预后 npm1_NPM1突变型AML患者移植后的分子学MRD状态与转归

Richard Dillon,^1-3 Robert Hills,⁴ Sylvie Freeman,⁵ Nicola Potter,^1,2 Jelena Jovanovic,¹ Adam Ivey,¹ Anju Shankar Kanda,¹ Manohursingh Runglall,¹ Nicola Foot,² Mikel Valganon,² Asim Khwaja,⁶ Jamie Cavenagh,⁷ Matthew Smith,⁷ Hans Beier Ommen,⁸ Ulrik Malthe Overgaard,⁹ Mike Dennis,¹⁰ Steven Knapper,¹¹ Harpreet Kaur,¹² David Taussig,¹³ Priyanka Mehta,¹⁴ Kavita Raj,³ Igor Novitzky-Basso,¹⁵ Emmanouil Nikolousis,¹⁶ Robert Danby,¹⁷ Pramila Krishnamurthy,¹⁸ Kate Hill,¹⁹ Damian Finnegan,²⁰ Samah Alimam,^1,3 Erin Hurst,²¹ Peter Johnson,²² Anjum Khan,²³ Rahuman Salim,²⁴ Charles Craddock,²⁵ Ruth Spearing,²⁶ Amanda Gilkes,¹¹ Rosemary Gale,⁶ Alan Burnett,²⁷ Nigel H. Russell,^3,28 David Grimwade,^1,3 on behalf of the UK National Cancer Research Institute Acute Myeloid Leukaemia Working Group ¹Department of Medical and Molecular Genetics, King’s College, London, United Kingdom; ²Cancer Genetics Service, Viapath, Guy’s Hospital, London, United Kingdom; ³Department of Haematology, Guy’s Hospital, London, United Kingdom; ⁴Nuffield Department of Population Health, University of Oxford, United Kingdom; ⁵Institute of Immunology and Immunotherapy, University of Birmingham, United Kingdom; ⁶Department of Haematology, University College, London, United Kingdom; ⁷Bart’s Hospital, London, United Kingdom; ⁸University Hospital, Aarhus, Denmark; ⁹Rigshospitalet, Copenhagen, Denmark; ¹⁰Christie Hospital, Manchester, United Kingdom; ¹¹Department of Haematology, Cardiff University, Cardiff, United Kingdom; ¹²Royal Hallamshire Hospital, Sheffield, United Kingdom; ¹³Royal Marsden Hospital, Sutton, United Kingdom; ¹⁴Bristol Haematology and Oncology Centre, Bristol, United Kingdom; ¹⁵Beatson Cancer Centre, Glasgow, United Kingdom; ¹⁶Heartlands Hospital, Birmingham, United Kingdom; ¹⁷Churchill Hospital, Oxford, United Kingdom; ¹⁸Addenbrooke’s Hospital, Cambridge, United Kingdom; ¹⁹University Hospital, Southampton, United Kingdom; ²⁰Belfast City Hospital, Belfast, United Kingdom; ²¹Royal Victoria Infirmary, Newcastle, United Kingdom; ²²Western General Hospital, Edinburgh, United Kingdom; ²³St James’ Hospital, Leeds, United Kingdom; ²⁴Clatterbridge Cancer Centre, Liverpool, United Kingdom; ²⁵Queen Elizabeth Hospital, Birmingham, United Kingdom; ²⁶Christchurch Hospital, Christchurch, New Zealand;²⁷Blackwaterfoot, Isle of Arran, United Kingdom; ²⁸Nottingham University Hospital, Nottingham, United Kingdom 翻译：黄燕 福建医科大学附属协和医院血液科 审校：胡建达 福建医科大学附属协和医院血液科 摘要 关键点：

• 移植前MRD水平可预测结局；外周血中200个拷贝/10⁵ ABL和骨髓中1,000个拷贝/10⁵ ABL的阈值是有区别的。
• 移植前MRD阳性低于这些水平的患者的复发主要限于FLT3-ITD患者。

摘要 对于接受异基因造血干细胞移植(allogeneic stem cell transplantation, alloSCT)的急性髓系白血病(acute myeloid leukemia, AML)患者来说，复发仍然是治疗失败的最常见原因，且预后不良。多项研究已表明，在alloSCT前通过流式细胞术评估存在微小残留病灶(measurable residual disease, MRD)是复发的有力预测因素。但是，尚不清楚如何将这些发现应用于由具有更高敏感性的分子学检测为MRD阳性的患者中。针对入组英国国家癌症研究中心AML17研究的107例NPM1突变型AML患者，我们进行了移植前血液和骨髓样本的逆转录聚合酶链式反应分析。在中位随访4.9年后，MRD阴性、低水平(外周血中<200个拷贝/10⁵ ABL，骨髓液中<1,000个拷贝/10⁵ ABL)和高水平患者的2年总生存率(2-year overall survival, 2y-OS)分别为83%、63%和13%(P<0.0001)。对alloSCT前MRD低水平患者来说，存在FLT3内部串联重复序列(internal tandem duplications, ITDs)的患者预后明显较差(风险比[hazard ratio, HR]，6.14；P=0.01)。结合这些具有高预测价值的变量将患者分为2组，其2y-OS分别为17%和82%(HR，13.2；P<0.0001)。在整个队列和MRD阳性的患者中，去T细胞治疗与显著降低的生存率有关，2y-OS分别为 56% vs 96%(HR，3.24；P=0.0005)及34% vs 100%(HR，3.78；P=0.003)，但是预处理方案或供者来源则对其没有显著影响。本研究注册于ISRCTN(http://www.ISRCTN.com/ISRCTN55675535)。(Blood. 2020;135(9):680-688) 表1.每个MRD定义的组中的临床、分子和移植相关变量。 Spearman相关性P值用于年龄比较，Mantel-Haenszel P值用于所有其他变量。CR1，首次完全缓解；PB，外周血。 https://doi.org/10.1182/blood.2019002959 美国血液学会授权富博思开发Blood中文版，内容摘自Blood原刊。版权 ©2019 美国血液学会，版权所有。“美国血液学会”、“ASH”以及ASH的标志皆为美国血液学会的注册商标。