我們如何治療高危骨髓增生異常綜合徵(MDS)？作者：邁克爾 A.Sekeres 克利夫蘭臨床腫瘤研究所（讀書心得）河南省腫瘤醫院血液科劉新建
2014年12月6日在美國舊金山參加美國血液病年會期間，有幸聆聽了美國克利夫蘭臨床腫瘤研究所的邁克爾教授的《骨髓增生異常綜合徵的治療及新藥進展》，感覺很受鼓舞。今天再次找出邁克爾教授發表在2014年2月的《BLOOD》上的《我們如何治療高危骨髓增生異常綜合徵》拜讀，現將讀書心得給大家共享：
高危骨髓增生異常綜合徵(MDS)是指按照IPSS評分：中危-2、高危組的MDS患者。或者IPSS-R評分：高危、非常高危及部分中危患者。或者按照WHO組織學分類RAEB-1RAEB-2患者。這組患者生存時間較短，一旦確診，應儘快進行治療。這組患者的標準治療方案是去甲基化治療，有合適供者及身體條件合適者應著手進行造血幹細胞移植。去甲基化治療的藥物主要有阿扎胞苷、地西他濱。這兩種藥物至少要應用6個週期，然後繼續每三個月進行一次維持治療，直到患者對藥物無反應。患者如果對藥物無反應，其他的治療方法有限，患者的生存期也很短。這時應該考慮臨床試驗，進行新的藥物治療。
患者如果體能狀態很好，無明顯的共患病，有合適的造血幹細胞供者，應該提前進行造血幹細胞移植準備。至於移植前治療，去甲基化治療及誘導化療均要進行，或者進入臨床試驗。儘管移植前的最好治療方法我們換不知道，但是這些治療可以阻止疾病進展。
How we treat higher-risk myelodysplastic syndromes
Mikkael A. Sekeres and Corey Cutler
Higher-risk myelodysplastic syndromes (MDS) are defined by patients who fall into higher-risk group categories in the original or revised International Prognostic Scoring System. Survival for these patients is dismal, and treatment should be initiated rapidly. Standard therapies include the hypomethylating agents azacitidine and decitabine, which should be administered for a minimum of 6 cycles, and continued for as long as a patient is responding. Once a drug fails in one of these patients, further treatment options are limited, median survival is<6 months, and consideration should be given to clinical trials. Higher-risk eligible patients should be offered consultation to discuss hematopoietic stem cell transplantation close to the time of diagnosis, depending on patient goals of therapy, with consideration given to proceeding to transplantation soon after an optimal donor is located. In the interim period before transplantation, hypomethylating agent therapy, induction chemotherapy, or enrollment in a clinical trial should be considered to prevent disease progression, although the optimal pretransplantation therapy is unknown.
Introduction
The myelodysplastic syndromes (MDS) are the most commonly diagnosed myeloid neoplasms in the United States, with an incidence rate of 4.6 in100 000 US citizens, translating to approximately 15 000 new diagnoses yearly.1 This figure is often considered to be an underestimate, because data derived from the National Cancer Institute’s Surveillance, Epidemiology, and End Results program and the North American Association of Central Cancer Registries are likely compromised by under-reporting (thought to be a result of misconceptions about the disease’s neoplastic basis and variability in diagnostic prowess) and misclassification (as evidenced by the 50% of patients in such registries identified as “MDSCunclassifiable”).2,3
MDS represents a constellation of diagnoses increasingly identified by underlying genetic abnormalities, such as the del(5q) syndrome, SF3B1 mutations in MDS with ring sideroblasts along with other splicing factors, abnormalities along tyrosine kinase pathways (such as CBL and NRAS), mutated genes involved with epigenetic dysregulation (TET2, DNMT3A, EZH2, IDH1 and 2, and ASXL1), and mutations in transcription factors (RUNX1, ETV6)4⇓⇓⇓⇓⇓⇓⇓⇓⇓⇓⇓⇓⇓⇓⇓⇓⇓⇓⇓⇓⇓⇓⇓⇓⇓⇓⇓⇓-33; and on a disease biology that at some extremes is typified by excessive production of proapoptotic, proinflammatory cytokines and premature death of hematopoietic stem cells, and at others by excessive proliferations, epigenetic regulation, and a block in differentiation.34⇓⇓⇓-38 Molecular data are becoming disease defining (as with spliceosome mutations in MDS with ring sideroblasts), have been incorporated into prognostic scoring systems and are anticipated to provide additional resolution to these systems, and have been linked to therapeutic responsiveness (discussed later). However, the degree to which they will modify risk estimates in MDS is being explored by an international working group.5,7,22,39,40
Treatment decisions in MDS are based on pathology, or a prognostic scoring system appropriated as a default staging system, and are now incorporated into drug labeling.41 As a result, the classification of MDS patients has become reductionist, with patients divided into those with lower-risk or higher-risk disease, as determined by prognostic systems that are based most commonly on blast percentage, cytogenetic risk groups, and cytopenias, but which may also include age, performance status, transfusion needs, and other clinical (and increasingly molecular) factors.42⇓-44 Patients with higher-risk disease fall into International Prognostic Scoring System (IPSS) categories of Intermediate-2 and High groups, corresponding largely to IPSS-R groups Very High, High, and, sometimes, Intermediate, and which often correspond to World Health Organization (WHO) histologic subtypes of refractory anemia with excess blasts (RAEB)-1 and RAEB-2, with an expected median overall survival of<2 years.4,41,45 Whether survival estimates can be adjusted within the modern therapeutic era has not yet been determined. Correlations between IPSS/IPSS-R and WHO classifications are loose, because some patients with excess blasts but normal karyotype and limited cytopenias can live for years, whereas those with few blasts, complex karyotype, and profound cytopenias may have a shortened survival rate.
Treatment options for patients with lower-risk MDS have recently been reviewed.46 The treatment of an MDS patient with higher-risk disease starts with recognition of the imperative to initiate therapy. Accepting the premise that the IPSS is a default MDS staging system, with Low-High reflecting stages I-IV, and comparing it stage-for-stage with American Joint Committee on Cancer staging for nonCsmall-cell lung cancer, overall survival is worse for patients with MDS.47,48 Just as it would be poor practice in a patient with stage III or IV lung cancer, acceptable comorbidities, a good performance status, and a desire to receive treatment to recommend watchful waiting simply because that patient does not yet have debilitating symptoms, so too would therapy avoidance be discouraged in a similar MDS patient with Intermediate-2 or High risk of disease. We offer examples of 2 patients and answer the typical questions posed to us by informed patients to illustrate how we approach higher-risk MDS.
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