Prognostic Significance of Complex Karyotypes in Acute Myeloid Leukemia

  • Yahya Daneshbod
  • Leila Kohan
  • Vahideh Taghadosi
  • Olga K. WeinbergEmail author
  • Daniel A. Arber
Leukemia (PH Wiernik, Section Editor)
Part of the following topical collections:
  1. Topical Collection on Leukemia

Opinion statement

Acute myeloid leukemia (AML) patients with a complex karyotype (CK-AML) show at least 3 unrelated clonal cytogenetic abnormalities with notoriously poor outcome. Such cases fall into either AML with myelodysplasia-related changes or therapy-related AML in the current World Health Organization classification of AML. Allogeneic stem cell transplantation is one of the only treatment modalities that can provide a long-term survival benefit and is recommended as a consolidative treatment in patients who are able to achieve complete remission. Unfortunately, transplantation is also associated with a higher relapse rate and more than half of CK-AML patients relapse from disease within the first 2 years. The probability of achieving remission with traditional induction using cytarabine and daunorubicin or idarubicin (“7 + 3”) is so small that investigational therapies should be considered up front in these patients. Less intensive therapeutic backbones, typically using one of the hypomethylating agents, azacitidine or decitabine, minimize toxicity and show a trend toward the improved overall survival. CPX 351 (Vyxeos) is a liposomal formulation of cytarabine and daunorubicin and this encapsulation leads to prolonged exposure to the two drugs. This drug is approved for AML patients with MDS-related changes and therapy-related AML, both of which are frequently associated with complex karyotype. Such patients show improved outcome in trials using this combination. Combination therapy that includes venetoclax (BCL2 inhibitor) with hypomethylating agents may also be appropriate for such patients.


Acute myeloid leukemia Cytogenetic abnormality Complex karyotype P53 mutations Prognosis 


Compliance with Ethical Standards

Conflict of Interest

Yahya Daneshbod, Leila Kohan, and Vahideh Taghadosi declare that they have no conflict of interest. Olga K. Weinberg has received compensation from Jazz Pharmaceuticals for service on an advisory board. Daniel A. Arber has received compensation from Jazz Pharmaceuticals for service on an advisory board and as a consultant.

Human and Animal Rights and Informed Consent

This article does not contain any studies with human or animal subjects performed by any of the authors.

References and Recommended Reading

Papers of particular interest, published recently, have been highlighted as: • Of importance •• Of major importance

  1. 1.
    Rubnitz JE, Gibson B, Smith FO. Acute myeloid leukemia. Pediatr Clin N Am. 2008;55(1):21–51.CrossRefGoogle Scholar
  2. 2.
    Haferlach T, Kern W, Schnittger S, Schoch C. Modern diagnostics in acute leukemias. Crit Rev Oncol Hematol. 2005;56(2):223–34.CrossRefGoogle Scholar
  3. 3.
    Haferlach T, Schoch C. Moderne Verfahren in der Leukämiediagnostik. Internist. 2002;43(10):1190–202.CrossRefGoogle Scholar
  4. 4.
    • Mrózek K. Cytogenetic, molecular genetic, and clinical characteristics of acute myeloid leukemia with a complex karyotype. Semin Oncol. 2008;35(4):365–77 Overview of complex karyotype definitions and clinical features of AML patients with complex karyotype.CrossRefGoogle Scholar
  5. 5.
    Jaffe ES. Pathology and genetics of tumours of haematopoietic and lymphoid tissues. In: Iarc; 2001.Google Scholar
  6. 6.
    Orozco JJ, Appelbaum FR. Unfavorable, complex, and monosomal karyotypes: the most challenging forms of acute myeloid leukemia. Oncology. 2012;26(8):706–12.PubMedGoogle Scholar
  7. 7.
    • Grimwade D, Hills RK, Moorman AV, Walker H, Chatters S, et al. National Cancer Research Institute Adult Leukaemia Working Group. 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(3):354–65 Cytogenetic classification in AML based on a large MRC trial.CrossRefGoogle Scholar
  8. 8.
    Meng CY, Noor PJ, Ismail A, Ahid MF, Zakaria Z. Cytogenetic profile of de novo acute myeloid leukemia patients in Malaysia. Int J Biomed Sci. 2013;9(1):26.PubMedPubMedCentralGoogle Scholar
  9. 9.
    Trivedi PJ, Patel DM, Brahmbhatt MM, Patel PS. Characterization of complex chromosomal rearrangements in acute myeloid leukemia: FISH and multicolor FISH add precision in defining abnormalities associated with poor prognosis. J Blood Res Hematol Dis. 2016;1(2).
  10. 10.
    •• Mrózek K, Marcucci G, Nicolet D, Maharry KS, Becker H, Whitman SP, et al. Prognostic significance of the European LeukemiaNet standardized system for reporting cytogenetic and molecular alterations in adults with acute myeloid leukemia. J Clin Oncol. 2012;30(36):4515 ELN recommendations for reporting genetic abnormalities in AML.CrossRefGoogle Scholar
  11. 11.
    Röllig C, Bornhäuser M, Thiede C, Taube F, Kramer M, Mohr B, et al. Long-term prognosis of acute myeloid leukemia according to the new genetic risk classification of the European LeukemiaNet recommendations: evaluation of the proposed reporting system. J Clin Oncol. 2011;29(20):2758–65.CrossRefGoogle Scholar
  12. 12.
    Grimwade D, Walker H, Harrison G, Oliver F, Chatters S, Harrison CJ, et al. The predictive value of hierarchical cytogenetic classification in older adults with acute myeloid leukemia (AML): analysis of 1065 patients entered into the United Kingdom Medical Research Council AML11 trial. Blood. 2001;98(5):1312–20.CrossRefGoogle Scholar
  13. 13.
    • 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(13):4075–83 SWOG trial reported importance of karyotype analysis on outcome of preremission and postremission therapy in AML patients.PubMedGoogle Scholar
  14. 14.
    Appelbaum FR, Kopecky KJ, Tallman MS, Slovak ML, Gundacker HM, Kim HT, et al. The clinical spectrum of adult acute myeloid leukaemia associated with core binding factor translocations. Br J Haematol. 2006;135(2):165–73.CrossRefGoogle Scholar
  15. 15.
    Burnett A, Wetzler M, Lowenberg B. Therapeutic advances in acute myeloid leukemia. J Clin Oncol. 2011;29(5):487–94.CrossRefGoogle Scholar
  16. 16.
    Bae SY, Kim JS, Ryeu BJ, Lee KN, Lee CK, Kim YK, et al. Acute myeloid leukemia (AML-M2) associated with variant t (8; 21): report of three cases. Cancer Genet Cytogenet. 2010;199(1):31–7.CrossRefGoogle Scholar
  17. 17.
    Park J, Jurcic JG, Rosenblat T, Tallman MS. Emerging new approaches for the treatment of acute promyelocytic leukemia. Ther Adv Hematol. 2011;2(5):335–52.CrossRefGoogle Scholar
  18. 18.
    Bakshi SR, Brahmbhatt MM, Trivedi PJ, Dalal EN, Patel DM, Purani SS, et al. Trisomy 8 in leukemia: a GCRI experience. Indian J Hum Genet. 2012;18(1):106.CrossRefGoogle Scholar
  19. 19.
    Greer JP, Arber DA, Glader B, List AF, Means RT, Paraskevas, et al. Wintrobe’s clinical hematology: Thirteen ed. Philadelphia. Lippincott Williams & Wilkins, a Wolters Kluwer business; cytogenetics. 2013; chapter 3: p.52.Google Scholar
  20. 20.
    Wiktor A, Rybicki BA, Piao ZS, Shurafa M, Barthel B, Maeda K, et al. Clinical significance of Y chromosomeloss in hematologic disease. Genes Chromosom Cancer. 2000;27(1):11–6.CrossRefGoogle Scholar
  21. 21.
    United KC. Loss of the Y chromosome from normal and neoplastic bone marrows. Genes Chromosom Cancer. 1992;5:83–8.CrossRefGoogle Scholar
  22. 22.
    Bilhou-Nabera C. 12p abnormalities in myeloid malignancies. Atlas Genet Cytogenet Oncol Haematol. 1998;2(4):125–6.Google Scholar
  23. 23.
    Hosono N, Makishima H, Mahfouz R, Przychodzen B, Yoshida K, Jerez A, et al. Recurrent genetic defects on chromosome 5q in myeloid neoplasms. Oncotarget. 2017;8(4):6483.CrossRefGoogle Scholar
  24. 24.
    Zhang R. Kim Y2, Wang X, Li Y, Lu X, Sternenberger AR, Li S, Lee JY. Genomic copy number variations in the myelodysplastic syndrome and acute myeloid leukemia patients with del(5q) and/or -7/del(7q). Int J Med Sci. 2015;12(9):719–26.CrossRefGoogle Scholar
  25. 25.
    Appelbaum FR, Gundacker H, Head DR, Slovak ML, Willman CL, Godwin JE, et al. Age andacute myeloid leukemia. Blood. 2006;107(9):3481–5.CrossRefGoogle Scholar
  26. 26.
    Desangles F. 7/del(7q) in adults. Atlas Genet Cytogenet Oncol Haematol. 1999;3(3):139–40.Google Scholar
  27. 27.
    De Braekeleer E, Douet-Guilbert N, Basinko A, Bovo C, Gueganic N, Le Bris MJ, et al. Conventional cytogenetics and breakpoint distribution by fluorescent in situ hybridization in patients with malignant hemopathies associated with inv.(3)(q21;q26) and t(3;3)(q21;q26). Anticancer Res. 2011;31(10):3441–8.PubMedGoogle Scholar
  28. 28.
    Balgobind BV, Raimondi SC, Harbott J, Zimmermann M, Alonzo TA, Auvrignon A, et al. Novel prognostic subgroups in childhood 11q23/MLLrearranged acute myeloid leukemia: results of an international retrospective study. Blood. 2009;114(12):2489–96.CrossRefGoogle Scholar
  29. 29.
    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(4):836.CrossRefGoogle Scholar
  30. 30.
    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(18):3000–6.CrossRefGoogle Scholar
  31. 31.
    •• Swerdlow S, Campo E, Harris N, Jaffe E, Pileri S, Stein H, et al., editors. World Health Organization classification of tumours of haematopoietic and lymphoid tissues. 4th ed. Lyons: IARC Press; 2008. WHO classification of hematologic malignancies. Google Scholar
  32. 32.
    Arsham MS, Barch MJ, Lawce HJ. (Eds.) The AGT Cytogenetics Laboratory Manual, 4th ed. John Wiley & Sons, Hoboken, NJ. 2017.Google Scholar
  33. 33.
    Labis E. t(11;16)(q23;p13.3). Atlas Genet Cytogenet Oncol Haematol. 2009.
  34. 34.
    Fleischman EW, Reshmi S, Frenkel MA, Konovalova WI, Guleva GP, Kulagina OE, et al. MLL is involved in a t(2;11)(p21;q23) in a patient with acute myeloblastic leukemia. Genes Chromosom Cancer. 1999;24(2):151–5.CrossRefGoogle Scholar
  35. 35.
    Shi LH, Ma P, Liu JS, Li Y, Wang YF, Guo MF, et al. Current views of chromosomal abnormalities in pediatric acute myeloid leukemia (AML). Eur Rev Med Pharmacol Sci. 2017;21(4 Suppl):25–30.PubMedGoogle Scholar
  36. 36.
    Bilhou-Nabera C. del(20q) in myeloid malignancies. Atlas Genet Cytogenet Oncol Haematol. 2001;5(1):33–4.Google Scholar
  37. 37.
    Ligon AH, DeAngelo DJ, Atkins L, Dal CP. Isochromosome of a deleted 20q may be a relatively common abnormality in myeloid malignancies. Cancer Genet Cytogenet. 2005;162(1):89–91.CrossRefGoogle Scholar
  38. 38.
    Wei CH, Yu IT, Tzeng CH, Fan FS, Hsieh RK, Chiou TJ, et al. Trisomy 21 in acute myeloid leukemia. Cancer Genet Cytogenet. 1996;86(2):177–80.CrossRefGoogle Scholar
  39. 39.
    Slovak ML, Gundacker H, Bloomfield CD, Dewald G, Appelbaum FR, Larson RA, et al. A retrospective study of 69 patients with t(6;9)(p23;q34) AML emphasizes the need for a prospective, multicenter initiative for rare ‘poor prognosis’ myeloid malignancies. Leukemia. 2006;20(7):1295–7.CrossRefGoogle Scholar
  40. 40.
    Gajendra S, Sahoo MK. Philadelphia-positive acute myeloblastic leukemia: a rare entity. J Neoplasm. 2016;1:1.CrossRefGoogle Scholar
  41. 41.
    Espersen AD, Noren, Nyström U, Abrahamsson J, Ha SY, Pronk CJ, et al. Acute myeloid leukemia (AML) with t (7; 12)(q36; p13) is associated with infancy and trisomy 19: data from Nordic Society for Pediatric Hematology and Oncology (NOPHO-AML) and review of the literature. Genes Chromosom Cancer. 2018;57(7):359–65.CrossRefGoogle Scholar
  42. 42.
    Coenen EA, Zwaan CM, Reinhardt D, Harrison CJ, Haas OA, de Haas V, et al. Pediatric acute myeloid leukemia with t (8; 16)(p11; p13): a distinct clinical and biological entity, a collaborative study by the International-Berlin-Frankfurt-Munster AML-study group. Blood. 2013;122:2704–13.Google Scholar
  43. 43.
    Bernstein J, Dastugue N, Haas OA, Harbott J, Heerema NA, Huret JL, et al. Nineteen cases of the t(1;22)(p13;q13) acute megakaryblastic leukaemia of infants/children and a review of 39 cases: report from a t(1;22) study group. Leukemia. 2000;14(1):216–8.CrossRefGoogle Scholar
  44. 44.
    • Breems DA, Van Putten WL, De Greef GE, 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. Monosomal karyotype definition and prognostic significance in AML.CrossRefGoogle Scholar
  45. 45.
    Weinberg OK, Ohgami RS, Ma L, Seo K, Ren L, Gotlib JR, et al. Acute myeloid leukemia with monosomal karyotype: morphologic, immunophenotypic, and molecular findings. Am J Clin Pathol. 2014;142(2):190–5.CrossRefGoogle Scholar
  46. 46.
    •• Dohner H, Estey EH, Amadori S, Appelbaum FR, Buchner T, Burnett AK, et al. Diagnosis and management of acute myeloid leukemia in adults: recommendations from an international expert panel, on behalf of the European LeukemiaNet. Blood. 2010;115:453–74 AML risk classification according to cytogenetic abnormality.CrossRefGoogle Scholar
  47. 47.
    • Stölzel F, Mohr B, Kramer M, Oelschlägel U, Bochtler T, Berdel WE, et al. Karyotype complexity and prognosis in acute myeloid leukemia. Blood Cancer J. 2017;6(1):e386 First clinical study on prognostic significance of karyotype abnormalities in AML.CrossRefGoogle Scholar
  48. 48.
    Göhring G, Michalova K, Beverloo HB, Betts D, Harbott J, Haas OA, et al. Complex karyotype newly defined: the strongest prognostic factor in advanced childhood myelodysplastic syndrome. Blood. 2010;116:3766–9.Google Scholar
  49. 49.
    Medeiros BC, Othus M, Fang M, Roulston D, Appelbaum FR. Prognostic impact of monosomal karyotype in young adult and elderly acute myeloid leukemia: the Southwest Oncology Group experience. Blood. 2010;116(13):2224–8.CrossRefGoogle Scholar
  50. 50.
    Harrison CJ, Hills RK, Moorman AV, Grimwade DJ, Hann I, Webb DK, et al. Cytogenetics of childhood acute myeloid leukemia: United Kingdom Medical Research Council Treatment trials AML 10 and 12. J Clin Oncol. 2010;28(16):2674–81.CrossRefGoogle Scholar
  51. 51.
    Pedersen-Bjergaard J, Andersen MK, Christiansen DH, Nerlov C. Genetic pathways in therapy-related myelodysplasia and acute myeloid leukemia. Blood. 2002;99(6):1909–12.CrossRefGoogle Scholar
  52. 52.
    Perrot A, Luquet I, Pigneux A, Mugneret F, Delaunay J, Harousseau JL, et al. Dismal prognostic value of monosomal karyotype in elderly patients with acute myeloid leukemia: a GOELAMS study of 186 patients with unfavorable cytogenetic abnormalities. Blood. 2011;118(3):679–85.CrossRefGoogle Scholar
  53. 53.
    Vaidya R, Caramazza D, Begna KH, et al. Monosomal karyotype in primary myelofibrosis is detrimental to both overall and leukemia-free survival. Blood. 2011;117:5612–5.CrossRefGoogle Scholar
  54. 54.
    Wierzbowska A, Wawrzyniak E, Siemieniuk-Rys M, Kotkowska A, Pluta A, Golos A, et al. Concomitance of monosomal karyotype with at least 5 chromosomal abnormalities is associated with dismal treatment outcome of AML patients with complex karyotype–retrospective analysis of Polish Adult Leukemia Group (PALG). Leuk Lymphoma. 2017;58(4):889–97.CrossRefGoogle Scholar
  55. 55.
    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(9):2122–5.CrossRefGoogle Scholar
  56. 56.
    Grimwade D. Impact of cytogenetics on clinical outcome in AML. In: Karp JE, editor. Acute Myelogenous Leukemia. Totowa, NJ: Humana Press. 2007;p.177–192.Google Scholar
  57. 57.
    Grimwade D, Hills RK. Independent prognostic factors for AML outcome. ASH Education Program Book. 2009;2009(1):385–95.Google Scholar
  58. 58.
    Hernandez JM, Martin G, Gutierrez NC, Cervera J, Ferro MT, Calasanz MJ, et al. Additional cytogenetic changes do not influence the outcome of patients with newly diagnosed acute promyelocytic leukemia treated with an ATRA plus anthracyclin based protocol. A report of the Spanish group PETHEMA. Haematologica. 2001;86(8):807–13.PubMedGoogle Scholar
  59. 59.
    Schlenk RF, Benner A, Krauter J, Buchner T, Sauerland C, Ehninger G, et al. Individual patient data–based meta-analysis of patients aged 16 to 60 years with core binding factor acute myeloid leukemia: a survey of the German Acute Myeloid Leukemia Intergroup. J Clin Oncol. 2004;22(18):3741–50.CrossRefGoogle Scholar
  60. 60.
    Chen EC, Fathi AT, Brunner AM. Reformulating acute myeloid leukemia: liposomal cytarabine and daunorubicin (CPX-351) as an emerging therapy for secondary AML. OncoTargets Ther. 2018;11:3425.CrossRefGoogle Scholar
  61. 61.
    Ohgami RS, Ma L, Merker JD, Gotlib JR, Schrijver I, Zehnder JL, et al. Next-generation sequencing of acute myeloid leukemia identifies the significance of TP53, U2AF1, ASXL1, and TET2 mutations. Mod Pathol. 2015;28(5):706.CrossRefGoogle Scholar
  62. 62.
    •• 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(23):2209–21 A large study on genomic classification and prognosis in AML.CrossRefGoogle Scholar
  63. 63.
    Hou HA, Chou WC, Kuo YY, Liu CY, Lin LI, Tseng MH, et al. TP53 mutations in de novo acute myeloid leukemia patients: longitudinal follow-ups show the mutation is stable during disease evolution. Blood Cancer J. 2015;5(7):e331.CrossRefGoogle Scholar
  64. 64.
    Fernandez-Pol S, Ma L, Ohgami RS, Arber DA. Immunohistochemistry for p53 is a useful tool to identify cases of acute myeloid leukemia with myelodysplasia-related changes that are TP53 mutated, have complex karyotype, and have poor prognosis. Mod Pathol. 2017;30(3):382.CrossRefGoogle Scholar
  65. 65.
    Dombret H, Gardin C. An update of current treatments for adult acute myeloid leukemia. Blood. 2016;127(1):53–61.CrossRefGoogle Scholar
  66. 66.
    Creutzig U, Van Den Heuvel-Eibrink MM, Gibson B, Dworzak MN, Adachi S, De Bont E, et al. Diagnosis and management of acute myeloid leukemia in children and adolescents: recommendations from an international expert panel. Blood. 2012;120(16):3187–205.CrossRefGoogle Scholar
  67. 67.
    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(4):424–47.CrossRefGoogle Scholar
  68. 68.
    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(10):2134–41.CrossRefGoogle Scholar
  69. 69.
    Umukoro, C. Post-transplant relapse is a main cause of treatment failure in patients with complex karyotype AML. 2018. Retrieved from Accessed 10 Sept 2018.
  70. 70.
    Dombret H, Seymour JF, Butrym A, Wierzbowska A, Selleslag D, Jang JH, et al. International phase 3 study of azacitidine vs conventional care regimens in older patients with newly diagnosed AML with >30% blasts. Blood 2015;126: 291–299.Google Scholar
  71. 71.
    Welch JS, Petti AA, Miller CA, Fronick CC, O’Laughlin M, Fulton RS, et al. TP53 and decitabine in acute myeloid leukemia and myelodysplastic syndromes. N Engl J Med. 2016;375(21):2023–36.CrossRefGoogle Scholar
  72. 72.
    Montalban-Bravo G, Benton CB, Wang SA, Ravandi F, Kadia T, Cortes J, et al. More than 1 TP53 abnormality is a dominant characteristic of pure erythroid leukemia. Blood. 2017;129(18):2584–7.CrossRefGoogle Scholar
  73. 73.
    Estey EH. Acute myeloid leukemia: 2019 update on riskstratification and management. Am J Hematol. 2018;93(10):1267–91.CrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2019

Authors and Affiliations

  • Yahya Daneshbod
    • 1
    • 2
  • Leila Kohan
    • 1
    • 3
  • Vahideh Taghadosi
    • 1
  • Olga K. Weinberg
    • 4
    Email author
  • Daniel A. Arber
    • 5
  1. 1.Shiraz Molecular Pathology Research CenterShirazIran
  2. 2.Department of PathologyMemorial Sloan Kettering Cancer CenterNew YorkUSA
  3. 3.Department of BiologyIslamic Azad UniversityArsanjanIran
  4. 4.Department of PathologyBoston Children’s HospitalBostonUSA
  5. 5.Department of PathologyUniversity of ChicagoChicagoUSA

Personalised recommendations