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Acute myeloid leukemia

Prognostic significance of recurring chromosomal abnormalities in transplanted patients with acute myeloid leukemia

Abstract

Baseline cytogenetic studies at diagnosis remain the single most important determinant of outcome in patients with acute myeloid leukemia (AML). However, the prognostic role of the complete gamut of cytogenetic aberrations in AML patients undergoing allogeneic hematopoietic stem cell transplantation (allo-HSCT) is currently undefined. In addition, their significance in conjunction with FLT3-ITD status has not been addressed thus far. Using the ALWP/EBMT registry we conducted a retrospective analysis to determine the clinical outcomes of AML patients undergoing allo-HSCT with respect to specific recurring cytogenetic abnormalities complemented with FLT3-ITD status. We analyzed a cohort consisting of 8558 adult AML patients who underwent allo-HSCT from either a matched sibling or a matched unrelated donor. Patients with inv(3)(q21q26)/t(3;3)(q21;q26), del(5q), monosomy 7, chromosome 17p abnormalities, t(10;11)(p11-14;q13-23), t(6;11)(q27;q23), as well as those patients with a monosomal or complex karyotype experienced significantly inferior leukemia-free survival (LFS) compared to patients with a normal karyotype. Trisomy 14, del(9q), and loss of chromosome X were associated with improved LFS rates. A novel prognostic model delineating 5 distinct groups incorporating cytogenetic complexity and FLT3-ITD status was constructed with significant prognostic implications. Our analysis supports the added prognostic significance of FLT3-ITD to baseline cytogenetics in patients undergoing allo-HSCT.

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References

  1. 1.

    Ding L, Ley TJ, Larson DE, Miller CA, Koboldt DC, Welch JS, et al. Clonal evolution in relapsed acute myeloid leukaemia revealed by whole-genome sequencing. Nature. 2012;481:506–10.

    CAS  Article  Google Scholar 

  2. 2.

    Welch JS, Ley TJ, Link DC, Miller CA, Larson DE, Koboldt DC, et al. The origin and evolution of mutations in acute myeloid leukemia. Cell. 2012;150: 264–78.

    CAS  Article  Google Scholar 

  3. 3.

    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 

  4. 4.

    Shlush LI, Zandi S, Mitchell A, Chen WC, Brandwein JM, Gupta V, et al. Identification of pre-leukaemic haematopoietic stem cells in acute leukaemia. Nature. 2014;506:328–33.

    CAS  Article  Google Scholar 

  5. 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.

    CAS  Article  Google Scholar 

  6. 6.

    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 

  7. 7.

    Cornelissen JJ, Blaise D. Hematopoietic stem cell transplantation for patients with AML in first complete remission. Blood. 2016;127:62–70.

    CAS  Article  Google Scholar 

  8. 8.

    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 

  9. 9.

    Slovak ML, Kopecky KJ, Cassileth PA, Harrington DH, Theil KS, Mohamed A, et al. Karyotypic analysis predicts outcome of preremission and postremission therapy in adult acute myeloid leukemia: a Southwest Oncology Group/Eastern Cooperative Oncology Group Study. Blood. 2000;96:4075–83.

    CAS  PubMed  Google Scholar 

  10. 10.

    Ciurea SO, Labopin M, Socie G, Volin L, Passweg J, Chevallier P, et al. Relapse and survival after transplantation for complex karyotype acute myeloid leukemia: A report from the Acute Leukemia Working Party of the European Society for Blood and Marrow Transplantation and the University of Texas MD Anderson Cancer Center. Cancer. 2018;124; 2134–41.

    CAS  Article  Google Scholar 

  11. 11.

    Breems DA, Van Putten WL, De Greef GE, Van Zelderen-Bhola SL, Gerssen-Schoorl KB, Mellink CH, et al. Monosomal karyotype in acute myeloid leukemia: a better indicator of poor prognosis than a complex karyotype. J Clin Oncol. 2008;26:4791–7.

    Article  Google Scholar 

  12. 12.

    Cornelissen JJ, Breems D, van Putten WL, Gratwohl AA, Passweg JR, Pabst T, et al. Comparative analysis of the value of allogeneic hematopoietic stem-cell transplantation in acute myeloid leukemia with monosomal karyotype versus other cytogenetic risk categories. J Clin Oncol. 2012;30:2140–6.

    Article  Google Scholar 

  13. 13.

    Brands-Nijenhuis AV, Labopin M, Schouten HC, Volin L, Socie G, Cornelissen JJ, et al. Monosomal karyotype as an adverse prognostic factor in patients with acute myeloid leukemia treated with allogeneic hematopoietic stem-cell transplantation in first complete remission: a retrospective survey on behalf of the ALWP of the EBMT. Haematologica. 2016;101:248–55.

    CAS  Article  Google Scholar 

  14. 14.

    Kurosawa S, Miyawaki S, Yamaguchi T, Kanamori H, Sakura T, Moriuchi Y, et al. Prognosis of patients with core binding factor acute myeloid leukemia after first relapse. Haematologica. 2013;98:1525–31.

    Article  Google Scholar 

  15. 15.

    Hospital MA, Prebet T, Bertoli S, Thomas X, Tavernier E, Braun T, et al. Core-binding factor acute myeloid leukemia in first relapse: a retrospective study from the French AML Intergroup. Blood. 2014;124:1312–9.

    CAS  Article  Google Scholar 

  16. 16.

    Grimwade D, Hills RK, Moorman AV, Walker H, Chatters S, Goldstone AH, et al. Refinement of cytogenetic classification in acute myeloid leukemia: determination of prognostic significance of rare recurring chromosomal abnormalities among 5876 younger adult patients treated in the United Kingdom Medical Research Council trials. Blood. 2010;116:354–65.

    CAS  Article  Google Scholar 

  17. 17.

    Stolzel F, Mohr B, Kramer M, Oelschlagel U, Bochtler T, Berdel WE, et al. Karyotype complexity and prognosis in acute myeloid leukemia. Blood Cancer J. 2016;6:e386.

    CAS  Article  Google Scholar 

  18. 18.

    Kang L, Chen W, Petrick NA, Gallas BD. Comparing two correlated C indices with right-censored survival outcome: a one-shot nonparametric approach. Stat Med. 2015;34:685–703.

    Article  Google Scholar 

  19. 19.

    Li S, Garrett-Bakelman FE, Chung SS, Sanders MA, Hricik T, Rapaport F, et al. Distinct evolution and dynamics of epigenetic and genetic heterogeneity in acute myeloid leukemia. Nat Med. 2016;22:792–9.

    CAS  Article  Google Scholar 

  20. 20.

    Wang M, Lindberg J, Klevebring D, Nilsson C, Mer AS, Rantalainen M, et al. Validation of risk stratification models in acute myeloid leukemia using sequencing-based molecular profiling. Leukemia. 2017;31:2029–36.

    CAS  Article  Google Scholar 

  21. 21.

    Herold T, Jurinovic V, Batcha AMN, Bamopoulos SA, Rothenberg-Thurley M, Ksienzyk B, et al. A 29-gene and cytogenetic score for the prediction of resistance to induction treatment in acute myeloid leukemia. Haematologica. 2018;103:456–65.

    CAS  Article  Google Scholar 

  22. 22.

    Byrd JC, Mrozek K, Dodge RK, Carroll AJ, Edwards CG, Arthur DC, et al. Pretreatment cytogenetic abnormalities are predictive of induction success, cumulative incidence of relapse, and overall survival in adult patients with de novo acute myeloid leukemia: results from Cancer and Leukemia Group B (CALGB 8461). Blood. 2002;100:4325–36.

    CAS  Article  Google Scholar 

  23. 23.

    Hackl H, Astanina K, Wieser R. Molecular and genetic alterations associated with therapy resistance and relapse of acute myeloid leukemia. J Hematol Oncol. 2017;10:51.

    Article  Google Scholar 

  24. 24.

    Brissot E, Labopin M, Stelljes M, Ehninger G, Schwerdtfeger R, Finke J, et al. Comparison of matched sibling donors versus unrelated donors in allogeneic stem cell transplantation for primary refractory acute myeloid leukemia: a study on behalf of the Acute Leukemia Working Party of the EBMT. J Hematol Oncol. 2017;10:130.

    Article  Google Scholar 

  25. 25.

    Krauter J, Wagner K, Schafer I, Marschalek R, Meyer C, Heil G, et al. Prognostic factors in adult patients up to 60 years old with acute myeloid leukemia and translocations of chromosome band 11q23: individual patient data-based meta-analysis of the German Acute Myeloid Leukemia Intergroup. J Clin Oncol. 2009;27:3000–6.

    Article  Google Scholar 

  26. 26.

    Bhatnagar B, Blachly JS, Kohlschmidt J, Eisfeld AK, Volinia S, Nicolet D, et al. Clinical features and gene- and microRNA-expression patterns in adult acute leukemia patients with t(11;19)(q23; p13.1) and t(11;19)(q23;p13.3). Leukemia. 2016;30:1586–9.

    CAS  Article  Google Scholar 

  27. 27.

    Chen Y, Kantarjian H, Pierce S, Faderl S, O’Brien S, Qiao W, et al. Prognostic significance of 11q23 aberrations in adult acute myeloid leukemia and the role of allogeneic stem cell transplantation. Leukemia. 2013;27:836–42.

    CAS  Article  Google Scholar 

  28. 28.

    Arber DA, Orazi A, Hasserjian R, Thiele J, Borowitz MJ, Le Beau MM, et al. The2016 revision to the World Health Organization classification of myeloid neoplasms and acute leukemia. Blood. 2016;127:2391–405.

    CAS  Article  Google Scholar 

  29. 29.

    Dumezy F, Renneville A, Mayeur-Rousse C, Nibourel O, Labis E, Preudhomme C. Acute myeloid leukemia with translocation t(3;5): new molecular insights. Haematologica. 2013;98:e52–4.

    Article  Google Scholar 

  30. 30.

    Johansson B, Billstrom R, Mauritzson N, Mitelman F. Trisomy 19 as the sole chromosomal anomaly in hematologic neoplasms. Cancer Genet Cytogenet. 1994;74:62–5.

    CAS  Article  Google Scholar 

  31. 31.

    Peniket AJ. Del(9q) acute myeloid leukaemia: clinical and cytological characteristics and prognostic implications. Br J Haematol. 2005;130:969. author reply

    CAS  Article  Google Scholar 

  32. 32.

    Prebet T, Boissel N, Reutenauer S, Thomas X, Delaunay J, Cahn JY, et al. Acute myeloid leukemia with translocation (8;21) or inversion (16) in elderly patients treated with conventional chemotherapy: a collaborative study of the French CBF-AML intergroup. J Clin Oncol. 2009;27:4747–53.

    Article  Google Scholar 

  33. 33.

    Kuchenbauer F, Schnittger S, Look T, Gilliland G, Tenen D, Haferlach T, et al. Identification of additional cytogenetic and molecular genetic abnormalities in acute myeloid leukaemia with t(8;21)/AML1-ETO. Br J Haematol. 2006;134:616–9.

    CAS  Article  Google Scholar 

  34. 34.

    Cui W, Bueso-Ramos CE, Yin CC, Sun J, Chen S, Muddasani R, et al. Trisomy 14 as a sole chromosome abnormality is associated with older age, a heterogenous group of myeloid neoplasms with dysplasia, and a wide spectrum of disease progression. J Biomed Biotechnol. 2010;2010:365318.

    PubMed  Google Scholar 

  35. 35.

    Kuwatsuka Y, Miyamura K, Suzuki R, Kasai M, Maruta A, Ogawa H, et al. Hematopoietic stem cell transplantation for core binding factor acute myeloid leukemia: t(8;21) and inv(16) represent different clinical outcomes. Blood. 2009;113:2096–103.

    CAS  Article  Google Scholar 

  36. 36.

    The 44th Annual Meeting of the European Society for Blood and Marrow Transplantation: Physicians Oral Session. Bone Marrow Transplantation. 2018; https://doi.org/10.1038/s41409-018-0318-y.

  37. 37.

    Ishiyama K, Takami A, Kanda Y, Nakao S, Hidaka M, Maeda T, et al. Allogeneic hematopoietic stem cell transplantation for acute myeloid leukemia with t(6;9)(p23; q34) dramatically improves the patient prognosis: a matched-pair analysis. Leukemia. 2012;26:461–4.

    CAS  Article  Google Scholar 

  38. 38.

    Schlenk RF, Dohner K, Krauter J, Frohling S, Corbacioglu A, Bullinger L, et al. Mutations and treatment outcome in cytogenetically normal acute myeloid leukemia. N Engl J Med. 2008;358:1909–18.

    CAS  Article  Google Scholar 

  39. 39.

    Brunet S, Labopin M, Esteve J, Cornelissen J, Socie G, Iori AP, et al. Impact of FLT3 internal tandem duplication on the outcome of related and unrelated hematopoietic transplantation for adult acute myeloid leukemia in first remission: a retrospective analysis. J Clin Oncol. 2012;30:735–41.

    Article  Google Scholar 

  40. 40.

    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;126:2062–9.

    CAS  Article  Google Scholar 

  41. 41.

    Haferlach C, Alpermann T, Schnittger S, Kern W, Chromik J, Schmid C, et al. Prognostic value of monosomal karyotype in comparison to complex aberrant karyotype in acute myeloid leukemia: a study on 824 cases with aberrant karyotype. Blood. 2012;119:2122–5.

    CAS  Article  Google Scholar 

  42. 42.

    Pasquini MC, Zhang MJ, Medeiros BC, Armand P, Hu ZH, Nishihori T, et al. Hematopoietic cell transplantation outcomes in monosomal karyotype myeloid malignancies. Biol Blood Marrow Transplant. 2016;22:248–57.

    Article  Google Scholar 

  43. 43.

    Yanada M, Kurosawa S, Yamaguchi T, Yamashita T, Moriuchi Y, Ago H, et al. Prognosis of acute myeloid leukemia harboring monosomal karyotype in patients treated with or without allogeneic hematopoietic cell transplantation after achieving complete remission. Haematologica. 2012;97:915–8.

    Article  Google Scholar 

  44. 44.

    Poire X, Labopin M, Cornelissen JJ, Volin L, Richard Espiga C, Veelken JH, et al. Outcome of conditioning intensity in acute myeloid leukemia with monosomal karyotype in patients over 45 year-old: A study from the acute leukemia working party (ALWP) of the European group of blood and marrow transplantation (EBMT). Am J Hematol. 2015;90:719–24.

    Article  Google Scholar 

  45. 45.

    Kayser S, Zucknick M, Dohner K, Krauter J, Kohne CH, Horst HA, et al. Monosomal karyotype in adult acute myeloid leukemia: prognostic impact and outcome after different treatment strategies. Blood. 2012;119:551–8.

    CAS  Article  Google Scholar 

  46. 46.

    Fang M, Storer B, Estey E, Othus M, Zhang L, Sandmaier BM, et al. Outcome of patients with acute myeloid leukemia with monosomal karyotype who undergo hematopoietic cell transplantation. Blood. 2011;118):1490–4.

    CAS  Article  Google Scholar 

  47. 47.

    Strickland SA, Sun Z, Ketterling RP, Cherry AM, Cripe LD, Dewald G, et al. Independent Prognostic Significance Of Monosomy 17 and Impact of Karyotype Complexity in Monosomal Karyotype/Complex Karyotype Acute Myeloid Leukemia: Results from Four ECOG-ACRIN Prospective Therapeutic Trials. Leuk Res. 2017;59:55–64.

    Article  Google Scholar 

  48. 48.

    Armand P, Kim HT, Zhang MJ, Perez WS, Dal Cin PS, Klumpp TR, et al. Classifying cytogenetics in patients with acute myelogenous leukemia in complete remission undergoing allogeneic transplantation: a Center for International Blood and Marrow Transplant Research study. Biol Blood Marrow Transplant. 2012;18:280–8.

    Article  Google Scholar 

  49. 49.

    Medeiros BC, Othus M, Fang M, Appelbaum FR, Erba HP. Cytogenetic heterogeneity negatively impacts outcomes in patients with acute myeloid leukemia. Haematologica. 2015;100:331–5.

    Article  Google Scholar 

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Acknowledgements

We thank all the European Group for Blood and Marrow Transplantation (EBMT) centers and national registries for contributing patients to the study and data managers for their excellent work.

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Correspondence to Arnon Nagler.

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Canaani, J., Labopin, M., Itälä-Remes, M. et al. Prognostic significance of recurring chromosomal abnormalities in transplanted patients with acute myeloid leukemia. Leukemia 33, 1944–1952 (2019). https://doi.org/10.1038/s41375-019-0439-3

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