基因图谱可为MDS患者进行干细胞移植

根据丹娜法伯癌症研究所和布列根和妇女医院科学家的一项新研究，单一的血液检测以及有关医疗状况的基本信息表明骨髓增生异常综合征（MDS）患者可能获益于干细胞移植，而且移植前化疗和/或放疗的强度可能会产生佳的治疗结果。

在新英格兰医学杂志出版的一项研究中，研究者报告当考虑到患者年龄和其他因素时，患者血细胞的基因图谱能预测患者对干细胞移植的反应，并且帮助医生选择有效的移植前联合疗法。研究结果基于1514名MDS患者的血液样本分析，其中患者年龄分布从6个月龄到70岁以上不等，该项研究是与血液骨髓移植研究中心的研究者合作进行研究的。

MDS是起源于造血干细胞的一组异质性髓系克隆性疾病，特点是髓系细胞分化及发育异常，表现为无效造血、难治性血细胞减少、造血功能衰竭以及高风险白细胞转化。治疗方法会因骨髓增生异常综合征患者的具体类型而有所差异。供体干细胞移植通常用于标准治疗中有高风险死亡率的患者。

该项研究的主要作者，即丹娜法伯的医学博士R.Coleman Lindsley说道：“虽然供体干细胞移植是治疗MDS的治疗方法，但是在很大程度上由于该疾病的复发或与移植自身相关的并发症等原因，大部分患者在移植后都会死亡。而作为一名医生，主要的一个挑战就是能够预测有可能获益于移植的患者。提高医者自身能力确定有可能出现复发或移植后出现危及生命的并发症患者，进而能够获得更好的移植前治疗方法和手段，以预防疾病复发。”

研究者很早以前就了解到MDS患者血细胞内的特定基因突变与疾病发生的过程密切相关。本研究旨在寻求突变是否还可以用于预测供体干细胞移植后患者的状况。

数据分析表明MDS患者重要的一个特征是他们的血液细胞是否在基因TP53中携带突变。与缺乏细胞突变的患者相比，这些患者趋向于移植后存活较短时间，而且还会加快复发的速率。在移植前不管是接受标准“调节”治疗（包括化疗和/或放疗），还是降低强度调节（即该治疗是采用低剂量的一种治疗方法），上述表述都是正确的。根据上述研究结果，现如今丹娜法伯的医生正在致力于研究新的治疗手段以克服MDS中TP53突变所产生的问题。

在40岁及40岁以上患MDS且未携带TP53突变的患者中，与没有RAS或JAK2突变的患者相比，RAS通路基因或JAK2基因突变的患者趋向于较短的生存期。与TP53突变相比，RAS突变的生存率和复发风险的副作用在降低强度调节中显而易见。研究者指出该结果表明上述患者受益于较高的强度调节方案。

该项研究还在特殊患者群体中获得了有关MDS生物学的重要见解。令人惊奇的是，发现25例MDS患者中（年龄均介于18至40岁之间）有一例出现髓增生异常症候症（髓增生异常症候症是一种罕见的遗传疾病，其通常会影响骨髓、胰腺和骨骼系统。）导致的突变，但是大部分患者先前都没有被诊断为该疾病。各个病例中，患者的血细胞已获得TP53突变，不仅表明MDS在髓增生异常症候症患者中如何形成，而且还指明了移植后预后较差的原因。

研究者还分析了先前癌症治疗导致出现MDS（治疗相关的MDS）的患者。其发现与缺乏既往癌症治疗而出现此疾病的患者相比，TP53突变和PPM1D突变（其是一种能够调节TP53功能的基因）在这些患者中更加常见。

Lindsley说道：“在决定干细胞移植对MDS患者是否合适时，平衡潜在受益和并发症的风险是很有必要的。基于疾病的基因图谱和某种临床因素，我们的研究结果给医生提供了一种指导，以确定移植对患者来说是合适的，而且治疗的强度也是有效的。”

该项研究的资深作者是布列根和妇女医院（BWH）的Benjamin Ebert博士。共同作者是丹娜法伯和布列根和妇女医院的Brenton Mar博士、Robert Redd、Corey Cutler博士、Joseph Antin和Donna Neuberg;以及在威斯康兴医学院国际血液和骨髓移植研究中心（CIBMTR）的Wael Saber、胡振欢和王涛博士；CIBMTR的Michael Haagenson和Stephen Spellman。

本项研究获得了由爱德华·埃文斯基金会、哈佛催化剂KL2-CMeRIT奖、国家骨髓捐赠计划免疫生物学研究助学金、美国国立卫生研究院（R01HL082945，R24DK099808，以及5P30 CA006516）和白血病和淋巴瘤协会提供的资助。

Genetic profiling can guide stem cell transplantation for patients with myelodysplastic syndrome, study finds

A single blood test and basic information about a patient’s medical status can indicate which patients with myelodysplastic syndrome (MDS) are likely to benefit from a stem cell transplant, and the intensity of pre-transplant chemotherapy and/or radiation therapy that is likely to produce the best results, according to new research by scientists at Dana-Farber Cancer Institute and Brigham and Women’s Hospital.

In a study published in the New England Journal of Medicine, the investigators report that genetically profiling a patient’s blood cells, while factoring in a patient’s age and other factors, can predict the patient’s response to a stem cell transplant and help doctors select the most effective combination of pre-transplant therapies. The findings are based on an analysis of blood samples from 1,514 patients with MDS, ranging in age from six months to more than 70 years, performed in collaboration with investigators from the Center for Blood and Marrow Transplant Research.

MDS is a family of diseases in which the bone marrow produces an insufficient supply of healthy blood cells. Treatments vary depending on the specific type of MDS a patient has; donor stem cell transplants are generally used for patients with a high risk of mortality with standard treatments.

“Although donor stem cell transplantation is the only curative therapy for MDS, many patients die after transplantation, largely due to relapse of the disease or complications relating to the transplant itself,” said the study’s lead author, R. Coleman Lindsley, MD, PhD, of Dana-Farber. “As physicians, one of our major challenges is to be able to predict which patients are most likely to benefit from a transplant. Improving our ability to identify patients who are most likely to have a relapse or to experience life-threatening complications from a transplant could lead to better pre-transplant therapies and strategies for preventing relapse.”

Researchers have long known that the specific genetic mutations within MDS patients’ blood cells are closely related to the course the disease takes. The current study sought to discover whether mutations also can be used to predict how patients will fare following a donor stem cell transplant.

Analysis of the data showed that the single most important characteristic of a patient’s MDS was whether their blood cells carried a mutation in the gene TP53. These patients tended to survive for a shorter time after a transplant, and also relapse more quickly, than patients whose cells lacked that mutation. This was true whether patients received standard “conditioning” therapy (which includes chemo- and/or radiation therapy) prior to transplant or received reduced-intensity conditioning, which uses lower doses of these therapies. Based on these results, doctors at Dana-Farber are now working on new strategies to overcome the challenges posed by TP53 mutations in MDS.

In patients 40 years old and over whose MDS didn’t carry TP53 mutations, those with mutations in RAS pathway genes or the JAK2 gene tended to have a shorter survival than those without RAS or JAK2 mutations. In contrast to TP53 mutations, the adverse effect of RAS mutations on survival and risk of relapse was evident only in reduced-intensity conditioning. This suggests that these patients may benefit from higher intensity conditioning regimens, the researchers indicated.

The study also yielded key insights about the biology of MDS in specific groups of patients. Surprisingly, one in 25 patients with MDS between the ages of 18 and 40 were found to have mutations associated with Shwachman-Diamond syndrome (a rare inherited disorder that often affects the bone marrow, pancreas, and skeletal system), but most of them had not previously been diagnosed with it. In each case, the patients’ blood cells had acquired a TP53 mutation, suggesting not only how MDS develops in patients with Schwachman-Diamond syndrome but also what underlies their poor prognosis after transplantation.

The researchers also analyzed patients whose MDS arose as a result of previous cancer therapy (therapy-related MDS). They found that TP53 mutations and mutations in PPM1D, a gene that regulates TP53 function, were far more common in these patients than in those whose disease occurred in the absence of previous cancer treatment.

“In deciding whether a stem cell transplant is appropriate for a patient with MDS, it’s always necessary to balance the potential benefit with the risk of complications,” Lindsley remarked. “Our findings offer physicians a guide – based on the genetic profile of the disease and certain clinical factors – to identifying patients for whom a transplant is appropriate, and the intensity of treatment most likely to be effective.”

The senior author of the study is Benjamin Ebert, MD, PhD, of Brigham and Women’s Hospital (BWH). Co-authors are Brenton Mar, MD, PhD, Robert Redd, MS, Corey Cutler, MD, MPH, Joseph Antin, MD, and Donna Neuberg, ScD, of Dana-Farber and BWH; Wael Saber, MD, MS, Zhenhuan Hu, MPH, and Tao Wang, PhD, of the Center for International Blood and Marrow Transplant Research (CIBMTR) at the Medical College of Wisconsin; Michael Haagenson, MS, and Stephen Spellman, MBS, of CIBMTR, National Marrow Donor Program/Be The Match®, Minneapolis, Minn.; Peter Grauman, of BWH; Stephanie Lee, MD, of Fred Hutchinson Cancer Research Center; Michael Verneris, MD, of the University of Minnesota; Katharine Hsu, MD, PhD, of Memorial Sloan-Kettering Cancer Center; and Katharina Fleischhauer, MD, of University Hospital Essen, Essen, Germany.

Support for the study was provided by a grant from the Edward P. Evans Foundation; a Harvard Catalyst KL2–CMeRIT Award; a National Marrow Donor Program Immunobiology Research Study grant; grants from the National Institutes of Health (R01HL082945, R24DK099808, and 5P30 CA006516); and a grant from the Leukemia & Lymphoma Society.

媒体链接:基因图谱可为MDS患者进行干细胞移植