Multigene Measurable Residual Disease Assessment Improves Acute Myeloid Leukemia Relapse Risk Stratification in Autologous Hematopoietic Cell Transplantation.
Multigene Measurable Residual Disease Assessment Improves Acute Myeloid Leukemia Relapse Risk Stratification in Autologous Hematopoietic Cell Transplantation.
复制标题
DOI：
10.1016/j.bbmt.2016.08.014
复制
发表时间：
2016-11
影响因子：
4.3
通讯作者：
Hourigan, Christopher S.
中科院分区：
文献类型：
--
作者：
Mule, Matthew P.;Mannis, Gabriel N.;Wood, Brent L.;Radich, Jerald R.;Hwang, Jimmy;Ramos, Nestor R.;Andreadis, Charalambos;Damon, Lloyd;Logan, Aaron C.;Martin, Thomas G.;Hourigan, Christopher S.
我们在此报告迄今为止最大规模的成人 AML 患者在自体造血细胞移植 (auto-HCT) 时检测可测量残留病 (MRD) 的研究。基于冷冻保存的 GCSF 动员自体外周血祖细胞 (PBPC) 白细胞去除术标本（“自体移植物”）的可用性，2004 年至 2013 年间在单一学术医疗中心 (UCSF) 进行移植的 72 名成年患者符合参加这项回顾性研究的资格。自体移植物 MRD 通过分子方法（单独 WT1 或多基因组的 RQ-PCR）和多参数流式细胞术 (MPFC) 进行评估。自体移植物的 WT1 RQ-PCR 检测对复发预测的敏感性较低 (14%)，阴性预测值为 51%。 MPFC 在测试的 34 个自体移植物中均未能识别出 MRD。然而，分子 MRD 检测的组合改善了对自体 HCT 复发后的预测。在对临床变量（包括年龄、性别、种族、细胞遗传学风险类别和 CD34+ 细胞剂量）的多变量分析中，只有通过 RQ-PCR 评估的自体移植多基因 MRD 与复发具有统计学显着相关性。移植一年后，只有 28% 可检测到自体移植 MRD 的患者没有复发，而 MRD 阴性队列中这一比例为 67%。多基因 MRD 虽然比其他测试方法有所改进，但对于未经选择的患者的复发预测并不是最理想的，特异性为 83%，敏感性为 46%。然而，在已知染色体异常或突变的患者中，与 MRD 阳性患者的复发率 83% 相比，自动 HCT 后第一年 MRD 阴性患者没有观察到复发，观察到更好的预测价值（HR 12.45，p=0.0016）。总之，通过使用多基因组增强 MRD 监测的个性化，提高了对患者进行自动 HCT 复发风险分层的能力。自体移植样本中 AML MRD 的 WT1 RQ-PCR 和流式细胞术评估对于预测自体 HCT 后复发的价值有限。我们证明，由于先前 GCSF 暴露对基因表达和流式细胞术特征的掩盖效应，冷冻保存的自体移植材料对 AML MRD 测试提出了独特的挑战。在缺乏有关诊断特征的信息的情况下，对于接受自动 HCT 的 AML 患者，应考虑使用 GCSF 刺激的 PBSC 白细胞分离标本以外的来源作为 MRD 检测的替代方法。
We report here the largest study to date of adult AML patients tested for measurable residual disease (MRD) at the time of autologous hematopoietic cell transplantation (auto-HCT). Seventy-two adult patients transplanted between 2004–2013 at a single academic medical center (UCSF) were eligible for this retrospective study based on availability of cryopreserved GCSF mobilized autologous peripheral blood progenitor cell (PBPC) leukapheresis specimens (“autografts”). Autograft MRD was assessed by molecular methods (RQ-PCR for WT1 alone or a multigene panel) and by multi-parameter flow cytometry (MPFC). WT1 RQ-PCR testing of the autograft had low sensitivity for relapse prediction (14%) and a negative predictive value of 51%. MPFC failed to identify MRD in any of 34 autografts tested. Combinations of molecular MRD assays however improved prediction of post auto-HCT relapse. In multivariate analysis of clinical variables, including age, gender, race, cytogenetic risk category, and CD34+ cell dose, only autograft multigene MRD as assessed by RQ-PCR was statistically significantly associated with relapse. One year after transplantation only 28% patients with detectable autograft MRD were relapse free, compared with 67% in the MRD negative cohort. Multigene MRD, while an improvement on other methods tested, was however suboptimal for relapse prediction in unselected patients with specificity of 83% and sensitivity of 46%. In patients with known chromosomal abnormalities or mutations, however, better predictive value was observed with no relapses observed in MRD negative patients in the first year after auto-HCT compared with 83% incidence of relapse in the MRD positive patients (HR 12.45, p=0.0016). In summary, increased personalization of MRD monitoring by use of a multigene panel improved the ability to risk stratify patients for post auto-HCT relapse. WT1 RQ-PCR and flow cytometric assessment for AML MRD in autograft samples had limited value for predicting relapse following auto-HCT. We demonstrate that cryopreserved autograft material presents unique challenges for AML MRD testing due to masking effects of previous GCSF exposure on gene expression and flow cytometry signatures. In the absence of information regarding diagnostic characteristics, sources other than GCSF-stimulated PBSC leukapheresis specimens should be considered as alternatives for MRD testing in AML patients undergoing auto-HCT.
登录
查看更多内容
影响因子：
20.3
作者：
Buccisano, Francesco;Maurillo, Luca;Venditti, Adriano
通讯作者：
Venditti, Adriano
影响因子：
158.5
作者：
Cassileth, PA;Harrington, DP;Wiernik, PH
通讯作者：
Wiernik, PH
影响因子：
3
作者：
Beumer, Jan H.;Owzar, Kouros;Lewis, Lionel D.;Jiang, Chen;Holleran, Julianne L.;Christner, Susan M.;Blum, William;Devine, Steven;Kolitz, Jonathan E.;Linker, Charles;Vij, Ravi;Alyea, Edwin P.;Larson, Richard A.;Ratain, Mark J.;Egorin, Merrill J.
通讯作者：
Egorin, Merrill J.
影响因子：
45.3
作者：
Araki, Daisuke;Wood, Brent L.;Walter, Roland B.
通讯作者：
Walter, Roland B.
影响因子：
45.3
作者：
Cilloni, Daniela;Renneville, Aline;Grimwade, David
通讯作者：
Grimwade, David