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.

Allogeneic hematopoietic cell transplantation can overcome the adverse prognosis indicated by secondary-type mutations in de novo acute myeloid leukemia

Abstract

Secondary-type mutations (STMs), namely SRSF2, SF3B1, U2AF1, ZRSR2, ASXL1, EZH2, BCOR, and STAG2, are more frequently detected in secondary acute myeloid leukemia (AML) than in de novo AML. Whether de novo AML with STMs should be differently managed is, however, unclear. In 394 patients diagnosed with de novo AML who had a normal karyotype, the genetic profiling via targeted deep sequencing of 45 genes revealed 59 patients carrying STMs (STM+). The STM+ group showed shorter overall survival (OS) than the STM group (5-year OS, 15.3 vs. 31.0%) (hazard ratio [HR]: 1.975, 95% confidence interval [CI]: 1.446–2.699, p < 0.001). Among the 40 STM+ patients who achieved CR, those who received allogeneic HCT (n = 15) showed better OS (5-year OS, 40.0 vs. 12.0%) (HR: 0.423, 95% CI: 0.184–0.975, p = 0.043) and relapse-free survival (5-year, 40.0 vs. 8.0%) (HR: 0.438, 95% CI: 0.189–1.015, p = 0.054) than those who received consolidation chemotherapy only. The cumulative incidence of relapse was lower in the patients who received allogeneic HCT (5-year, 33.3 vs. 60.0%) (HR: 0.288, 95% CI: 0.111–0.746, p = 0.011), and non-relapse mortality was similar between the two groups (p = 0.935). In conclusion, STM is an independent prognostic factor for adverse outcomes in AML that can be overcome by allogeneic HCT.

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

Access options

Buy article

Get time limited or full article access on ReadCube.

$32.00

All prices are NET prices.

Fig. 1: Flow chart of the patients and genetic mutation analysis result.
Fig. 2: Prognostic significance of secondary-type mutation (STM).
Fig. 3: Clinical outcome of the patients with secondary-type mutation (STM) according to allogeneic HCT.

Data availability

The dataset is available from the corresponding author upon reasonable request.

References

  1. Granfeldt Østgård LS, Medeiros BC, Sengeløv H, Nørgaard M, Andersen MK, Dufva IH, et al. Epidemiology and clinical significance of secondary and therapy-related acute myeloid leukemia: a national population-based cohort study. J Clin Oncol. 2015;33:3641–9. https://doi.org/10.1200/jco.2014.60.0890.

    Article  PubMed  Google Scholar 

  2. Hulegårdh E, Nilsson C, Lazarevic V, Garelius H, Antunovic P, Rangert Derolf Å, et al. Characterization and prognostic features of secondary acute myeloid leukemia in a population-based setting: a report from the Swedish Acute Leukemia Registry. Am J Hematol. 2015;90:208–14. https://doi.org/10.1002/ajh.23908.

    Article  PubMed  Google Scholar 

  3. Lancet JE, Uy GL, Cortes JE, Newell LF, Lin TL, Ritchie EK, et al. CPX-351 (cytarabine and daunorubicin) liposome for injection versus conventional cytarabine plus daunorubicin in older patients with newly diagnosed secondary acute myeloid leukemia. J Clin Oncol. 2018;36:2684–92. https://doi.org/10.1200/jco.2017.77.6112.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Löwenberg B, Ossenkoppele GJ, van Putten W, Schouten HC, Graux C, Ferrant A, et al. High-dose daunorubicin in older patients with acute myeloid leukemia. N Engl J Med. 2009;361:1235–48. https://doi.org/10.1056/NEJMoa0901409

    Article  PubMed  Google Scholar 

  5. Lindsley RC, Mar BG, Mazzola E, Grauman PV, Shareef S, Allen SL, et al. Acute myeloid leukemia ontogeny is defined by distinct somatic mutations. Blood. 2015;125:1367–76. https://doi.org/10.1182/blood-2014-11-610543.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Weinberg OK, Gibson CJ, Blonquist TM, Neuberg D, Pozdnyakova O, Kuo F, et al. Association of mutations with morphological dysplasia in de novo acute myeloid leukemia without 2016 WHO Classification-defined cytogenetic abnormalities. Haematologica. 2018;103:626–33. https://doi.org/10.3324/haematol.2017.181842.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Rowe JM. Graft-versus-disease effect following allogeneic transplantation for acute leukaemia. Best Pract Res Clin Haematol. 2008;21:485–502. https://doi.org/10.1016/j.beha.2008.07.002.

    Article  CAS  PubMed  Google Scholar 

  8. Schlenk RF, Döhner K, Mack S, Stoppel M, Király F, Götze K, et al. Prospective evaluation of allogeneic hematopoietic stem-cell transplantation from matched related and matched unrelated donors in younger adults with high-risk acute myeloid leukemia: German-Austrian trial AMLHD98A. J Clin Oncol. 2010;28:4642–8. https://doi.org/10.1200/jco.2010.28.6856.

    Article  PubMed  Google Scholar 

  9. Ho AD, Schetelig J, Bochtler T, Schaich M, Schäfer-Eckart K, Hänel M, et al. Allogeneic stem cell transplantation improves survival in patients with acute myeloid leukemia characterized by a high allelic ratio of mutant FLT3-ITD. Biol Blood Marrow Transplant. 2016;22:462–9. https://doi.org/10.1016/j.bbmt.2015.10.023.

    Article  CAS  PubMed  Google Scholar 

  10. Kim T, Moon JH, Ahn J-S, Kim Y-K, Lee S-S, Ahn S-Y, et al. Next-generation sequencing–based posttransplant monitoring of acute myeloid leukemia identifies patients at high risk of relapse. Blood. 2018;132:1604–13. https://doi.org/10.1182/blood-2018-04-848028.

    Article  CAS  PubMed  Google Scholar 

  11. 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. https://doi.org/10.18632/oncotarget.23575.

    Article  PubMed  Google Scholar 

  12. Ley TJ, Miller C, Ding L, Raphael BJ, Mungall AJ, Robertson A, et al. Genomic and epigenomic landscapes of adult de novo acute myeloid leukemia. N Engl J Med. 2013;368:2059–74. https://doi.org/10.1056/NEJMoa1301689.

    Article  CAS  PubMed  Google Scholar 

  13. 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 

  14. Kanda Y. Investigation of the freely available easy-to-use software ‘EZR’ for medical statistics. Bone Marrow Transplant. 2013;48:452–8. https://doi.org/10.1038/bmt.2012.244.

    Article  CAS  PubMed  Google Scholar 

  15. 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 

  16. Fernandez-Mercado M, Yip BH, Pellagatti A, Davies C, Larrayoz MJ, Kondo T, et al. Mutation patterns of 16 genes in primary and secondary acute myeloid leukemia (AML) with normal cytogenetics. PLoS ONE. 2012;7:e42334 https://doi.org/10.1371/journal.pone.0042334.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Martignoles JA, Delhommeau F, Hirsch P. Genetic hierarchy of acute myeloid leukemia: from clonal hematopoiesis to molecular residual disease. Int J Mol Sci. 2018;19:3850. https://doi.org/10.3390/ijms19123850.

  18. Meggendorfer M, de Albuquerque A, Nadarajah N, Alpermann T, Kern W, Steuer K, et al. Karyotype evolution and acquisition of FLT3 or RAS pathway alterations drive progression of myelodysplastic syndrome to acute myeloid leukemia. Haematologica. 2015;100:e487–e490. https://doi.org/10.3324/haematol.2015.127985.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Yokoyama K, Shimizu E, Yokoyama N, Nakamura S, Kasajima R, Ogawa M, et al. Cell-lineage level-targeted sequencing to identify acute myeloid leukemia with myelodysplasia-related changes. Blood Adv. 2018;2:2513–21. https://doi.org/10.1182/bloodadvances.2017010744.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Winer ES. Secondary acute myeloid leukemia: a primary challenge of diagnosis and treatment. Hematol Oncol Clin North Am. 2020;34:449–63. https://doi.org/10.1016/j.hoc.2019.11.003.

    Article  PubMed  Google Scholar 

  21. Anderson JE, Gooley TA, Schoch G, Anasetti C, Bensinger WI, Clift RA, et al. Stem cell transplantation for secondary acute myeloid leukemia: evaluation of transplantation as initial therapy or following induction chemotherapy. Blood. 1997;89:2578–85.

    Article  CAS  PubMed  Google Scholar 

  22. Nilsson C, Hulegårdh E, Garelius H, Möllgård L, Brune M, Wahlin A, et al. Secondary acute myeloid leukemia and the role of allogeneic stem cell transplantation in a population-based setting. Biol Blood Marrow Transplant. 2019;25:1770–8. https://doi.org/10.1016/j.bbmt.2019.05.038.

    Article  PubMed  Google Scholar 

  23. Sengsayadeth S, Labopin M, Boumendil A, Finke J, Ganser A, Stelljes M, et al. Transplant outcomes for secondary acute myeloid leukemia: Acute Leukemia Working Party of the European Society for Blood and Bone Marrow Transplantation Study. Biol Blood Marrow Transplant. 2018;24:1406–14. https://doi.org/10.1016/j.bbmt.2018.04.008.

    Article  PubMed  Google Scholar 

  24. Michelis FV, Atenafu EG, Gupta V, Kim DD, Kuruvilla J, Lipton JH, et al. Comparable outcomes post allogeneic hematopoietic cell transplant for patients with de novo or secondary acute myeloid leukemia in first remission. Bone Marrow Transplant. 2015;50:907–13. https://doi.org/10.1038/bmt.2015.59.

    Article  CAS  PubMed  Google Scholar 

  25. Tyner JW, Tognon CE, Bottomly D, Wilmot B, Kurtz SE, Savage SL, et al. Functional genomic landscape of acute myeloid leukaemia. Nature. 2018;562:526–31. https://doi.org/10.1038/s41586-018-0623-z.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. 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 

Download references

Funding

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 the National R&D Program for Cancer Control, Ministry of Health & Welfare, Republic of Korea (1720160). This study was supported by a grant (HCRI21006) 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 Korean government (MSIT) (No. 2018R1A2A1A05078480). 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.

Author information

Authors and Affiliations

Authors

Contributions

H-JK, J-SA, and DDHK designed the study and all authors prepared the manuscript. All authors have read and approved the final manuscript.

Corresponding authors

Correspondence to Jae-Sook Ahn, Hyeoung-Joon Kim or Dennis Dong Hwan Kim.

Ethics declarations

Competing interests

The authors declare no competing interests.

Ethics approval and consent to participate

This retrospective study was approved by the institutional ethics committee of each participating institution and conducted in accordance with the Declaration of Helsinki. The committee waived the need for informed patient consent because of the retrospective nature of the work.

Additional information

Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Supplementary information

Rights and permissions

Springer Nature or its licensor holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Song, GY., Kim, T., Ahn, SY. et al. Allogeneic hematopoietic cell transplantation can overcome the adverse prognosis indicated by secondary-type mutations in de novo acute myeloid leukemia. Bone Marrow Transplant 57, 1810–1819 (2022). https://doi.org/10.1038/s41409-022-01817-0

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/s41409-022-01817-0

Search

Quick links