title: Quantitative fragment analysis of FLT3-ITD efficiently identifying poor prognostic group with high mutant allele burden or long ITD length.
abstract: Mutation of the fms-like tyrosine kinase 3-internal tandem duplication (FLT3-ITD), which is one of the most frequent genetic alterations, strongly contributes to an increased risk of treatment failure and to poor prognosis. In this study, we established quantitative fragment analysis of FLT3-ITD simultaneously measuring mutant allele burden and length, verified the analytical performance and evaluated the clinical significance in adult acute myeloid leukemia (AML) patients. FLT3-ITD was detected in 73 of 363 adult AML patients (20.1%) and high mutant allelic burden (⩾50%, n=13) and long ITD length (⩾70 base pairs, n=15) were significantly associated with inferior overall survival (OS; P=0.002 and 0.005, respectively) and event-free survival (EFS; P=0.004 and 0.007, respectively). FLT3-ITD poor prognostic group was identified as patients with high allele burden or long ITD length (n=24), which revealed significant adverse clinical outcome for both OS (P<0.001) and EFS (P<0.001). In cytogenetically normal AML, even FLT3-ITD low allele burden and short length was associated with poorer OS (P=0.037) and EFS (P=0.044) than wild type, whose influence was overcome when hematopoietic stem cell transplantation was performed. In minimal residual disease monitoring, FLT3-ITD negativity after consolidation therapy was a valuable predictor of better OS (P<0.001) and EFS (P<0.001). FLT3-ITD poor prognostic group with high mutant allele burden or long ITD length is efficiently identified by quantitative fragment analysis.
authors.affiliation: Department of Laboratory Medicine, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea.|Catholic Genetic Laboratory Center, College of Medicine, Seoul St Mary's Hospital, The Catholic University of Korea, Seoul, Republic of Korea.
authors.forename: Y
authors.initials: Y
authors.lastname: Kim
authors.affiliation: Catholic Genetic Laboratory Center, College of Medicine, Seoul St Mary's Hospital, The Catholic University of Korea, Seoul, Republic of Korea.
authors.forename: G D
authors.initials: GD
authors.lastname: Lee
authors.affiliation: Department of Laboratory Medicine, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea.|Catholic Genetic Laboratory Center, College of Medicine, Seoul St Mary's Hospital, The Catholic University of Korea, Seoul, Republic of Korea.
authors.forename: J
authors.initials: J
authors.lastname: Park
authors.affiliation: Cancer Research Institute, Division of Hematology, Department of Internal Medicine, Catholic Blood and Marrow Transplantation Center, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea.
authors.forename: J-H
authors.initials: JH
authors.lastname: Yoon
authors.affiliation: Cancer Research Institute, Division of Hematology, Department of Internal Medicine, Catholic Blood and Marrow Transplantation Center, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea.
authors.forename: H-J
authors.initials: HJ
authors.lastname: Kim
authors.affiliation: Cancer Research Institute, Division of Hematology, Department of Internal Medicine, Catholic Blood and Marrow Transplantation Center, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea.
authors.forename: W-S
authors.initials: WS
authors.lastname: Min
authors.affiliation: Department of Laboratory Medicine, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea.|Catholic Genetic Laboratory Center, College of Medicine, Seoul St Mary's Hospital, The Catholic University of Korea, Seoul, Republic of Korea.
authors.forename: M
authors.initials: M
authors.lastname: Kim
mesh_terms: D000328:Adult; D005260:Female; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000175:diagnosis / Q000188:drug therapy* / Q000235:genetics; D008297:Male; D008875:Middle Aged; D009154:Mutation; D016133:Polymerase Chain Reaction; D011379:Prognosis; D051941:fms-Like Tyrosine Kinase 3 / Q000235:genetics*
chemical_list: C497970:FLT3 protein, human; D051941:fms-Like Tyrosine Kinase 3
references.citation: J Mol Diagn. 2003 May;5(2):96-102
references.pmid: 12707374
references.citation: Blood. 2003 Oct 1;102(7):2387-94
references.pmid: 12816873
references.citation: Bone Marrow Transplant. 2004 Aug;34(3):215-20
references.pmid: 15170169
references.citation: J Clin Oncol. 1990 May;8(5):813-9
references.pmid: 2185339
references.citation: Semin Hematol. 1996 Oct;33(4 Suppl 3):24-9
references.pmid: 8916313
references.citation: Leukemia. 2005 Jan;19(1):141-3
references.pmid: 15510198
references.citation: Blood. 2006 May 1;107(9):3724-6
references.pmid: 16368883
references.citation: Blood. 2008 Mar 1;111(5):2776-84
references.pmid: 17957027
references.citation: N Engl J Med. 2008 May 1;358(18):1909-18
references.pmid: 18450602
references.citation: Blood. 2008 May 15;111(10):4930-3
references.pmid: 18305215
references.citation: Blood. 2010 Jan 21;115(3):453-74
references.pmid: 19880497
references.citation: Blood. 2011 Jun 30;117(26):6987-90
references.pmid: 21586749
references.citation: Leuk Res. 2012 Mar;36(3):316-23
references.pmid: 22129478
references.citation: J Clin Oncol. 2012 Mar 1;30(7):735-41
references.pmid: 22291086
references.citation: Haematologica. 2012 Aug;97(8):1242-5
references.pmid: 22532519
references.citation: Cancer. 2012 Dec 15;118(24):6110-7
references.pmid: 22736495
references.citation: Diagn Mol Pathol. 2013 Mar;22(1):1-9
references.pmid: 23370424
references.citation: Am J Hematol. 2013 Apr;88(4):318-27
references.pmid: 23526416
references.citation: Blood. 2013 Apr 4;121(14):2734-8
references.pmid: 23377436
references.citation: J Natl Compr Canc Netw. 2013 Sep 1;11(9):1047-55
references.pmid: 24029121
references.citation: Am J Hematol. 2013 Dec;88(12):1074-81
references.pmid: 23983148
references.citation: Hematology Am Soc Hematol Educ Program. 2013;2013:220-6
references.pmid: 24319184
references.citation: Biol Blood Marrow Transplant. 2014 Dec;20(12):1989-95
references.pmid: 25240816
references.citation: Biol Blood Marrow Transplant. 2015 Jan;21(1):119-29
references.pmid: 25300871
references.citation: Blood. 2002 Oct 1;100(7):2393-8
references.pmid: 12239147
references.citation: Blood. 2001 Jan 1;97(1):89-94
references.pmid: 11133746
references.citation: Cancer Res. 2001 Oct 1;61(19):7233-9
references.pmid: 11585760
references.citation: Leuk Res. 2001 Dec;25(12):1085-8
references.pmid: 11684280
references.citation: Blood. 2002 Jun 15;99(12):4326-35
references.pmid: 12036858
references.citation: Blood. 2002 Jul 1;100(1):59-66
references.pmid: 12070009