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Therapy-related myeloid neoplasms: Acute myeloid leukemia and myelodysplastic syndrome

Richard A Larson, MD
Section Editor
Bob Lowenberg, MD, PhD
Deputy Editor
Alan G Rosmarin, MD


Persons who are exposed to cytotoxic agents are at risk of developing acute myeloid leukemia (t-AML), myelodysplastic syndrome (t-MDS), and myelodysplastic syndrome/myeloproliferative neoplasms (t-MDS/MPN). These conditions lie along a continuum of disease and are categorized by the World Health Organization (WHO) classification system as therapy-related myeloid neoplasms (t-MN) [1,2]. t-MN is a clinical syndrome that is distinguished by iatrogenic exposure to mutagenic agents. Excluded from this category is progression of myeloproliferative neoplasms (MPNs) and evolution of primary MDS to AML (so-called "secondary" AML); in both of these latter cases, evolution to AML is part of the natural history of the primary disease and it may be impossible to distinguish natural progression from therapy-induced changes [3].

Patients with t-MN comprise a heterogeneous and poorly defined group who have a shorter median survival than patients with de novo AML, MDS, or MDS/MPN. This subset of myeloid neoplasms shares many clinical and biological characteristics of leukemias and MDS/MPN that appear de novo (ie, with no known exposure to mutagenic agents). However, the t-MN cases most often have high-risk or adverse features, and as a group have had poor outcomes independent of other established AML prognostic factors. They are identified and classified as a defined subgroup largely to better understand how known mutagenic exposures impact human hematopoietic stem cells to give rise to malignancy. Undoubtedly, some patients who fall into this category based solely on their medical history have developed a myeloid malignancy independent from prior cytotoxic exposures, but these de novo cases cannot be distinguished currently.

The epidemiology, diagnosis, and treatment of t-MN are discussed here. The treatment of de novo AML and MDS are discussed separately. Additional information regarding the pathophysiology behind the development of t-AML is also presented separately. (See "Induction therapy for acute myeloid leukemia in younger adults" and "Treatment of acute myeloid leukemia in older adults" and "Pathogenesis of acute myeloid leukemia".)


Therapy-related myeloid neoplasms (t-MN) account for approximately 10 to 20 percent of all cases of AML, MDS, and MDS/MPN [4]. The incidence among patients treated with cytotoxic agents varies according to the underlying disease, specific agents, timing of exposure, and dose [5]. Patients can present at any age, but the median age at diagnosis is 61 years [6,7]. The risk associated with alkylating agents and radiation appears to increase with age, while the risk associated with topoisomerase II inhibitors appears to be constant across all ages [1]. Only a small percentage of patients treated with identical cytotoxic regimens develop t-MN; this may suggest that some individuals may have a heritable predisposition due to mutations in DNA damage sensing or repair genes (eg, BRCA1/2 or TP53), or polymorphisms in genes that affect drug metabolism, transport, or DNA-repair mechanisms [8,9].

The proportion of patients with a prior hematologic malignancy or a prior solid tumor is approximately equal and accounts for the large majority of cases. Five to 20 percent of patients will have a history of exposure to cytotoxic therapy for benign disorders while a similar proportion will have undergone an autologous hematopoietic cell transplantation (HCT) [4].


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Literature review current through: Sep 2016. | This topic last updated: Oct 5, 2016.
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  1. Swerdlow SH, Campo E, Harris NL, et al. (Eds). World Health Organization Classification of Tumours of Haematopoietic and Lymphoid Tissues, IARC Press, Lyon 2008.
  2. Arber DA, Orazi A, Hasserjian R, et al. The 2016 revision to the World Health Organization classification of myeloid neoplasms and acute leukemia. Blood 2016; 127:2391.
  3. Björkholm M, Hultcrantz M, Derolf ÅR. Leukemic transformation in myeloproliferative neoplasms: therapy-related or unrelated? Best Pract Res Clin Haematol 2014; 27:141.
  4. Granfeldt Østgård LS, Medeiros BC, Sengeløv H, 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.
  5. Morton LM, Dores GM, Tucker MA, et al. Evolving risk of therapy-related acute myeloid leukemia following cancer chemotherapy among adults in the United States, 1975-2008. Blood 2013; 121:2996.
  6. Takeyama K, Seto M, Uike N, et al. Therapy-related leukemia and myelodysplastic syndrome: a large-scale Japanese study of clinical and cytogenetic features as well as prognostic factors. Int J Hematol 2000; 71:144.
  7. Dores GM, Devesa SS, Curtis RE, et al. Acute leukemia incidence and patient survival among children and adults in the United States, 2001-2007. Blood 2012; 119:34.
  8. Churpek JE, Larson RA. The evolving challenge of therapy-related myeloid neoplasms. Best Pract Res Clin Haematol 2013; 26:309.
  9. Churpek JE, Marquez R, Neistadt B, et al. Inherited mutations in cancer susceptibility genes are common among survivors of breast cancer who develop therapy-related leukemia. Cancer 2016; 122:304.
  10. Smith SM, Le Beau MM, Huo D, et al. Clinical-cytogenetic associations in 306 patients with therapy-related myelodysplasia and myeloid leukemia: the University of Chicago series. Blood 2003; 102:43.
  11. Pedersen-Bjergaard J, Philip P. Two different classes of therapy-related and de-novo acute myeloid leukemia? Cancer Genet Cytogenet 1991; 55:119.
  12. Rowley JD, Golomb HM, Vardiman JW. Nonrandom chromosome abnormalities in acute leukemia and dysmyelopoietic syndromes in patients with previously treated malignant disease. Blood 1981; 58:759.
  13. Traweek ST, Slovak ML, Nademanee AP, et al. Clonal karyotypic hematopoietic cell abnormalities occurring after autologous bone marrow transplantation for Hodgkin's disease and non-Hodgkin's lymphoma. Blood 1994; 84:957.
  14. Kantarjian HM, Keating MJ, Walters RS, et al. Therapy-related leukemia and myelodysplastic syndrome: clinical, cytogenetic, and prognostic features. J Clin Oncol 1986; 4:1748.
  15. Gundestrup M, Klarskov Andersen M, Sveinbjornsdottir E, et al. Cytogenetics of myelodysplasia and acute myeloid leukaemia in aircrew and people treated with radiotherapy. Lancet 2000; 356:2158.
  16. Pedersen-Bjergaard J, Rowley JD. The balanced and the unbalanced chromosome aberrations of acute myeloid leukemia may develop in different ways and may contribute differently to malignant transformation. Blood 1994; 83:2780.
  17. Ratain MJ, Rowley JD. Therapy-related acute myeloid leukemia secondary to inhibitors of topoisomerase II: from the bedside to the target genes. Ann Oncol 1992; 3:107.
  18. Pedersen-Bjergaard J. Insights into leukemogenesis from therapy-related leukemia. N Engl J Med 2005; 352:1591.
  19. Tebbi CK, London WB, Friedman D, et al. Dexrazoxane-associated risk for acute myeloid leukemia/myelodysplastic syndrome and other secondary malignancies in pediatric Hodgkin's disease. J Clin Oncol 2007; 25:493.
  20. Pui CH, Relling MV. Topoisomerase II inhibitor-related acute myeloid leukaemia. Br J Haematol 2000; 109:13.
  21. Zhang MH, Wang XY, Gao LS. [140 cases of acute leukemia caused by bimolane]. Zhonghua Nei Ke Za Zhi 1993; 32:668.
  22. Xue Y, Lu D, Guo Y, Lin B. Specific chromosomal translocations and therapy-related leukemia induced by bimolane therapy for psoriasis. Leuk Res 1992; 16:1113.
  23. Takahashi K, Pemmaraju N, Strati P, et al. Clinical characteristics and outcomes of therapy-related chronic myelomonocytic leukemia. Blood 2013; 122:2807.
  24. Arana-Yi C, Block AW, Sait SN, et al. Therapy-related myelodysplastic syndrome and acute myeloid leukemia following treatment of acute myeloid leukemia: possible role of cytarabine. Leuk Res 2008; 32:1043.
  25. Montesinos P, González JD, González J, et al. Therapy-related myeloid neoplasms in patients with acute promyelocytic leukemia treated with all-trans-retinoic Acid and anthracycline-based chemotherapy. J Clin Oncol 2010; 28:3872.
  26. Imagawa J, Harada Y, Shimomura T, et al. Clinical and genetic features of therapy-related myeloid neoplasms after chemotherapy for acute promyelocytic leukemia. Blood 2010; 116:6018.
  27. Singh ZN, Huo D, Anastasi J, et al. Therapy-related myelodysplastic syndrome: morphologic subclassification may not be clinically relevant. Am J Clin Pathol 2007; 127:197.
  28. Anderson JE, Gooley TA, Schoch G, et al. Stem cell transplantation for secondary acute myeloid leukemia: evaluation of transplantation as initial therapy or following induction chemotherapy. Blood 1997; 89:2578.
  29. Yakoub-Agha I, de La Salmonière P, Ribaud P, et al. Allogeneic bone marrow transplantation for therapy-related myelodysplastic syndrome and acute myeloid leukemia: a long-term study of 70 patients-report of the French society of bone marrow transplantation. J Clin Oncol 2000; 18:963.
  30. Hale GA, Heslop HE, Bowman LC, et al. Bone marrow transplantation for therapy-induced acute myeloid leukemia in children with previous lymphoid malignancies. Bone Marrow Transplant 1999; 24:735.
  31. Kröger N, Brand R, van Biezen A, et al. Autologous stem cell transplantation for therapy-related acute myeloid leukemia and myelodysplastic syndrome. Bone Marrow Transplant 2006; 37:183.
  32. Rizzieri DA, O'Brien JA, Broadwater G, et al. Outcomes of patients who undergo aggressive induction therapy for secondary acute myeloid leukemia. Cancer 2009; 115:2922.
  33. Dayyani F, Kantarjian H, O'Brien S, et al. Outcome of therapy-related acute promyelocytic leukemia with or without arsenic trioxide as a component of frontline therapy. Cancer 2011; 117:110.
  34. Larson RA, Wernli M, Le Beau MM, et al. Short remission durations in therapy-related leukemia despite cytogenetic complete responses to high-dose cytarabine. Blood 1988; 72:1333.
  35. Schoch C, Kern W, Schnittger S, et al. Karyotype is an independent prognostic parameter in therapy-related acute myeloid leukemia (t-AML): an analysis of 93 patients with t-AML in comparison to 1091 patients with de novo AML. Leukemia 2004; 18:120.
  36. Armand P, Kim HT, DeAngelo DJ, et al. Impact of cytogenetics on outcome of de novo and therapy-related AML and MDS after allogeneic transplantation. Biol Blood Marrow Transplant 2007; 13:655.
  37. Nardi V, Winkfield KM, Ok CY, et al. Acute myeloid leukemia and myelodysplastic syndromes after radiation therapy are similar to de novo disease and differ from other therapy-related myeloid neoplasms. J Clin Oncol 2012; 30:2340.
  38. Bacher U, Haferlach C, Alpermann T, et al. Patients with therapy-related myelodysplastic syndromes and acute myeloid leukemia share genetic features but can be separated by blast counts and cytogenetic risk profiles into prognostically relevant subgroups. Leuk Lymphoma 2013; 54:639.
  39. Larson RA, Le Beau MM. Prognosis and therapy when acute promyelocytic leukemia and other "good risk" acute myeloid leukemias occur as a therapy-related myeloid neoplasm. Mediterr J Hematol Infect Dis 2011; 3:e2011032.
  40. Larson RA. Cytogenetics, not just previous therapy, determines the course of therapy-related myeloid neoplasms. J Clin Oncol 2012; 30:2300.
  41. Borthakur G, Lin E, Jain N, et al. Survival is poorer in patients with secondary core-binding factor acute myelogenous leukemia compared with de novo core-binding factor leukemia. Cancer 2009; 115:3217.
  42. Kayser S, Döhner K, Krauter J, et al. The impact of therapy-related acute myeloid leukemia (AML) on outcome in 2853 adult patients with newly diagnosed AML. Blood 2011; 117:2137.
  43. Kern W, Haferlach T, Schnittger S, et al. Prognosis in therapy-related acute myeloid leukemia and impact of karyotype. J Clin Oncol 2004; 22:2510.
  44. Lindsley RC, Mar BG, Mazzola E, et al. Acute myeloid leukemia ontogeny is defined by distinct somatic mutations. Blood 2015; 125:1367.
  45. Shih AH, Chung SS, Dolezal EK, et al. Mutational analysis of therapy-related myelodysplastic syndromes and acute myelogenous leukemia. Haematologica 2013; 98:908.
  46. Wong TN, Ramsingh G, Young AL, et al. Role of TP53 mutations in the origin and evolution of therapy-related acute myeloid leukaemia. Nature 2015; 518:552.
  47. Ok CY, Patel KP, Garcia-Manero G, et al. Mutational profiling of therapy-related myelodysplastic syndromes and acute myeloid leukemia by next generation sequencing, a comparison with de novo diseases. Leuk Res 2015; 39:348.
  48. Cleven AH, Nardi V, Ok CY, et al. High p53 protein expression in therapy-related myeloid neoplasms is associated with adverse karyotype and poor outcome. Mod Pathol 2015; 28:552.
  49. Fianchi L, Pagano L, Piciocchi A, et al. Characteristics and outcome of therapy-related myeloid neoplasms: Report from the Italian network on secondary leukemias. Am J Hematol 2015; 90:E80.
  50. Andersen MK, Larson RA, Mauritzson N, et al. Balanced chromosome abnormalities inv(16) and t(15;17) in therapy-related myelodysplastic syndromes and acute leukemia: report from an international workshop. Genes Chromosomes Cancer 2002; 33:395.
  51. Slovak ML, Bedell V, Popplewell L, et al. 21q22 balanced chromosome aberrations in therapy-related hematopoietic disorders: report from an international workshop. Genes Chromosomes Cancer 2002; 33:379.
  52. Litzow MR, Tarima S, Pérez WS, et al. Allogeneic transplantation for therapy-related myelodysplastic syndrome and acute myeloid leukemia. Blood 2010; 115:1850.