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Subclonal patterns in follow-up of acute myeloid leukemia combining whole exome sequencing and ultrasensitive IBSAFE digital droplet analysis

Pettersson, Louise LU orcid ; Chen, Yilun LU ; George, Anthony M. LU ; Rigo, Robert LU ; Lazarevic, Vladimir LU ; Juliusson, Gunnar LU ; Saal, Lao H. LU orcid and Ehinger, Mats LU (2020) In Leukemia and Lymphoma 61(9). p.2168-2179
Abstract

We studied mutation kinetics in ten relapsing and four non-relapsing patients with acute myeloid leukemia by whole exome sequencing at diagnosis to identify leukemia-specific mutations and monitored selected mutations at multiple time-points using IBSAFE droplet digital PCR. Five to nine selected mutations could identify and track leukemic clones prior to clinical relapse in 10/10 patients at the time-points where measurable residual disease was negative by multicolor flow cytometry. In the non-relapsing patients, the load of mutations gradually declined in response to different therapeutic strategies. Three distinct patterns of relapse were observed: (1) one or more different clones with all monitored mutations reappearing at relapse;... (More)

We studied mutation kinetics in ten relapsing and four non-relapsing patients with acute myeloid leukemia by whole exome sequencing at diagnosis to identify leukemia-specific mutations and monitored selected mutations at multiple time-points using IBSAFE droplet digital PCR. Five to nine selected mutations could identify and track leukemic clones prior to clinical relapse in 10/10 patients at the time-points where measurable residual disease was negative by multicolor flow cytometry. In the non-relapsing patients, the load of mutations gradually declined in response to different therapeutic strategies. Three distinct patterns of relapse were observed: (1) one or more different clones with all monitored mutations reappearing at relapse; (2) one or more separate clones of which one prevailed at relapse; and (3) persistent clonal hematopoiesis with high variant allele frequency and most mutations present at relapse. These pilot results demonstrate that IBSAFE analyses detect leukemic clones missed by flow cytometry with possible clinical implications.Highlights The IBSAFE ddPCR MRD method seems applicable on virtually all newly diagnosed AML patients and was more sensitive than flow cytometry. Monitoring a few mutations captured the kinetics of the evolving recurrent leukemia. NPM1-mutation alone may not be a reliable MRD-marker.

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author
; ; ; ; ; ; and
organization
publishing date
type
Contribution to journal
publication status
published
subject
keywords
AML, clonal patterns, ddPCR, genetic evolution, MRD, subclones
in
Leukemia and Lymphoma
volume
61
issue
9
pages
12 pages
publisher
Taylor & Francis
external identifiers
  • pmid:32425124
  • scopus:85085337133
ISSN
1042-8194
DOI
10.1080/10428194.2020.1755855
project
Translational development and clinical applications of circulating tumor DNA for patient stratification, therapy guidance, and disease monitoring
language
English
LU publication?
yes
id
f09e59f7-e118-4bb4-a547-a6800b81baf8
date added to LUP
2020-06-04 06:27:43
date last changed
2024-04-03 08:03:01
@article{f09e59f7-e118-4bb4-a547-a6800b81baf8,
  abstract     = {{<p>We studied mutation kinetics in ten relapsing and four non-relapsing patients with acute myeloid leukemia by whole exome sequencing at diagnosis to identify leukemia-specific mutations and monitored selected mutations at multiple time-points using IBSAFE droplet digital PCR. Five to nine selected mutations could identify and track leukemic clones prior to clinical relapse in 10/10 patients at the time-points where measurable residual disease was negative by multicolor flow cytometry. In the non-relapsing patients, the load of mutations gradually declined in response to different therapeutic strategies. Three distinct patterns of relapse were observed: (1) one or more different clones with all monitored mutations reappearing at relapse; (2) one or more separate clones of which one prevailed at relapse; and (3) persistent clonal hematopoiesis with high variant allele frequency and most mutations present at relapse. These pilot results demonstrate that IBSAFE analyses detect leukemic clones missed by flow cytometry with possible clinical implications.Highlights The IBSAFE ddPCR MRD method seems applicable on virtually all newly diagnosed AML patients and was more sensitive than flow cytometry. Monitoring a few mutations captured the kinetics of the evolving recurrent leukemia. NPM1-mutation alone may not be a reliable MRD-marker.</p>}},
  author       = {{Pettersson, Louise and Chen, Yilun and George, Anthony M. and Rigo, Robert and Lazarevic, Vladimir and Juliusson, Gunnar and Saal, Lao H. and Ehinger, Mats}},
  issn         = {{1042-8194}},
  keywords     = {{AML; clonal patterns; ddPCR; genetic evolution; MRD; subclones}},
  language     = {{eng}},
  month        = {{05}},
  number       = {{9}},
  pages        = {{2168--2179}},
  publisher    = {{Taylor & Francis}},
  series       = {{Leukemia and Lymphoma}},
  title        = {{Subclonal patterns in follow-up of acute myeloid leukemia combining whole exome sequencing and ultrasensitive IBSAFE digital droplet analysis}},
  url          = {{http://dx.doi.org/10.1080/10428194.2020.1755855}},
  doi          = {{10.1080/10428194.2020.1755855}},
  volume       = {{61}},
  year         = {{2020}},
}