The DOT1L inhibitor pinometostat reduces H3K79 methylation and has modest clinical activity in adult acute leukemia

Eytan M. Stein, Guillermo Garcia-Manero, David A. Rizzieri, Raoul Tibes, Jesus G. Berdeja, Michael R. Savona, Mojca Jongen-Lavrenic, Jessica K. Altman, Blythe Thomson, Stephen J. Blakemore, Scott R. Daigle, Nigel J. Waters, A. Benjamin Suttle, Alicia Clawson, Roy Pollock, Andrei Krivtsov, Scott A. Armstrong, Jorge DiMartino, Eric Hedrick, Bob Löwenberg and Martin S. Tallman

Key points

  • Pinometostat demonstrates first evidence of DOT1L target inhibition and clinical responses in a subset of MLL-r advanced leukemia patients.

  • The observed safety profile of pinometostat shows potential for exploration of combination therapies in leukemia.


Pinometostat (EPZ-5676) is a first-in-class, small-molecule inhibitor of the histone methyltransferase DOT1L. In this phase 1 study, pinometostat was evaluated for safety and efficacy in adult patients with advanced acute leukemias, particularly those involving MLL rearrangements (MLL-r) resulting from 11q23 translocations. Fifty-one patients were enrolled into 6 dose escalation cohorts (n=26) and 2 expansion cohorts (n=25) at pinometostat doses of 54 and 90 mg/m2/day by continuous intravenous infusion in 28-day cycles. As a maximum tolerated dose was not established in the dose escalation phase, the expansion doses were selected based upon safety and clinical response data combined with pharmacodynamic evidence of reduction in H3K79 methylation during dose escalation. Across all dose levels, plasma pinometostat concentrations increased in an approximately dose-proportional fashion, reaching an apparent steady state by 4-8 hours after infusion, and rapidly decreased following treatment cessation. The most common adverse events, of any cause, were fatigue (39%), nausea (39%), constipation (35%), and febrile neutropenia (35%). Overall, 2 patients, both with t(11;19), experienced complete remissions at 54 mg/m2/day by continuous intravenous infusion, demonstrating proof of concept for delivering clinically meaningful responses through targeting DOT1L using single agent pinometostat in MLL-r leukemia patients. Administration of pinometostat was generally safe with the maximum tolerated dose not being reached, although efficacy as a single agent was modest. This study demonstrates the therapeutic potential for targeting DOT1L in MLL-r leukemia and lays the groundwork for future combination approaches in this patient population. This clinical trial is registered at as no. NCT01684150.

  • Submitted December 4, 2017.
  • Accepted April 13, 2018.