Detection of minimal residual disease in circulating cell-free DNA in acute myeloid leukemia
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Springer Nature
Abstract
Minimal/measurable residual disease (MRD) in Acute Myeloid Leukemia (AML) is defined as persistent
leukemic cells below cytomorphological detection threshold. Next generation sequencing (NGS) of
circulating cell-free DNA (cfDNA) to profile cancer-associated mutations has been shown to allow for
quantification of disease burden in solid tumors and has also been suggested to enable minimally
invasive follow-up of AML patients. In this pilot study we investigated the technical sensitivity and
potential prognostic implications of cfDNA-based MRD monitoring in AML after allogeneic stem
cell transplantation in comparison to donor chimerism analysis or, respectively, after consolidation
chemotherapy. 75 cfDNA samples from 29 patients were analyzed by targeted NGS using a
commercially available 10- or 37-gene hotspot panel (VariantPlex Core AML or Core Myeloid panel,
ArcherDx). Patients’ leukemias exhibited 1–7 mutations as determined by routine diagnostics. Only
previously identified mutations were considered for MRD evaluation. cfDNA was isolated in sufficient
amounts for NGS from all samples (total yield 24 ng–5.2 μg). The sensitivity of variant detection
increased with higher overall read count and higher mutation-specific coverage (variant allele
frequency [VAF] range 0.08–100%). At least one previously known mutation was identified in 32/55
samples (58%, VAF 0.08–78.04%) which were taken during hematological complete remission (CR)
in both patients after allogeneic stem cell transplantation (aHSCT) and patients after consolidation
chemotherapy. In patients after aHSCT (n = 25), at least one previously known mutation was detected
in 16/29 cfDNA samples (55.1%, VAF 0.08–6.7%) obtained when donor chimerism was ≥ 90% and in
6/6 samples (100%, VAF: 0.88–63.77%) with reduced donor chimerism. Probability of progressionfree
survival 17 months after aHSCT in patients with donor chimerism ≥ 90% but mutation-positive
cfDNA was 64% compared to 100% in patients with undetectable MRD. In patients after consolidation
chemotherapy, cfDNA was positive in all samples taken during CR (n = 4; VAF 0.26–29.84%) and non-CR
(n = 4; VAF 8.46–100%). Our results indicate that NGS of cfDNA is suitable for MRD monitoring in AML
and offers higher sensitivity for detecting residual leukemic cells than chimerism analysis in patients
after aHSCT. Further studies are needed to evaluate clinical relevance of MRD status as determined in
cfDNA.
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