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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

Bone Marrow Transplantation volume 56, pages 1159–1170 (2021)Cite this article

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Abstract

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.

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References

  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  PubMed  PubMed Central  Google Scholar 

  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  PubMed  Google Scholar 

  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. 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.

    Article  CAS  PubMed  Google Scholar 

  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  PubMed  PubMed Central  Google Scholar 

  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  PubMed  Google Scholar 

  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  PubMed  Google Scholar 

  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. 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  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

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

    Article  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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  PubMed  Google Scholar 

  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  PubMed  PubMed Central  Google Scholar 

  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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  Google Scholar 

  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  PubMed  PubMed Central  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  Google Scholar 

  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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

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, http://coda.nih.go.kr) under accession # R000007.

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  1. These two authors contributed equally: Jae-Sook Ahn, TaeHyung Kim

Authors and Affiliations

  1. Department of Internal Medicine, Chonnam National University Hwasun Hospital, Chonnam National University, Gwangju, Republic of Korea

    Jae-Sook Ahn, Sung-Hoon Jung, Seo-Yeon Ahn, Ga-Young Song, Mihee Kim, Deok-Hwan Yang, Je-Jung Lee & Hyeoung-Joon Kim

  2. Genomic Research Center for Hematopoietic Diseases, Chonnam National University Hwasun Hospital, Jeollanam-do, Republic of Korea

    Jae-Sook Ahn, SeungHyun Choi, Ja-Yeon Lee & Hyeoung-Joon Kim

  3. The Donnelly Centre for Cellular and Biomolecular Research, University of Toronto, Toronto, ON, Canada

    Jae-Sook Ahn, TaeHyung Kim & Zhaolei Zhang

  4. Department of Computer Science, University of Toronto, Toronto, ON, Canada

    TaeHyung Kim & Zhaolei Zhang

  5. Department of Hematology-Oncology, St Carollo Hospital, Jeollanam-do, Republic of Korea

    Seung-Yeon Jung

  6. Department of Hematology-Oncology, Soon Chun Hyang University Hospital, Bucheon, Republic of Korea

    Seong-Kyu Park

  7. Department of Hematology-Oncology, Kyungpook National University Hospital, School of Medicine, Kyungpook National University, Daegu, Republic of Korea

    Joon Ho Moon

  8. Department of Internal Medicine, Kangwon National University Hospital, Kangwon National University School of Medicine, Chuncheon, South Korea

    Hui Young Lee

  9. Department of Medical Oncology and Hematology, Princess Margaret Cancer Centre, University of Toronto, Toronto, Canada

    Hui Young Lee, Kyoung Ha Kim, Yu Cai, Seong Yoon Yi, Igor Novitzky-Basso & Dennis Dong Hwan Kim

  10. Department of Internal Medicine, Soonchunhyang University Hospital, Seoul, Korea

    Kyoung Ha Kim

  11. Department of Hematology, Shanghai General Hospital affiliated to Shanghai Jiaotong University, Shanghai, (200080), PR China

    Yu Cai

  12. Department of Internal Medicine, Inje University Ilsan Paik Hospital, Goyang-si, Republic of Korea

    Seong Yoon Yi

  13. Department of Molecular Genetics, University of Toronto, Toronto, ON, Canada

    Zhaolei Zhang

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Correspondence to Zhaolei Zhang, 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 56, 1159–1170 (2021). https://doi.org/10.1038/s41409-020-01165-x

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