AUTHOR=Wong Hong Yuen , Sung Anthony D. , Lindblad Katherine E. , Sheela Sheenu , Roloff Gregory W. , Rizzieri David , Goswami Meghali , Mulé Matthew P. , Ramos Nestor R. , Tang Jingrong , Thompson Julie , DeStefano Christin B. , Romero Kristi , Dillon Laura W. , Kim Dong-Yun , Lai Catherine , Hourigan Christopher S. 

TITLE=Molecular Measurable Residual Disease Testing of Blood During AML Cytotoxic Therapy for Early Prediction of Clinical Response

JOURNAL=Frontiers in Oncology

VOLUME=8

YEAR=2019

URL=https://www.frontiersin.org/journals/oncology/articles/10.3389/fonc.2018.00669

DOI=10.3389/fonc.2018.00669

ISSN=2234-943X

ABSTRACT=<p>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 (<italic>n</italic> = 35) or salvage (<italic>n</italic> = 10) cytotoxic chemotherapy was collected for both quantitative real-time PCR (qPCR) assessment (<italic>WT1</italic>) and next generation sequencing (&gt;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. <italic>WT1</italic> 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 <italic>DNMT3A, TET2</italic>, and <italic>ASXL1</italic>. The kinetics of <italic>NPM1</italic> and <italic>TP53</italic> 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 <italic>NPM1</italic> and <italic>TP53</italic> kinetics in blood during cytotoxic therapy.</p>