Abstract

Complex karyotype (CK) with ≥ 3 abnormalities is detected in 10–12% of patients with acute myeloid leukemia (AML) and associated with poor prognosis. The most common unbalanced abnormalities found in CK result in loss of material from the 5q, 7q, and/or 17p chromosome arms. The presence of 5q, 7q, and/or 17p abnormalities denotes typical CK and their absence denotes atypical CK. Since molecular features of CK-AML are not well characterized, we investigated mutational status of 81 leukemia/cancer-associated genes in 160 clinically well-characterized patients. They included 136 patients with ≥ 3 exclusively unbalanced chromosome abnormalities, 96 of whom had a typical CK and 40 atypical CK, and 24 patients with ≥ 1 balanced abnormality in addition to ≥ 2 unbalanced ones. Patients with atypical CK-AML differed from those with typical CK-AML: they carried TP53 mutations less often (P < 0.001) and more often PHF6 (P = 0.008), FLT3-TKD (P = 0.02), MED12 (P = 0.02), and NPM1 (P = 0.02) mutations. They were younger (P= 0.007), had higher WBC (P = 0.001) and percentages of marrow (P < 0.001) and blood (P = 0.006) blasts, higher complete remission rates (P = 0.02), and longer overall survival (P < 0.001), thus indicating that atypical and typical CK-AMLs constitute distinct disease subtypes. We also identified smaller patient subsets within both typical and atypical CK-AML that differed molecularly and clinically.

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References

  1. 1.

    Mrózek K, Heerema NA, Bloomfield CD. Cytogenetics in acute leukemia. Blood Rev. 2004;18:115–36.

  2. 2.

    Byrd JC, Mrózek 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.

  3. 3.

    Schoch C, Haferlach T, Haase D, Fonatsch C, Löffler H, Schlegelberger B, et al. Patients with de novo acute myeloid leukaemia and complex karyotype aberrations show a poor prognosis despite intensive treatment: a study of 90 patients. Br J Haematol. 2001;112:118–26.

  4. 4.

    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.

  5. 5.

    Farag SS, Archer KJ, Mrózek K, Ruppert AS, Carroll AJ, Vardiman JW, et al. Pretreatment cytogenetics add to other prognostic factors predicting complete remission and long-term outcome in patients 60 years of age or older with acute myeloid leukemia: results from Cancer and Leukemia Group B 8461. Blood. 2006;108:63–73.

  6. 6.

    Fröhling S, Schlenk RF, Kayser S, Morhardt M, Benner A, Döhner K, et al. Cytogenetics and age are major determinants of outcome in intensively treated acute myeloid leukemia patients older than 60 years: results from AMLSG trial AML HD98-B. Blood. 2006;108:3280–8.

  7. 7.

    Schoch C, Haferlach T, Bursch S, Gerstner D, Schnittger S, Dugas M, et al. Loss of genetic material is more common than gain in acute myeloid leukemia with complex aberrant karyotype: a detailed analysis of 125 cases using conventional chromosome analysis and fluorescence in situ hybridization including 24-color FISH. Genes Chromosomes Cancer. 2002;35:20–29.

  8. 8.

    Rücker FG, Schlenk RF, Bullinger L, Kayser S, Teleanu V, Kett H, et al. TP53 alterations in acute myeloid leukemia with complex karyotype correlate with specific copy number alterations, monosomal karyotype, and dismal outcome. Blood. 2012;119:2114–21.

  9. 9.

    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.

  10. 10.

    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. 2016;6:e386.

  11. 11.

    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.

  12. 12.

    Mrózek K, Heinonen K, Theil KS, Bloomfield CD. Spectral karyotyping in patients with acute myeloid leukemia and a complex karyotype shows hidden aberrations, including recurrent overrepresentation of 21q, 11q, and 22q. Genes Chromosomes Cancer. 2002;34:137–53.

  13. 13.

    Mrózek K. Cytogenetic, molecular genetic, and clinical characteristics of acute myeloid leukemia with a complex karyotype. Semin Oncol. 2008;35:365–77.

  14. 14.

    Eisfeld A-K, Mrózek K, Kohlschmidt J, Nicolet D, Orwick S, Walker CJ, et al. The mutational oncoprint of recurrent cytogenetic abnormalities in adult patients with de novo acute myeloid leukemia. Leukemia. 2017;31:2211–8.

  15. 15.

    Fenaux P, Jonveaux P, Quiquandon I, Laï JL, Pignon JM, Loucheux-Lefebvre MH, et al. P53 gene mutations in acute myeloid leukemia with 17p monosomy. Blood. 1991;78:1652–7.

  16. 16.

    Laï J-L, Preudhomme C, Zandecki M, Flactif M, Vanrumbeke M, Lepelley P, et al. Myelodysplastic syndromes and acute myeloid leukemia with 17p deletion. An entity characterized by specific dysgranulopoiesis and a high incidence of P53 mutations. Leukemia. 1995;9:370–81.

  17. 17.

    Christiansen DH, Andersen MK, Pedersen-Bjergaard J. Mutations with loss of heterozygosity of p53 are common in therapy-related myelodysplasia and acute myeloid leukemia after exposure to alkylating agents and significantly associated with deletion or loss of 5q, a complex karyotype, and a poor prognosis. J Clin Oncol. 2001;19:1405–13.

  18. 18.

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

  19. 19.

    Metzeler KH, Herold T, Rothenberg-Thurley M, Amler S, Sauerland MC, Görlich D, et al. Spectrum and prognostic relevance of driver gene mutations in acute myeloid leukemia. Blood. 2016;128:686–98.

  20. 20.

    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.

  21. 21.

    Kolitz JE, George SL, Marcucci G, Vij R, Powell BL, Allen SL, et al. P-glycoprotein inhibition using valspodar (PSC-833) does not improve outcomes for patients under age 60 years with newly diagnosed acute myeloid leukemia: Cancer and Leukemia Group B study 19808. Blood. 2010;116:1413–21.

  22. 22.

    Blum W, Sanford BL, Klisovic R, DeAngelo DJ, Uy G, Powell BL, et al. Maintenance therapy with decitabine in younger adults with acute myeloid leukemia in first remission: a phase 2 Cancer and Leukemia Group B study (CALGB 10503). Leukemia. 2017;31:34–39.

  23. 23.

    Baer MR, George SL, Caligiuri MA, Sanford BL, Bothun SM, Mrózek K, et al. Low-dose interleukin-2 immunotherapy does not improve outcome of patients age 60 years and older with acute myeloid leukemia in first complete remission: Cancer and Leukemia Group B study 9720. J Clin Oncol. 2008;26:4934–9.

  24. 24.

    Baer MR, George SL, Sanford BL, Mrózek K, Kolitz JE, Moore JO, et al. Escalation of daunorubicin and addition of etoposide in the ADE regimen in acute myeloid leukemia patients aged 60 years and older: Cancer and Leukemia Group B Study 9720. Leukemia. 2011;25:800–7.

  25. 25.

    Marcucci G, Moser B, Blum W, Stock W, Wetzler M, Koltiz JE, et al. A phase III randomized trial of intensive induction and consolidation chemotherapy ± oblimersen, a pro-apoptotic Bcl-2 antisense oligonucleotide in untreated acute myeloid leukemia patients >60 years old. J Clin Oncol. 2007;25:360s (abstract 7012).

  26. 26.

    Kolitz JE, George SL, Dodge RK, Hurd DD, Powell BL, Allen SL, et al. Dose escalation studies of cytarabine, daunorubicin, and etoposide with and without multidrug resistance modulation with PSC-833 in untreated adults with acute myeloid leukemia younger than 60 years: final induction results of Cancer and Leukemia Group B study 9621. J Clin Oncol. 2004;22:4290–301.

  27. 27.

    Attar EC, Johnson JL, Amrein PC, Lozanski G, Wadleigh M, DeAngelo DJ, et al. Bortezomib added to daunorubicin and cytarabine during induction therapy and to intermediate-dose cytarabine for consolidation in patients with previously untreated acute myeloid leukemia age 60 to 75 years: CALGB (Alliance) study 10502. J Clin Oncol. 2012;31:923–9.

  28. 28.

    Mayer RJ, Davis RB, Schiffer CA, Berg DT, Powell BL, Schulman P, et al. Intensive postremission chemotherapy in adults with acute myeloid leukemia. N Engl J Med. 1994;331:896–903.

  29. 29.

    Moore JO, George SL, Dodge RK, Amrein PC, Powell BL, Kolitz JE, et al. Sequential multiagent chemotherapy is not superior to high-dose cytarabine alone as postremission intensification therapy for acute myeloid leukemia in adults under 60 years of age: Cancer and Leukemia Group B study 9222. Blood. 2005;105:3420–7.

  30. 30.

    Moore JO, Dodge RK, Amrein PC, Kolitz J, Lee EJ, Powell B, et al. Granulocyte-colony stimulating factor (filgrastim) accelerates granulocyte recovery after intensive postremission chemotherapy for acute myeloid leukemia with aziridinyl benzoquinone and mitoxantrone: Cancer and Leukemia Group B study 9022. Blood. 1997;89:780–8.

  31. 31.

    Lee EJ, George SL, Caligiuri M, Szatrowski TP, Powell BL, Lemke S, et al. Parallel phase I studies of daunorubicin given with cytarabine and etoposide with or without the multidrug resistance modulator PSC-833 in previously untreated patients 60 years of age or older with acute myeloid leukemia: results of Cancer and Leukemia Group B study 9420. J Clin Oncol. 1999;17:2831–9.

  32. 32.

    Stone RM, Berg DT, George SL, Dodge RK, Paciucci PA, Schulman P, et al. Granulocyte-macrophage colony-stimulating factor after initial chemotherapy for elderly patients with primary acute myelogenous leukemia. N Engl J Med. 1995;332:1671–7.

  33. 33.

    Stone RM, Mandrekar SJ, Sanford BL, Laumann K, Geyer S, Bloomfield CD, et al. Midostaurin plus chemotherapy for acute myeloid leukemia with a FLT3 mutation. N Engl J Med. 2017;377:454–64.

  34. 34.

    Roboz GJ, Mandrekar SJ, Desai P, Laumann K, Walker AR, Wang ES, et al. A randomized trial of 10 days of decitabine alone or with bortezomib in previously untreated older patients with acute myeloid leukemia: CALGB 11002 (Alliance). Blood Adv. 2018;2:3608–17.

  35. 35.

    Mitelman F (ed). ISCN (1995): An International System for Human Cytogenetic Nomenclature. Basel, Switzerland: Karger; 1995.

  36. 36.

    Mrózek K, Carroll AJ, Maharry K, Rao KW, Patil SR, Pettenati MJ, et al. Central review of cytogenetics is necessary for cooperative group correlative and clinical studies of adult acute leukemia: the Cancer and Leukemia Group B experience. Int J Oncol. 2008;33:239–44.

  37. 37.

    Mitelman F, Johansson B, Mertens F (eds). Mitelman database of chromosome aberrations and gene fusions in cancer. http://cgap.nci.nih.gov/Chromosomes/Mitelman. Accessed 5 Jun 2018.

  38. 38.

    Kroll KW, Eisfeld A-K, Lozanski A, Bloomfield CD, Byrd JC, Blachly JS. MuCor: mutation aggregation and correlation. Bioinformatics. 2016;32:1557–8.

  39. 39.

    Marcucci G, Maharry K, Radmacher MD, Mrózek K, Vukosavljevic T, Paschka P, et al. Prognostic significance of, and gene and microRNA expression signatures associated with, CEBPA mutations in cytogenetically normal acute myeloid leukemia with high-risk molecular features: a Cancer and Leukemia Group B study. J Clin Oncol. 2008;26:5078–87.

  40. 40.

    Whitman SP, Archer KJ, Feng L, Baldus C, Becknell B, Carlson BD, et al. Absence of the wild-type allele predicts poor prognosis in adult de novo acute myeloid leukemia with normal cytogenetics and the internal tandem duplication of FLT3: a Cancer and Leukemia Group B study. Cancer Res. 2001;61:7233–9.

  41. 41.

    Vittinghoff E, Glidden DV, Shiboski SC, McCulloch CE. Regression methods in biostatistics: linear, logistic, survival and repeated measures models. New York, NY, USA: Springer; 2005.

  42. 42.

    Kämpjärvi K, Järvinen TM, Heikkinen T, Ruppert AS, Senter L, Hoag KW, et al. Somatic MED12 mutations are associated with poor prognosis markers in chronic lymphocytic leukemia. Oncotarget. 2015;6:1884–8.

  43. 43.

    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;375:2023–36.

  44. 44.

    Bykov VJN, Eriksson SE, Bianchi J, Wiman KG. Targeting mutant p53 for efficient cancer therapy. Nat Rev Cancer. 2018;18:89–102.

  45. 45.

    Gröschel S, Schlenk RF, Engelmann J, Rockova V, Teleanu V, Kühn MWM, et al. Deregulated expression of EVI1 defines a poor prognostic subset of MLL-rearranged acute myeloid leukemias: a study of the German-Austrian Acute Myeloid Leukemia Study Group and the Dutch-Belgian-Swiss HOVON/SAKK Cooperative Group. J Clin Oncol. 2013;31:95–103.

  46. 46.

    Bhatnagar B, Blachly JS, Kohlschmidt J, Eisfeld A-K, 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.

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Acknowledgements

The authors thank the patients who participated in clinical trials and the families who supported them; Donna Bucci and the CALGB/Alliance Leukemia Tissue Bank at The Ohio State University Comprehensive Cancer Center, Columbus, OH, for sample processing and storage services and Lisa J. Sterling and Christine Finks for data management. This work was supported in part by the National Cancer Institute (grants CA101140, CA140158, CA180861, CA196171, CA016058, CA180821, CA180882, and CA077658), the Leukemia Clinical Research Foundation, the Warren D. Brown Foundation, the Pelotonia Fellowship Program (to A-KE), and by an allocation of computing resources from The Ohio Supercomputer Center. The content of this article is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.

Author contributions

KM, A-KE, and CDB designed the study; KM, A-KE, CJW, MB, JCB, and CDB contributed to the data interpretation, KM, A-KE, JK, and CDB wrote the manuscript; A-KE, CJW, and DP performed laboratory-based research; JSB performed the data processing; JK and DN performed statistical analysis; KM, AJC, ESW, GLU, JEK, BLP, WB, RMS, JCB, and CDB were involved directly or indirectly in the care of patients and/or sample procurement. All authors reviewed the manuscript and approved its final version.

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Author notes

  1. These authors contributed equally: Krzysztof Mrózek, Ann-Kathrin Eisfeld

Affiliations

  1. The Ohio State University Comprehensive Cancer Center, Columbus, OH, USA

    • Krzysztof Mrózek
    • , Ann-Kathrin Eisfeld
    • , Jessica Kohlschmidt
    • , Christopher J. Walker
    • , Deedra Nicolet
    • , Marius Bill
    • , Dimitrios Papaioannou
    •  & Clara D. Bloomfield
  2. Alliance Statistics and Data Center, The Ohio State University Comprehensive Cancer Center, Columbus, OH, USA

    • Jessica Kohlschmidt
    •  & Deedra Nicolet
  3. University of Alabama at Birmingham, Birmingham, AL, USA

    • Andrew J. Carroll
  4. Division of Hematology, Department of Internal Medicine, The Ohio State University Comprehensive Cancer Center, Columbus, OH, USA

    • James S. Blachly
    •  & John C. Byrd
  5. Department of Medicine, Roswell Park Cancer Institute, Buffalo, NY, USA

    • Eunice S. Wang
  6. Washington University School of Medicine in St. Louis, Siteman Cancer Center, St. Louis, MO, USA

    • Geoffrey L. Uy
  7. Monter Cancer Center, Hofstra Northwell School of Medicine, Lake Success, NY, USA

    • Jonathan E. Kolitz
  8. Wake Forest Baptist Comprehensive Cancer Center, Winston-Salem, NC, USA

    • Bayard L. Powell
  9. Emory University School of Medicine, Atlanta, GA, USA

    • William Blum
  10. Dana-Farber/Partners CancerCare, Boston, MA, USA

    • Richard M. Stone

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The authors declare that they have no conflict of interest.

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https://doi.org/10.1038/s41375-019-0390-3