Phase II trial of cytarabine and mitoxantrone with devimistat in acute myeloid leukemia.
Phase II trial of cytarabine and mitoxantrone with devimistat in acute myeloid leukemia.
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阿糖胞苷和米托蒽醌联合迪米司他治疗急性髓性白血病的II期试验。
DOI：
10.1038/s41467-022-29039-4
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发表时间：
2022-03-30
影响因子：
16.6
通讯作者：
Pardee TS
中科院分区：
文献类型：
--
作者：
Anderson R;Miller LD;Isom S;Chou JW;Pladna KM;Schramm NJ;Ellis LR;Howard DS;Bhave RR;Manuel M;Dralle S;Lyerly S;Powell BL;Pardee TS
德维米特是一种三氯乙酸周期抑制剂。先前完成的一项联合阿糖胞苷和米托蒽醌治疗复发或难治性急性髓细胞白血病患者的第一阶段研究显示，有希望的应答率。在这里，我们报告了一项单一ARM II期研究(NCT02484391)的结果。在联合大剂量阿糖胞苷和米托蒽醌诱导和巩固后，维持偏差的可行性没有达到初步结果，因为21名应答者中只有2人使用了维持偏差。次要疗效(CR、 + 、CRI)和中位生存期分别为44%(21/48)和5.9月。没有观察到意外的毒性。一项对I期和II期数据集的计划外后继分析表明，在年龄较大但不是较年轻的患者中存在剂量反应的趋势。来自患者样本的RNA测序数据显示，线粒体基因集随着年龄的增长而下降。Devimisat损害了ATP的合成，我们发现线粒体膜电位与化疗敏感性之间存在相关性。德维米特还可诱导线粒体产生与吞丝分裂相一致的氧自由基和转化率。我们发现，药物或遗传抑制线粒体分裂或自噬使细胞对偏差敏感。这些发现表明，与年龄相关的线粒体质量和自噬能力的下降可能与对DEVERMISAT的反应有关，然而，这需要通过适当的试验设计在更大的队列中得到证实。阿糖胞苷和米托蒽醌与三羧酸循环抑制剂devimisat联合应用于复发或难治性急性髓系白血病(AML)的I期临床试验已有报道。在这里，作者报告了第二阶段研究的结果，分析了两个阶段的样本，并进行了临床前分析，表明线粒体分裂或自噬抑制使AML细胞对偏差敏感。
Devimistat is a TCA cycle inhibitor. A previously completed phase I study of devimistat in combination with cytarabine and mitoxantrone in patients with relapsed or refractory AML showed promising response rates. Here we report the results of a single arm phase II study (NCT02484391). The primary outcome of feasibility of maintenance devimistat following induction and consolidation with devimistat in combination with high dose cytarabine and mitoxantrone was not met, as maintenance devimistat was only administered in 2 of 21 responders. The secondary outcomes of response (CR + CRi) and median survival were 44% (21/48) and 5.9 months respectively. There were no unexpected toxicities observed. An unplanned, post-hoc analysis of the phase I and II datasets suggests a trend of a dose response in older but not younger patients. RNA sequencing data from patient samples reveals an age-related decline in mitochondrial gene sets. Devimistat impairs ATP synthesis and we find a correlation between mitochondrial membrane potential and sensitivity to chemotherapy. Devimistat also induces mitochondrial reactive oxygen species and turnover consistent with mitophagy. We find that pharmacological or genetic inhibition of mitochondrial fission or autophagy sensitizes cells to devimistat. These findings suggest that an age related decline in mitochondrial quality and autophagy may be associated with response to devimistat however this needs to be confirmed in larger cohorts with proper trial design. Combining cytarabine and mitoxantrone with the tricarboxylic acid cycle inhibitor devimistat has been reported in a phase I clinical trial with relapsed or refractory acute myeloid leukaemia (AML). Here, the authors report the outcomes of a phase II study, analyse samples from both phases and perform preclinical analyses that show mitochondrial fission or autophagy inhibition sensitizes AML cells to devimistat.
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影响因子：
64.5
作者：
López-Otín C;Blasco MA;Partridge L;Serrano M;Kroemer G
通讯作者：
Kroemer G
DOI：
10.1126/science.1201940
发表时间：
2011-08-26
期刊：
Science (New York, N.Y.)
影响因子：
--
作者：
Green DR;Galluzzi L;Kroemer G
通讯作者：
Kroemer G
影响因子：
--
作者：
Lamb R;Ozsvari B;Lisanti CL;Tanowitz HB;Howell A;Martinez-Outschoorn UE;Sotgia F;Lisanti MP
通讯作者：
Lisanti MP
影响因子：
20.3
作者：
Marlein, Christopher R.;Zaitseva, Lyubov;Rushworth, Stuart A.
通讯作者：
Rushworth, Stuart A.
影响因子：
4.8
作者：
Michelis, F. V.;Messner, H. A.;Kim, D. D.
通讯作者：
Kim, D. D.