KMT2A重排（KMT2A-r）的B细胞前体急性淋巴细胞白血病（BCP-ALL）被广泛认为是儿童和成人中的高危白血病。然而，在最近的治疗方案中，成人患者的相关数据很少，对于这些患者的最佳治疗策略仍然存在争议。在本研究中，我们旨在改进用现代化化疗方案治疗成人KMT2A-r BCP-ALL的预后，并研究共同突变和最小残留病（MRD）的预后影响。在连续进行的三个GRAALL试验中，共有1091名不含费城染色体的BCP-ALL成年患者入组，其中141例（12.9%）为KMT2A-r，其5年复发累积发生率（CIR）和总生存率（OS）分别为40.7%和53.3%。分子分析显示，在这个亚型中存在着较低的突变负荷，类似于婴儿BCP-ALL。然而，TP53和/或IKZF1的突变定义了一组CIR（69.3% vs 36.2%，p=0.001）和OS（28.1% vs 60.7%，p=0.006）显著较差的患者。我们接下来分析了诱导治疗和首次巩固治疗后，使用免疫球蛋白（IG）/T细胞受体（TR）重排和KMT2A基因融合作为标记的MRD的预后意义。在大约三分之一的患者中，IG/TR重排在疾病过程中缺失或出现克隆进化，从而影响了MRD监测。相比之下，基于KMT2A的MRD具有高度的可靠性，并且与预后密切相关，早期良好反应者具有出色的预后（3年CIR为7.1%，OS为92.9%）。总之，我们的研究揭示了成人KMT2A-r BCP-ALL中的显著异质性，并提供了新的生物标志物来指导以风险为基础的治疗分层。版权所有©2023年美国血液学会。

KMT2A-rearranged (KMT2A-r) B-cell precursor acute lymphoblastic leukemia (BCP-ALL) is widely recognized as a high-risk leukemia in both children and adults. However, there is a paucity of data on adults treated in recent protocols and the optimal treatment strategy for these patients is still a matter of debate. In this study, we set out to refine the prognosis of adult KMT2A-r BCP-ALL treated with modern chemotherapy regimen and investigate the prognostic impact of co-mutations and minimal residual disease (MRD). Of 1091 adult patients with Philadelphia-negative BCP-ALL enrolled in three consecutive GRAALL trials, 141 (12.9%) had KMT2A-r, with 5-year cumulative incidence of relapse (CIR) and overall survival (OS) rates of 40.7% and 53.3%, respectively. Molecular profiling highlighted a low mutational burden in this subtype, reminiscent of infant BCP-ALL. However, the presence of TP53 and/or IKZF1 alterations defined a subset of patients with significantly poorer CIR (69.3% vs 36.2%, p=0.001) and OS (28.1% vs 60.7%, p=0.006). We next analyzed the prognostic implication of MRD measured after induction and first consolidation, using both immunoglobulin (IG)/T-cell receptor (TR) rearrangements and KMT2A genomic fusion as markers. In approximately one third of patients, IG/TR rearrangements were absent or displayed clonal evolution during the disease course, compromising MRD monitoring. By contrast, KMT2A-based MRD was highly reliable and was strongly associated with outcome, with early good responders having an excellent outcome (3-year CIR 7.1% and OS 92.9%). Altogether, our study reveals striking heterogeneity in outcomes within adults with KMT2A-r BCP-ALL and provides new biomarkers to guide risk-based therapeutic stratification.Copyright © 2023 American Society of Hematology.