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Clinical impact of measurable residual disease monitoring by ultradeep next generation sequencing in NPM1 mutated acute myeloid leukemia.

Authors
  • Patkar, Nikhil1
  • Kodgule, Rohan1, 2
  • Kakirde, Chinmayee1
  • Raval, Goutham1
  • Bhanshe, Prasanna1
  • Joshi, Swapnali1
  • Chaudhary, Shruti1
  • Badrinath, Y1
  • Ghoghale, Sitaram1
  • Kadechkar, Shraddha1
  • Khizer, Syed Hasan3
  • Kannan, Sadhana4
  • Shetty, Dhanalaxmi5
  • Gokarn, Anant3
  • Punatkar, Sachin3
  • Jain, Hasmukh3
  • Bagal, Bhausaheb3
  • Menon, Hari6
  • Sengar, Manju3
  • Khattry, Navin3
  • And 3 more
  • 1 Haematopathology Laboratory, ACTREC, Tata Memorial Centre, Navi Mumbai, India. , (India)
  • 2 Homi Bhabha National Institute, Training School Complex, Mumbai, India. , (India)
  • 3 Adult Haematolymphoid Disease Management Group, Tata Memorial Centre, Mumbai, India. , (India)
  • 4 Biostatistics, ACTREC, Tata Memorial Centre, Navi Mumbai, India. , (India)
  • 5 Dept of Cytogenetics, ACTREC, Tata Memorial Centre, Navi Mumbai, India. , (India)
  • 6 Haemato-Oncology, CyteCare Cancer Hospital, Bangalore, India. , (India)
Type
Published Article
Journal
Oncotarget
Publisher
"Impact Journals, LLC "
Publication Date
Nov 27, 2018
Volume
9
Issue
93
Pages
36613–36624
Identifiers
DOI: 10.18632/oncotarget.26400
PMID: 30564301
Source
Medline
Keywords
Language
English
License
Unknown

Abstract

Detection of measurable residual disease (MRD) by mutation specific techniques has prognostic relevance in NPM1 mutated AML (NPM1 mut AML). However, the clinical utility of next generation sequencing (NGS) to detect MRD in AML remains unproven. We analysed the clinical significance of monitoring MRD using ultradeep NGS (NGS-MRD) and flow cytometry (FCM-MRD) in 137 samples obtained from 83 patients of NPM1 mut AML at the end of induction (PI) and consolidation (PC). We could monitor 12 different types of NPM1 mutations at a sensitivity of 0.001% using NGS-MRD. We demonstrated a significant correlation between NGS-MRD and real time quantitative PCR (RQ-PCR). Based upon a one log reduction between PI and PC time points we could classify patients as NGS-MRD positive (<1log reduction) or negative (>1log reduction). NGS-MRD, FCM-MRD as well as DNMT3A mutations were predictive of inferior overall survival (OS) and relapse free survival (RFS). On a multivariate analysis NGS-MRD emerged as an independent, most important prognostic factor predictive of inferior OS (hazard ratio, 3.64; 95% confidence interval [CI] 1.58 to 8.37) and RFS (hazard ratio, 4.8; 95% CI:2.24 to 10.28). We establish that DNA based NPM1 NGS MRD is a highly useful test for prediction of relapse and survival in NPM1 mut AML.

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