骨髓增生异常综合征预后因素分析

目的：探讨ＭＤＳ初诊时临床表现及实验室多参数对预后的影响。以利于采取有效的防治对策。方法：采用病例对照方法研究不同年龄、性别、初诊临床表现、ＦＡＢ分型、实验室检查的ＭＤＳ患者的转白率和中数生存期，并对ＭＤＳ死亡危险因素进行多元回归分析。结果：剧烈骨痛、Ｈｂ＜ ３０ｇ／Ｌ、外周血粒系发育异常、ＲＡＥＢ、ＲＡＥＢ－Ｔ ＭＤＳ亚型、骨髓或外周血原始细胞＞ ５％ 、伴发ＭＦ和ＡＬＩＰ（＋ ）、－ ７／７ｑ－ ，＋ ８ 染色体异常或复合染色体异常为ＭＤＳ预后不良因素。而Ｈｂ＞ ９０ ｇ／Ｌ、核型正常或单纯５ ｑ－ 、２０ ｑ－ 、１３ ｑ－ 则预后较好。结论：ＭＤＳ患者初诊时临床表现、实验室指标与预后有关。综合分析上述因素将可能提供ＭＤＳ有价值的预后信息。     

Immunomodulatory Therapy for Myelodysplastic Syndromes

Thalidomide and lenalidomide belong to the proprietary group of immunomodulatory drugs (IMiDs) that display broad biologic and pharmacologic properties. Encouraging results of clinical studies that evaluated the efficacy of thalidomide in patients with myelodysplastic syndromes (MDSs) led to the investigation of its structural analogue, lenalidomide, in patients with lower-risk MDS. The cumulative results of studies that tested lenalidomide in patients with interstitial deletion of chromosome 5q, ie, del(5q), showed a high frequency of both erythroid and cytogenetic responses (approximately 75% of patients), which led to US Food and Drug Administration approval of this agent for this cytogenetically defined MDS subset. A multicenter phase III study (MDS-002) that investigated the frequency of transfusion response in lower-risk non-del(5q) MDS patients showed that lenalidomide had significant erythropoietic activity, albeit less robust in lower-risk MDS without del(5q). These studies established lenalidomide as an active erythropoietic-remitting agent with novel cytogenetic-remitting activity in lower-risk MDS patients who would not otherwise benefit from therapy with erythropoietic growth factors. The National Comprehensive Cancer Network Clinical Practice Guidelines recently added lenalidomide to the therapeutic algorithm for MDS as front-line therapy for lower-risk MDS patients with del(5q) and transfusion-dependent anemia.     

Oxidative Stress and the Myelodysplastic Syndromes

The evolution of higher organisms from anaerobic to aerobic living has promoted an elaborate mechanism of defense against potentially toxic oxidants. Many environmental toxicants implicated in the pathogenesis of myelodysplastic syndromes (MDS), including benzene and ionizing radiation, exert toxicity via pro-oxidant mechanisms. The emerging data suggest a probable genetic susceptibility to environmental carcinogenesis through functional polymorphic variants in enzymes that metabolize toxicants and/or protect against oxidative stress. The most studied enzyme is NAD(P)H:quinone oxidoreductase (NQO1). CD34+ cells from individuals homozygous for the NQO1 C609T nonfunctional allelic variant are incapable of enzyme induction following exposure to benzene, thus potentially increasing the hematotoxicity of benzene metabolites. Serologic and molecular markers of oxidative stress are present in many patients with MDS and include an increased concentration of the lipid peroxidation product malondialdehyde and the presence of oxidized bases in CD34+ cells. Potential mechanisms of oxidative stress include mitochondrial dysfunction via iron overload and mitochondrial DNA mutation, systemic inflammation, and bone marrow stromal defects. The biological activity of the antioxidant aminothiol amifostine in vivo suggests that these pathways may be meaningful targets for future therapy in MDS patients.     

Room for Improvement: A 20-Year Single Center Experience with Allogeneic Stem Cell Transplantation for Myelodysplastic Syndromes

Allogeneic stem cell transplantation (allo-SCT) remains the only curative therapeutic approach for patients with myelodysplastic syndromes (MDS). The aim of the study was to assess the efficacy/safety of allo-SCT as well as to identify factors influencing post-transplant survival. One hundred and two MDS patients (median age: 48 years; 57 males) who underwent allo-SCT were retrospectively evaluated. Twenty seven patients were transplanted from HLA-matched sibling and 75 patients received grafts from unrelated donors. Peripheral blood was a source of stem cell for 79 patients. Reduced intensity conditioning was used in 64 subjects. Acute and chronic graft versus host disease (GvHD) developed in 61 and 19 of patients, respectively. In total, 61 patients have died. The causes of deaths included infectious complications (n = 30), steroid-resistant GvHD (n = 17), MDS relapse (n = 9) and transformation to AML (n = 5). Non-relapse mortality and cumulative incidence of relapse at 2 years were 49.8% and 9%, respectively. 41 patients are alive at last contact and present full donor chimerism. 38 patients remain in complete hematological remission (CHR), 3 patients had CHR with incomplete platelet recovery. Median follow-up from diagnosis of MDS and transplantation are 27.1 months and 7 months respectively. Overall survival and relapse-free survival were 41% at 2 years. Increased serum ferritin level > 1000 ng/ml, presence of acute GvHD, grades III–IV acute GvHD and high hematopoietic cell transplantation-comorbidity index were found to negatively influenced survival. Allo-SCT for MDS is feasible procedure with a proportion of patients to be cured.     

高危骨髓增生异常综合征,继发白血病常规剂量联合化疗

报告常规剂量联合方案治疗病危骨髓增生异常综合征及其继发白血病20例，完全缓解率45．0％，部分缓解率5．0％，总有效率50．0％、用小剂量阿精胞对治疗高危骨髓增生异常综合征20例，完全缓解率25．0％，部分缓解率20．0％，总有效节45．0％。二组骨髓增生异常综合征患者疗效之间比较差异不明显（P＞0．05）。对年轻高危骨髓增生异常综合征患者采用常规剂量联合化疗，在延长病人生存期和提高生存质量上都具有重要临床意义。     

Preliminary Studies on Melatonin in the Treatment of Myelodysplastic Syndromes Following Cancer Chemotherapy

Experimental studies have suggested that the pineal hormone melatonin, in addition to its documented antineoplastic action, plays a role in the physiological regulation of blood cell proliferation. Based on these data, we evaluated the clinical effects of melatonin therapy in patients with myelodysplastic syndrome (MDS) secondary to cancer chemotherapy for primary neoplasms. The study was carried out on six patients, and melatonin was given orally at a dose of 20 mg/daily, following a schedule prepared to reproduce the circadian rhythm of the pineal hormone. A transient improvement in platelet and neutrophil count was achieved in two of five patients with thrombocytopenia and in two of four patients with neutropenia before therapy, respectively, while no effect was seen on hemoglobin concentration. Mean survival time was 12.5 months, and a long survival, greater than 30 months, was achieved in two of six patients. These preliminary results seem to suggest that melatonin may have a role in the treatment of MDS induced by previous cancer chemotherapy.     

Myelodysplastic syndromes

The authors review the epidemiological biological, diagnostic, prognostic and therapeutic aspects of myelodysplastic syndromes.     

骨髓增生异常综合征患者血清GM-CSF水平测定及意义

目的 :了解 MDS患者血清 GM- CSF水平并探讨其意义。方法 :采用放射免疫法测定 32例MDS、35例健康人血清 GM- CSF水平 ,t检验行统计学处理。结果 :同正常人相比 ,MDS患者血清GM- CSF水平明显下降 ( 54.86± 17pg/ ml;34 .0 1± 14pg/ ml)。结论 :MDS患者 GM- CSF自分泌水平较正常人降低 ,GM- CSF分泌水平与 MDS分型无明显相关性 ,与疗效无肯定关系。     

骨髓增生异常综合征红细胞酶谱测定临床应用研究

本文比较了２３例ＭＤＳ和９例ＡＡ患者４种红细胞酶的活性，除醛缩酶外，丙酮酸激酶嘌呤核苷磷酸化酶、腺苷脱氨酸在ＡＡ患者均接近正常，和ＭＤＳ差异显著，尤其是ＰＫ和ＰＮＰ差异显著。据此联合检测红细胞４种酶活性，建立了ＭＤＳ和ＡＡ的差别函数式：ＰＭＤＳ＝－５．０４１０７＋０．２５６７４ＰＫ＋１．６７６５１ＡＬＤ＋０．０３４８１ＰＮＰ＋０．２５０２４ＡＤＡ，ＰＡＡ＝－７．９００３８＋０．３８４６ＰＫ＋１．４     

骨髓增生异常综合征骨髓活检的临床意义和预后价值

本文对82例初诊的骨髓增生异常综合征(MDS)进行骨髓活检,分析组织学特征与临床的关系。研究表明:未成熟前体细胞异常定位(ALIP)、原红细胞小岛、异形巨核细胞和红细胞是MDS的主要组织学特征,并伴有骨髓基质成分的病理改变。同时,对骨髓造血组织增生程度的判断有重要的预后价值,增生愈活跃,预后愈差。     

Myelodysplastic syndrome associated with multiple autoimmune disorders

The association between myelodysplastic syndromes (MDS) and autoimmune manifestations is not uncommon. As a rule, autoimmune abnormalities follow the diagnosis of MDS. We describe here a patient with MDS who developed a striking spectrum of diverse autoimmune disorders, including dermatitis, polyarthritis, and vasculitis, which preceded the clinical appearance of MDS.     

Epidemiology, classification and prognosis of adults and children with myelodysplastic syndromes

Myelodysplastic syndromes (MDS) belong to the most frequent bone marrow diseases with a crude incidence of about 4 in 100,000 per year. The diagnosis of MDS still is mainly based on morphologic findings in blood and marrow. The new WHO classification system takes into account the medullary and peripheral blast count as well as the degree of dysplasia in the different cell lines. To correctly identify MDS types, cytogenetic evaluation is of importance, as the WHO classification introduced the entity MDS with del(5q), which is characterized by special morphologic and hematologic features. The separation of MDS from acute leukemias has been redefined using a cutoff value of 20% peripheral and/or medullary blasts. The International Prognostic Scoring System still is the gold standard in prognostication, but new items like transfusion need will be used more and more and have been incorporated into the WHO adapted Prognostic Scoring System. In childhood, MDS is uncommon, accounting for less than 5% of all hematopoietic neoplasms in patients less than 14 years of age. To accommodate for the characteristics of pediatric MDS, a simple classification scheme based on morphological features and conforming with the WHO suggestions was proposed. The dysplastic prodrome of acute myeloid leukemia in Down syndrome is classified within myeloid leukemia in Down syndrome and excluded from the population-based studies of MDS.     

Treatment of Myelodysplastic Syndrome with Cyclosporin A

A multicenter prospective study was carried out to evaluate the efficacy of cyclosporin A (CsA) in 32 patients with myelodysplastic syndromes. The FAB subtypes of the patients included refractory anemia, refractory anemia with ringed sideroblasts, and refractory anemia with excess blasts. The dosage of CsA was 3 to 6 mg/kg per day and was adjusted according to the blood concentration of CsA and the responses of patients. The drug was administered twice a day for more than 3 months. After 3 months of treatment, hematological improvement was observed in 18 of 32 patients (56.3%) by the criteria of the International Working Group. At the end of the follow-up (median time, 14 months), 4 patients showed alteration of disease progression, including 1 complete remission and 3 partial remissions, and 16 patients showed hematological improvement. There were a total of 20 responders. The response rate was 62.5% (20/32). It was shown that the CsA therapy was effective in patients with refractory anemia or refractory anemia with excess blasts and both hypo- and hyperplastic bone marrows might respond to the therapy. The survival time was significantly longer in responders than in nonresponders. The study shows that CsA therapy is potentially the most effective therapy for myelodysplastic syndromes.     

1，25二羟维生素D_3、全反式维甲酸、阿糖胞苷联合治疗骨髓增生异常综合征

应用１，２５二羟维生素Ｄ_３（１．２５（ＯＨ）２Ｄ３）、全反式维甲酸（ＲＡ）和小剂量阿糖胞苷（ＡｒａＣ）或无细胞胎肝液联合治疗骨髓增生异常综合征（ＭＤＳ）１８例，完全缓解（ＣＲ）２例，部分缓解（ＰＲ）８例，总有效率５５．６％，平均生效时间４５．９天，平均达标准时间５５．９天，疗效持续３个月至４年；未达疗效标准者血像也有不同程度改善，毒性可耐受。     

小剂量马法兰治疗高危骨髓增生异常综合征的临床观察

目的：观察小剂量马法兰治疗高危骨髓增生异常综合征,即原始细胞过多的难治性贫血（ＲＡＥＢ）和转变中的原始细胞过多的难治性贫血（ＲＡＥＢ－Ｔ）的疗效。方法：应用马法兰２ｍｇ,隔日一次口服,治疗高危骨髓增生异常综合征１３例。结果：完全缓解５例,部分缓解２例,进步１例,总有效率６１．５％。除２例轻度骨髓抑制外,无其他毒副反应。结论：小剂量马法兰治疗高危骨髓增生异常综合征具有安全有效、服用方便、费用低廉等特     

Practical recommendations on the use of lenalidomide in the management of myelodysplastic syndromes

Lenalidomide, an oral immunomodulatory agent, has received approval in the USA from the Food and Drug Administration (FDA) for the management of myelodysplastic syndromes (MDS) classified by the International Prognostic Scoring System (IPSS) as low risk or intermediate-1 risk and with a deletion 5q (del(5q)) cytogenetic abnormality. Although some patients with del(5q) have a relatively good prognosis, all del(5q) patients will become transfusion-dependent at some point during the course of their disease. The results of two clinical trials in more than 160 patients with MDS have demonstrated clear therapeutic benefits of lenalidomide, with >60% of patients achieving independence from transfusion during therapy, irrespective of age, prior therapy, sex, or disease-risk assessment. The recommendations presented in this review will aid the safe administration of lenalidomide for the treatment of patients with low-risk or intermediate-1-risk MDS and a del(5q) cytogenetic abnormality, and they will help physicians avoid unnecessary dose reduction or interruption, thus assuring the best efficacy for patients.     

骨髓增生异常综合征多指标综合诊断的前瞻性研究

目的建立多指标综合诊断骨髓增生异常综合征(MDS)诊断标准。方法以前瞻性方法验证从回顾性研究中得出的综合诊断MDS的8项指标。观察中国医学科学院血液病医院2000年1月至2004年6月住院MDS患者,其中多指标诊断组38例,同期对照组79例,既往对照组123例,对比分析3组患者转化为白血病的情况。结果随访期间多指标诊断组18例转化为白血病,转白率为47.37%,中位转白时间6(1～33)个月。同期对照组18例转化为白血病,转白率为22.78%(与多指标诊断组相比,P<0.01),中位转白时间6(1～33)个月。既往对照组16例转化为白血病,转白率为13.01%(与多指标诊断组相比P<0.01),中位转白时间5(1～23)个月。多指标转白的相对危险度:骨髓原始粒细胞和单核细胞≥0.020的相对危险度(RR)为9.11,髓系细胞分化指数≥1.8的RR为6.50,有淋巴样微巨核RR=4.55,外周血中出现幼稚粒、单核细胞RR=4.40,骨髓有核红细胞糖原染色阳性RR=4.26,染色体核型异常RR=2.87,骨髓细胞体外培养粒、单核细胞系集簇与集落比值≥4.0的RR为2.14。结论多指标综合诊断较全面反映MDS恶性造血克隆的生物学本质,能更准确地诊断MDS患者。     

Prise en charge des syndromes myélodysplasiques en 2019 : mise au point

Myelodysplastic syndromes are a heterogeneous group of clonal myeloid disorders characterized by peripheral cytopenias and an increased risk of progression to acute myeloid leukemia. Inflammatory, auto-immune or syndromic symptoms can make the diagnosis difficult. Diagnosis is currently based on bone marrow cytology but cytogenetics and molecular features are currently overpassing their initial prognostic function (allowing early diagnosis and prediction of therapeutic response). The prognostic classification is based on the Revised International Prognostic Scoring System, which also provides guidance for therapeutic management. The treatment of low-risk myelodysplastic syndromes is based on the correction of cytopenias (erythropoiesis stimulating agents, transfusions, lenalidomide, etc.), whereas in high-risk group, the goal is the control of the leukemic clone (hypomethylating agents, allograft of hematopoietic stem cell transplantation). Other molecules are used to manage complications of cytopenias or transfusion (anti-infectious prophylaxis and treatments, martial chelation). New molecules are being studied with some interesting results (luspatercept, venetoclax). This article aims to provide an update on the knowledge that an internist should know for the practical management of myelodysplastic syndromes in 2019.