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. 2018 Nov 27;9(93):36613-36624.
doi: 10.18632/oncotarget.26400.

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

Nikhil Patkar  1 , Rohan Kodgule  1   2 , Chinmayee Kakirde  1 , Goutham Raval  1 , Prasanna Bhanshe  1 , Swapnali Joshi  1 , Shruti Chaudhary  1 , Y Badrinath  1 , Sitaram Ghoghale  1 , Shraddha Kadechkar  1 , Syed Hasan Khizer  3 , Sadhana Kannan  4 , Dhanalaxmi Shetty  5 , Anant Gokarn  3 , Sachin Punatkar  3 , Hasmukh Jain  3 , Bhausaheb Bagal  3 , Hari Menon  6 , Manju Sengar  3 , Navin Khattry  3 , Prashant Tembhare  1 , Papagudi Subramanian  1 , Sumeet Gujral  1
Affiliations

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

Nikhil Patkar et al. Oncotarget. .

Erratum in

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.

Keywords: NPM1; acute myeloid leukemia; measurable residual disease; multiparameter flow cytometry; next-generation sequencing.

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Conflict of interest statement

CONFLICTS OF INTEREST The authors have no commercial or other relationships that could contribute a conflict of interest.

Figures

Figure 1
Figure 1. Types and frequencies of NPM1 mutations
Figure 2
Figure 2. Kaplan-Meier graphs of NGS-MRD and presence of DNMT3A mutation
Plots (A) and (B) demonstrate that the presence of NGS MRD is highly predictive of inferior OS and RFS. The plots (C) & (D) show that presence of DNMT3A mutation is predictive of the inferior OS (C) and likely RFS (D).
Figure 3
Figure 3
Plot (A) and (B) represent the trends of VAF during treatment for DNMT3A and NPM1 in dual mutated patients. Plots (C) and (D) show Kaplan-Meier graphs of FCM-MRD, depicting that FCM-MRD at the end of induction is predictive of inferior OS (C) and RFS (D).
See this image and copyright information in PMC

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