Molecular disease monitoring using circulating tumor DNA in myelodysplastic syndromes

The diagnosis andmonitoring of myelodysplastic syndromes (MDSs) are highly relianton bone marrow morphology, which is associated with substantial interobserver variability. Although azacitidine is the mainstay of treatment in MDS, only half of all patients respond. Therefore, there is an urgent need for improved modalities for the diagnosis and monitoring of MDSs. The majority of MDS patients have either clonal somatic karyotypic abnormalities and/or gene mutations that aid in the diagnosis and can be used to monitor treatment response. Circulating cell-free DNA is primarily derived from hematopoietic cells, and we surmised that the malignant MDS genome would be a major contributor to cell-free DNA levels in MDS patients as a result of ineffective hematopoiesis. Through analysis of serial bone marrow and matched plasmasamples(n = 575), we demonstrate that cell- free circulating tumor DNA(ctDNA) is directly comparable to bone marrow biopsy in representing the genomichetero geneity of malignant clonesin MDS. Remarkably, wedemonstrate thatserialmonitoringof ctDNAallows concurrent tracking of both mutations and karyotypic abnormalities throughout therapy and is able to anticipate treatment failure. These data highlight the role of ctDNA as aminimally invasive molecular diseasemonitoring strategy in MDS.