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Allogeneic transplant can abrogate the risk of relapse in the patients of first remission acute myeloid leukemia with detectable measurable residual disease by next-generation sequencing


In patients with acute myeloid leukemia (AML) consolidation treatment options are between allogeneic hematopoietic stem cell transplantation (HCT) and chemotherapy, based on disease risk at the time of initial presentation and age. Measurable residual disease (MRD) following induction chemotherapy could be incorporated as a useful parameter for treatment decisions. The present study evaluated treatment outcomes according to the next-generation sequencing (NGS)-based MRD status and the type of consolidation therapy in patients with normal karyotype (NK)-AML. By sequencing 278 paired samples collected at diagnosis and first remission (CR1), we identified 361 mutations in 124 patients at diagnosis and tracked these at CR1. After excluding mutations associated with age-related clonal hematopoiesis, 82 mutations in 50 of the 124 patients (40.3%) were detected at CR1. Survival benefit was observed in favor of allogeneic HCT over chemotherapy consolidation in the MRDpos subgroup with respect to overall survival (HR 0.294, p = 0.003), relapse-free survival (HR 0.376, p = 0.015) and cumulative incidence of relapse (HR 0.279, p = 0.004) in multivariate analysis, but not in the MRDneg subgroup. In summary, these data support allogeneic HCT in NK-AML patients with detectable MRD by NGS in CR1. Randomized clinical trials will be required to confirm this observation.

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Fig. 1: Frequency of mutations and flow chart of patients with normal karyotype acute myeloid leukemia (NK-AML).
Fig. 2: Survival, relapse risks, and non-relapse mortalities according to the measurable residual disease (MRD) status and the type of consolidation therapy in patients with normal karyotype acute myeloid leukemia (NK-AML).
Fig. 3: Survival, relapse risks, and non-relapse mortalities according to the measurable residual disease (MRD) status at first complete remission.


  1. 1.

    Dohner H, Estey E, Grimwade D, Amadori S, Appelbaum FR, Buchner T, et al. Diagnosis and management of AML in adults: 2017 ELN recommendations from an international expert panel. Blood. 2017;129:424–47.

    Article  Google Scholar 

  2. 2.

    O’Donnell MR, Tallman MS, Abboud CN, Altman JK, Appelbaum FR, Arber DA, et al. Acute myeloid leukemia, version 3.2017, NCCN clinical practice guidelines in oncology. J Natl Compr Canc Netw. 2017;15:926–57.

    Article  Google Scholar 

  3. 3.

    Preisler H, Davis RB, Kirshner J, Dupre E, Richards F 3rd, Hoagland HC, et al. Comparison of three remission induction regimens and two postinduction strategies for the treatment of acute nonlymphocytic leukemia: a cancer and leukemia group B study. Blood. 1987;69:1441–9.

    CAS  PubMed  Google Scholar 

  4. 4.

    Wiernik PH, Banks PL, Case DC Jr, Arlin ZA, Periman PO, Todd MB, et al. Cytarabine plus idarubicin or daunorubicin as induction and consolidation therapy for previously untreated adult patients with acute myeloid leukemia. Blood. 1992;79:313–9.

    CAS  Article  Google Scholar 

  5. 5.

    Li D, Wang L, Zhu H, Dou L, Liu D, Fu L, et al. Efficacy of allogeneic hematopoietic stem cell transplantation in intermediate-risk acute myeloid leukemia adult patients in first complete remission: a meta-analysis of prospective studies. PLoS ONE. 2015;10:e0132620.

    Article  Google Scholar 

  6. 6.

    Stelljes M, Krug U, Beelen DW, Braess J, Sauerland MC, Heinecke A, et al. Allogeneic transplantation versus chemotherapy as postremission therapy for acute myeloid leukemia: a prospective matched pairs analysis. J Clin Oncol. 2014;32:288–96.

    Article  Google Scholar 

  7. 7.

    Ahn JS, Kim HJ, Kim YK, Lee SS, Ahn SY, Jung SH, et al. Assessment of a new genomic classification system in acute myeloid leukemia with a normal karyotype. Oncotarget. 2018;9:4961–8.

    Article  Google Scholar 

  8. 8.

    Cancer Genome Atlas Research N, Ley TJ, Miller C, Ding L, Raphael BJ, Mungall AJ, et al. Genomic and epigenomic landscapes of adult de novo acute myeloid leukemia. N. Engl J Med. 2013;368:2059–74.

    Article  Google Scholar 

  9. 9.

    Bastos-Oreiro M, Perez-Corral A, Martinez-Laperche C, Bento L, Pascual C, Kwon M, et al. Prognostic impact of minimal residual disease analysis by flow cytometry in patients with acute myeloid leukemia before and after allogeneic hemopoietic stem cell transplantation. Eur J Haematol. 2014;93:239–46.

    Article  Google Scholar 

  10. 10.

    Ivey A, Hills RK, Simpson MA, Jovanovic JV, Gilkes A, Grech A, et al. Assessment oF Minimal Residual Disease in Standard-risk AML. N. Engl J Med. 2016;374:422–33.

    CAS  Article  Google Scholar 

  11. 11.

    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.

    CAS  Article  Google Scholar 

  12. 12.

    Jourdan E, Boissel N, Chevret S, Delabesse E, Renneville A, Cornillet P, et al. Prospective evaluation of gene mutations and minimal residual disease in patients with core binding factor acute myeloid leukemia. Blood. 2013;121:2213–23.

    CAS  Article  Google Scholar 

  13. 13.

    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.

    CAS  Article  Google Scholar 

  14. 14.

    Schnittger S, Kern W, Tschulik C, Weiss T, Dicker F, Falini B, et al. Minimal residual disease levels assessed by NPM1 mutation-specific RQ-PCR provide important prognostic information in AML. Blood. 2009;114:2220–31.

    CAS  Article  Google Scholar 

  15. 15.

    Shayegi N, Kramer M, Bornhauser M, Schaich M, Schetelig J, Platzbecker U, et al. The level of residual disease based on mutant NPM1 is an independent prognostic factor for relapse and survival in AML. Blood. 2013;122:83–92.

    CAS  Article  Google Scholar 

  16. 16.

    Terwijn M, van Putten WL, Kelder A, van der Velden VH, Brooimans RA, Pabst T, et al. High prognostic impact of flow cytometric minimal residual disease detection in acute myeloid leukemia: data from the HOVON/SAKK AML 42A study. J Clin Oncol. 2013;31:3889–97.

    Article  Google Scholar 

  17. 17.

    Zhou Y, Othus M, Araki D, Wood BL, Radich JP, Halpern AB, et al. Pre- and post-transplant quantification of measurable (‘minimal’) residual disease via multiparameter flow cytometry in adult acute myeloid leukemia. Leukemia. 2016;30:1456–64.

    CAS  Article  Google Scholar 

  18. 18.

    Balsat M, Renneville A, Thomas X, de Botton S, Caillot D, Marceau A, et al. Postinduction minimal residual disease predicts outcome and benefit from allogeneic stem cell transplantation in acute myeloid leukemia with NPM1 mutation: a study by the Acute Leukemia French Association Group. J Clin Oncol. 2017;35:185–93.

    CAS  Article  Google Scholar 

  19. 19.

    Forghieri F, Comoli P, Marasca R, Potenza L, Luppi M. Minimal/measurable residual disease monitoring in NPM1-mutated acute myeloid leukemia: a clinical viewpoint and perspectives. Int J Mol Sci. 20186;19:3492.

  20. 20.

    Kronke J, Schlenk RF, Jensen KO, Tschurtz F, Corbacioglu A, Gaidzik VI, et al. J Clin Oncol. 2011;29:2709–16.

    Article  Google Scholar 

  21. 21.

    Ommen HB, Schnittger S, Jovanovic JV, Ommen IB, Hasle H, Ostergaard M, et al. Strikingly different molecular relapse kinetics in NPM1c, PML-RARA, RUNX1-RUNX1T1, and CBFB-MYH11 acute myeloid leukemias. Blood. 2010;115:198–205.

    CAS  Article  Google Scholar 

  22. 22.

    Kronke J, Bullinger L, Teleanu V, Tschurtz F, Gaidzik VI, Kuhn MW, et al. Clonal evolution in relapsed NPM1-mutated acute myeloid leukemia. Blood. 2013;122:100–8.

    Article  Google Scholar 

  23. 23.

    Martinez-Losada C, Serrano-Lopez J, Serrano-Lopez J, Noguera NI, Garza E, Piredda L, et al. Clonal genetic evolution at relapse of favorable-risk acute myeloid leukemia with NPM1 mutation is associated with phenotypic changes and worse outcomes. Haematologica. 2018;103:e400–3.

    Article  Google Scholar 

  24. 24.

    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.

    CAS  Article  Google Scholar 

  25. 25.

    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.

    CAS  Article  Google Scholar 

  26. 26.

    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.

    CAS  Article  Google Scholar 

  27. 27.

    Kim T, Moon JH, Ahn JS, Kim YK, Lee SS, Ahn SY, et al. Next-generation sequencing-based posttransplant monitoring of acute myeloid leukemia identifies patients at high risk of relapse. Blood. 2018;132:1604–13.

    CAS  Article  Google Scholar 

  28. 28.

    Kim T, Yoshida K, Kim YK, Tyndel MS, Park HJ, Choi SH, et al. Clonal dynamics in a single AML case tracked for 9 years reveals the complexity of leukemia progression. Leukemia. 2016;30:295–302.

    CAS  Article  Google Scholar 

  29. 29.

    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;122:3616–27.

    CAS  Article  Google Scholar 

  30. 30.

    Kanda Y. Investigation of the freely available easy-to-use software ‘EZR’ for medical statistics. Bone Marrow Transpl. 2013;48:452–8.

    CAS  Article  Google Scholar 

  31. 31.

    Delgado J, Pereira A, Villamor N, Lopez-Guillermo A, Rozman C. Survival analysis in hematologic malignancies: recommendations for clinicians. Haematologica. 2014;99:1410–20.

    Article  Google Scholar 

  32. 32.

    Gorello P, Cazzaniga G, Alberti F, Dell’Oro MG, Gottardi E, Specchia G, et al. Quantitative assessment of minimal residual disease in acute myeloid leukemia carrying nucleophosmin (NPM1) gene mutations. Leukemia. 2006;20:1103–8.

    CAS  Article  Google Scholar 

  33. 33.

    Tallman MS, Wang ES, Altman JK, Appelbaum FR, Bhatt VR, Bixby D, et al. Acute myeloid leukemia, version 3.2019, NCCN clinical practice guidelines in oncology. J Natl Compr Cancer Netw. 2019;17:721–49.

    CAS  Article  Google Scholar 

  34. 34.

    Thol F, Gabdoulline R, Liebich A, Klement P, Schiller J, Kandziora C, et al. Measurable residual disease monitoring by NGS before allogeneic hematopoietic cell transplantation in AML. Blood. 2018;132:1703–13.

    CAS  Article  Google Scholar 

  35. 35.

    Freeman SD, Hills RK, Virgo P, Khan N, Couzens S, Dillon R, et al. Measurable residual disease at induction redefines partial response in acute myeloid leukemia and stratifies outcomes in patients at standard risk without NPM1 mutations. J Clin Oncol. 2018;36:1486–97.

    CAS  Article  Google Scholar 

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This research was supported by the Basic Science Research Program through the National Research Foundation of Korea (NRF), funded by the Ministry of Science, ICT, and Future Planning (NRF-2015R1A2A1A10054579 and NRF-2017R1C1B5017389) and the National R&D Program for Cancer Control, Ministry of Health & Welfare, Republic of Korea (1720160). This study was supported by a grant (HCRI20018) Chonnam National University Hwasun Hospital Institute for Biomedical Science. This work was also supported by a National Research Foundation of Korea (NRF) grant funded by the Korea government (MSIT) (No. 2018R1A2A1A05078480) and by the Princess Margaret Cancer Foundation, Toronto, ON, Canada. TK was supported by a scholarship from the Natural Sciences and Engineering Research Council of Canada (NSERC, PGS-D). The biospecimens used in this study were provided by the Biobank of Chonnam National University Hwasun Hospital, a member of the Korea Biobank. The whole-exome data used in this study have been deposited in the Clinical & Omics Data Archive (CODA, under accession # R000007.

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Correspondence to Zhaolei Zhang or Hyeoung-Joon Kim or Dennis Dong Hwan Kim.

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Ahn, JS., Kim, T., Jung, SH. et al. Allogeneic transplant can abrogate the risk of relapse in the patients of first remission acute myeloid leukemia with detectable measurable residual disease by next-generation sequencing. Bone Marrow Transplant (2020).

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