title: Dynamic changes in the clonal structure of MDS and AML in response to epigenetic therapy.
abstract: Traditional response criteria in myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML) are based on bone marrow morphology and may not accurately reflect clonal tumor burden in patients treated with non-cytotoxic chemotherapy. We used next-generation sequencing of serial bone marrow samples to monitor MDS and AML tumor burden during treatment with epigenetic therapy (decitabine and panobinostat). Serial bone marrow samples (and skin as a source of normal DNA) from 25 MDS and AML patients were sequenced (exome or 285 gene panel). We observed that responders, including those in complete remission (CR), can have persistent measurable tumor burden (that is, mutations) for at least 1 year without disease progression. Using an ultrasensitive sequencing approach, we detected extremely rare mutations (equivalent to 1 heterozygous mutant cell in 2000 non-mutant cells) months to years before their expansion at disease relapse. While patients can live with persistent clonal hematopoiesis in a CR or stable disease, ultimately we find evidence that expansion of a rare subclone occurs at relapse or progression. Here we demonstrate that sequencing of serial samples provides an alternative measure of tumor burden in MDS or AML patients and augments traditional response criteria that rely on bone marrow blast percentage.
authors.affiliation: Division of Oncology, Department of Medicine, Washington University School of Medicine, St Louis, MO, USA.
authors.forename: G L
authors.initials: GL
authors.lastname: Uy
authors.affiliation: Department of Pathology and Immunology, Washington University School of Medicine, St Louis, MO, USA.
authors.forename: E J
authors.initials: EJ
authors.lastname: Duncavage
authors.affiliation: McDonnell Genome Institute, Washington University School of Medicine, St Louis, MO, USA.
authors.forename: G S
authors.initials: GS
authors.lastname: Chang
authors.affiliation: Division of Oncology, Department of Medicine, Washington University School of Medicine, St Louis, MO, USA.
authors.forename: M A
authors.initials: MA
authors.lastname: Jacoby
authors.affiliation: McDonnell Genome Institute, Washington University School of Medicine, St Louis, MO, USA.|Division of Genomics and Bioinformatics, Department of Medicine, Washington University School of Medicine, St Louis, MO, USA.
authors.forename: C A
authors.initials: CA
authors.lastname: Miller
authors.affiliation: Division of Oncology, Department of Medicine, Washington University School of Medicine, St Louis, MO, USA.
authors.forename: J
authors.initials: J
authors.lastname: Shao
authors.affiliation: Division of Oncology, Department of Medicine, Washington University School of Medicine, St Louis, MO, USA.
authors.forename: S
authors.initials: S
authors.lastname: Heath
authors.affiliation: Division of Oncology, Department of Medicine, Washington University School of Medicine, St Louis, MO, USA.
authors.forename: K
authors.initials: K
authors.lastname: Elliott
authors.affiliation: Division of Oncology, Department of Medicine, Washington University School of Medicine, St Louis, MO, USA.
authors.forename: T
authors.initials: T
authors.lastname: Reineck
authors.affiliation: McDonnell Genome Institute, Washington University School of Medicine, St Louis, MO, USA.
authors.forename: R S
authors.initials: RS
authors.lastname: Fulton
authors.affiliation: McDonnell Genome Institute, Washington University School of Medicine, St Louis, MO, USA.
authors.forename: C C
authors.initials: CC
authors.lastname: Fronick
authors.affiliation: McDonnell Genome Institute, Washington University School of Medicine, St Louis, MO, USA.
authors.forename: M
authors.initials: M
authors.lastname: O'Laughlin
authors.affiliation: Division of Oncology, Department of Medicine, Washington University School of Medicine, St Louis, MO, USA.
authors.forename: L
authors.initials: L
authors.lastname: Ganel
authors.affiliation: Division of Oncology, Department of Medicine, Washington University School of Medicine, St Louis, MO, USA.
authors.forename: C N
authors.initials: CN
authors.lastname: Abboud
authors.affiliation: Division of Oncology, Department of Medicine, Washington University School of Medicine, St Louis, MO, USA.
authors.forename: A F
authors.initials: AF
authors.lastname: Cashen
authors.affiliation: Division of Oncology, Department of Medicine, Washington University School of Medicine, St Louis, MO, USA.
authors.forename: J F
authors.initials: JF
authors.lastname: DiPersio
authors.affiliation: McDonnell Genome Institute, Washington University School of Medicine, St Louis, MO, USA.|Division of Genomics and Bioinformatics, Department of Medicine, Washington University School of Medicine, St Louis, MO, USA.
authors.forename: R K
authors.initials: RK
authors.lastname: Wilson
authors.affiliation: Division of Oncology, Department of Medicine, Washington University School of Medicine, St Louis, MO, USA.
authors.forename: D C
authors.initials: DC
authors.lastname: Link
authors.affiliation: Division of Oncology, Department of Medicine, Washington University School of Medicine, St Louis, MO, USA.
authors.forename: J S
authors.initials: JS
authors.lastname: Welch
authors.affiliation: Division of Oncology, Department of Medicine, Washington University School of Medicine, St Louis, MO, USA.
authors.forename: T J
authors.initials: TJ
authors.lastname: Ley
authors.affiliation: Massachusetts General Hospital/Harvard Medical School, Boston, MA, USA.
authors.forename: T A
authors.initials: TA
authors.lastname: Graubert
authors.affiliation: Division of Oncology, Department of Medicine, Washington University School of Medicine, St Louis, MO, USA.
authors.forename: P
authors.initials: P
authors.lastname: Westervelt
authors.affiliation: Division of Oncology, Department of Medicine, Washington University School of Medicine, St Louis, MO, USA.
authors.forename: M J
authors.initials: MJ
authors.lastname: Walter
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D001853:Bone Marrow / Q000473:pathology; D060965:Clonal Evolution / Q000235:genetics*; D044127:Epigenesis, Genetic / Q000187:drug effects*; D059472:Exome; D005260:Female; D016158:Genes, p53; D059014:High-Throughput Nucleotide Sequencing; D056572:Histone Deacetylase Inhibitors / Q000008:administration & dosage; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000175:diagnosis / Q000188:drug therapy* / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D009154:Mutation; D009190:Myelodysplastic Syndromes / Q000175:diagnosis / Q000188:drug therapy* / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide; D012074:Remission Induction; D016896:Treatment Outcome; D047368:Tumor Burden
chemical_list: D056572:Histone Deacetylase Inhibitors