Measurable residual disease in elderly acute myeloid leukemia: results from the PETHEMA-FLUGAZA phase III clinical trial

The value of measurable residual disease (MRD) in elderly patients with acute myeloid leukemia (AML) is inconsistent between those treated with intensive vs hypomethylating drugs, and unknown after semi-intensive therapy. We investigated the role of MRD in refining complete remission (CR) and treatment duration in the phase III PETHEMA-FLUGAZA clinical trial, that randomized 283 elderly AML patients to induction and consolidation with fludarabine plus cytarabine or induction and consolidation with 5-azacitidine. After consolidation, patients continued treatment if MRD≥0.01% or stopped if MRD<0.01%, assessed by multidimensional flow cytometry (MFC). On multivariate analysis including genetic risk and treatment arm, MRD status in patients achieving CR (N=72) was the only independent prognostic factor for cumulative-incidence of relapse (HR:2.95;P=.002) and relapse-free survival (HR:3.45;P=.002). A trend for longer overall survival was observed in patients with undetectable MRD (N=13/72). Although leukemic cells from most elderly AML patients display phenotypic aberrancies vs their normal counterpart (N=258/265), CD34 progenitors from cases with undetectable MRD by MFC displayed extensive genetic abnormalities identified by whole-exome sequencing. This study supports MRD assessment to refine CR after semi-intensive therapy or hypomethylating agents, but unveils that improved sensitivity is warranted to individualize treatment and prolong survival of elderly AML patients achieving undetectable MRD.EGA study EGAS00001004574

可测量残留病灶（measurable residual disease, MRD）在老年急性髓系白血病（acute myeloid leukemia, AML）患者中的价值，在接受强化治疗与低甲基化药物治疗的人群中存在不一致性，且半强化治疗后的相关情况尚不明确。我们在III期PETHEMA-FLUGAZA临床试验中探究了MRD在优化完全缓解（complete remission, CR）及治疗时长中的作用，该试验将283例老年AML患者随机分配至氟达拉滨联合阿糖胞苷诱导及巩固治疗组，或阿扎胞苷诱导及巩固治疗组。巩固治疗后，通过多参数流式细胞术（multidimensional flow cytometry, MFC）评估MRD水平：若MRD≥0.01%则继续治疗，若MRD<0.01%则停止治疗。在纳入遗传风险与治疗组的多因素分析中，达到CR的患者（N=72）的MRD状态是累积复发率（风险比HR=2.95；P=0.002）与无复发生存期（HR=3.45；P=0.002）的唯一独立预后因素。在MRD不可检测的患者中观察到总生存期更长的趋势（N=13/72）。尽管多数老年AML患者的白血病细胞相较于正常对照存在表型异常（N=258/265），但经MFC检测为MRD不可检测的病例，其CD34阳性祖细胞存在通过全外显子测序（whole-exome sequencing）鉴定出的广泛遗传学异常。本研究支持通过MRD评估优化半强化治疗或低甲基化药物治疗后的完全缓解状态，但同时揭示，需提升检测灵敏度以实现个体化治疗，进而延长达到MRD不可检测状态的老年AML患者的生存期。本研究关联EGA研究EGAS00001004574