治疗骨髓增生异常综合征的药物介绍:第56届美国血液学会年会报道

介绍第56届美国血液学会(ASH)年会上治疗骨髓增生异常综合征(MDS)的药物.MDS是最常诊断的髓系恶性肿瘤,预后积分系统把患者分为低危和高危MDS.治疗低危MDS的目标是减少输血次数,提高生活质量.对于高危MDS则是延长生存期和延缓向急性白血病(AL)进展.对于单系血细胞减少的低危患者,其治疗包括促红细胞生成素和促血小板生成素.对del(5q)综合征或初始治疗无效的患者可以应用来那度胺或试验药物治疗.对于伴多系病态造血的低危患者,治疗上可以应用免疫抑制剂或小剂量去甲基化药物.对于高危患者,应首选去甲基化药物作为初始治疗,并在诊断时评价进行造血干细胞移植的可能性.目前正在研制几种新药针对去甲基化药物无效的患者.     

骨髓增生异常综合征去甲基化药物治疗的研究进展

骨髓增生异常综合征(myelodysplastic syndrome,MDS)的发病机制涉及多阶段、多因素,基因改变与表观遗传修饰可能共同参与了这一过程.DNA甲基化是表观遗传学中一种最为重要的修饰,MDS患者常表现为总体DNA高甲基化.使用DNA甲基转移酶(DNA methyltransferase,DNMT)抑制剂降低总体甲基化水平,在MDS患者中取得了富有成效的临床反应及血液学改善.DNMT抑制剂可分为两类:5-氮杂胞苷(5-azacytidine,5-Aza-CdR)、地西他滨(5-Aza-2-deoxycytidine,decitabine)等核苷和核苷衍生物类抑制剂,它们可提高MDS患者的临床完全反应率、部分反应率及血液学改善,但缓解率、疗效尚不够令人满意;肼苯哒嗪等非核苷类抑制剂.非核苷类抑制剂与丙戊酸镁联合应用治疗MDS获得成功,为MDS去甲基化治疗药物的研究开启了一种新思路.     

地西他滨低剂量逐疗程爬坡治疗高龄骨髓增生异常综合征一例并文献复习

目的探讨地西他滨低剂量逐疗程爬坡治疗高龄骨髓增生异常综合征(MDS)患者的疗效及安全性方法回顾性分析东莞市人民医院收治的1例80岁高龄的高危MDS患者,采用地西他滨每天15mg/m^2静脉注射,第1个疗程连续3d、第2个疗程连续4d、第3个疗程连续5d.观察其疗效、不良反应,并进行相关文献复习,结果患者耐受性良好,经1个疗程治疗后输血依赖明显减轻.血小板获得显著提高,未继发严重感染。第2、3个疗程按计划序贯治疗,患者完全摆脱输血依赖结论对于老年MDS患者,摆脱输血依赖及尽可能延长预期寿命是最为现实的治疗目标。地西他滨治疗老年人MDS的剂量及策略仍有优化空间;对于高龄MDS患者,低剂量逐疗程爬坡的治疗策略值得临床尝试。     

骨髓增生异常综合征患者低甲基化治疗失败后的治疗选择

骨髓增生异常综合征(MDS)的主要治疗包括支持治疗(如输血、集落刺激因子、螯合铁等)和靶向药物(5-氮杂胞苷、地西他滨、来那度胺).如果患者对以上药物无效,则缺乏有效的治疗方法.治疗失败后,目前努力的方向是继续调整并优化去甲基化药物(HMT)方案,改善药物制剂[口服制剂和(或)新制剂],根据突变筛选患者,提高HMT治疗MDS的针对性和有效性.此外,正在进行的研究重点是确定用来作为HMT治疗失败后挽救MDS患者的独特药物.如rigosertib最有可能使特定人群[原发性难治性和国际预后评分系统(IPSS)评分为高危的患者]受益.鉴于实体肿瘤免疫逃逸的重要进展,程序性死亡受体1(PD-1)和PD-1抑制剂单剂可在早期治疗和复发时联合HMT治疗MDS.对于那些有特定靶向突变基因的少数民族患者,有替代药物(IDH1/2)是非常有希望的.骨髓移植是治愈MDS的唯一方法,但因MDS进展时大多患者都年老体弱,所以移植的可行性不大.     

低危骨髓增生异常综合征的治疗策略

低危骨髓增生异常综合征（MDS）是指国际预后积分系统修订版（IPSS．R）评分≤3．5分的MDS,支持治疗仍是主要的治疗手段。对于染色体5q缺失[del（5q）]MDS患者,如果内源性促红细胞生成素（EPO）水平〈500U／L（最好〈200U／L）,红系造血刺激剂（ESA）仍是最佳选择。对应用EPO无效或脱离输血后复发的患者,可以选择免疫抑制剂、转化生长因子抑制剂和来那度胺。del（5q）患者可以从来那度胺长期受益。血小板减少造成严重出血的情况较少,血小板生成素受体类似物可以减少出血,提高血小板数,可用于骨髓原始细胞比例〈0．05的患者。治疗失败或有进展为高危MDS和急性髓系白血病风险者,可能需要造血干细胞移植治疗。文章结合第59届美国血液学会（ASH）年会报道,介绍有关低危MDS的治疗策略。     

伴自身免疫性疾病的骨髓增生异常综合征的临床特点

目的 探讨骨髓增生异常综合征(MDS)与自身免疫性疾病的相关性及其临床意义。方法 回顾分析7例伴自身免疫性疾病的MDS的临床及实验特点。结果 7例伴发的自身免疫性疾病中,白塞病2例,类风湿性关节炎、Crohn’s病、抗D抗体阳性的输血性溶血性贫血、Sweet's综合征及坏疽性脓皮病各1例。3例自身免疫性疾病发生于MDS之前,1例与MDS同时发生,3例发生于MDS之后。7例患者经糖皮质激素及免疫抑制剂治疗后,自身免疫性疾病均得以明显缓解,但MDS预后仍较差,其中2例在半年内转变为急性髓细胞白血病,化疗后均未缓解而死亡,3例死于RA期,其他正在治疗中。结论 部分MDS与自身免疫性疾病有密切联系,伴自身免疫性疾病是MDS预后不良的因素。     

骨髓增生异常综合征的研究进展:2011年美国血液学会年会报道

骨髓增生异常综合征（MDS）是一组骨髓细胞分化障碍的克隆性异源性恶性血液疾病。参与组织功能调节的基因（EAH2、ASXL1及UTX）和在MDS中不断突变的DNA甲基化（DNMT3A、IDH1／IDH2、TET2）在该疾病的遗传学及表观遗传学中间起重要的桥梁作用。AZA-001前沿研究在使用DNA甲基转移酶（DNMT）抑制剂方面提供了重要经验。通过阿扎胞苷的治疗改善了高风险MDS患者甚至是国际工作组定义的血液学反应患者的生存状态。DNMT抑制剂对免疫系统及干细胞的影响可能开辟了这些药物在治疗MDS和其他血液及非血液恶性肿瘤中的新用途。免疫调节剂沙利度胺及其衍生物来那度胺已被用于治疗MDS,主要用于低危MDS。     

骨髓增生异常综合征的干预性治疗

 骨髓增生异常综合征（MDS）为一组恶性克隆性造血干／祖细胞疾病，近年来有关MDS的治疗取得了较大的进展，包括免疫抑制剂治疗、化学治疗、造血干细胞移植以及抑制MDS克隆的药物治疗等，就MDS干预性治疗以及疗效作一概述。     

骨髓增生异常综合征表观遗传学治疗进展

 表观遗传改变与基因改变有一个重要的区别就是表观遗传改变是可逆的,通过使用相应的表观遗传药物可使沉默的抑癌基因重新表达。骨髓增生异常综合征（MDS）的表观遗传治疗已经取得了很大的发展,当前应用于临床的表观遗传药物主要包括DNA去甲基化药物和去乙酰化酶抑制剂。得到FDA批准上市的DNA去甲基化药物5-氮杂胞苷和地西他滨均为MDS治疗药物,可作为中高危患者尤其是不能耐受化疗的老年患者重要的治疗选择;去乙酰化酶抑制剂如丙戊酸等目前在治疗MDS中大多处于I期临床试验阶段,可能在治疗低危MDS中有一定价值,但其剂量和治疗效果尚需进一步评估;去甲基化药物和去乙酰化抑制剂二者联用治疗MDS可能具有协同作用,但目前的临床试验尚不能证实其优于去甲基化药物的单用,仍需大样本的临床病例和合理的治疗方案来验证其安全有效性。     

骨髓增生异常综合征合并自身免疫性溶血性贫血一例并文献复习

目的 探讨骨髓增生异常综合征（MDS）合并自身免疫性溶血性贫血的临床特点及预后的影响因素.方法 回顾性分析1例MDS合并自身免疫性溶血性贫血患者的临床资料并进行相关文献复习.结果 该例合并自身免疫性溶血的MDS患者至截稿时病程5年,无明显转白血病表现,近3年余脱离输血,生活质量较好.结论 MDS与自身免疫性疾病存在密切联系,自身免疫性疾病可能对MDS预后存在影响.     

Lenalidomide in Myelodysplastic Syndromes: An Erythropoiesis-Stimulating Agent or More?

Anemia remains the most challenging clinical manifestation to treat in patients with lower-risk myelodysplastic syndromes (MDS). Erythropoiesis-stimulating agents are widely used to treat anemia in such patients, but less than one third respond to these agents, and the duration of response is often limited. Lenalidomide, a second-generation immunomodulatory drug (IMiD), is approved by the US Food and Drug Administration for treatment of transfusion-dependent anemia in lower-risk MDS patients with deletion 5q chromosomal abnormality. Lenalidomide also has meaningful clinical activity in lower-risk patients without deletion 5q. The experience with lenalidomide in MDS is a modern example of reciprocal translational research, in which bench work led to an approved drug for patients, and clinical observations led to better understanding of the mechanism of action of the drug itself and even more understanding of the biology of the underlying disease. This article reviews the clinical experience with lenalidomide, highlighting recent understanding of the dual karyotype-dependent mechanisms of action.     

Short- and long-term benefits of lenalidomide treatment in patients with lower-risk del(5q) myelodysplastic syndromes

The treatment of patients with myelodysplastic syndromes (MDS) begins with assessment of karyotype and risk. Lenalidomide is approved for the treatment of patients who have transfusion-dependent anemia due to lower-risk MDS with chromosome 5q deletion (del(5q)) with or without additional cytogenetic abnormalities, and isolated del(5q) only in the European Union. Mounting evidence suggests that lenalidomide is effective not only in reducing red blood cell (RBC) transfusion burden, but also in modifying the disease natural history by suppressing the malignant clone. Data discussed here from the pivotal phase 2 (MDS-003) and phase 3 (MDS-004) studies of lenalidomide demonstrate that lenalidomide treatment was associated with both short- and long-term benefits. These clinical benefits included high rates of RBC-transfusion independence (TI) with prolonged durations of response, high rates of cytogenetic response (CyR) associated with achievement of durable RBC-TI, no significant difference in rates of progression to acute myeloid leukemia (AML), and improvements in health-related quality of life (HRQOL). Achievement of RBC-TI and CyR with lenalidomide treatment was associated with extended survival and time to AML progression. Achievement of RBC-TI and hemoglobin response was additionally associated with HRQOL benefits. Recent data describing the impact of TP53 mutations and p53 expression on the prognosis of patients with del(5q) and the impact on response to lenalidomide are also discussed. The authors provide practical recommendations for the use of lenalidomide in patients with lower-risk del(5q) MDS.     

Impaired osteogenic differentiation of mesenchymal stem cells derived from bone marrow of patients with lower-risk myelodysplastic syndromes

The pathogenesis of myelodysplastic syndromes (MDS) has not been completely understood, and insufficiency of the hematopoietic microenvironment can be an important factor. Mesenchymal stem cells (MSCs) and osteoblasts are key components of the hematopoietic microenvironment. Here, we measured the expression of multiple osteogenic genes in 58 MSCs from MDS patients with different disease stages and subtypes by real-time PCR and compared the osteogenic differentiation of MSCs from 20 MDS patients with those of MSCs from eight normal controls quantitatively and dynamically. The mRNA level of Osterix and RUNX2, two key factors involved in the early differentiation process toward osteoblasts, was significantly reduced in undifferentiated MSCs from lower-risk MDS. After osteogenic induction, lower-risk MDS showed lower alkaline phosphatase activity, less intense alizarin red S staining, and lower gene expression of osteogenic differentiation markers; however, higher-risk MDS was normal. Finally, in bone marrow biopsy, the number of osteoblasts was significantly decreased in lower-risk MDS. These results indicate that MSCs from lower-risk MDS have impaired osteogenic differentiation functions, suggesting their insufficient stromal support in MDS.     

Management of anemia in low-risk myelodysplastic syndromes treated with erythropoiesis-stimulating agents newer and older agents

The myelodysplastic syndromes (MDSs) are clonal hematopoietic stem cell disorders. The International Prognostic Score System (IPSS) groups MDS in lower-risk (IPSS low and intermediate-1) and higher-risk disease (IPSS intermediate-2 and high). AML transformation is the main concern in higher-risk MDS, while anemia and transfusion dependency represent the major issues for low-risk MDS patients. Improving erythropoiesis, and eliminating fatigue and symptoms, is the main therapeutic goal for low-risk MDS patients. Around 50% of MDS patients present with anemia with an Hb level <?100 g/L. Severe anemia increases the negative effects of comorbidities, such as heart and lung failure. Erythropoiesis-stimulating agents (ESAs), with or without granulocyte colony-stimulating factor, induce erythroid response rates in 40–50% of lower-risk anemic MDS patients. The median response duration of 24 months. Apoptosis of erythroid cells is inhibited by ESAs leading to erythrocyte production. Our paper considers the state of the art of treatment of anemia in low-risk MDS patients and the treatment options in MDS resistant or refractory to ESAs.     

Therapeutic Modalities for Patients with Lower-Risk Myelodysplastic Syndromes: Current Options and Future Directions

The treatment of myelodysplastic syndromes (MDS) involves a complex algorithm that depends on multiple factors, including symptoms, performance status, and severity of disease. Current therapies are aimed at promoting hematopoiesis, inhibiting apoptosis, and reducing the risk of transformation to acute myeloid leukemia. Although there is no cure for MDS outside of allogeneic stem cell transplantation, goals of treatment include improvement of peripheral blood cytopenias, reduction of transfusions, improvement of the quality of life, and prolongation of survival. Patients with lower-risk MDS are often asymptomatic and can be monitored for long periods without therapeutic intervention. Anemia, the most common symptomatic cytopenia, warrants treatment in an attempt to eliminate transfusion dependence. This article reviews current treatment strategies for lower-risk MDS and examines the data for selected novel agents that are available or are being developed for the treatment of this disease.     

The role of erythropoietin in the anemia of myelodysplastic syndrome

Although erythropoietin (EPO) deficiency is not responsible for the anemia of myelodysplasia, pharmacologic doses of recombinant human EPO (rHuEPO, epoetin alfa) and epoetin beta have been studied extensively as treatment of anemia in myelodysplastic syndrome (MDS). When an epoetin is used as a single growth factor in patients with MDS, clinically meaningful responses occur in only a small minority of patients (16%). Patients who are transfusion-dependent are less likely to respond than patients who are transfusion-independent. Serum EPO level has a weak association with response rate and cannot be used to select or exclude patients from empirical trials of epoetins. The dose schedule commonly used as initial treatment 40,000 U/week, is consistent with clinical observations, but an optimal dose schedule has not been determined. The combination of an epoetin and granulocyte colony-stimulating factor (G-CSF) produces a higher erythroid response rate (36%) than the regimen of epoetin alone, but we have found no randomized trial data to support this point. However, the design of the clinical trials, which included adding G-CSF after epoetin alone had failed, supports the hypothesis that combined use of growth factors, rather than just higher doses of epoetin, is responsible for the high response rate observed with the combination of epoetin and G-CSF. Unfortunately, as in the case of epoetin alone, patients who are transfusion-dependent (> or =2 U red blood cells/month) are less likely to respond to combined growth factor therapy. Although the ability of patients with MDS to show an erythroid response to epoetin is of biologic interest, because of high costs and the limited response rate in transfusion-dependent patients, epoetin therapy, with or without G-CSF, cannot be regarded as a definitive therapy for the anemia of MDS.     

Clinical Outcomes of Decitabine Treatment for Patients With Lower-Risk Myelodysplastic Syndrome on the Basis of the International Prognostic Scoring System

IntroductionDecitabine has shown clinical benefits in patients with intermediate (INT)-2 or high-risk myelodysplastic syndrome (MDS), determined according to the International Prognostic Scoring System (IPSS), but the benefits have not been well demonstrated in patients with lower-risk (IPSS low or INT-1) disease. Recently, it was proposed that the prognosis for patients with IPSS lower-risk disease is heterogeneous, with a substantial proportion of these patients having poor survival.Patients and MethodsThis study included patients with IPSS lower-risk MDS from the DRAMA (An Observational Study for Dacogen Long-Term Treatment in Patients With Myelodysplastic Syndrome; NCT01400633) and DIVA (A Study for Dacogen Treatment in Patients With Myelodysplastic Syndrome; NCT01041846) studies, which were prospective observational studies on the efficacy and safety of decitabine treatment in patients with MDS. Using the Lower-Risk Prognostic Scoring System [LR-PSS], we classified IPSS lower-risk MDS. Patients in each LR-PSS category were divided according to overall response (OR) to decitabine treatment, and survival outcomes were compared.ResultsOne hundred sixteen patients were enrolled: LR-PSS category 1 (n = 12; 10.3%), category 2 (n = 56; 48.3%), and category 3 (n = 48; 41.4%). Survival outcomes differed among the 3 categories (P = .046). The overall survival according to OR showed a significant difference in total patients (P = .008) and category 3 patients (P = .003). We analyzed predictive factors for OR, but no variable was found to significantly affect OR.ConclusionDecitabine treatment showed a survival benefit in the higher-risk group of IPSS lower-risk MDS patients who responded to treatment, and classification using the LR-PSS category was helpful for this subgroup, indicating that decitabine treatment might alter the natural course of disease in these patients.     

Resuscitating a Dying Marrow: the Role of Hematopoietic Growth Factors

The treatment landscape for myelodysplastic syndromes (MDS) has evolved over the last two decades, with a better understanding of the disease pathophysiology and the use of newer or combination therapies. For lower-risk MDS patients, hematopoietic growth factors have continued to be the mainstay of therapy. However, better patient selection criteria and decision tools to predict responses have made these therapies more beneficial to patients. As the range of newer drugs continues to expand in our treatment armamentarium for lower-risk MDS, questions still remain regarding the safety of these drugs with long-term use. This review will discuss the role of growth factors in MDS, focusing on dosing and combination strategies to improve responses, selecting the appropriate patient population, and recognizing the safety profile based on evidence from published literature.     

Revisiting use of growth factors in myelodysplastic syndromes

Myelodysplastic syndromes (MDS) represent a heterogeneous group of clonal hematologic neoplasms characterized by morphologic dysplasia, aberrant hematopoiesis and peripheral blood refractory cytopenias. MDS is recognized to be associated with an increased risk of symptomatic anemia, infectious complications and bleeding diathesis, as well as a risk of progression to acute myeloid leukemia, particularly in patients with a high IPSS score. The advent of use of hematopoietic growth factors such as granulocyte colony-stimulating factor (G-CSF) and recombinant erythropoietin (EPO) has improved symptoms in MDS patients in addition to some data that suggest there might be an improvement in survival. G-CSF is an effective therapeutic option in MDS patients, and it should be considered for the management of refractory symptomatic cytopenias. G-CSF and EPO in combination can improve outcomes in appropriate MDS patients such as those with lower-risk MDS and refractory anemia with ring sideroblasts (RARS) . This article reviews use of growth factors for lower-risk MDS patients, and examines the data for G-CSF, EPO and thrombopietic growth factors (TPO) that are available or being developed as therapeutic modalities for this challenging disease.