Myelodysplastic syndrome

Dynamic changes in the clonal structure of MDS and AML in response to epigenetic therapy

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Traditional response criteria in myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML) are based on bone marrow morphology and may not accurately reflect clonal tumor burden in patients treated with non-cytotoxic chemotherapy. We used next-generation sequencing of serial bone marrow samples to monitor MDS and AML tumor burden during treatment with epigenetic therapy (decitabine and panobinostat). Serial bone marrow samples (and skin as a source of normal DNA) from 25 MDS and AML patients were sequenced (exome or 285 gene panel). We observed that responders, including those in complete remission (CR), can have persistent measurable tumor burden (that is, mutations) for at least 1 year without disease progression. Using an ultrasensitive sequencing approach, we detected extremely rare mutations (equivalent to 1 heterozygous mutant cell in 2000 non-mutant cells) months to years before their expansion at disease relapse. While patients can live with persistent clonal hematopoiesis in a CR or stable disease, ultimately we find evidence that expansion of a rare subclone occurs at relapse or progression. Here we demonstrate that sequencing of serial samples provides an alternative measure of tumor burden in MDS or AML patients and augments traditional response criteria that rely on bone marrow blast percentage.

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This work was supported by Novartis, NIH/NCI K23CA140707 (GLU) and a SPORE in Leukemia (P50CA171963 to DCL, EJD, JFD, JSW, TJL, TAG, and MJW), ICTS-CTSA (to EJD), Gabrielle’s Angel Foundation (to MJW), a Leukemia and Lymphoma Society Scholar Award (to MJW), and the Lottie Caroline Hardy Trust (TAG, MJW). Support for procurement of human samples was provided by an NIH/NCI grant (P01 CA101937). Technical assistance was provided by the Alvin J Siteman Cancer Center Tissue Procurement Core supported by an NCI Cancer Center Support Grant (P30CA91842).

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Correspondence to G L Uy or M J Walter.

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GLU has received compensation as a consultant for Novartis. The other authors declare no conflict of interest.

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Uy, G., Duncavage, E., Chang, G. et al. Dynamic changes in the clonal structure of MDS and AML in response to epigenetic therapy. Leukemia 31, 872–881 (2017) doi:10.1038/leu.2016.282

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