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


Authors: Stein, E. M.; Garcia-Manero, G.; Rizzieri, D. A.; Tibes, R.; Berdeja, J. G.; Savona, M. R.; Jongen-Lavrenic, M.; Altman, J. K.; Thomson, B.; Blakemore, S. J.; Daigle, S. R.; Waters, N. J.; Suttle, A. B.; Clawson, A.; Pollock, R.; Krivtsov, A.; Armstrong, S. A.; DiMartino, J.; Hedrick, E.; Löwenberg, B.; Tallman, M. S.
Article Title: The DOT1L inhibitor pinometostat reduces H3K79 methylation and has modest clinical activity in adult acute leukemia
Abstract: Pinometostat (EPZ-5676) is a first-in-class small-molecule inhibitor of the histone methyltransferase disrupter of telomeric silencing 1-like (DOT1L). In this phase 1 study, pinometostat was evaluated for safety and efficacy in adult patients with advanced acute leukemias, particularly those involving mixed lineage leukemia (MLL) gene rearrangements (MLL-r) resulting from 11q23 translocations. Fifty-one patients were enrolled into 6 doseescalation cohorts (n 5 26) and 2 expansion cohorts (n 5 25) at pinometostat doses of 54 and 90 mg/m2 per day by continuous intravenous infusion in 28-day cycles. Because a maximum tolerated dose was not established in the dose-escalation phase, the expansion doses were selected based on 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 doseproportional 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 remission at 54 mg/m2 per day by continuous intravenous infusion, demonstrating proof of concept for delivering clinically meaningful responses through targeting DOT1L using the 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. © 2018 by The American Society of Hematology.
Journal Title: Blood
Volume: 131
Issue: 24
ISSN: 0006-4971
Publisher: American Society of Hematology  
Date Published: 2018-06-14
Start Page: 2661
End Page: 2669
Language: English
DOI: 10.1182/blood-2017-12-818948
PROVIDER: scopus
PUBMED: 29724899
DOI/URL:
Notes: Article -- Export Date: 2 July 2018 -- Source: Scopus
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MSK Authors
  1. Eytan Moshe Stein
    122 Stein
  2. Martin Stuart Tallman
    443 Tallman