title: Strikingly different molecular relapse kinetics in NPM1c, PML-RARA, RUNX1-RUNX1T1, and CBFB-MYH11 acute myeloid leukemias.
abstract: Early relapse detection in acute myeloid leukemia is possible using standardized real-time quantitative polymerase chain reaction (RQ-PCR) protocols. However, optimal sampling intervals have not been defined and are likely to vary according to the underlying molecular lesion. In 74 patients experiencing hematologic relapse and harboring aberrations amenable to RQ-PCR (mutated NPM1 [designated NPM1c], PML-RARA, RUNX1-RUNX1T1, and CBFB-MYH11), we observed strikingly different relapse kinetics. The median doubling time of the CBFB-MYH11 leukemic clone was significantly longer (36 days) than that of clones harboring other markers (RUNX1-RUNX1T1, 14 days; PML-RARA, 12 days; and NPM1c, 11 days; P < .001). Furthermore, we used a mathematical model to determine frequency of relapse detection and median time from detection of minimal residual disease to hematologic relapse as a function of sampling interval length. For example, to obtain a relapse detection fraction of 90% and a median time of 60 days, blood sampling every sixth month should be performed for CBFB-MYH11 leukemias. By contrast, in NPM1c(+)/FLT3-ITD(-), NPM1c(+)/FLT3-ITD(+), RUNX1-RUNX1T1, and PML-RARA leukemias, bone marrow sampling is necessary every sixth, fourth, and fourth and second month, respectively. These data carry important implications for the development of optimal RQ-PCR monitoring schedules suitable for evaluation of minimal residual disease-directed therapies in future clinical trials.
authors.affiliation: Laboratory of Immunohematology, Department of Hematology, Aarhus University Hospital, Aarhus, Denmark.
authors.forename: Hans Beier
authors.initials: HB
authors.lastname: Ommen
authors.forename: Susanne
authors.initials: S
authors.lastname: Schnittger
authors.forename: Jelena V
authors.initials: JV
authors.lastname: Jovanovic
authors.forename: Ingrid Beier
authors.initials: IB
authors.lastname: Ommen
authors.forename: Henrik
authors.initials: H
authors.lastname: Hasle
authors.forename: Mette
authors.initials: M
authors.lastname: Østergaard
authors.forename: David
authors.initials: D
authors.lastname: Grimwade
authors.forename: Peter
authors.initials: P
authors.lastname: Hokland
mesh_terms: D014408:Biomarkers, Tumor / Q000096:biosynthesis* / Q000235:genetics; D001853:Bone Marrow / Q000378:metabolism; D050676:Core Binding Factor Alpha 2 Subunit / Q000096:biosynthesis* / Q000235:genetics; D050658:Core Binding Factor beta Subunit / Q000096:biosynthesis* / Q000235:genetics; D005260:Female; D015973:Gene Expression Regulation, Leukemic; D006801:Humans; D007700:Kinetics; D015470:Leukemia, Myeloid, Acute / Q000235:genetics / Q000378:metabolism* / Q000628:therapy; D008297:Male; D008991:Monitoring, Physiologic / Q000379:methods; D018995:Myosin Heavy Chains / Q000096:biosynthesis* / Q000235:genetics; D018365:Neoplasm, Residual; D009687:Nuclear Proteins / Q000096:biosynthesis* / Q000235:genetics; D000090243:Nucleophosmin; D015514:Oncogene Proteins, Fusion / Q000096:biosynthesis* / Q000235:genetics; D000075142:RUNX1 Translocation Partner 1 Protein; D012008:Recurrence; D012189:Retrospective Studies; D013997:Time Factors
chemical_list: C107844:AML1-ETO fusion protein, human; D014408:Biomarkers, Tumor; C493692:CBFB protein, human; D050676:Core Binding Factor Alpha 2 Subunit; D050658:Core Binding Factor beta Subunit; C509903:MYH11 protein, human; C000716967:NPM1 protein, human; D009687:Nuclear Proteins; D015514:Oncogene Proteins, Fusion; D000075142:RUNX1 Translocation Partner 1 Protein; C093476:promyelocytic leukemia-retinoic acid receptor alpha fusion oncoprotein; D000090243:Nucleophosmin; D018995:Myosin Heavy Chains