal of Hematology

, Volume 106, Issue 4, pp 552–561 | Cite as

FLT3-ITD with DNMT3A R882 double mutation is a poor prognostic factor in Chinese patients with acute myeloid leukemia after chemotherapy or allogeneic hematopoietic stem cell transplantation

  • Shanhao Tang
  • Hongjie Shen
  • Xinliang Mao
  • Haiping Dai
  • Xiaming Zhu
  • Shengli Xue
  • Zixuan Ding
  • Jing Lu
  • Depei Wu
  • Xiaowen Tang
Original Article

Abstract

To investigate clinical characteristics and outcomes of transplantation in AML patients with FLT3-ITD/DNMT3A double mutation, we retrospectively analyzed 206 Chinese patients with AML after Sanger sequencing. Our analysis showed that AML patients with FLT3-ITD and DNMT3A R882 mutations had a higher white blood cell count and a lower complete remission (CR) rate after first induction chemotherapy. All 206 patients received allogeneic hematopoietic stem cell transplantation (allo-HSCT) in status of CR. These results indicate that AML patients with FLT3-ITD and DNMT3A R882 double mutation show a higher 2-year cumulative incidence of relapse (CIR), lower 2-year overall survival (OS) rate, and lower 2-year leukocyte-free survival (LFS) after allo-HSCT. The univariate and multivariate analyses confirmed that disease status prior to transplantation, FLT3-ITD, FLT3-ITD, and DNMT3A R882 double mutation were independent factors for poor prognosis after allo-HSCT. In summary, the present cohort study demonstrated that FLT3-ITD and DNMT3A R882 double mutation predicts poor prognosis in Chinese AML patients receiving chemotherapy or allo-HSCT treatment.

Keywords

Hematopoietic stem cell transplantation Acute myeloid leukemia FLT3-ITD mutation DNMT3A R882 mutation 

Supplementary material

12185_2017_2256_MOESM1_ESM.docx (12 kb)
Supplementary material 1 (DOCX 11 kb)

References

  1. 1.
    Goryainova NV. The clinical significance of genetic mutations in acute myeloid leukemia. Lik Sprava. 2014;12:10–8.Google Scholar
  2. 2.
    Volpe G, Clarke M, Garcia P, Walton DS, Vegiopoulos A, Del Pozzo W, et al. Regulation of the Flt3 gene in haematopoietic stem and early progenitor cells. PLoS One. 2015;10(9):e0138257.CrossRefPubMedPubMedCentralGoogle Scholar
  3. 3.
    Pemmaraju N, Kantarjian H, Andreeff M, Cortes J, Ravandi F. Investigational FMS-like tyrosine kinase 3 inhibitors in treatment of acute myeloid leukemia. Expert Opin Investig Drugs. 2014;23(7):943–54.CrossRefPubMedPubMedCentralGoogle Scholar
  4. 4.
    Govedarovic N, Marjanovic G. Frequency and prognostic impact of FLT3/ITD mutation in patients with acute myeloid leukaemia. J BUON. 2011;16(1):108–11.PubMedGoogle Scholar
  5. 5.
    Peng HL, Zhang GS, Gong FJ, Shen JK, Zhang Y, Xu YX, et al. Fms-like tyrosine kinase (FLT) 3 and FLT3 internal tandem duplication in different types of adult leukemia: analysis of 147 patients. Croat Med J. 2008;49(5):650–69.CrossRefPubMedPubMedCentralGoogle Scholar
  6. 6.
    Thol F, Damm F, Lüdeking A, Winschel C, Wagner K, Morgan M, et al. Incidence and prognostic influence of DNMT3A mutations in acute myeloid leukemia. J Clin Oncol. 2011;29(21):2889–96.CrossRefPubMedGoogle Scholar
  7. 7.
    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 theAML Study Group (AMLSG). Blood. 2013;121(23):4769–77.CrossRefPubMedGoogle Scholar
  8. 8.
    Kao HW, Liang DC, Kuo MC, Wu JH, Dunn P, Wang PN, et al. High frequency of additional gene mutations in acute myeloid leukemia with MLL partial tandem duplication: DNMT3A mutation is associated with poor prognosis. Oncotarget. 2015;6(32):33217–25.CrossRefPubMedPubMedCentralGoogle Scholar
  9. 9.
    Cancer Genome Atlas Research Network. Genomic and epigenomic landscapes of adult de novo acute myeloid leukemia. N Engl J Med. 2013;368(22):2059–74.CrossRefGoogle Scholar
  10. 10.
    Patel JP, Gönen M, Figueroa ME, Fernandez H, Sun Z, Racevskis J, et al. Prognostic relevance of integrated genetic profiling in acute myeloid leukemia. N Engl J Med. 2012;366(12):1079–89.CrossRefPubMedPubMedCentralGoogle Scholar
  11. 11.
    O’Donnell MR, Abboud CN, Altman J, Appelbaum FR, Arber DA, Attar E, et al. NCCN clinical practice guidelines acute myeloid leukemia. J Natl Compr Canc Netw. 2012;10(8):984–1021.CrossRefPubMedGoogle Scholar
  12. 12.
    Wu X, He G, Fa Y, Ma X, Wu D, Ai H, et al. Comparable outcomes of partially matched related and matched related allogeneic hematopoietic cell transplantation following reduced-intensity conditioning in adult patients with Philadelphia chromosome-negative acute lymphoblastic leukemia. Int J Hematol. 2013;98(4):456–62.CrossRefPubMedGoogle Scholar
  13. 13.
    Tian H, Xu Y, Liu L, Yan L, Jin Z, Tang X, et al. Comparison of outcomes in mixed phenotype acute leukemia patients treated with chemotherapy and stemcell transplantation versus chemotherapy alone. Leuk Res. 2016;45:40–6.CrossRefPubMedGoogle Scholar
  14. 14.
    Zhang YY, Liu DH, Liu KY, Xu LP, Chen H, Han W, et al. HLA-haploidentical hematopoietic SCT from collateral related donors without in vitro T-cell depletion for hematological malignancies. Bone Marrow Transpl. 2014;49(4):496–501.CrossRefGoogle Scholar
  15. 15.
    Lin PH, Lin CC, Yang HI, Li LY, Bai LY, Chiu CF, et al. Prognostic impact of allogeneic hematopoietic stem cell transplantation for acute myeloid leukemia patients with internal tandem duplication of FLT3. Leuk Res. 2013;37(3):287–92.CrossRefPubMedGoogle Scholar
  16. 16.
    Xu Y, Sun Y, Shen H, Ding L, Yang Z. Qiu Het al: allogeneic hematopoietic stem cell transplantation could improve survival of cytogenetically normal adult acute myeloidleukemia patients with DNMT3A mutations. Am J Hematol. 2015;90(11):992–7.CrossRefPubMedGoogle Scholar
  17. 17.
    Ofran Y, Rowe JM. Genetic profiling in acute myeloid leukaemia–where are we and what is its role in patient management. Br J Haematol. 2013;160(3):303–20.CrossRefPubMedGoogle Scholar
  18. 18.
    Wu X, Feng X, Zhao X, Ma F, Liu N, Guo H, et al. Prognostic significance of FLT3-ITD in pediatric acute myeloid leukemia: a meta-analysis of cohort studies. Mol Cell Biochem. 2016;420(1–2):121–8.CrossRefPubMedGoogle Scholar
  19. 19.
    Kiyoi H, Naoe T, Nakano Y, Yokota S, Minami S, Miyawaki S, et al. Prognostic implication of FLT3 and N-RAS gene mutations in acute myeloid leukemia. Blood. 1999;93(9):3074–80.PubMedGoogle Scholar
  20. 20.
    Kottaridis PD, Gale RE, Frew ME, Harrison G, Langabeer SE, Belton AA, et al. The presence of a FLT3 internal tandem duplication in patients with acute myeloid leukemia (AML) adds important prognostic information to cytogenetic risk group and response to the first cycle of chemotherapy: analysis of 854 patients from the United Kingdom Medical Research Council AML 10 and 12 trials. Blood. 2001;98(6):1752–9.CrossRefPubMedGoogle Scholar
  21. 21.
    Schmid C, Labopin M, Socie G, Daguindau E, Volin L, Huynh A, et al. Outcome of patients with distinct molecular genotypes and cytogenetically normal AML after allogeneic transplantation. Blood. 2015;126(17):2062–9.CrossRefPubMedGoogle Scholar
  22. 22.
    Luskin MR, Carroll M, Lieberman D, Morrissette JJ, Zhao J, Crisalli L, et al. Clinical utility of next-generation sequencing for oncogenic mutations in patients with acute myeloid leukemia undergoing allogeneic stem cell transplantation. Biol Blood Marrow Transpl. 2016;22(11):1961–7.CrossRefGoogle Scholar
  23. 23.
    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(1):61–70.CrossRefPubMedGoogle Scholar
  24. 24.
    Yuan XQ, Peng L, Zeng WJ, Jiang BY, Li GC, Chen XP. DNMT3A R882 Mutations predict a poor prognosis in AML: a meta-analysis from 4474 patients. Medicine (Baltimore). 2016;95(18):e3519.CrossRefGoogle Scholar
  25. 25.
    Brunetti L, Gundry MC, Goodell MA. DNMT3A in Leukemia. Cold Spring Harb Perspect Med. 2017;7(2):a030320.Google Scholar
  26. 26.
    Gale RE, Lamb K, Allen C, El-Sharkawi 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(18):2072–83.CrossRefPubMedGoogle Scholar
  27. 27.
    Gaidzik VI, Schlenk RF, Paschka P, Stolzle A, Spath 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(23):4769–77.CrossRefPubMedGoogle Scholar
  28. 28.
    Russler-Germain DA, Spencer DH, Young MA, Lamprecht TL, Miller CA, Fulton R, et al. The R882H DNMT3A mutation associated with AML dominantly inhibits wild-type DNMT3A by blocking its ability to form active tetramers. Cancer Cell. 2014;25(4):442–54.CrossRefPubMedPubMedCentralGoogle Scholar
  29. 29.
    Yang L, Rodriguez B, Mayle A, Park HJ, Lin X, Luo M, et al. DNMT3A loss drives enhancer hypomethylation in FLT3-ITD-associated leukemias. Cancer Cell. 2016;29(6):922–34.CrossRefPubMedPubMedCentralGoogle Scholar
  30. 30.
    Wakita S, Yamaguchi H, Omori I, Terada K, Ueda T, Manabe E, et al. Mutations of the epigenetics-modifying gene (DNMT3a, TET2, IDH1/2) at diagnosis may induce FLT3-ITD at relapse in de novo acute myeloid leukemia. Leukemia. 2013;27(5):1044–52.CrossRefPubMedGoogle Scholar

Copyright information

© The Japanese Society of Hematology 2017

Authors and Affiliations

  • Shanhao Tang
    • 4
  • Hongjie Shen
    • 1
    • 2
    • 3
  • Xinliang Mao
    • 5
  • Haiping Dai
    • 1
    • 2
    • 3
  • Xiaming Zhu
    • 1
    • 2
    • 3
  • Shengli Xue
    • 1
    • 2
    • 3
  • Zixuan Ding
    • 1
    • 2
    • 3
  • Jing Lu
    • 1
    • 2
    • 3
  • Depei Wu
    • 1
    • 2
    • 3
  • Xiaowen Tang
    • 1
    • 2
    • 3
  1. 1.Department of HematologyThe First Affiliated Hospital of Soochow University, Jiangsu Institute of HematologySuzhouChina
  2. 2.Institute of Blood and Marrow TransplantationSuzhouChina
  3. 3.Collaborative Innovation Center of HematologySoochow UniversitySuzhouChina
  4. 4.Department of HematologyYinzhou People HospitalNingboChina
  5. 5.Department of Pharmacology, College of Pharmaceutical SciencesSoochow UniversitySuzhouChina

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