Clofarabine for myelodysplastic syndromes

INTRODUCTION: Treatment options in myelodysplastic syndromes (MDS) remain limited. The introduction of novel therapies that can improve response rates and survival outcomes in MDS remains a challenge. Clofarabine is a purine nucleoside analog that works primarily via inhibition of DNA biosynthesis and the ribonucleotide reductase enzyme with recent evidence suggesting that at low doses it may affect DNA methylation. It has been successfully used in the treatment of acute myeloid leukemia (AML) and is under investigation in MDS. AREAS COVERED: A PubMed search for articles pertaining to clofarabine was conducted and streamlined to only include data on MDS or AML that evolved from MDS. Also included were clofarabine-related response and safety data from presentations at the 52(nd) Annual American Society of Hematology Meeting in Orlando, Florida, USA. EXPERT OPINION: Clinical trials using clofarabine in MDS and MDS/myeloproliferative neoplasms have produced overall response rates of 31 - 43% including complete responders. Although myelosuppression is an important side effect, clofarabine is generally well tolerated in MDS. Clofarabine is currently available in an intravenous form with an oral formulation presently under investigation, either as a single agent or in combination therapy in MDS. Larger studies may help clarify the viability of clofarabine in the treatment of MDS patients.     

Clofarabine: emerging role in leukemias

Clofarabine is a second-generation purine nucleoside analogue. It works mainly by inhibiting ribonucleotide reductase and incorporating into DNA. Clofarabine has shown efficacy in selected pediatric leukemias. It has also shown significant efficacy alone and in combination with other drugs in treating adult myeloid leukemias and high-risk myelodysplastic syndromes. Further, there is significant promise for clofarabine in the treatment of older patients with acute myeloid leukemia who are unlikely to benefit from standard induction chemotherapy due to unfavorable baseline prognostic factors. An oral formulation of clofarabine is also currently under development.     

氯法拉滨的合成

1-乙酰基-2，3，5-三-O-苯甲酰基-β-D-呋喃核糖经重排获得的1，3，5-三-O-苯甲酰基-α-D-呋喃核糖，与硫酰氯、咪唑反应生成易离去基团磺酰咪唑酯，经氟代、溴化得1-溴-2-脱氧-2-氟-3，5-二-D-苯甲酰基-α-D-阿拉伯糖，再与2-氯腺嘌呤缩合后脱保护即可制得抗白血病药氯法拉滨，总收率5％。     

氯法拉滨的合成

以鸟苷为原料,经乙酰化、氯代、重氮化后氯代及氨解反应制得关键中间体2-氯-2-,3',5'-三-O-乙酰基腺苷(6).6在盐酸羟胺-乙酸钠-吡啶体系中选择性脱2'-乙酰基,再经三氟甲磺酰化、氟代及脱保护反应制得抗白血病药氯法拉滨,总收率8%.     

氯法拉滨的合成工艺改进

目的合成标题化合物,并进行工艺改进。方法以1-乙酰基-2,3,5三-O-苯甲酰基-β-D-呋喃核糖为起始原料,制得1-氯-2-脱氧-2-氟-3,5-二-O-苯甲酰基-α—D-阿拉伯糖（化合物6）。化合物6与2-氯腺嘌呤在四氯化锡作用下发生缩合反应生成氯法拉滨。结果总收率为8．4％,目标化合物的结构经IR、^1H—NMR、MS等方法确证。结论该合成工艺具有原料易得,操作简便,易于工业化生产等特点。     

抗急性淋巴细胞白血病新药——氯法拉滨

氯法拉滨是第2代嘌呤核苷酸类似物,对患有难治性或复发性急性淋巴细胞白血病的1～21岁病人有显著疗效,是近10年来首个FDA批准的专门用于治疗儿童白血病的新药。本文综述了氯法拉滨的作用机制、药动学、药效学、临床研究及不良反应。     

Emerging biological therapies for the treatment of myelodysplastic syndromes

Introduction: No drug has resulted in a survival advantage in patients with lower-risk myelodysplastic syndromes (MDS). While hypomethylating agents (HMA) have revolutionized treatment options for patients with higher-risk MDS, the prognosis remains dismal after HMA treatment failure. Novel effective therapies are urgently needed especially after HMA failure.

Areas covered: This review covers the current approach to disease prognostication and risk-adaptive therapy, as well as novel therapeutic approaches. We discuss the recent advancements in the understanding of MDS disease biology as a basis of targeted drug development. Several classes of novel agents are reviewed including drugs targeting dysregulated epigenetic control mechanisms, signaling pathways, abnormal splicing, as well as agents that target the immune system and the MDS bone marrow niche.

Expert opinion: Significant advancements in the understanding of the underlying biology of MDS are only starting to be translated into novel treatment options for MDS. Epigenetic therapy has shown significant clinical activity with HMA but the results of clinical trials combining HMAs with histone deacetylase inhibitors (HDACi) have been disappointing to date. Similarly, targeting several aberrant pathways in MDS has not resulted in significant improvements in therapy. Future therapies will focus both on synergic combination of existing drugs as well as novel agents targeting dysregulated immune responses and abnormal RNA splicing in MDS.     

Clofarabine: a new treatment option for patients with acute myeloid leukemia

Clofarabine is a rationally designed, second-generation deoxyadenosine analog that incorporates characteristics of two other purine analogs, fludarabine and cladribine. It has shown efficacy in hematologic malignancies such as acute lymphoblastic leukemia, acute myeloid leukemia and myelodysplastic syndrome. It has already been approved for use in pediatric acute lymphoblastic leukemia after two lines of previous therapy. Clinical trials have also shown clofarabine to have activity both as a single agent and in combination with other cytotoxic drugs in adult myeloid leukemia. This compound seems to have efficacy in older patients, as well as those with adverse cytogenetics.     

骨髓增生异常综合征骨髓血管新生的研究

目的 探讨骨髓增生异常综合征(MDS)患者骨髓是否存在血管新生,及其在MDS发病机制、病情进展及预后判断中的价值.方法 用CD34单抗免疫组织化学染色方法标记MDS患者和正常人骨髓绀织m管内皮细胞,盲法计数骨髓微血管密度(MVD).结果 MDS患者MVD显著高于正常对照组(P＜0.01),并且随着病程的进展患者的骨髓MVD呈增高趋势(P＜0.01).结论 MIDS患者骨髓MVD增高,可能与白血病进展有关.     

The role of azacitidine in the treatment of myelodysplastic syndromes

Myelodysplastic syndromes (MDS) are a heterogeneous group of hematopoietic disorders characterized by ineffective hematopoiesis and potential transformation to acute myeloid leukemia. Supportive care including transfusions and growth factors remained the mainstay of treatment for decades; however, further understanding of the biology behind these diseases led to the investigation of novel agents. As hypermethylation of tumor suppressor genes, such as p15, was believed to play a key role in the pathogenesis of these diseases, hypomethylating agents were investigated. Azacitidine is one of two hypomethylating agents used in the treatment of MDS, and the first approved by US FDA. In preclinical studies, azacitidine demonstrated hypomethylating/differentiating activity with low concentration, whereas high concentration was associated with cytotoxic effects. In clinical trials, azacitidine not only improved the cytopenias associated with MDS but also delayed leukemic transformation, improved quality of life and improved overall survival in many patients so treated. Azacitidine was the first agent noted to change the natural history of the disease. Further studies are underway evaluating the role of azacitidine pre- and post-transplantation, in combination with other agents, as well as in treatment of acute myeloid leukemia patients who are not good candidates for intensive chemotherapy. Azacitidine is also likely to be studied in the treatment of other malignant conditions. Although both subcutaneous and intravenous administrations have been approved, oral azacitidine is presently under investigation.     

Clofarabine in the treatment of acute myeloid leukaemia and acute lymphoblastic leukaemia: a review

Clofarabine, a synthesised adenosine nucleoside, has recently demonstrated single-agent activity in the acute leukaemias. Originally developed to capture the best qualities of cladribine and fludarabine, clofarabine contains halogenated carbons, rendering it resistant to inactivating enzymes and maintaining its stability in acidic environments. Like other adenosine nucleosides, clofarabine acts by inhibiting ribonucleotide reductase and DNA polymerase, thereby depleting the amount of intracellular deoxynucleoside triphosphates available for DNA replication and also resulting in premature DNA chain termination. Clofarabine has also been shown to induce apoptosis in transformed cell lines, indicating that clofarabine results in cell death in both cycling and non-cycling cells. Interest in the development of clofarabine was initially hampered by the availability of other active nucleoside analogues for the treatment of haematological malignancies. However, the results of several early-phase trials evaluating the use of clofarabine in acute leukaemias in adults and children have rekindled enthusiasm for further investigation into its use. This article describes the development, pharmacology, toxicity and clinical activity of clofarabine, as well as discuss its potential role in the treatment of acute leukaemia.     

Immunosuppressive therapy for myelodysplastic syndromes

Myelodysplastic syndromes (MDS) comprise a heterogeneous group of diseases characterized by bone marrow failure, marrow dysplasia, and a tendency to evolve to acute leukemia. Pathophysiologically, low risk MDS are separated from the high risk category by an increased rate of apoptosis of the bone marrow cells which causes the morphological paradoxon of a peripheral cytopenia and hypercellular bone marrow known as ineffective hematopoesis. Laboratory findings and clinical evidence suggest that some patients with myelodysplastic syndrome have immunologically mediated disease. MDS shares some of the features of acquired aplastic anemia and up to 30% of patients with MDS respond to immunosuppressive treatment. In the last decades, significant advances have been made in the diagnostic and prognostic classifications of myelodysplastic syndromes. While allogeneic transplantation still offers the only available option with a probability of cure in a minority of patients, the mainstay of therapy in low-risk patients remains supportive care, stimulation of ineffective hematopoiesis with growth factors, and immunomodulatory therapy. However, the correct selection of patients for the respective therapeutic intervention continues to be an enormous challenge as this will decide about the probability of therapeutic efficacy. This is important not only because of the high costs involved but also because of the possible side effects that can be difficult to manage. Here we review the pathophysiologic basis for the use of immunosuppressive agents in MDS and summarize the trials leading to the establishment of these therapy strategies in a subgroup of low-risk MDS patients.     

Treating myelodysplastic syndromes

The myelodysplastic syndromes (MDS) are a diverse group of disorders of hematopoietic stem cells that are characterized by ineffective hematopoiesis, and a variable risk of transformation to acute myeloid leukemia. The prognosis (as estimated by the International Prognostic Scoring System), co-morbidities and age of a patient must all be considered when deciding treatment strategies. Therapeutic modalities vary from supportive care to allogeneic stem cell transplantation (SCT), and growth factors and immunosuppressive therapy may benefit selected patients. The re-emergence of compounds such as thalidomide and arsenic trioxide, and new 'targeted therapy', such as DNA methlytransferase inhibitors and farnesyl tranferase inhibition, provide novel therapeutic options. Furthermore, development of reduced intensity conditioning regimens may result in more patients with MDS benefiting from SCT approaches.     

Lenalidomide for treatment of myelodysplastic syndromes

Lenalidomide is a second generation immunomodulatory agent (IMiD), which currently represents the standard of care for treatment of transfusion dependent lower risk myelodysplastic syndrome (MDS) patients with deletion (5q). Lenalidomide has unique activity with a high transfusion independence rate observed in this subset of patients. In this article we summarize the clinical experience using lenalidomide for treatment of del (5q) MDS. We highlight the mechanism of action and the recent advances in understanding the biology of del (5q) MDS. We also explore its potential use and the efforts to further improve its activity in non-del (5q) MDS.     

Pharmacotherapy of myelodysplastic syndromes

Importance of the field: Despite the remarkable progress in the treatment of patients with myelodysplastic syndromes (MDS) in the past decade, response to the hypomethylating agents azacitidine and decitabine in non-del(5q) MDS patients remains at ～ 50%, leaving half of patients needing treatment with essentially no options. As biologic insight into the molecular pathways that account for disease evolution and clinical heterogeneity is expanded, the arsenal of potential drugs that may elicit significant response is also increasing. One of the greatest challenges for the treating physician is to decide when to initiate therapy and which therapy (approved drug or newer agents still in clinical trial) is likely to be the most beneficial. While there is no single answer to these issues, there are several approaches that may be considered, and these are addressed in this review.

Areas covered in this review: This review examines the clinical outcomes of the FDA-approved drugs as well as of the promising new therapies that are in current clinical trials.

What the reader will gain: The clinician now has multiple treatment options for patients with MDS. It is important to consider multiple factors before initiating therapy with disease-modifying drugs. This review presents some of the decision-making approaches that are in practice at present.

Take home message: For the first time, various treatment options are available for patients with MDS. In light of the intense efforts now in progress, the next decade promises to be one of hope and excitement for both MDS patients and treating clinicians.     

Update on the pharmacotherapy for myelodysplastic syndromes

Introduction: For many decades, myelodysplastic syndromes (MDS) were a poorly understood disease group with no approved therapies, and patient management largely relied upon supportive care and intensive chemotherapy. The last decade has seen many scientific and therapeutic advances culminating in the US FDA approval of three drugs for the treatment of these complex malignancies: lenalidomide, azacitidine and decitabine.

Areas covered: This review summarizes the major prognostic risk models that guide treatment decisions and examines the available literature on the mechanism of action and efficacy of each of the approved agents. The authors also discuss evidence supporting the use of other therapies that have entered the standard of care including growth factors, immunosuppressive therapy and stem-cell transplantation.

Expert opinion: While significant progress has been made in understanding the molecular basis of MDS, much of this has yet to translate into therapeutic benefit. Each of the available treatment modalities has shortcomings, and both combination strategies and novel agents are under investigation in clinical trials to improve outcomes.     

Immunomodulatory drugs in myelodysplastic syndromes

This review summarises the mechanism of action of immunomodulatory analogues of thalidomide and their use in myelodysplastic syndromes. Thalidomide was found to have a response rate of ～ 20% in these patients. Lenalidomide – which is more potent and less toxic than thalidomide – has been used in three clinical trials and produced the best responses (60 – > 90%) in low- and intermediate-1-risk transfusion-dependent patients with del(5q). The responses are purely erythroid in nature, and are associated with major cytogenetic responses in > 50% of the del(5q) patients. Non-del(5q) low- and intermediate-1-risk transfusion-dependent patients also had a ～ 25% incidence of transfusion independence following therapy with lenalidomide. Median time to response is ～ 4 weeks and 90% of patients respond within 12 weeks. The precise mechanism of action remains unknown but anticytokine, antiangiogenic and immunomodulatory properties are thought to play a role.     

Immunomodulatory drugs in myelodysplastic syndromes

This review summarises the mechanism of action of immunomodulatory analogues of thalidomide and their use in myelodysplastic syndromes. Thalidomide was found to have a response rate of approximately 20% in these patients. Lenalidomide--which is more potent and less toxic than thalidomide--has been used in three clinical trials and produced the best responses (60 - > 90%) in low- and intermediate-1-risk transfusion-dependent patients with del(5q). The responses are purely erythroid in nature, and are associated with major cytogenetic responses in > 50% of the del(5q) patients. Non-del(5q) low- and intermediate-1-risk transfusion-dependent patients also had a approximately 25% incidence of transfusion independence following therapy with lenalidomide. Median time to response is approximately 4 weeks and 90% of patients respond within 12 weeks. The precise mechanism of action remains unknown but anticytokine, antiangiogenic and immunomodulatory properties are thought to play a role.     

骨髓增生异常综合征预后评分

骨髓增生异常综合征 （MDS） 是一组起源于造血干/祖细胞的克隆性疾病, 呈现高度的异质性和复杂性。精确的预后评估是本病的一个核心难题, 主要因为该病复杂的发病机制 （基因组、 表观遗传、 骨髓微环境和免疫因素）决定了临床特征的异质性 （年龄、 感染、 出血风险及合并症） 和差异化的临床转归 （骨髓衰竭和白血病转化）。因此,如何综合考量各种因素建立预后积分系统来预测MDS患者的预后和临床转归非常重要。在过去的二十年中, 许多学者致力于研究各种MDS预后评分系统, 典型的预后评分系统例如国际预后评分系统 （IPSS） 及其修订版 （IPSS-R）已被广泛应用。除此之外, 随着众多具有潜在预后预测价值的临床标志和分子学改变的发现, 基于这些新的预后因素的预后评分系统也展现了良好的预后价值。本文总结了近几年MDS的预后评分系统以供临床实践借鉴。