Introduction

Acute myeloid leukemia bearing a RUNX1 gene mutation (RUNX1+ AML) has been proposed as a provisional entity in the 2016 WHO classification. Clinically, it has been associated with inferior response rates and outcome after conventional chemotherapy. Accordingly, RUNX1+ AML is allocated in the unfavorable prognostic category of the 2017 European Leukemia Net classification. Following allogeneic stem cell transplantation (alloSCT), RUNX1 was an unfavorable factor in one study in MDS/secondary AML, while data in de novo AML are scarce.

Objectives

Here, we present a retrospective study by the EBMT Acute Leukemia Working Party, aiming to elucidate the prognostic value of RUNX1 mutation in patients undergoing alloSCT for AML in first complete remission (CR1).

Methods

Adults undergoing alloSCT for AML in CR1 from matched related or unrelated donors between 2013 and 2018 with complete information on conventional cytogenetics and RUNX1 mutational status were selected from the EBMT registry. Variables of interest were overall and leukemia-free survival (OS/LFS), GvHD/relapse free survival (GRFS), cumulative relapse incidence (RI), non-relapse mortality (NRM) and GvHD. Log rank test, Gray test and Cox regression models were used.

Results

128 RUNX+ and 388 RUNX- patients were identified, >80% of both subgroups presenting as de novo AML. As expected, RUNX1+ patients rarely had co-mutations in NPM1 (6% vs. 26%, p=10⁻³), and showed a positive correlation with ASXL1 mutations (50% vs. 16%, p=10⁻⁴). Cytogenetic categories and other mutations (FLT3-ITD, CEBPA) were equally distributed between the two groups, as were age, donor and graft type, CMV, conditioning and T cell depletion (TCD).

Median follow-up was 16.4 (RUNX+) and 19.8 (RUNX-) months. 2y OS/LFS of the entire cohort were 64% [59-69]/57% [52-62], with no difference between RUNX1+ and RUNX1- patients either in univariate or multivariate analysis (2y OS: 67.9% [57.3-78.5] vs. 63.1%v[57.4-68.7]p=0.15; 2y LFS: 57.6% [46.4-68.7] vs. 57% [51.4-62.6], p=0.38], figure 1). RUNX1 mutation neither had any impact among patients with normal karyotype (figure 2). Similarly, no other outcome parameter was influenced by RUNX1 mutational status. Instead, multivariate analysis revealed age and donor type as risk factors for OS, LFS and NRM. Poor cytogenetic was associated with higher RI and inferior LFS/GRFS, in vivo TCD with a lower rate of aGvHD II-IV, cGvHD, and better GRFS. Among patients with available information, FLT3-ITD was an independent risk factor for relapse, LFS and GRFS. RUNX1 did not modify the role of FLT3-ITD.

Conclusion

Within the limits of a retrospective registry analysis, we could not find a negative influence of RUNX1 mutation on outcome after allogeneic SCT in CR1. Hence, transplantation in CR1 might overcome the unfavorable prognostic value of RUNX1 mutation and can be recommended as consolidation treatment in this entity.

中文翻译：

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首次完全缓解的RUNX1突变的AML患者的同种异体干细胞移植：代表EBMT的ALWP的研究

介绍

在2016年世界卫生组织分类中，已提议将带有RUNX1基因突变（RUNX1 + AML）的急性髓细胞白血病作为临时实体。临床上，它与常规化疗后不良反应率和预后相关。因此，RUNX1 + AML被分配在2017年欧洲白血病网分类的不良预后类别中。在异基因干细胞移植（alloSCT）之后，RUNX1在MDS /继发性AML中的一项研究中是不利因素，而从头AML中的数据却很少。

目标

在这里，我们提出了一项由EBMT急性白血病工作组进行的回顾性研究，旨在阐明在首次完全缓解（CR1）中接受alloSCT治疗AML的患者中RUNX1突变的预后价值。

方法

从EBMT注册中心选择了2013年至2018年之间来自相配相关或不相关供体的CR1中接受AML的alloSCT AML的成年人，这些成年人具有常规细胞遗传学和RUNX1突变状态的完整信息。感兴趣的变量是总体和无白血病生存期（OS / LFS），GvHD /无复发生存期（GRFS），累积复发率（RI），非复发死亡率（NRM）和GvHD。使用对数秩检验，格雷检验和Cox回归模型。

结果

确定了128例RUNX +和388例RUNX-患者，两个亚组中> 80％表现为从头AML。如预期的那样，RUNX1 +患者很少在NPM1中发生突变（6％对26％，p = 10 ^-3），并且与ASXL1突变呈正相关（50％对16％，p = 10 ^-4）。细胞遗传学类别和其他突变（FLT3- ITD，CEBPA ）在年龄，供体和移植物类型，CMV，条件和T细胞耗竭（TCD）等两组之间均等分布。

中位随访时间为16.4（RUNX +）和19.8（RUNX-）月。整个队列的2y OS / LFS为64％[59-69] / 57％[52-62]，在RUNX1 +和RUNX1之间无差异-单因素或多因素分析的患者（2y OS：67.9％[57.3- 78.5] vs. 63.1％v [57.4-68.7] p = 0.15； 2y LFS：57.6％[46.4-68.7] vs. 57％[51.4-62.6]，p = 0.38]，图1）。RUNX1突变在核型正常的患者中也没有任何影响（图2）。同样，RUNX1也不会影响其他结果参数突变状态。相反，多变量分析显示年龄和供体类型是OS，LFS和NRM的危险因素。细胞遗传学不良与较高的RI和较低的LFS / GRFS，体内TCD以及较低的aGvHD II-IV，cGvHD和更好的GRFS率相关。在可获得信息的患者中，FLT3- ITD是复发，LFS和GRFS的独立危险因素。RUNX1并未修改FLT3- ITD的角色。

结论

在回顾性注册表分析的范围内，我们没有发现RUNX1突变对CR1的同种SCT后结局有负面影响。因此，在CR1中进行移植可能会克服RUNX1突变的不利预后价值，因此可以推荐作为该实体的巩固治疗。