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
Subscribe to this journal
Receive 12 print issues and online access
$259.00 per year
only $21.58 per issue
Buy this article
- Purchase on Springer Link
- Instant access to full article PDF
Prices may be subject to local taxes which are calculated during checkout
Similar content being viewed by others
Data availability
The dataset is available from the corresponding author upon reasonable request.
References
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.
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.
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.
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
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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
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
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.
About this article
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
Received:
Revised:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1038/s41409-022-01817-0
This article is cited by
-
Validation of the 2022 European LeukemiaNet risk stratification for acute myeloid leukemia
Scientific Reports (2024)
-
U2AF1 pathogenic variants in myeloid neoplasms and precursor states: distribution of co-mutations and prognostic heterogeneity
Blood Cancer Journal (2023)
-
Prognostic impact of the AML ELN2022 risk classification in patients undergoing allogeneic stem cell transplantation
Blood Cancer Journal (2022)