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Quantification of measurable residual disease using duplex sequencing in adults with acute myeloid leukemia.

Authors
  • Dillon, Laura W1
  • Higgins, Jake2
  • Nasif, Hassan3
  • Othus, Megan3
  • Beppu, Lan4
  • Smith, Thomas H2
  • Schmidt, Elizabeth2
  • Valentine Iii, Charles C2
  • Salk, Jesse J2
  • Wood, Brent L5
  • Erba, Harry P6
  • Radich, Jerald P7
  • Hourigan, Christopher S8
  • 1 Laboratory of Myeloid Malignancies, Hematology Branch, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD. , (Mali)
  • 2 TwinStrand Biosciences, Seattle, WA.
  • 3 Public Health Sciences Division, Fred Hutchinson Cancer Center, Seattle, WA.
  • 4 Clinical Research Division, Fred Hutchinson Cancer Center, Seattle, WA.
  • 5 Dept. of Pathology and Laboratory Medicine, Children's Hospital Los Angeles, Los Angeles, CA.
  • 6 Duke University School of Medicine, Durham, NC.
  • 7 Clinical Research Division, Fred Hutchinson Cancer Center, Seattle, WA; Division of Medical Oncology, Department of Medicine, University of Washington, Seattle, WA.
  • 8 Laboratory of Myeloid Malignancies, Hematology Branch, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD; Myeloid Malignancies Program, National Institutes of Health, Bethesda, MD. [email protected]. , (Mali)
Type
Published Article
Journal
Haematologica
Publisher
Ferrata Storti Foundation
Publication Date
Feb 01, 2024
Volume
109
Issue
2
Pages
401–410
Identifiers
DOI: 10.3324/haematol.2023.283520
PMID: 37534515
Source
Medline
Language
English
License
Unknown

Abstract

The presence of measurable residual disease (MRD) is strongly associated with treatment outcomes in acute myeloid leukemia (AML). Despite the correlation with clinical outcomes, MRD assessment has yet to be standardized or routinely incorporated into clinical trials and discrepancies have been observed between different techniques for MRD assessment. In 62 patients with AML, aged 18-60 years, in first complete remission after intensive induction therapy on the randomized phase III SWOG-S0106 clinical trial (clinicaltrials gov. Identifier: NCT00085709), MRD detection by centralized, high-quality multiparametric flow cytometry was compared with a 29-gene panel utilizing duplex sequencing (DS), an ultrasensitive next-generation sequencing method that generates double-stranded consensus sequences to reduce false positive errors. MRD as defined by DS was observed in 22 (35%) patients and was strongly associated with higher rates of relapse (68% vs. 13%; hazard ratio [HR] =8.8; 95% confidence interval [CI]: 3.2-24.5; P<0.001) and decreased survival (32% vs. 82%; HR=5.6; 95% CI: 2.3-13.8; P<0.001) at 5 years. DS MRD strongly outperformed multiparametric flow cytometry MRD, which was observed in ten (16%) patients and marginally associated with higher rates of relapse (50% vs. 30%; HR=2.4; 95% CI: 0.9-6.7; P=0.087) and decreased survival (40% vs. 68%; HR=2.5; 95% CI: 1.0-6.3; P=0.059) at 5 years. Furthermore, the prognostic significance of DS MRD status at the time of remission for subsequent relapse was similar on both randomized arms of the trial. These findings suggest that next-generation sequencing-based AML MRD testing is a powerful tool that could be developed for use in patient management and for early anti-leukemic treatment assessment in clinical trials.

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