Increased mitochondrial apoptotic priming with targeted therapy predicts clinical response to re-induction chemotherapy
Increased mitochondrial apoptotic priming with targeted therapy predicts clinical response to re-induction chemotherapy
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DOI：
10.1002/ajh.25692
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发表时间：
2019-12-22
影响因子：
12.8
通讯作者：
Letai, Anthony
中科院分区：
文献类型：
--
作者：
Garcia, Jacqueline S.;Bhatt, Shruti;Letai, Anthony
大多数复发性或难治性（R/R）急性髓性白血病（AML）患者无法从当前的再诱导或获批的靶向治疗中获益。在缺乏靶向基因突变的情况下，最佳治疗选择的指导很少，特别是在R/R环境中，突出了对临床有用的功能性生物标志物的未满足需求。来自两项临床试验中接受治疗的患者的血液和骨髓样本用于检测来那度胺（LEN）和MEC（米托蒽醌，依托泊苷和阿糖胞苷）化疗在R/R AML患者中的组合。骨髓样本可用于检测线粒体凋亡BH 3和动态BH 3谱（DBP）测定在预测缓解中的临床效用，因为没有明确的遗传生物标志物识别缓解者。为了测试LEN诱导的线粒体引发是否预测对LEN-MEC疗法的临床反应，我们对患者成髓细胞进行DBP。我们发现，来那度胺的短期离体治疗基于药物诱导的引发变化（δ引发）区分临床应答者和非应答者。使用临床LEN治疗前后（MEC给药前）收集的配对患者样本，我们证实了LEN诱导的体内细胞凋亡引发增加，表明LEN增强了成髓细胞对细胞毒性MEC化疗的脆弱性。这是第一项证明DBP在预测联合治疗方案临床应答方面的潜在作用的研究。我们的研究结果表明，复发性AML的功能特性可以识别积极的治疗方法。
Most patients with relapsed or refractory (R/R) acute myeloid leukemia (AML) do not benefit from current re-induction or approved targeted therapies. In the absence of targetable genetic mutations, there is minimal guidance on optimal treatment selection particularly in the R/R setting highlighting an unmet need for clinically useful functional biomarkers. Blood and bone marrow samples from patients treated on two clinical trials were used to test the combination of lenalidomide (LEN) and MEC (mitoxantrone, etoposide, and cytarabine) chemotherapy in R/R AML patients. The bone marrow samples were available to test the clinical utility of the mitochondrial apoptotic BH3 and dynamic BH3 profiling (DBP) assays in predicting response, as there was no clear genetic biomarker identifying responders. To test whether LEN-induced mitochondrial priming predicted clinical response to LEN-MEC therapy, we performed DBP on patient myeloblasts. We found that short-term ex vivo treatment with lenalidomide discriminated clinical responders from non-responders based on drug-induced change in priming (delta priming). Using paired patient samples collected before and after clinical LEN treatment (prior to MEC dosing), we confirmed LEN-induced increased apoptotic priming in vivo, suggesting LEN enhanced vulnerability of myeloblasts to cytotoxic MEC chemotherapy. This is the first study demonstrating the potential role of DBP in predicting clinical response to a combination regimen. Our findings demonstrate that functional properties of relapsed AML can identify active therapies.