Chemotherapy options for previously untreated acute myeloid leukemia

Introduction: Intensive chemotherapy with cytarabine and an anthracycline for untreated acute myeloid leukemia (AML) has remained largely unchanged over the past 40 years, despite many large trials examining the choice and dosing of these agents.

Areas covered: We will review the major published clinical trials for untreated AML that have established the dosing choice and schedule for intensive therapy, as well as trials for patients not eligible for more intensive therapy. We will also discuss treatment considerations for subgroups of patients.

Expert opinion: While one or two cycles of anthracycline and cytarabine-based combination regimens remain the standard of care for younger and older patients with AML deemed fit to receive induction chemotherapy, controversy remains regarding the optimal selection and dosing schedule for anthracyclines. Low-intensity regimens, such as low-dose cytarabine and hypomethylating agents, can achieve a complete response even with adverse risk features, and can be used in a fit subset of older patients not eligible for clinical trial or transplant. Incorporation of new targeted agents, such as tyrosine kinase and small-molecule inhibitors, combined with better selection of drugs for unique patient cohorts, will likely be necessary to substantially improve outcomes in AML.     

New therapeutic approaches to acute myeloid leukemia

Background: The heterogeneity of acute myeloid leukemia (AML) has been established by many new insights into the pathogenesis and treatment of patients with AML. Understanding the basic cellular and molecular pathogenesis of leukemic cells is vital to the development of new treatment approaches. Objective/methods: To review progress until now with agents that are showing promise in the treatment of AML, we summarize the published preclinical and clinical trials that have been completed. Results: Based on recent progress of investigations, more specifically targeted agents have been developed for the treatment of AML such as tyrosine kinase inhibitors, monoclonal antibodies, epigenetic agents, antiangiogenic agents, and farnesyl transferase inhibitors. Conclusion: In the future, in addition to performing therapeutic trials of these agents, it will be important to identify other highly specific therapeutic agents based on our evolving understanding of the biology of AML.     

The safety of treatment options for elderly people with acute myeloid leukemia

ABSTRACT

Introduction: Life expectancy in elderly patients with acute myeloid leukemia (AML) is a function of age, disability, and co-morbidity, combined with leukemia characteristics. There is currently no consensus regarding the optimal therapeutic strategy for older adults with AML. Although selected older adults with AML can benefit from intensive therapies, recent evidence supports the use of lower-intensity therapies in most patients and emphasizes the importance of tolerability and quality of life.

Areas covered: Results of the current clinical trials and safety data are reviewed.

Expert opinion: Treatment recommendations for elderly patients with AML need to be individualized. In order to avoid toxicities, hematologists should collaborate more with geriatricians to identify clues of vulnerability in elderly patients through the study of functional physical, physiological, cognitive, social, and psychological parameters.     

维奈克拉联合用药治疗急性髓系白血病的研究进展

Bcl-2是调控肿瘤细胞凋亡的关键分子,也是近年研究证实的白血病治疗新靶点.针对该靶点的Bcl-2抑制剂维奈克拉与去甲基化药物的联合用药方案于2018年11月获美国食品和药物管理局批准,用于治疗75岁及以上初治或有合并症不适合高强度化疗的急性髓系白血病(AML)患者.多项研究证实维奈克拉联合去甲基化药物或小分子抑制剂在...     

The efficacy of sapacitabine in treating patients with acute myeloid leukemia

ABSTRACT

Introduction: Acute myeloid leukemia (AML) remains a poor prognosis hematological malignancy. The introduction of aggressive chemotherapy with allogeneic stem cell transplantation has resulted in improved clinical outcomes in younger patients. However, the treatment results in unfit elderly AML population remain disappointing. New strategies should be introduced to improve the prognosis in this group of patients.

Areas covered: This review presents and discusses the mechanism of action, safety and efficacy of sapacitabine in AML patients.

Expert opinion: Sapacitabine, a novel nucleoside analog, seemed to be a promising new agent for AML treatment. Its oral bioavailability and tolerable toxicity profile allow the drug to be used in an outpatient setting, especially in elderly unfit patients. Sapacitabine is known to have antileukemic activity in randomized clinical trials. In AML patients, sapacitabine monotherapy offered no advantage over low-intensity cytarabine treatment, and the combination of sapacitabine with decitabine was not significantly more effective than decitabine alone. However, the oral administration of sapacitabine allows it to be used in AML maintenance therapy.     

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.     

CAG方案用于治疗相关性急性髓系白血病诱导化疗的临床观察

目的观察CAG方案（阿克拉霉素＋阿糖胞苷＋粒细胞集落刺激因子）用于治疗相关性急性髓系白血病诱导化疗的疗效及不良反应。方法对13例治疗相关性急性髓系白血病患者采用CAG方案化疗2疗程的缓解率及不良反应进行统计分析。结果 13例治疗相关性急性髓系白血病采用CAG方案诱导化疗1疗程后完全缓解率53.8%（7/13）,部分缓解率7.7%（1/13）;化疗2疗程后完全缓解率69.2%（9/13）。主要不良反应为恶心、呕吐、骨髓抑制和感染。结论 CAG方案用于治疗相关性急性髓系白血病诱导化疗的有效率高,多数患者不良反应不严重,可作为一种安全有效的推荐方案。     

Genetic mutations in epigenetic modifiers as therapeutic targets in acute myeloid leukemia

Introduction: Despite enormous insights into the molecular mechanisms of acute myeloid leukemia (AML) pathophysiology, this disease is still fatal in the majority of patients, highlighting the urgent need for novel biomarkers useful in AML prognosis and therapy.

Areas covered: The advent of modern sequencing technologies has allowed the identification of genetic mutations in genes encoding for specific enzymes involved in the epigenetic regulation of gene expression. The authors review recent data demonstrating the involvement of mutations in genes encoding for epigenetic players and their complex combination with somatic genetic mutations in the pathogenesis of AML. They also discuss the prognostic and therapeutic implications of these findings.

Expert opinion: Current clinical and preclinical studies are underscoring the importance of targeting epigenetic modifiers as new biomarkers for a better prognostic risk stratification and therapeutic evaluation of intermediate-risk patients. Combining data from traditional and modern methodologies will allow a definition of the complex networks of epigenetic changes and molecular interactions between candidate epitargets and key regulators of hematopoiesis. It will thus be possible to achieve an overview of potential aberrant mechanisms driving leukemogenesis in different classes of AML patients. Such an improved approach could pave the way towards ‘personalized’ therapies.     

Drug delivery in acute myeloid leukemia

Background: Acute myeloid leukemia was among the first malignancies to be cured by drug therapy alone, but overall survival rates remain unsatisfactory and have changed little over the past 20 years. Conventional chemotherapeutic regimens, which almost invariably include cytarabine and anthracyclines, are untargeted, and more specific therapies are needed. Objective: We have chosen acute myeloid leukemia as a disease prototype to review established and novel targeted approaches in leukemia treatment. Methods: Our selection of the reviewed literature focused on drug delivery aspects. Conclusion: While the toxicity profile of chemotherapeutics has been improved by liposomal formulations and antibody conjugation for leukemia-directed uptake, their efficacy has probably not changed significantly. Drugs with an alternative mode of action, including kinase inhibitors, hold great promise. Further improvements may result from the characterization of novel acute myeloid leukemia (AML) cell surface receptors and of leukemic stem cells, as well as from the design of leukemia-targeted gene therapy vectors.     

The preclinical discovery of vosaroxin for the treatment of acute myeloid leukemia

Introduction: Acute myeloid leukemia (AML) represents a disease with a very poor outcome and remains an area of significant unmet need necessitating novel therapeutic strategies. Among novel therapeutic agents, vosaroxin is a first-in-class anticancer quinolone derivative that targets topoisomerase II and induces site-selective double-strand breaks in DNA, leading to tumor cell apoptosis.

Areas covered: Herein, the authors provide a comprehensive review of the preclinical development of vosaroxin. This includes coverage of vosaroxin’s mechanism of action in addition to its pharmacology and of the main studies reported over the past few years with vosaroxin when used to treat adult AML.

Expert opinion: Given that vosaroxin is associated with fewer potential side effects, it may be of benefit to elderly patients with relapsed/refractory AML and to those with additional comorbidities who have previously received an anthracycline and cytarabine combination. Furthermore, vosaroxin also was seen to be active in multidrug-resistant preclinical models. However, further studies have to be performed to better evaluate its place in the armamentarium against AML.     

p16和p15第二外显子HapⅡ位点在成人急性髓性白血病中的突变

目的　探讨p16和p15基因第二外显子HapⅡ位点在成人急性髓性白血病 (AML)中的突变。方法　用甲基敏感和甲基非敏感限制性内切酶切消化基因组DNA后 ,经PCR扩增和琼脂糖电泳研究 3 1例AML中无p16/p15基因第二外显子缺失的患者中HapⅡ位点的突变情况。结果　在 3 1例成人AML样本中 ,p16E2 的 4个HapⅡ位点和p15E2 的 6个HapⅡ位点均未发生突变。结论　本研究提示p16和p15基因第二外显子中因甲基化而引起的CCGG位点的突变在成人AML患者中不是主要失活方式。     

儿童急性白血病化疗常用药物的心脏毒性研究进展

儿童急性白血病的治疗以联合化疗为主,由于多种化疗药物具有心肌毒性,限制了其临床应用.如何降低化疗药物心肌损害的发生率,是摆在临床医师面前的一道难题.结合近年相关研究,就小儿急性白血病联合化疗涉及的一些化疗药物的心脏毒性的临床特点、作用机制、危险因素和治疗方法等做一综述.     

Chemotherapy of acute leukemia in adults

Background: General therapeutic options for adult patients with acute leukemia are reviewed and specific new treatment strategies are described. Objective: Treatment results and controversial issues on current and future antileukemic strategies are discussed. Methods: Data in this review came from the published literature. Results/conclusion: In the past years, striking new developments have been noticeable in the treatment of adult acute leukemia. However, the overall outcome of adult acute leukemia remains poor, particularly in older patients. Intensive chemotherapy remains the standard for leukemia treatment but several approaches using new cytotoxic agents seem promising. Therapeutic targeting of specific biologic abnormalities present in the leukemia cell population might, in a near future, improve outcome of adult leukemia patients.     

大剂量阿糖胞苷对急性髓性白血病缓解后巩固治疗的影响

目的观察大剂量阿糖胞苷（HD—AraC）（3g/m^2）治疗急性髓性白血病（AML）患者的近期疗效及安全性。方法回顾分析我院血液科收治的应用HD—AraC治疗的12例AML患者的病例资料,治疗方案为AraC3g／m^2,1次／12h,第1、3、5天,连续3—4个疗程,其中2例患者只进行2个疗程。观察治疗后效果。结果全部患者均可耐受,有较好的安全性,中位随访时间为24．1（7—54）个月,随访观察至2012年7月,10例患者处于持续缓解状态,只完成2个疗程的患者复发死亡。全组治疗相关死亡率为0％（0／12）,复发相关病死率为16．7％（2／12）,中位生存期为35．8（7～66）个月,2年总生存率为83．3％（10／12）。结论HD—AraC应用于AML缓解后的巩固化疗疗效较好,有较好的安全性,值得临床更大规模的应用。     

Vorinostat in acute myeloid leukemia and myelodysplastic syndromes

Introduction: The results of conventional treatment for acute myeloid leukemia (AML) and myelodysplastic syndromes (MDS) remain poor and innovative strategies are warranted. With this aim, epigenetic modulation became a promising approach over the last years. Vorinostat is an epigenetic targeted drug belonging to the histone deacetylase (HDAC) inhibitors family. It is the second-generation HDAC inhibitor that has been more extensively studied in AML and MDS.

Areas covered: In this review, we will present the rationale for its use in AML and MDS, describe the drug pharmacologic properties and review the current data available from clinical trials. The data presented here will allow the reader to overview the common mechanisms of action of this class of compounds in AML and MDS, as well as to better understand the biological specificities of vorinostat, and its current and future clinical development in the field.

Expert opinion: Vorinostat has shown an acceptable toxicity profile with mainly gastrointestinal and constitutional side effects. Efficacy as a single agent is limited in that group of patients, but promising results are currently observed with combinations of vorinostat and either conventional chemotherapy or investigational agents, including demethylating agents.     

The role of quizartinib in the treatment of acute myeloid leukemia

Introduction: Approximately one-third of the patients with acute myeloid leukemia (AML) harbor internal tandem duplication (ITD) in the gene encoding FMS-like tyrosine kinase 3 (FLT3-ITD), which is associated with poor prognosis. Over the course of the last decade, several FLT3 inhibitors have been developed. Nevertheless, the pharmacokinetic limitations of some of these compounds as well as their potency have limited their therapeutic efficacy. Quizartinib (AC220) is a second-generation FLT3 inhibitor that has shown promising activity in AML in Phase II clinical trials.

Areas covered: The pharmacokinetic, mechanism of action and resistance as well as clinical studies of quizartinib in AML are reported here in detail

Expert opinion: Quizartinib is potent and selective FLT3 tyrosine kinase inhibitor with significant activity in both FLT3-mutant and wild-type AML. The quality and duration of achievable response thus far seen with this agent is suboptimal. Quizartinib in combination with chemotherapy might result in improved outcome and results of these trials are eagerly awaited. In addition, quizartinib in combination with other agents tackling the bone marrow microenvironment and FLT3 cooperative pathways may enhance response to quizartinib.     

HAG方案治疗老年急性髓系白血病16例疗效分析

目的探讨老年急性髓系白血病（AML）的治疗方法。方法应用HAG预激方案（阿糖胞苷10mg·m^-1,每12h皮下注射1次,第1～14d;高三尖杉酯碱1mg·m^-2·d^-1,第1—14d,静脉滴注;粒细胞集落刺激因子300μg·d^-1,第1—14d皮下注射）,治疗老年急性髓系白血病16例,观察疗效及毒副作用结果16例患者中,达到完全缓解5例,部分缓解2例,早期死亡3例,骨髓抑制比常规化疗抑制较轻,未见严重心、肝、肾等重要器官损害。结论HAG方案治疗老年AML效果较好,化疗耐受性高。     

Guadecitabine (SGI-110): an investigational drug for the treatment of myelodysplastic syndrome and acute myeloid leukemia

ABSTRACT

Introduction: The incidence of acute myeloid leukemia (AML) and myelodysplastic syndromes (MDS) is increasing with the aging population. Prognosis and overall survival (OS) remain poor in elderly patients and in those not eligible for intensive treatment. Hypomethylating agents (HMAs) have played an important role in this group of patients but their efficacy is limited.

Areas covered: This article reviews the mechanism of action, pharmacology, safety profile and clinical efficacy of subcutaneous guadecitabine, a second-generation DNA methylation inhibitor in development for the treatment of AML and MDS.

Expert opinion: Although guadecitabine did not yield improved complete remission (CR) rates and OS compared to the control arm in patients with treatment-naïve AML who were ineligible for intensive chemotherapy, subgroup analysis in patients who received ≥4 cycles of therapy demonstrated superior outcomes in favor of guadecitabine. Given its stability, ease of administration, safety profile and prolonged exposure time, guadecitabine would be the more appropriate HMA, replacing azacitidine and decitabine, to be used combination treatment regimens in patients with myeloid malignancies.     

Investigational CHK1 inhibitors in early stage clinical trials for acute myeloid leukemia

Introduction: Acute myeloid leukemia (AML) is the most common myeloid malignancy in adults. Despite recent discoveries of targeted therapies, the frontline therapy consisting of chemotherapy remains unchanged for the past four decades. Like other cancers, AML is characterized by deranged DNA damage repair (DDR) pathway. Although impaired DDR may contribute to the pathogenesis of AML it also allows leukemia cells with damaged DNA to attempt repair resulting in resistance. CHK1 inhibitors reverse the cell cycle arrest, disallowing the cell to repair the chemotherapy-induced DNA damage, driving the cell to enter into mitotic catastrophe.

Areas covered: This paper reviews the preclinical and clinical development of CHK1 inhibitors and we discussed their promising role as a potential addition to the therapeutic arsenal of AML.

Expert opinion: Targeting the cell cycle checkpoints is an intriguing approach to treat cancer in general and AML in particular. CHK1 inhibitors in combination with chemotherapy have the potential of improving outcome in high-risk AML characterized by DDR activation.