KMT2D-mutated cells were more sensitive to decitabine (IC50, Mean ± SEM, 22.2 ± 3.9 vs. 73.6 ± 25.4 μM; p = 0.029; Figure S4C), reduced sensitivity to ibrutinib (IC50 5.3 ± 0.9 vs. 2.9 ± 0.9 μM; p = 0.095) and similar sensitivity to chidamide (IC50 0.6 ± 0.11 vs. 6.9 ± 6.1 μM; p = 0.218) compared with KMT2D wild-type cells. Ibrutinib and decitabine were synergistic (Fig. 2C; p < 0.05) suggesting decitabine increases ibrutinib sensitivity in KMT2D-mutated CLL cells. We calculated a combination index (CI) and confirmed ibrutinib and decitabine have strong synergistic cytotoxicity (Fig. S4D).