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

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

Blood, 2018-06, Vol.131 (24), p.2661-2669 [Periódico revisado por pares]

United States: Elsevier Inc

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Título:
The DOT1L inhibitor pinometostat reduces H3K79 methylation and has modest clinical activity in adult acute leukemia
Autor: Stein, Eytan M. ; Garcia-Manero, Guillermo ; Rizzieri, David A. ; Tibes, Raoul ; Berdeja, Jesus G. ; Savona, Michael R. ; Jongen-Lavrenic, Mojca ; Altman, Jessica K. ; Thomson, Blythe ; Blakemore, Stephen J. ; Daigle, Scott R. ; Waters, Nigel J. ; Suttle, A. Benjamin ; Clawson, Alicia ; Pollock, Roy ; Krivtsov, Andrei ; Armstrong, Scott A. ; DiMartino, Jorge ; Hedrick, Eric ; Löwenberg, Bob ; Tallman, Martin S.
Assuntos: Adult ; Aged ; Aged, 80 and over ; Antineoplastic Agents - adverse effects ; Antineoplastic Agents - therapeutic use ; Benzimidazoles - adverse effects ; Benzimidazoles - therapeutic use ; Clinical Trials and Observations ; Female ; Histone-Lysine N-Methyltransferase ; Histones - metabolism ; Humans ; Leukemia, Myeloid, Acute - drug therapy ; Leukemia, Myeloid, Acute - metabolism ; Leukemia, Myeloid, Acute - pathology ; Male ; Methylation - drug effects ; Methyltransferases - antagonists & inhibitors ; Methyltransferases - metabolism ; Middle Aged ; Young Adult
É parte de: Blood, 2018-06, Vol.131 (24), p.2661-2669
Descrição: 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 dose-escalation cohorts (n = 26) and 2 expansion cohorts (n = 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 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 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. This clinical trial is registered at www.clinicaltrials.gov as NCT01684150. •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. [Display omitted]
Editor: United States: Elsevier Inc
Idioma: Inglês

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

United States: Elsevier Inc

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