In TP53 wild-type acute myeloid leukemia (AML), inhibition of MDM2 can enhance p53 protein expression and potentiate leukemic cell apoptosis. MDM2 inhibitor (MDM2i) monotherapy in AML has shown modest responses in clinical trials but combining options of MDM2i with other potent AML-directed agents like cytarabine and venetoclax could improve its efficacy. We conducted a phase I clinical trial (NCT03634228) to study the safety and efficacy of milademetan (an MDM2i) with low-dose cytarabine (LDAC)±venetoclax in adult patients with relapsed refractory (R/R) or newly diagnosed (ND; unfit) TP53 wild-type AML and performed comprehensive CyTOF analyses to interrogate multiple signaling pathways, the p53-MDM2 axis and the interplay between pro/anti-apoptotic molecules to identify factors that determine response and resistance to therapy. Sixteen patients (14 R/R, 2 N/D treated secondary AML) at a median age of 70 years (range, 23–80 years) were treated in this trial. Two patients (13%) achieved an overall response (complete remission with incomplete hematological recovery). Median cycles on trial were 1 (range 1–7) and at a median follow-up of 11 months, no patients remained on active therapy. Gastrointestinal toxicity was significant and dose-limiting (50% of patients ≥ grade 3). Single-cell proteomic analysis of the leukemia compartment revealed therapy-induced proteomic alterations and potential mechanisms of adaptive response to the MDM2i combination. The response was associated with immune cell abundance and induced the proteomic profiles of leukemia cells to disrupt survival pathways and significantly reduced MCL1 and YTHDF2 to potentiate leukemic cell death. The combination of milademetan, LDAC±venetoclax led to only modest responses with recognizable gastrointestinal toxicity. Treatment-induced reduction of MCL1 and YTHDF2 in an immune-rich milieu correlate with treatment response.
在TP53野生型急性髓系白血病（AML）中，抑制MDM2可增强p53蛋白表达并促进白血病细胞凋亡。临床试验显示，MDM2抑制剂（MDM2i）单药治疗AML疗效有限，但将MDM2i与阿糖胞苷、维奈托克等其他强效AML靶向药物联用有望提升疗效。我们开展了一项I期临床试验（NCT03634228），旨在研究米拉美坦（一种MDM2i）联合小剂量阿糖胞苷（LDAC）±维奈托克在复发难治性（R/R）或新诊断（ND；不耐受）TP53野生型AML成年患者中的安全性与有效性，并通过全面的飞行时间质谱流式细胞术（CyTOF）分析，探究多条信号通路、p53-MDM2轴以及促凋亡/抗凋亡分子间的相互作用，以确定影响治疗应答与耐药的关键因素。该试验共纳入16例患者（14例R/R，2例ND治疗的继发性AML），中位年龄70岁（范围23-80岁）。其中2例患者（13%）达到总体缓解（血液学恢复不完全的完全缓解）。中位治疗周期数为1（范围1-7），中位随访11个月时，无患者仍在接受积极治疗。胃肠道毒性显著且呈剂量限制性（50%患者出现≥3级毒性）。对白血病细胞区室的单细胞蛋白质组学分析揭示了治疗诱导的蛋白质组学改变及对MDM2i联合方案的适应性应答潜在机制。治疗应答与免疫细胞丰度相关，并诱导白血病细胞的蛋白质组学特征改变，从而破坏生存通路，显著降低MCL1和YTHDF2表达以促进白血病细胞死亡。米拉美坦联合LDAC±维奈托克的治疗方案仅产生有限应答，且存在明显的胃肠道毒性。在免疫富集环境中，治疗诱导的MCL1和YTHDF2下调与治疗应答相关。
肿瘤(癌症)患者之家