Preclinically, enasidenib and azacitidine (ENA + AZA) synergistically enhance cell differentiation, and venetoclax (VEN), a small molecule Bcl2 inhibitor (i) is particularly effective in IDH2 mutated acute myeloid leukemia (IDH2mutAML). This open label phase II trial enrolled patients (pts) with documented IDH2mutAML. All patients received AZA 75 mg/m2/d x 7 d/cycle and ENA 100 mg QD continuously. Concomitant Bcl2i and FLT3i were allowed (NCT03683433).Twenty-six pts received ENA + AZA (median 68 years, range, 24–88); 7 newly diagnosed (ND) and 19 relapsed/refractory (R/R). In R/R AML patients, three had received prior ENA and none had received prior VEN. The composite complete remission rate (CRc) [complete remission (CR) or complete remission with incomplete hematologic recovery (CRi)] was 100% in ND AML, and 58% in R/R AML. Median OS was not reached in ND AML with median follow-up of 13.1 months (mo); Pts treated in first relapse had improved OS than those with ≥2 relapse (median OS not reached vs 5.2 mo; HR 0.24, 95% CI 0.07–0.79, p = 0.04). Two patients received ENA + AZA with a concomitant FLT3i, one responding ND AML patient and one nonresponding R/R AML patient. Seven R/R AML pts received ENA + AZA + VEN triplet, and with median follow up of 11.2 mo, median OS was not reached and 6-mo OS was 70%. The most frequent treatment-emergent adverse events include febrile neutropenia (23%). Adverse events of special interest included all-grade IDH differentiation syndrome (8%) and indirect hyperbilirubinemia (35%). ENA + AZA was a well-tolerated, and effective therapy for elderly pts with IDH2mut ND AML as well as pts with R/R AML. The addition of VEN to ENA + AZA appears to improve outcomes in R/R IDH2mutAML. Clinical trial registration information: https://clinicaltrials.gov/.NCT03683433
临床前研究表明，恩西地平与阿扎胞苷（ENA+AZA）可协同增强细胞分化，而Bcl2小分子抑制剂维奈克拉（VEN）对IDH2突变的急性髓系白血病（IDH2mutAML）尤其有效。这项开放标签II期试验纳入了经确诊的IDH2mutAML患者。所有患者均接受AZA（75 mg/m²/日，每周期连续7天）及ENA（100 mg每日一次持续给药）治疗。允许联合使用Bcl2抑制剂与FLT3抑制剂（试验注册号：NCT03683433）。
共26例患者接受ENA+AZA治疗（中位年龄68岁，范围24-88岁），其中7例为新诊断（ND）患者，19例为复发/难治性（R/R）患者。在R/R AML患者中，3例曾接受过ENA治疗，无一例曾接受VEN治疗。新诊断AML患者的复合完全缓解率（CRc）[包括完全缓解（CR）及血象未完全恢复的完全缓解（CRi）]达100%，R/R AML患者为58%。新诊断AML患者中位总生存期（OS）未达到（中位随访时间13.1个月）；首次复发患者的OS优于≥2次复发者（中位OS未达到 vs 5.2个月；风险比0.24，95%置信区间0.07–0.79，p=0.04）。2例患者接受ENA+AZA联合FLT3抑制剂治疗，其中1例为新诊断缓解者，1例为R/R未缓解者。7例R/R AML患者接受ENA+AZA+VEN三联方案治疗，中位随访11.2个月后中位OS未达到，6个月OS率为70%。最常见的治疗期间不良事件包括发热性中性粒细胞减少症（23%）。特别关注的不良事件包括各级别IDH分化综合征（8%）和间接胆红素升高（35%）。对于老年IDH2mut新诊断AML及R/R AML患者，ENA+AZA是一种耐受性良好且有效的治疗方案。在ENA+AZA基础上联合VEN可改善R/R IDH2mutAML患者的临床结局。临床试验注册信息：https://clinicaltrials.gov/.NCT03683433
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