Candoni Anna, De Marchi Federico, Zannier Maria Elena, Lazzarotto Davide, Filì Carla, Dubbini Maria Vittoria, Rabassi Nicholas, Toffoletti Eleonora, Lau Bonnie W, Fanin Renato
Division of Hematology and SCT, University Hospital, Udine, Udine, Italy.
Division of Hematology and SCT, University Hospital, Udine, Udine, Italy.
Leuk Res. 2017 Dec;63:22-27. doi: 10.1016/j.leukres.2017.10.010. Epub 2017 Oct 27.
We analyzed the outcome of allogeneic stem cell transplantation (allo-SCT) in acute myeloid leukemia (AML) patients according to molecular Minimal Residual Disease (MRD) status prior to allo-SCT. MRD was assessed by the quantitative expression of the pan-leukemic marker Wilms' tumor (WT1) gene, according to the validated LeukemiaNet method. Between 2005 and 2016, 122 consecutive AML patients, WT1 positive at diagnosis, received allo-SCT in cytologic complete remission (cCR). The median age at SCT was 53 years (range 18-70). Quantitative analysis of WT1 gene expression (bone marrow samples) was available in all cases both at diagnosis (100% of samples overexpressed WT1 with a mean of 8607±8187 copies/10 Abelson) and immediately before allo-SCT. Eighty one cases (66%) were MRD-WT1 negative (WT1 <250 copies) and 41/122 (44%) cases were MRD-WT1 positive (WT1 >250 copies) prior to allo-SCT. We evaluated post-SCT overall survival (OS), disease free survival (DFS) and relapse rate (RR), according to MRD-WT1 status pre-SCT. Both post-allo-SCT OS and DFS were significantly improved in patients who were MRD-WT1 negative at the time of SCT compared with those who were MRD-WT1 positive, with a median OS and DFS not reached in the MRD-WT1 negative group and 9 and 8 months, respectively, in the WT1 positive group (OS log-rank p<0.0001; hazard ratio [HR] 3.9, 95% confidence interval [95% CI] 2.0-7.38; DFS log-rank p<0.0001; HR 3.73, 95% CI 2.0-6.72). The RR after SCT was 15% (12/81) in pre-SCT MRD-WT1 negative cases and 44% (18/41) in MRD-WT1 positive cases (p=0.00073). Univariate analysis showed that MRD-WT1 negativity pre-SCT and grade <2 acute GVHD were significant prognostic factors for improved OS and DFS. However multivariate analysis showed MRD-WT1 negativity pre-SCT was the only independent prognostic factor for improved OS and DFS. These data show that pre allo-SCT molecular MRD evaluation using WT1 expression is a powerful predictor of post allo-SCT outcomes in AML undergoing SCT in cCR. Patients with both cCR and MRD-WT1 negativity before SCT have a very good outcome with lower RR and improved OS. The pre allo-SCT MRD-WT1 stratification in AML is a valuable tool to identify patients at high risk of post-SCT relapse, and can influence conditioning regimen intensification and/or post-SCT preemptive strategies.
我们根据异基因造血干细胞移植（allo-SCT）前的分子微小残留病（MRD）状态，分析了急性髓系白血病（AML）患者接受异基因干细胞移植的结果。根据经过验证的白血病网络（LeukemiaNet）方法，通过泛白血病标志物威尔姆斯瘤（WT1）基因的定量表达来评估MRD。2005年至2016年期间，122例诊断时WT1呈阳性的连续AML患者在细胞学完全缓解（cCR）状态下接受了allo-SCT。SCT时的中位年龄为53岁（范围18 - 70岁）。所有病例在诊断时（100%的样本WT1过表达，平均为8607±8187拷贝/10阿贝尔森）以及allo-SCT前即刻均有WT1基因表达（骨髓样本）的定量分析结果。81例（66%）在allo-SCT前为MRD-WT1阴性（WT1 <250拷贝），41/122例（44%）为MRD-WT1阳性（WT1 >250拷贝）。我们根据SCT前的MRD-WT1状态评估了SCT后的总生存期（OS）、无病生存期（DFS）和复发率（RR）。与MRD-WT1阳性患者相比，SCT时MRD-WT1阴性的患者allo-SCT后的OS和DFS均显著改善，MRD-WT1阴性组的中位OS和DFS未达到，WT1阳性组分别为9个月和8个月（OS对数秩检验p<0.0001；风险比[HR] 3.9，95%置信区间[95% CI] 2.0 - 7.38；DFS对数秩检验p<0.0001；HR 3.73，95% CI 2.0 - 6.72）。SCT前MRD-WT1阴性病例的SCT后RR为15%（12/81），MRD-WT1阳性病例为44%（18/41）（p = 0.00073）。单因素分析显示，SCT前MRD-WT1阴性和<2级急性移植物抗宿主病（GVHD）是OS和DFS改善的显著预后因素。然而，多因素分析显示SCT前MRD-WT1阴性是OS和DFS改善的唯一独立预后因素。这些数据表明，使用WT1表达进行allo-SCT前分子MRD评估是cCR状态下接受SCT的AML患者allo-SCT后结果的有力预测指标。SCT前cCR且MRD-WT1阴性的患者预后非常好，RR较低且OS改善。AML患者allo-SCT前MRD-WT1分层是识别SCT后高复发风险患者的有价值工具，并且可以影响预处理方案强度和/或SCT后抢先治疗策略。
