Sustained global H3K79me2 inhibition is dependent on uninterrupted DOT1L inhibition. (A) Global H3K79me2 inhibition in bulk PBMCs representing patients from all dosing cohorts vs the mean Css. Percent inhibition was calculated by taking the cycle 1 time point with maximum H3K79me2 inhibition relative to a pretreatment baseline sample. Decreases in H3K79me2 levels were exhibited by all patients who could be reliably measured, but the magnitude of inhibition was only weakly proportional to Css. (B) Inhibition of H3K79me2 levels in bulk PBMCs collected from patients at days 15 and 28 relative to preinfusion baseline controls. Inhibition levels from patients treated continuously for 21 days, followed by a 7-day-off period, were compared with those from patients treated for the full 28-day treatment cycle. After initial decreases with both regimens, global H3K79me2 levels recovered toward baseline in patients receiving the 7-day break in treatment compared with those patients treated continuously for 28 days (P = .005, Mann-Whitney 2-tailed Student t test). Consistent with rapid drug clearance, continuous treatment with pinometostat was needed to sustain H3K79me2 inhibition. Data are mean ± SEM.
