The DOT1L inhibitor pinometostat reduces H3K79 methylation and has modest clinical activity in adult acute leukemia
The DOT1L inhibitor pinometostat reduces H3K79 methylation and has modest clinical activity in adult acute leukemia
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DOI：
10.1182/blood-2017-12-818948
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发表时间：
2018-06-14
期刊：
影响因子：
20.3
通讯作者：
Tallman, Martin S.
中科院分区：
文献类型：
--
作者：
Stein, Eytan M.;Garcia-Manero, Guillermo;Tallman, Martin S.
Pinometostat（EPZ-5676）是一类端粒沉默1样组蛋白甲基转移酶破坏物（DOT 1 L）的小分子抑制剂。在这项I期研究中，评价了pinometostat在晚期急性白血病成人患者中的安全性和疗效，特别是涉及11 q23易位导致的混合系白血病（MLL）基因重排（MLL-r）的患者。51例患者入组6个剂量递增队列（n = 26）和2个扩展队列（n = 25），pinometostat剂量为54和90 mg/m2/天，连续静脉输注，28天为一个周期。由于在剂量递增阶段未确定最大耐受剂量，因此基于安全性和临床应答数据以及剂量递增期间H3 K79甲基化降低的药效学证据选择扩展剂量。在所有剂量水平下，血浆pinometostat浓度以近似与剂量成比例的方式增加，在输注后4-8小时达到表观稳态，并在治疗停止后迅速降低。最常见的任何原因的不良事件是疲劳（39%）、恶心（39%）、便秘（35%）和发热性中性粒细胞减少症（35%）。总体而言，2例患者（均为t（11;19））通过持续静脉输注每天54 mg/m2达到完全缓解，证明了通过使用单药pinometostat靶向DOT 1 L在MLL-r白血病患者中提供有临床意义的反应的概念证据。pinometostat的给药通常是安全的，未达到最大耐受剂量，但作为单一药物的疗效是中等的。这项研究证明了靶向DOT 1 L在MLL-r白血病中的治疗潜力，并为该患者人群未来的联合治疗奠定了基础。
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/m(2) 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/m(2) 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.