The evolution of epigenetic therapy in myelodysplastic syndromes and acute myeloid leukemia

Mutations in the group of epigenetic modifiers are the largest group of mutated genes in Myelodysplastic Syndromes (MDS) and are very frequently found in Acute Myeloid Leukemia (AML). Our advancements in the understanding of epigenetics in these diseases have helped develop groundbreaking therapeutics that have changed the treatment landscape of MDS and AML, significantly improving outcomes. In this review we describe the most common epigenetic aberrations in MDS and AML, and current treatments that target mutations in epigenetic modifiers, as well as novel treatment combinations, from standard therapies to investigational treatments.     

Farnesyltransferase inhibitors and their potential role in therapy for myelodysplastic syndromes and acute myeloid leukaemia

Novel strategies are required for treatment of acute myeloid leukaemia (AML) and higher risk myelodysplastic syndrome (MDS) patients who are not eligible for intensive chemotherapy and/or allogenic stem cell transplantation. As activating RAS mutations are frequent in these diseases, one novel approach, consisting of interfering with isoprenylation of RAS proteins by farnesyltransferase inhibitors (FTIs), has been proposed. Clinical phase II studies with the oral FTIs tipifarnib and lonafarnib in previously untreated AML, MDS and chronic myelomonocytic leukaemia yielded rather encouraging results while results in relapsed and/or refractory AML were disappointing. Results of a phase III trial in untreated AML in the elderly with tipifarnib were also disappointing. Clinical responses were not related to RAS mutations, suggesting additional actions of FTIs on other molecular targets. The combination of existing FTIs with other treatments, such as chemotherapy (in AML) and hypomethylating agents (in MDS and AML), is under investigation. Ongoing studies will also determine if gene profiling analysis may help to identify patients that will respond to FTIs.     

Aberrant methylation of DAP-kinase in therapy-related acute myeloid leukemia and myelodysplastic syndromes

Death-associated protein kinase (DAP-kinase), a proapoptotic serine/threonine kinase, is a candidate tumor suppressor gene. We studied the methylation status of DAP-kinase of 194 bone marrow samples from 160 patients with acute myeloid leukemia (AML) and 34 with a myelodysplastic syndrome (MDS) at the time of initial diagnosis by polymerase chain reaction (PCR). Hypermethylation of DAP-kinase was present in 27.5% (44 of 160) of AML and in 47% (16 of 34) of MDS specimens and significantly correlated to loss of DAP-kinase expression (P =.008). It was significantly more frequent in AML secondary to therapy for other malignancies (s-AML; 14 of 29, 48.3%), as compared to de novo AML (30 of 131, 22.9%, P =.01). DAP-kinase hypermethylation in AML was associated with myelodysplastic changes in the bone marrow at the time of the initial diagnosis (P =.002) and with the presence of cytogenetic abnormalities (P =.02). Alteration in the apoptotic response due to the loss of DAP-kinase function may be an early event in the transformation pathway to secondary leukemia via myelodysplasia.     

Molecular pathways in myelodysplastic syndromes and acute myeloid leukemia: relationships and distinctions-a review

The myelodysplastic syndromes (MDS) and acute myeloid leukemia (AML) are both hematopoietic stem cell disorders. However, while leukemic stem cells have been revealed by clonal tracking experiments, dysplastic stem cells have never been demonstrated by xeno-transplantation assays because of poor engraftment problems. These engraftment difficulties may be due to the unique nature of MDS genetic lesions that are truly able to recapitulate the disease phenotype. MDS and AML of younger patients harbour clonal yet different chromosomal markers, whereas MDS and AML of the elderly present similar defects. Potential involvement of tumor suppressor genes in MDS has been hypothesized but never confirmed, while cooperation between class I and class II mutations has been identified in AML. The reciprocal interactions between stromal cells and neoplastic clones are disrupted in both MDS and AML. In early MDS, stromal and neoplastic cells produce high levels of inhibitory cytokines, whereas in advanced MDS and AML they produce high levels of anti-apoptotic molecules.     

Predictors of clinical responses to hypomethylating agents in acute myeloid leukemia or myelodysplastic syndromes

Azacitidine and decitabine, two hypomethylating agents, are known to be effective in the treatment of high-risk myelodysplastic syndromes (MDS) and acute myeloid leukemia (AML) patients who cannot endure intensive cytotoxic chemotherapy or are not eligible for transplantation. However, the treatment response rate is low. The molecular mechanisms underlying the resistance to demethylation therapy are unclear. Though a wide range of predictors of treatment response have been investigated, no consensus has been reached. It is imperative to identify certain parameters that can help distinguish between patients who will obtain a favorable outcome from demethylation therapy and those who will not. Here, we describe currently researched potential predictors based on clinical characteristics, DNA methylation, gene mutation, gene expression, microRNAs, and protein expression. Although these parameters are not currently used in clinical practice, this review provides new sights into available clinical and experimental research. Moreover, this paper provides useful information on AML/MDS management.     

Angiogenesis in acute myeloid leukemia and myelodysplastic syndrome

Increased angiogenesis is important in the pathophysiology of solid tumors. Recent studies show that angiogenesis and angiogenic factors play an important role in hematological malignancies. Both acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS) are associated with a substantial increase in vascularity in the bone marrow as well as increased levels of various angiogenic factors including vascular endothelial growth factor (VEGF), basic fibroblast growth factor, angiogenin, angiopoietin-1, platelet-derived growth factor, hepatocyte growth factor, epidermal growth factor, tumor necrosis factor-alpha, and transforming growth factor-alpha and transforming growth factor-beta. Most of these angiogenic factors appear to be secreted by the neoplastic hematopoietic cells and appear to promote the growth and proliferation of the leukemic cells in an autocrine fashion. More importantly, angiogenic factors play a role in the clinical behavior and outcome of both AML and MDS. Despite significant overlap between MDS and AML in many aspects, higher levels of cellular VEGF and lower levels KDR are seen in MDS than in AML. Antiangiogenic therapy may play a role in AML and MDS and some differences in response may exist between MDS and AML.     

Efficacy and toxicity of low-dose melphalan in myelodysplastic syndromes and acute myeloid leukemia with multilineage dysplasia

Effective therapy of myelodysplatic syndromes and acute myeloid leukemia originating from myelodysplastic syndrome has remained an unresolved problem. Advanced age of the patients and persistent pancytopenia make the treatment difficult. Despite large number of therapeutic options none of them is satisfactory. Recently palliative treatment with low-dose melphalan has been reported to have certain activity. The aim of the study was to evaluate the efficacy of low-dose melphalan in high-risk myelodysplastic syndromes (MDS) and acute myeloid leukemia with multilineage dysplasia (AML). Twenty three patients were eligible for the study: 8 with MDS and 15 with AML with multilineage dysplasia. All of them received oral melphalan in a daily dose of 2 mg. Median total dose of the drug was 120 mg (40-840 mg). Ten patients responded to the therapy. We observed complete remission (CR) in 4, partial remission (PR) in 3 and stabilization of the disease in 3 patients. Thirteen patients did not respond to the therapy. The survival time of the patients from the day of diagnosis and from the beginning of the treatment with melphalan was longer in patients responding to the therapy (median 15 and 10 months, respectively) than in non-responders (4.5 and 4 months, p=0.003 and p=0.008, respectively). Low-dose melphalan shows significant activity in high-risk MDS and AML with multilineage dysplasia with acceptable toxicity.     

骨髓增生异常综合征中的亚急性髓性白血病临床与细胞遗传学研究

目的从临床和细胞遗传学的角度分析骨髓增生异常综合征(MDS)中部分病例是否可更早的诊断为白血病,并探讨亚急性髓性白血病(Sub-AML)作为白血病一种类型的可能性。方法应用骨髓细胞短期培养法和染色体G显带技术,部分病例联合应用荧光原位杂交技术(FISH),对42例细胞遗传学检查具有 8异常克隆,16例具有-7／7q-异常克隆,以及55例虽然经常规细胞遗传学检查未检出异常克隆,但是骨髓涂片原始细胞≥0．10,按照FAB或WHO标准既往诊断为MDS的病例进行了临床及血液形态学和细胞遗传学的系列研究。结果在同期173例有异常克隆的患者中, 8患者最多42．8％(74例),其次-7／7q-为15．0％(26例);42例 8患者中位原始细胞计数0．08,在18个月的中位随访时间内,40．0％(12例)的患者进展为显著的白血病(FL),总的中位生存时间为20个月;16例-7／7q-患者中位原始细胞计数0．135,在20个月的中位随访时间内,43．8％(7例)的患者进展为FL,总的中位生存时间仅10个月;55例核型正常的患者,骨髓中位原始细胞为0．148,52．7％(16例)的患者进展为FL,总的中位生存时间为34个月。结论 8和-7／7q-的患者均有恶性的白血病细胞克隆存在,亚急性而进行性的疾病经过表明宜归人Sub-AML。对于细胞遗传学检查为正常核型,但骨髓中原始细胞≥0．10的患者,应严密随访,他们中的部分患者实际也可能是早期Sub—AML。     

Molecular cytogenetic characterization of acute myeloid leukemia and myelodysplastic syndromes with multiple chromosome rearrangements.

BACKGROUND AND OBJECTIVES: Multiple chromosome rearrangements (MCRs) are found in 5-10% of newly diagnosed patients with acute myeloid leukemia (AML) and 15-30% of patients with myelodysplastic syndromes (MDS). However, the initial causes of MCRs and the molecular mechanisms involved are largely unresolved. Nor are the karyotypic patterns well studied, mainly because of the difficulties of obtaining complete karyotypes by G-banding. In this study, we applied spectral karyotyping (SKY) and comparative genomic hybridization (CGH) to investigate further the resulting chromosome imbalances and rearrangements in AML and MDS bone marrow cells with MCRs. DESIGN AND METHODS: Bone marrow cells from 12 AML and 10 MDS patients with MCRs were collected at diagnosis and analyzed by G-banding, SKY and CGH. The patients' characteristics were also collected to pinpoint potential similarities and/or differences between the patients. RESULTS: Our results show that some MCRs seen in AML are similar to MCRs seen in MDS. These MCRs often result in chromosome loss of 5q, 7q and 17p and gain of chromosome 8. INTERPRETATION AND CONCLUSIONS: The characteristics associated with MRCs include old age, previous exposure to radio- and/or chemotherapy and a short survival time. Probably, these patients should be distinguished from AML patients with primary chromosome rearrangements among other unbalanced chromosome rearrangements. In our experience, SKY and CGH facilitated this process.     

Molecularly targeted therapies in myelodysplastic syndromes and acute myeloid leukemias

Although there has been significant progress in acute myeloid leukemia (AML) treatment in younger adults during the last decade, standard induction therapy still fails to induce remission in up to 40% of AML patients. Additionally, relapses are common in 50–70% of patients who achieve a complete remission, and only 20–30% of patients enjoy long-term disease-free survival. The natural history of myelodysplastic syndrome (MDS) is variable, with about half of the patients dying from cytopenic complications, and an additional 20–30% transforming to AML. The advanced age of the majority of MDS patients limits the therapeutic strategies often to supportive care. To address these shortcomings, much effort has been directed toward the development of novel treatment strategies that target the evolution and proliferation of malignant clones. Presented here is an overview of molecularly targeted therapies currently being tested in AML and MDS patients, with a focus on FMS-like tyrosine kinase 3 inhibitors, farnesyltransferase inhibitors, antiangiogenesis agents, DNA hypomethylation agents, and histone deacetylase inhibitors.