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.
Highlights
The use of high sensitivity techniques to measure residual leukemic burden in patients achieving a complete remission by cytomorphological criteria is increasingly considered part of the standard of care for acute myeloid leukemia (AML) [1,2,3,4]
Acute myeloid leukemia (AML) offers a unique opportunity to study the validity of bloodbased assessments of residual tumor, as both the primary site of disease and blood are repeatedly sampled as part of the clinical standard of care
It is increasingly recognized that blood, except in cases of leukopenia or low circulating blast count, may substitute for marrow examination in some circumstances for morphology, cytogenetics, and molecular testing in AML patients [33,34,35]
Summary
The use of high sensitivity techniques to measure residual leukemic burden in patients achieving a complete remission by cytomorphological criteria is increasingly considered part of the standard of care for acute myeloid leukemia (AML) [1,2,3,4]. The utility of WT1 testing is limited to a subset of AML MRD cases and more recently the quantitative assessment by DNA sequencing of variants in genes known to be recurrently mutated in myeloid malignancies has been proposed as a more broadly applicable measure of AML MRD [6, 9, 14]. We used both these molecular techniques to determine if early assessment of blood from AML patients during the first 4 days of intensive cytotoxic therapy can predict subsequent clinical response
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