Subclonal emergence of polycythemia vera, chronic myelomonocytic leukemia, and chronic myeloid leukemia.

The present longitudinal study reports a unique patient followed over almost three decades who sequentially developed polycythemia vera, chronic myelomonocytic leukemia, and chronic myeloid leukemia. The patient received successive hydroxyurea, ruxolitinib, and a combination of ruxolitinib and nilotinib. The clonal architecture dynamic was reconstructed using targeted high throughput asymmetric capture sequencing, allowing detection and quantification of mutations in 43 myeloid genes and BCR::ABL1 fusion in multiple bone marrow or peripheral blood samples and in single cell-derived colonies obtained from bone marrow colony-forming cell assays. This analysis has uncovered an unexpected subclonal link between three myeloid malignancies, all stemming from a DNMT3A/TET2 double mutant clone. Over a period of more than 30 years, this clone underwent major telomere shortening. However, a striking sustained major molecular response of the terminal dominant clone carrying all driver mutations was achieved by combination therapy with nilotinib and ruxolitinib. The remaining clone driving both polycythemia and chronic myelomonocytic leukemia remained unaffected and evolved to myelofibrosis and proliferative CMML.