Does occupational exposure to formaldehyde cause hematotoxicity and leukemia-specific chromosome changes in cultured myeloid progenitor cells?

Several cross-sectional studies of a single population of workers exposed to formaldehyde at one of two factories using or producing formaldehyde–melamine resins in China have concluded that formaldehyde exposure induces damage to hematopoietic cells that originate in the bone marrow. Moreover, the investigators interpret observed differences between groups as evidence that formaldehyde induces myeloid leukemias, although the mechanisms for inducing these diseases are not obvious and recently published scientific findings do not support causation. Our objective was to evaluate hematological parameters and aneuploidy in relation to quantitative exposure measures of formaldehyde. We obtained the study data for the original study (Zhang et al. 2010 Zhang L, Tang X, Rothman N, Vermeulen R, Ji Z, Shen M, Qiu C, Guo W, Liu S, Reiss B, et al. 2010. Occupational exposure to formaldehyde, hematotoxicity, and leukemia-specific chromosome changes in cultured myeloid progenitor cells. Cancer Epidemiol Biomarkers Prev. 19:80–88.[Crossref], [PubMed], [Web of Science ®] , [Google Scholar]) and performed linear regression analyses. Results showed that differences in white blood cell, granulocyte, platelet, and red blood cell counts are not exposure dependent. Among formaldehyde-exposed workers, no association was observed between individual average formaldehyde exposure estimates and frequency of aneuploidy, suggested by the original study authors to be indicators of myeloid leukemia risk.     

Curative chemotherapy for acute myeloid leukemia: the development of high-dose ara-C from the laboratory to bedside

Summary In the bench to bedside development of drugs to treat patients with cancer, the common guide to dose and schedule selection is toxicity to normal organs patterned after the preclinical profile of the drug. An understanding of the cellular pharmacology of the drug and specifically the cellular targets linked to the drug's effect is of substantial value in assisting the clinical investigator in selecting the proper dose and schedule of drug administration. The clinical development of ara-C for the treatment of acute myeloid leukemia (AML) provides a useful paradigm for the study of this process. An understanding of the cellular pharmacology, cytokinetics and pharmacokinetics of ara-C in leukemic mice showed substantial schedule-dependency. Exposure to high doses for a short duration (C × t) resulted in a palliative therapeutic outcome. In marked contrast, exposure to lower doses for a protracted period (c × T) was curative. Clinical use of ara-C in patients with AML patterned after the murine experience, c × T approach, has been of limited benefit in terms of long-term disease-free survival. Studies with human leukemia blasts from patients have shown that for the majority of patients, the initial rate-limiting step is membrane transport, the characteristics of which are substantially affected by extracellular drug concentration (dose). This pharmacologic impediment is eliminated with the blood levels attained during the infusion of gram doses (1–3 gm/m²) of the drug (high-dose ara-C, HiDaC) for shorter periods of time, a C × t approach. Clinical confirmation of these pharmacologic observations is evident in the therapeutic efficacy of HiDaC in patients with relapsed or SDaC-refractory acute leukemia. This is further emphasized by the significantly improved leukemia-free survival of patients with AML treated with HiDaC intensification during remission compared to those patients treated with milligram doses typical of SDaC protocols. Thus, the identification and monitoring of important parameters of drug action in tumors during the course of a clinical trial can be of substantial assistance in optimizing drug dose and schedule so as to attain the best therapeutic index.     

AML,MAL及RAEB-2中Auer小体检出率及其形态学观察

目的:观察急性髓细胞白血病(AML)、急性混合细胞白血病(MAL)及原始细胞过多难治性贫血-2型(RAEB-2)标本中Auer小体的形态及其检出率。方法:瑞-姬氏染色,油镜观察。结果:阳性检出率为39.3%。其中M3的检出率最高,为72.7%,与M5及M6比较有显著差异(P<0.01),而M5中仅见于M5b。观察中发现多种形态的Auer小体并进行了相关组化鉴定。结论:Auer小体的形态是多种多样的,不典形Auer小体的鉴别必须辅以POX及PAS等组化染色。一旦发现Auer小体,即标志为AML、MAL或MDS。     

急性髓系白血病基因水平发病机制的研究进展

白血病是一种常见的血液系统恶性肿瘤,其中急性髓系白血病(acute myeloid leukemia,AML)是所有白血病中最常见的一类以克隆性髓系原始细胞增高为主的造血系统恶性疾病,其发病机制尚不完全清楚,现认为是由多种因素在多个层面、多个阶段的相互作用而导致的。随着国内外现代医学事业的不断发展和进步,对急性髓系白血病在基因水平上发病机制的深入研究,开发出的新型基因靶向治疗药物因其能特异性地作用于病变部位,而且效果显著、毒性相对低等特点,使AML的治疗方案不断得以优化,预后也有很大的改善,为临床上高效安全地治疗AML带来新希望。本文拟对AML在基因水平上发病机制的研究进展进行综述,旨在寻找潜在的基因靶点,为开发精准治疗AML的新型基因靶向药物提供参考。     

老年髓系抗原阳性急性淋巴细胞白血病1例报告并文献分析

目的:提高对老年髓系抗原阳性急性淋巴细胞白血病(M y+ALL)的认识。方法:报告1例老年髓系抗原阳性M y+ALL患者的临床资料和实验室检查特征、治疗经过、预后并结合文献复习讨论。结果:患者骨髓原幼淋巴细胞占42.5%,CD 7+细胞占86.99%,cCD 3+细胞占77.24%,CD 33+占91.87%,CD 13+占11.80%,M PO,CD 117,CD 22,CD 19,CD 20,CD 34均阴性,给予长春新碱+柔红霉素+泼尼松(VDP方案)化疗1周期,未缓解,之后给予长春新碱+泼尼松+阿克拉霉素+阿糖胞苷(VP+AA方案)化疗2周期达缓解。结论:老年髓系M y+ALL恶性程度高,对常规化疗方案治疗无效,需给予兼顾髓系和淋系的化疗方案为宜。     

抗肿瘤药阿扎胞苷

阿扎胞苷是一种新型表观遗传学抗肿瘤药,是目前唯一被临床证明可延长高风险骨髓增生异常综合征患者总生存期的抗肿瘤药。     

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。     

Efficacy of Azacitidine in the treatment of adult patients aged 65 years or older with AML

Introduction: Therapy for acute myeloid leukemia (AML) in elderly populations (>65 years) is still a challenge for scientists and hematologists worldwide, and represents an urgent medical need. Notably, the identification and the recognition of molecular and epigenetic mechanisms involved in the pathogenesis of such a heterogeneous disease, are providing new tools for a more successful and ‘targeted’ approach. Azacitidine is a hypomethylating agent (HMA) with relevant activity in patients affected by myelodysplastic syndrome (MDS) and AML with low blast cells percentage (>30%), in terms of reduction of transfusion dependence, and improvement of quality of life.

Areas covered: This review summarizes the mechanism of action, safety profile and efficacy of azacitidine in the field of elderly AML populations, providing up-to-date references on this subset of high-risk patients.

Expert opinion: HMAs are the first successful treatment for elderly patients with high-risk MDS and are effective for some AML subtypes. Translational studies based on gene expression profiling and molecular sequencing, would be able to identify, in the near future, patients with a favorable profile of response to these compounds suggesting new potential treatment combinations also.     

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.     

较高剂量柔红霉素诱导老年急性髓性白血病缓解的疗效分析

目的 探讨较高剂量柔红霉素(DNR)对诱导老年急性髓性白血病（AML）缓解及疗效的作用。方法 随机将123例老年AML分为三组,分别给予标准剂量、低于标准剂量和高于标准剂量的DNR,联合阿糖胞苷（Ara-c）作为首次诱导缓解方案,对比分析化疗产生的不良反应、完全缓解率和两年生存情况。结果 DNR高于标准剂量组血液学毒性反应的发生较标准剂量组未明显增加,而缓解所用时间短（P<0.01）、完全缓解率（63.4% vs 29.3%）和两年无事件生存率（58.5% vs 26.8%）提高（P值均<0.05）。结论 较高剂量DNR可作为诱导老年AML缓解较理想的选择。     

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.     

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.     

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.     

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。     

超小剂量地西他滨治疗骨髓增生异常综合征和急性髓系白血病11例疗效观察

目的 分析超小剂量地西他滨治疗骨髓增生异常综合征(MDS)和急性髓系白血病(AML)的近期临床疗效和不良反应.方法 观察11例接受超小剂量地西他滨治疗的患者临床疗效和不良反应发生率.其中,6例中危-Ⅰ组MDS患者接受地西他滨5~7 mg· m-2· d-1,连用5~6 d的超小剂量方案;2例中危-Ⅱ组和1例高危组MDS患者接受地西他滨联合半程CAG治疗方案;1例高危组MDS患者接受地西他滨联合HA治疗方案;1例AML患者接受地西他滨联合DA治疗方案.结果 11例接受地西他滨治疗的患者中,3例完全缓解,4例部分缓解,1例血液学改善,2例疾病无进展,1例死亡.总有效率为72.7%,完全缓解率为27.3%.3例患者出现肺部感染,1例出现消化道出血.3例出现Ⅱ级血液学不良反应,3例出现Ⅲ级血液学不良反应,均治疗后好转.结论 超小剂量地西他滨治疗方案在中高危组MDS患者中安全有效,耐受性好,且感染及血液学不良反应发生率较低,可在临床进一步推广.     

烯二炔类高效抗肿瘤抗生素Calicheamicin的研究进展

烯二炔类抗生素是由放线菌产生的一类高活性抗肿瘤化合物,因其具有烯二炔环这一独特结构以及很强的抗肿瘤活性而备受人们的关注.其中,针对抗生素calicheamicin(CLM)的研究较为全面,并已用于临床治疗.本文对CLM的发现、结构特点与作用机制、单克隆抗体-CLM偶联物的临床疗效及毒副作用、CLM的化学修饰与合成作简要综述.     

异柠檬酸脱氢酶及其突变体抑制剂在急性髓系白血病治疗领域的研究进展

异柠檬酸脱氢酶（IDH）是人体代谢过程中重要的酶,参与三羧酸循环,催化异柠檬酸转化为α-酮戊二酸（α-KG）。突变的IDH能催化α-KG转化为2-羟基戊二酸（2-HG）,2-HG不是体内正常的代谢产物,高浓度的2-HG与急性髓系白血病（AML）及各种肿瘤的发生紧密相关。针对IDH突变的抑制剂能显著降低2-HG的水平,成为一些肿瘤药物开发的热点。综述IDH突变在AML和肿瘤中的作用及目前在研IDH突变体抑制剂的研究进展。

     

砷剂联合方案抗血液肿瘤的临床应用与研究进展

三氧化二砷(砷剂)即中药\     

减量FLAG方案治疗难治老年急性髓细胞白血病30例临床观察

目的：探讨减量阿糖胞苷的FLAG方案治疗难治老年急性髓细胞白血病（AML）的疗效及不良反应。方法：本研究采用减量阿糖胞苷FLAG方案,氟达拉滨150mg,静脉滴注,30min滴完,第1～5天;阿糖胞苷150mg/m2,静脉滴注,第1～5天;G-CSF化疗前1d开始应用,直至化疗结束。治疗30例难治性老年急性髓细胞性白血病。结果：30例患者中,13例难治性老年急性髓细胞白血病达完全缓解（CR率为43.3%）,6例达部分缓解（PR率为20.0%）,总有效率为63.3%,无效7例,死亡4例。减量阿糖胞苷的FLAG方案的主要不良反应为骨髓抑制、消化道症状、轻度肝损害等。结论：减量阿糖胞苷的FLAG方案对难治老年急性髓细胞白血病治疗缓解率相对较高,不良反应可以接受。