Department of Internal Medicine III, Ulm University Hospital, Ulm, Germany.
Australian Centre for Blood Diseases, Monash University, Melbourne, Australia.
Blood. 2022 Oct 13;140(15):1674-1685. doi: 10.1182/blood.2022016293.
The randomized, placebo-controlled, phase 3 QUAZAR AML-001 trial (ClinicalTrials.gov identifier: NCT01757535) evaluated oral azacitidine (Oral-AZA) in patients with acute myeloid leukemia (AML) in first remission after intensive chemotherapy (IC) who were not candidates for hematopoietic stem cell transplantation. Eligible patients were randomized 1:1 to Oral-AZA 300 mg or placebo for 14 days per 28-day cycle. We evaluated relapse-free survival (RFS) and overall survival (OS) in patient subgroups defined by NPM1 and FLT3 mutational status at AML diagnosis and whether survival outcomes in these subgroups were influenced by presence of post-IC measurable residual disease (MRD). Gene mutations at diagnosis were collected from patient case report forms; MRD was determined centrally by multiparameter flow cytometry. Overall, 469 of 472 randomized patients (99.4%) had available mutational data; 137 patients (29.2%) had NPM1 mutations (NPM1mut), 66 patients (14.1%) had FLT3 mutations (FLT3mut; with internal tandem duplications [ITD], tyrosine kinase domain mutations [TKDmut], or both), and 30 patients (6.4%) had NPM1mut and FLT3-ITD at diagnosis. Among patients with NPM1mut, OS and RFS were improved with Oral-AZA by 37% (hazard ratio [HR], 0.63; 95% confidence interval [CI], 0.41-0.98) and 45% (HR, 0.55; 95% CI, 0.35-0.84), respectively, vs placebo. Median OS was improved numerically with Oral-AZA among patients with NPM1mut whether without MRD (48.6 months vs 31.4 months with placebo) or with MRD (46.1 months vs 10.0 months with placebo) post-IC. Among patients with FLT3mut, Oral-AZA improved OS and RFS by 37% (HR, 0.63; 95% CI, 0.35-1.12) and 49% (HR, 0.51; 95% CI, 0.27-0.95), respectively, vs placebo. Median OS with Oral-AZA vs placebo was 28.2 months vs 16.2 months, respectively, for patients with FLT3mut and without MRD and 24.0 months vs 8.0 months for patients with FLT3mut and MRD. In multivariate analyses, Oral-AZA significantly improved survival independent of NPM1 or FLT3 mutational status, cytogenetic risk, or post-IC MRD status.
QUAZAR AML-001 是一项随机、安慰剂对照、3 期临床试验（ClinicalTrials.gov 标识符：NCT01757535），评估了在接受强化化疗（IC）后处于缓解期的、不适合进行造血干细胞移植的急性髓系白血病（AML）患者中，口服阿扎胞苷（Oral-AZA）的疗效。符合条件的患者以 1:1 的比例随机分配至 Oral-AZA 300mg 或安慰剂组，每 28 天为一个周期，口服 14 天。我们评估了无复发生存（RFS）和总生存（OS），并根据 AML 诊断时 NPM1 和 FLT3 突变状态以及这些亚组中生存结果是否受 IC 后可测量残留疾病（MRD）的影响进行了亚组分析。基因突变数据来自患者病例报告表；MRD 通过多参数流式细胞术进行中心检测。共有 472 名随机患者中的 469 名（99.4%）有可用的突变数据；137 名患者（29.2%）存在 NPM1 突变（NPM1mut），66 名患者（14.1%）存在 FLT3 突变（FLT3mut，包括内部串联重复[ITD]、酪氨酸激酶结构域突变[TKDmut]或两者兼有），30 名患者（6.4%）在诊断时同时存在 NPM1mut 和 FLT3-ITD。在 NPM1mut 患者中，与安慰剂相比，Oral-AZA 使 OS 和 RFS 分别提高了 37%（风险比[HR]，0.63；95%置信区间[CI]，0.41-0.98）和 45%（HR，0.55；95% CI，0.35-0.84）。无论是否存在 IC 后 MRD（Oral-AZA 组的中位 OS 为 48.6 个月，安慰剂组为 31.4 个月），还是存在 MRD（Oral-AZA 组的中位 OS 为 46.1 个月，安慰剂组为 10.0 个月），NPM1mut 患者的中位 OS 数值上均得到改善。在 FLT3mut 患者中，与安慰剂相比，Oral-AZA 使 OS 和 RFS 分别提高了 37%（HR，0.63；95% CI，0.35-1.12）和 49%（HR，0.51；95% CI，0.27-0.95）。FLT3mut 且无 MRD 的患者中，Oral-AZA 组的中位 OS 为 28.2 个月，安慰剂组为 16.2 个月，FLT3mut 且存在 MRD 的患者中，Oral-AZA 组的中位 OS 为 24.0 个月，安慰剂组为 8.0 个月。在多变量分析中，Oral-AZA 可改善生存，与 NPM1 或 FLT3 突变状态、细胞遗传学风险或 IC 后 MRD 状态无关。
