Clinical impact of measurable residual disease monitoring by ultradeep next generation sequencing in NPM1 mutated acute myeloid leukemia
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Nikhil Patkar1,*, Rohan Kodgule1,5,*, Chinmayee Kakirde1, Goutham Raval1, Prasanna Bhanshe1, Swapnali Joshi1, Shruti Chaudhary1, Y. Badrinath1, Sitaram Ghoghale1, Shraddha Kadechkar1, Syed Hasan Khizer2, Sadhana Kannan3, Dhanalaxmi Shetty4, Anant Gokarn2, Sachin Punatkar2, Hasmukh Jain2, Bhausaheb Bagal2, Hari Menon6, Manju Sengar2, Navin Khattry2, Prashant Tembhare1, Papagudi Subramanian1 and Sumeet Gujral1
1Haematopathology Laboratory, ACTREC, Tata Memorial Centre, Navi Mumbai, India
2Adult Haematolymphoid Disease Management Group, Tata Memorial Centre, Mumbai, India
3Biostatistics, ACTREC, Tata Memorial Centre, Navi Mumbai, India
4Dept of Cytogenetics, ACTREC, Tata Memorial Centre, Navi Mumbai, India
5Homi Bhabha National Institute, Training School Complex, Mumbai, India
6Haemato-Oncology, CyteCare Cancer Hospital, Bangalore, India
*These authors contributed equally to this work
Nikhil Patkar, email: firstname.lastname@example.org
Keywords: acute myeloid leukemia; NPM1; measurable residual disease; next-generation sequencing; multiparameter flow cytometry
Received: April 16, 2018 Accepted: November 16, 2018 Published: November 27, 2018
Detection of measurable residual disease (MRD) by mutation specific techniques has prognostic relevance in NPM1 mutated AML (NPM1mut 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 NPM1mut 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 NPM1mut AML.
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