Montesinos Pau, Marchione Dylan M, Récher Christian, Heuser Michael, Vives Susana, Zarzycka Ewa, Wang Jianxiang, Riva Marta, Calado Rodrigo T, Schuh Andre C, Yeh Su-Peng, Tron Adriana E, Hui Jianan, Gianolio Diego A, Choe Sung, Patel Prapti A, De Botton Stéphane, DiNardo Courtney D, Döhner Hartmut
Hospital Universitari i Politècnic La Fe, Valencia, Spain.
Servier BioInnovation, Boston, MA, United States.
Blood Adv. 2025 Jul 24. doi: 10.1182/bloodadvances.2025016399.
In the phase 3 AGILE study, after a 12.4-month median follow-up, ivosidenib, a mutant isocitrate dehydrogenase 1 (IDH1) inhibitor, combined with azacitidine significantly improved event-free survival, overall survival (OS), and complete remission rates compared with placebo-azacitidine in patients with newly diagnosed IDH1-mutated acute myeloid leukemia who were unfit for intensive chemotherapy. This post hoc analysis reports long-term follow-up results from AGILE after a median follow-up of 28.6 months. Overall, 148 patients were randomized to receive ivosidenib-azacitidine (N=73) or placebo-azacitidine (N=75). Median OS was significantly longer with ivosidenib (29.3 months; 95% CI 13.2, not reached) than with placebo (7.9 months; 95% CI 4.1, 11.3; hazard ratio 0.42 [0.27, 0.65]; p<.0001). Hematologic recovery was faster, more durable, and conversion to transfusion independence (53.8% vs 17.1%; p=.0004) was more common with ivosidenib than with placebo. Of 33 ivosidenib-treated patients evaluable for molecular measurable residual disease (MRD), 10 converted to MRD negativity. Although OS did not differ significantly between MRD-negative and MRD-positive responders at the 0.1% variant allele frequency (VAF) threshold, MRD-negative patients had numerically longer survival. MRD status appeared more predictive of long-term OS when an exploratory 1% VAF threshold was applied. MRD response was not associated with IDH1 variant, VAF, inferred clonality, or number of baseline comutations. The previously reported safety profile was maintained. These long-term efficacy and safety results confirm the benefit of ivosidenib-azacitidine in this challenging-to-treat population and support its use as a standard of care with the longest reported survival benefit for intensive chemotherapy-ineligible patients with IDH1-mutated AML. ClinicalTrials.gov registration ID: NCT03173248.
在3期AGILE研究中，经过12.4个月的中位随访，与安慰剂联合阿扎胞苷相比，异柠檬酸脱氢酶1（IDH1）突变抑制剂艾伏尼布联合阿扎胞苷显著改善了新诊断的IDH1突变型急性髓系白血病且不适合强化化疗患者的无事件生存期、总生存期（OS）和完全缓解率。这项事后分析报告了AGILE研究中位随访28.6个月后的长期随访结果。总体而言，148例患者被随机分配接受艾伏尼布 - 阿扎胞苷（N = 73）或安慰剂 - 阿扎胞苷（N = 75）。艾伏尼布组的中位OS显著长于安慰剂组（29.3个月；95%CI 13.2，未达到）（7.9个月；95%CI 4.1，11.3；风险比0.42 [0.27，0.65]；p <.0001）。与安慰剂相比，艾伏尼布组血液学恢复更快、更持久，且转为无需输血的比例更高（53.8%对17.1%；p = 0.0004）。在33例可评估分子可测量残留病（MRD）的接受艾伏尼布治疗的患者中，10例转为MRD阴性。尽管在0.1%变异等位基因频率（VAF）阈值时，MRD阴性和MRD阳性缓解者的OS无显著差异，但MRD阴性患者的生存期在数值上更长。当应用探索性的1%VAF阈值时，MRD状态似乎更能预测长期OS。MRD反应与IDH1变异、VAF、推断的克隆性或基线共突变数量无关。维持了先前报告的安全性概况。这些长期疗效和安全性结果证实了艾伏尼布 - 阿扎胞苷对这一难以治疗的人群有益，并支持其作为护理标准用于对强化化疗不适用的IDH1突变型AML患者，且报告的生存获益最长。ClinicalTrials.gov注册号：NCT03173248。
