title: Therapy-related myeloid neoplasms after autologous hematopoietic stem cell transplantation in lymphoma patients.
abstract: Lymphoma patients treated with autologous transplantation (ASCT) live an increasingly long life with the recent advancement in therapeutic modalities. This has resulted in an increase in the incidence of therapy-related myeloid neoplasms (t-MN), which is one of the leading causes of non-relapse mortality. Several observational studies have linked the development of t-MN after ASCT with the intensity and frequency of chemotherapy, particularly alkylating agents, use of total body irradiation (TBI), and peripheral blood progenitor cells. In addition, role of genetic factors is increasingly being identified. It is postulated that the use of chemotherapy prior to ASCT results in DNA damage of progenitor cells, mitochondrial dysfunction, and altered gene expression related to DNA repair, metabolism as well as hematopoietic regulation. Cytogenetic studies have shown the presence of abnormalities in the peripheral blood progenitor cells prior to ASCT. It is, therefore, likely that the reinfusion of peripheral blood progenitor cells, proliferative stress on infused progenitor cells during hematopoietic regeneration and associated telomere shortening ultimately result in clonal hematopoiesis and blastic transformation. Cytopenias, myelodysplasia, or cytogenetic abnormalities are common and can be transient after ASCT; therefore, only when present together, they do confirm the diagnosis of t-MN. Attempts to reduce the occurrence of t-MN should be directed toward minimizing the exposure to the identified risk factors. Although the median survival is few months to less than a year, studies have shown the promising role of allogeneic transplantation in select young t-MN patients without high-risk cytogenetics. In this review we will explain the recent findings in the field of t-MN in lymphoma patients that have implications for identifying the molecular and genetic mechanisms of leukemogenesis and discuss potential strategies to reduce the risk of t-MN in this patient population.
authors.affiliation: Division of Hematology and Oncology; Department of Internal Medicine; University of Nebraska Medical Center; Omaha, NE USA.
authors.forename: Mojtaba
authors.initials: M
authors.lastname: Akhtari
authors.affiliation: Division of Hematology and Oncology; Department of Internal Medicine; University of Nebraska Medical Center; Omaha, NE USA.
authors.forename: Vijaya Raj
authors.initials: VR
authors.lastname: Bhatt
authors.affiliation: Division of Hematology and Oncology; Department of Internal Medicine; University of Nebraska Medical Center; Omaha, NE USA.
authors.forename: Pavan Kumar
authors.initials: PK
authors.lastname: Tandra
authors.affiliation: Division of Hematology and Oncology; Department of Internal Medicine; University of Nebraska Medical Center; Omaha, NE USA.
authors.forename: Jairam
authors.initials: J
authors.lastname: Krishnamurthy
authors.affiliation: Division of Hematology and Oncology; Department of Internal Medicine; University of Nebraska Medical Center; Omaha, NE USA.
authors.forename: Heidi
authors.initials: H
authors.lastname: Horstman
authors.affiliation: Division of Hematology and Oncology; Department of Internal Medicine; University of Nebraska Medical Center; Omaha, NE USA.
authors.forename: Amy
authors.initials: A
authors.lastname: Dreessen
authors.affiliation: Division of Hematology and Oncology; Department of Internal Medicine; University of Nebraska Medical Center; Omaha, NE USA.
authors.forename: Pei Xian
authors.initials: PX
authors.lastname: Chen
authors.affiliation: Division of Hematology and Oncology; Department of Internal Medicine; University of Nebraska Medical Center; Omaha, NE USA.
authors.forename: James O
authors.initials: JO
authors.lastname: Armitage
mesh_terms: D018380:Hematopoietic Stem Cell Transplantation / Q000009:adverse effects*; D006412:Hematopoietic Stem Cells / Q000473:pathology; D006801:Humans; D007951:Leukemia, Myeloid / Q000209:etiology* / Q000235:genetics; D008223:Lymphoma / Q000235:genetics / Q000473:pathology / Q000628:therapy*; D016609:Neoplasms, Second Primary / Q000209:etiology* / Q000235:genetics; D014182:Transplantation, Autologous / Q000009:adverse effects
keywords: Hodgkin lymphoma; acute myeloid leukemia; autologous hematopoietic stem cell transplantation; myelodysplasia; non-Hodgkin lymphoma; therapy-related myeloid neoplasms
references.citation: J Clin Oncol. 1991 Sep;9(9):1575-9
references.pmid: 1875219
references.citation: J Clin Oncol. 2005 Nov 1;23(31):7994-8002
references.pmid: 16204014
references.citation: Br J Haematol. 2004 Jul;126(1):63-71
references.pmid: 15198733
references.citation: Haematologica. 2009 Sep;94(9):1250-8
references.pmid: 19586937
references.citation: Cancer Lett. 2005 Apr 18;221(1):91-5
references.pmid: 15797631
references.citation: Blood. 1998 Jun 15;91(12):4496-503
references.pmid: 9616144
references.citation: Clin Lymphoma Myeloma Leuk. 2010 Apr;10(2):129-33
references.pmid: 20371446
references.citation: Ann Rheum Dis. 2004 May;63(5):578-82
references.pmid: 15082491
references.citation: Bone Marrow Transplant. 1999 Aug;24(4):411-5
references.pmid: 10467331
references.citation: Leuk Lymphoma. 2011 Jul;52(7):1249-54
references.pmid: 21463129
references.citation: Br J Haematol. 2003 Jul;122(1):109-17
references.pmid: 12823352
references.citation: Neoplasma. 2011;58(1):1-8
references.pmid: 21067259
references.citation: Haematologica. 2000 Apr;85(4):403-9
references.pmid: 10756367
references.citation: Biomarkers. 2004 Jul-Oct;9(4-5):395-406
references.pmid: 15764301
references.citation: J Hematother Stem Cell Res. 2000 Dec;9(6):861-5
references.pmid: 11177598
references.citation: Blood. 1994 Aug 1;84(3):957-63
references.pmid: 8043877
references.citation: Haematologica. 2002 Jan;87(1):59-66
references.pmid: 11801466
references.citation: Semin Oncol. 2008 Aug;35(4):418-29
references.pmid: 18692692
references.citation: Bone Marrow Transplant. 1995 Jul;16(1):175-82
references.pmid: 7581119
references.citation: J Clin Oncol. 2008 Jul 1;26(19):3166-75
references.pmid: 18490650
references.citation: Haematologica. 2009 Apr;94(4):542-9
references.pmid: 19278968
references.citation: Cancer. 1997 Apr 15;79(8):1548-51
references.pmid: 9118037
references.citation: J Clin Oncol. 2003 Apr 1;21(7):1352-8
references.pmid: 12663726
references.citation: J Clin Invest. 2004 Jan;113(2):160-8
references.pmid: 14722605
references.citation: Blood. 2009 Sep 10;114(11):2236-43
references.pmid: 19561322
references.citation: Clin Lymphoma Myeloma Leuk. 2010 Dec;10(6):452-7
references.pmid: 21189660
references.citation: Br J Haematol. 1996 Apr;93(1):53-8
references.pmid: 8611475
references.citation: Hematology Am Soc Hematol Educ Program. 2008;:142-9
references.pmid: 19074072
references.citation: Blood. 1999 Sep 1;94(5):1814-9
references.pmid: 10477708
references.citation: Blood. 2000 Aug 15;96(4):1254-8
references.pmid: 10942365
references.citation: Bone Marrow Transplant. 1999 May;23(10):997-1002
references.pmid: 10373064
references.citation: Nucleic Acids Res. 2005 May 02;33(8):2512-20
references.pmid: 15867196
references.citation: Bone Marrow Transplant. 2000 Jul;26(2):241-2
references.pmid: 10918441
references.citation: Leukemia. 2005 Apr;19(4):644-51
references.pmid: 15716989
references.citation: J Clin Oncol. 2006 Aug 1;24(22):3604-10
references.pmid: 16877727
references.citation: Haematologica. 2009 Apr;94(4):496-506
references.pmid: 19229054
references.citation: Br J Haematol. 1999 Sep;106(4):1020-6
references.pmid: 10520006
references.citation: Lancet. 1998 Jan 17;351(9097):153-4
references.pmid: 9449864
references.citation: Blood. 1996 May 1;87(9):3633-9
references.pmid: 8611687
references.citation: J Clin Oncol. 2011 Mar 1;29(7):814-24
references.pmid: 21189387
references.citation: Blood Cancer J. 2012 Mar;2(3):e58
references.pmid: 22829253
references.citation: Blood. 1998 Sep 15;92(6):1933-40
references.pmid: 9731050
references.citation: J Clin Oncol. 1996 Feb;14(2):565-71
references.pmid: 8636772
references.citation: Blood. 1994 Jun 15;83(12):3780-6
references.pmid: 8204897
references.citation: Bone Marrow Transplant. 2003 Aug;32(3):317-24
references.pmid: 12858205
references.citation: Genes Chromosomes Cancer. 2002 Apr;33(4):413-23
references.pmid: 11921275
references.citation: J Clin Oncol. 2001 Dec 1;19(23):4314-21
references.pmid: 11731514
references.citation: Mod Pathol. 1995 Jan;8(1):59-64
references.pmid: 7731943
references.citation: Haematologica. 2006 Nov;91(11):1546-50
references.pmid: 17082012
references.citation: J Clin Oncol. 2005 Sep 20;23(27):6699-711
references.pmid: 16170178
references.citation: Ann Hematol. 2002 Jan;81(1):11-5
references.pmid: 11807629
references.citation: Mediterr J Hematol Infect Dis. 2012;4(1):e2012022
references.pmid: 22708037
references.citation: Leukemia. 2003 Nov;17(11):2101-6
references.pmid: 12931212
references.citation: Am J Clin Pathol. 1997 Oct;108(4):369-77
references.pmid: 9322588
references.citation: Leuk Lymphoma. 2012 Jan;53(1):96-102
references.pmid: 21740299
references.citation: Blood. 2000 Mar 1;95(5):1588-93
references.pmid: 10688812
references.citation: Hematol Oncol. 2011 Sep;29(3):161-3
references.pmid: 21922511
references.citation: J Clin Oncol. 1994 Dec;12(12):2535-42
references.pmid: 7989927
references.citation: Blood. 2010 Mar 4;115(9):1850-7
references.pmid: 20032503
references.citation: Bone Marrow Transplant. 2000 Feb;25(4):441-7
references.pmid: 10723589
references.citation: Br J Cancer. 1999 Oct;81(3):476-83
references.pmid: 10507773
references.citation: J Proteome Res. 2011 Jun 3;10(6):2873-81
references.pmid: 21510650
references.citation: J Clin Oncol. 2003 Mar 1;21(5):897-906
references.pmid: 12610191
references.citation: Ann Oncol. 2002;13 Suppl 1:40-3
references.pmid: 12078901
references.citation: J Clin Oncol. 2001 May 1;19(9):2472-81
references.pmid: 11331326
references.citation: Biol Blood Marrow Transplant. 2002;8(1):9-16
references.pmid: 11846355
references.citation: Leukemia. 1997 Oct;11(10):1654-60
references.pmid: 9324285
references.citation: Bone Marrow Transplant. 2013 Aug;48(8):1112-6
references.pmid: 23474805
references.citation: Br J Haematol. 2006 Jul;134(2):242-3
references.pmid: 16846486
references.citation: Genes Chromosomes Cancer. 1997 Jun;19(2):77-83
references.pmid: 9171997
references.citation: Cancer Cell. 2011 Nov 15;20(5):591-605
references.pmid: 22094254
references.citation: Leuk Lymphoma. 2009 Mar;50(3):380-6
references.pmid: 19347727
references.citation: Bone Marrow Transplant. 2012 Apr;47(4):488-93
references.pmid: 21572461
references.citation: Blood. 2003 Mar 1;101(5):2015-23
references.pmid: 12393427
references.citation: Cancer. 1982 Dec 1;50(11):2285-8
references.pmid: 7139526
references.citation: Ann Oncol. 2002 Mar;13(3):450-9
references.pmid: 11996478
references.citation: Br J Haematol. 2001 Jan;112(1):109-17
references.pmid: 11225603
references.citation: Eur J Clin Invest. 2004 Oct;34(10):690-700
references.pmid: 15473894
references.citation: J Clin Oncol. 1999 Oct;17(10):3128-35
references.pmid: 10506609
references.citation: J Clin Oncol. 2009 Feb 10;27(5):791-8
references.pmid: 19124806
references.citation: Exp Hematol. 2000 Sep;28(9):1096-104
references.pmid: 11008023
references.citation: Bone Marrow Transplant. 1998 Feb;21(4):395-9
references.pmid: 9509975
references.citation: J Clin Oncol. 1994 Dec;12(12):2527-34
references.pmid: 7989926
references.citation: Clin Transplant. 2008 Mar-Apr;22(2):191-9
references.pmid: 18339139
references.citation: J Clin Oncol. 2000 Mar;18(5):947-55
references.pmid: 10694543
references.citation: J Clin Oncol. 1989 Jan;7(1):67-74
references.pmid: 2642542
references.citation: J Clin Oncol. 2005 Apr 1;23(10):2208-14
references.pmid: 15753460
references.citation: Blood. 2000 Jun 1;95(11):3273-9
references.pmid: 10828005
references.citation: Bone Marrow Transplant. 2000 Aug;26(3):321-6
references.pmid: 10967573
references.citation: Nature. 1990 May 31;345(6274):458-60
references.pmid: 2342578