@article{9b08cda83bae4233a6a63ad443e4bed5,
title = "Molecular measurable residual disease testing of blood during AML cytotoxic therapy for early prediction of clinical response",
abstract = "Measurable residual disease (MRD) testing after initial chemotherapy treatment can predict relapse and survival in acute myeloid leukemia (AML). However, it has not been established if repeat molecular or genetic testing during chemotherapy can offer information regarding the chemotherapy sensitivity of the leukemic clone. Blood from 45 adult AML patients at day 1 and 4 of induction (n = 35) or salvage (n = 10) cytotoxic chemotherapy was collected for both quantitative real-time PCR (qPCR) assessment (WT1) and next generation sequencing (>500 × depth) of 49 gene regions recurrently mutated in MDS/AML. The median age of subjects was 62 (23-78); 42% achieved a complete response. WT1 was overexpressed in most patients tested but was uninformative for very early MRD assessment. A median of 4 non-synonymous variants (range 0-7) were detected by DNA sequencing of blood on day 1 of therapy [median variant allele frequency (VAF): 29%]. Only two patients had no variants detectable. All mutations remained detectable in blood on day 4 of intensive chemotherapy and remarkably the ratio of mutated to wild-type sequence was often maintained. This phenomenon was not limited to variants in DNMT3A, TET2, and ASXL1. The kinetics of NPM1 and TP53 variant burden early during chemotherapy appeared to be exceptions and exhibited consistent trends in this cohort. In summary, molecular testing of blood on day 4 of chemotherapy is not predictive of clinical response to cytotoxic induction therapy in AML. The observed stability in variant allele frequency suggests that cytotoxic therapy may have a limited therapeutic index for clones circulating in blood containing these mutations. Further validation is required to confirm the utility of monitoring NPM1 and TP53 kinetics in blood during cytotoxic therapy.",
keywords = "Acute myeloid leukemia (AML), MRD, Measurable residual disease (MRD), Next Gen Sequencing (NGS), Remission, Somatic mutations in cancer, WT1 = Wilms tumor 1",
author = "Wong, {Hong Yuen} and Sung, {Anthony D.} and Lindblad, {Katherine E.} and Sheenu Sheela and Roloff, {Gregory W.} and David Rizzieri and Meghali Goswami and Mul{\'e}, {Matthew P.} and Ramos, {Nestor R.} and Jingrong Tang and Julie Thompson and DeStefano, {Christin B.} and Kristi Romero and Dillon, {Laura W.} and Kim, {Dong Yun} and Catherine Lai and Hourigan, {Christopher S.}",
note = "Funding Information: This work was supported by the Intramural Research Program of the National Heart, Lung, and Blood Institute of, and grant 5KL2TR001115-03 from, the National Institutes of Health. We wish to acknowledge the assistance of Dr. Yuesheng Li and his team at the NHLBI Sequencing and Genomics Core, Dr. Yanqin Yang for bioinformatics support, Elena Cho, Therese Intrater, Sophie Grasmeder, Tat'Yana Worthy, and Debbie Draper for research nurse support, Dr. Qingguo Liu, Lemlem Alemu and Aasheen Qadri for laboratory technical support and to thank the clinical teams, regulatory staff, and patients at NIH and Duke. Funding Information: This work was supported by the Intramural Research Program of the National Heart, Lung, and Blood Institute of, and grant 5KL2TR001115-03 from, the National Institutes of Health. We wish to acknowledge the assistance of Dr. Yuesheng Li and his team at the NHLBI Sequencing and Genomics Core, Dr. Yanqin Yang for bioinformatics support, Elena Cho, Therese Intrater, Sophie Grasmeder, Tat{\textquoteright}Yana Worthy, and Debbie Draper for research nurse support, Dr. Qingguo Liu, Lemlem Alemu and Aasheen Qadri for laboratory technical support and to thank the clinical teams, regulatory staff, and patients at NIH and Duke. Publisher Copyright: This work is authored by Wong, Sung, Lindblad, Sheela, Roloff, Rizzieri, Goswami, Mul{\'e}, Ramos, Tang, Thompson, DeStefano, Romero, Dillon, Kim, Lai and Hourigan on behalf of the U.S. Government and, as regards Wong, Sung, Lindblad, Sheela, Roloff, Rizzieri, Goswami, Mul{\'e}, Ramos, Tang, Thompson, DeStefano, Romero, Dillon, Kim, Lai and Hourigan, and the U.S. Government, is not subject to copyright protection in the United States. Foreign and other copyrights may apply. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY).",
year = "2019",
doi = "10.3389/fonc.2018.00669",
language = "English (US)",
volume = "9",
journal = "Frontiers in Oncology",
issn = "2234-943X",
publisher = "Frontiers Media S. A.",
number = "JAN",
}