Prognostic Significance of Complex Karyotypes in Acute Myeloid Leukemia
- 3 Downloads
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.
KeywordsAcute 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
- 5.Jaffe ES. Pathology and genetics of tumours of haematopoietic and lymphoid tissues. In: Iarc; 2001.Google Scholar
- 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
- 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). https://doi.org/10.4172/jbrhd.1000104.
- 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.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.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.• 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
- 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
- 22.Bilhou-Nabera C. 12p abnormalities in myeloid malignancies. Atlas Genet Cytogenet Oncol Haematol. 1998;2(4):125–6.Google Scholar
- 26.Desangles F. 7/del(7q) in adults. Atlas Genet Cytogenet Oncol Haematol. 1999;3(3):139–40.Google Scholar
- 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
- 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.•• 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.Arsham MS, Barch MJ, Lawce HJ. (Eds.) The AGT Cytogenetics Laboratory Manual, 4th ed. John Wiley & Sons, Hoboken, NJ. 2017.Google Scholar
- 33.Labis E. t(11;16)(q23;p13.3). Atlas Genet Cytogenet Oncol Haematol. 2009. http://AtlasGeneticsOncology.org/Anomalies/t1116q23p13ID1120.html.
- 36.Bilhou-Nabera C. del(20q) in myeloid malignancies. Atlas Genet Cytogenet Oncol Haematol. 2001;5(1):33–4.Google Scholar
- 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
- 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.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
- 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
- 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
- 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
- 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.Grimwade D, Hills RK. Independent prognostic factors for AML outcome. ASH Education Program Book. 2009;2009(1):385–95.Google Scholar
- 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.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
- 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.Umukoro, C. Post-transplant relapse is a main cause of treatment failure in patients with complex karyotype AML. 2018. Retrieved from https://amlglobalportal.com. Accessed 10 Sept 2018.
- 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