预激方案HAG及CAG治疗老年初治急性髓性白血病的对比研究

目的:评价含粒细胞集落刺激因子(granulocyte colony-stimulating-factor,G-CSF)的预激HAG及CAG方案治疗老年初治急性髓性白血病(AML)的疗效及不良反应,并对两个方案的疗效及不良反应进行比较。方法:65例老年初治AML分为HAG预激治疗组及CAG预激方案治疗组,31例患者予以HAG预激方案治疗,34例患者予以预激方案CAG方案治疗,所有患者在第1疗程后间歇14d左右进行第2个疗程。结果:HAG预激方案治疗组的完全缓解率为74.2%,总有效率为83.8%;CAG预激治疗组完全缓解(CR)率为67.6%,总有效率达为82.4%。两治疗组的血液系统不良反应及非血液系统毒性不良反应比较无显著性差异。结论:HAG预激方案化疗强度温和、敏感性好、CR率及有效率高、毒副作用小;与CAG预激治疗比较,HAG预激方案可以取的相似的疗效及较少的不良反应,在老年初治AML患者值得推荐应用。     

A Modified Integrated Genetic Model for Risk Prediction in Younger Patients with Acute Myeloid Leukemia

BackgroundAlthough cytogenetics-based prognostication systems are well described in acute myeloid leukemia (AML), overall survival (OS) remains highly variable within risk groups. An integrated genetic prognostic (IGP) model using cytogenetics plus mutations in nine genes was recently proposed for patients ≤60 years to improve classification. This model has not been validated in clinical practice.ConclusionsThe IGP model was not completely validated in our cohort. However, mutations in six out of the nine genes can be used to characterize survival (NPMI, IDH1, IDH2, FLT3-ITD, TET2, DNMT3A) and allow for more robust prognostication in the patients who are re-categorized by the IGP model. These mutations should be incorporated into clinical testing for younger patients outside of clinical trials, in order to guide therapy.     

自体CIK细胞联合化疗治疗老年急性白血病的临床疗效评估

目的:探讨自体细胞因子诱导杀伤(CIK)细胞联合化疗方案治疗老年急性白血病的临床疗效。方法:采集6例在我院进行化疗治疗的老年急性白血病患者的静脉血制备自体CIK细胞,成熟后回输入体内,持续注射10天为一个疗程。观察培养前和培养13天后白细胞各亚型细胞所占百分比,并比较CIK细胞回输前后患者白细胞亚群、感染次数及输血量的变化。结果:培养后CD3~+、CD8~+、CD3~+CD8~+、CD3~+CD56~+亚型细胞百分比均显著高于培养前(P0.05),CIK细胞回输后患者体内CD3~+、CD3~+CD8~+、CD3~+CD56~+亚群细胞百分比显著高于回输前(P0.05);CIK细胞回输后,患者感染次数和持续时间均显著少于回输前(P0.05),疾病稳定期输血量显著低于回输前(P0.05),疾病进展期输血量与回输前差异无显著性意义(P0.05)。结论:自体CIK细胞联合化疗治疗老年急性白血病患者有效且安全,可维持病情的稳定、提高机体细胞免疫功能和抗感染能力,值得临床推广。     

自体DC、CIK细胞在急性髓细胞白血病治疗中的研究进展

树突状细胞(DC)是初级免疫应答的激发者,是最有活力的抗原递呈细胞(APC),可以有效地抑制白血病细胞逃逸。未成熟DC细胞从细胞外捕获各种抗原信息,成熟DC细胞传递各种抗原信息给宿主淋巴结的T细胞,激活抗原相关的主要组织相容性复合体(MHC)限制性特异性免疫应答,另外,亦可通过影响B细胞的增殖,不同程度的活化体液免疫应答。细胞因子诱导的杀伤细胞(CIK)是一组具有细胞毒作用的异质细胞群,是较LAK细胞溶瘤活性更强的一种免疫活性细胞,对包括白血病在内的多种恶性肿瘤具有抗肿瘤效应,具有非MHC限制性的杀瘤特点。二者联合培养及应用又增强了各自的活性。DC细胞与CIK细胞对于白血病的疗效不仅在实验室得以证实,而且已经逐步应用于临床,其在清除微小残留病以及预防造血干细胞移植后复发中取得了良好的效果。随着细胞制备技术的完善和研究的进一步深入,自体DC、CIK细胞治疗急性髓细胞白血病逐渐获得众多专家的认可。中国卫生部已经把自体免疫细胞治疗技术做为第三类医疗技术应用于临床,批准号200984。本文就目前DC、CIK、DC-CIK细胞免疫疗法在急性髓细胞白血病中的应用进展加以综述。     

High-Dose Cytarabine in Acute Myeloid Leukemia Treatment: A Systematic Review and Meta-Analysis

The optimal dose, scheme, and clinical setting for Ara-C in acute myeloid leukemia (AML) treatment remain uncertain. In this study, we performed a meta-analysis to systematically assess the impact of high-dose cytarabine (HDAC) on AML therapy during the induction and consolidation stages. Twenty-two trials with a total of 5,945 de novo AML patients were included in the meta-analysis. Only patients less than 60 year-old were included in the study. Using HDAC in induction therapy was beneficial for RFS (HR = 0.57; 95% CI, 0.35–0.93; P = 0.02) but not so for CR rate (HR = 1.01; 95% CI, 0.93–1.09; P = 0.88) and OS (HR = 0.83; 95% CI, 0.66–1.03; P = 0.1). In consolidation therapy, HDAC showed significant RFS benefits (HR = 0.67; 95% CI, 0.49–0.9; P = 0.008) especially for the favorable-risk group (HR = 0.38; 95% CI, 0.21–0.69; P = 0.001) compared with SDAC (standard dose cytarabine), although no OS advantage was observed (HR = 0.84; 95% CI, 0.55–1.27; P = 0.41). HDAC treatment seemed less effective than auto-BMT/allo-BMT treatment (HR = 1.66, 95% CI, 1.3–2.14; P<0.0001) with similar OS. HDAC treatment led to lower relapse rate in induction and consolidation therapy than SDAC treatment, especially for the favorable-risk group. Auto-BMT/allo-BMT was more beneficial in prolonging RFS than HDAC.     

High Risk of Hepatitis B Reactivation among Patients with Acute Myeloid Leukemia

BackgroundHepatitis B virus (HBV) infections are common and associated with significant morbidity and mortality in cancer patients. However, the incidence and risk factors of HBV reactivation in patients with acute myeloid leukemia (AML) are rarely investigated.MethodsAML patients followed-up at the National Taiwan University Hospital between 2006 and 2012 were analyzed. The clinical characteristics and laboratory data were retrospectively reviewed.ResultsFour hundred and ninety patients comprising 265 men and 225 women were studied. The median age was 52 years (range, 18 - 94). Chronic HBV carriage was documented at the time of leukemia diagnosis in 57 (11.6%) patients. Forty-six (80.7%) of the 57 HBV carriers received prophylaxis with anti-HBV agents. Sixteen HBV carriers (28.1%) developed hepatitis B reactivation during or after chemotherapy, including 7 patients who had discontinued antiviral therapy. The incidence of hepatitis B reactivation among AML patients with HBV carriage was 9.5 per 100 person-years. Prophylaxis with anti-HBV agents significantly decreased the risk of hepatitis B reactivation among HBV carriers (13% vs. 61%, p<0.001). Four (2.8%) of 142 patients with initial positive anti-HBsAb and anti-HBcAb experienced hepatitis B reactivation and lost their protective anti-HBsAb. Multivariate analysis revealed that diabetes mellitus (p=0.008, odds ratio (OR) = 2.841, 95% confident interval (CI): 0.985-8.193) and carriage of HBsAg (p<0.001, OR=36.878, 95% CI: 11.770-115.547) were independent risk factors for hepatitis B reactivation in AML patients.ConclusionsHepatitis B reactivation is not uncommon in the HBsAg positive AML patients. Prophylaxis with anti-HBV agent significantly decreased the risk of hepatitis B reactivation.     

Effective Non-Viral Delivery of siRNA to Acute Myeloid Leukemia Cells with Lipid-Substituted Polyethylenimines

Use of small interfering RNA (siRNA) is a promising approach for AML treatment as the siRNA molecule can be designed to specifically target proteins that contribute to aberrant cell proliferation in this disease. However, a clinical-relevant means of delivering siRNA molecules must be developed, as the cellular delivery of siRNA is problematic. Here, we report amphiphilic carriers combining a cationic polymer (2 kDa polyethyleneimine, PEI2) with lipophilic moieties to facilitate intracellular delivery of siRNA to AML cell lines. Complete binding of siRNA by the designed carriers was achieved at a polymer:siRNA ratio of ～0.5 and led to siRNA/polymer complexes of ～100 nm size. While the native PEI2 did not display cytotoxicity on AML cell lines THP-1, KG-1 and HL-60, lipid-modification on PEI2 slightly increased the cytotoxicity, which was consistent with increased interaction of polymers with cell membranes. Cellular delivery of siRNA was dependent on the nature of lipid substituent and the extent of lipid substitution, and varied among the three AML cell lines used. Linoleic acid-substituted polymers performed best among the prepared polymers and gave a siRNA delivery equivalent to better performing commercial reagents. Using THP-1 cells and a reporter (GFP) and an endogenous (CXCR4) target, effective silencing of the chosen targets was achieved with 25 to 50 nM of siRNA concentrations, and without adversely affecting subsequent cell growth. We conclude that lipid-substituted PEI2 can serve as an effective delivery of siRNA to leukemic cells and could be employed in molecular therapy of leukemia.     

自然杀伤细胞对妊娠期糖尿病患者并发高脂血症的影响

目的：观察自然杀伤细胞（NK 细胞）对妊娠期糖尿病患者并发高脂血症的影响。方法：选择2013 年2月至2015 年4 月在我 院确诊的妊娠期糖尿病高脂血症患者95 例,作为研究组,同期选择体检健康孕妇100 例,作为对照组,对比两组的血糖、糖化血 红蛋白、身体质量指数（BMI）、总胆固醇（TC）、甘油三酯（TG）、低密度脂蛋白胆固醇（LDL-C）、高密度脂蛋白胆固醇（HDL-C）、白 细胞介素-2（IL-2）、IL-6、干扰素-r（IFN-r）、NK 细胞及细胞亚型,并采用Person相关性分析NK细胞与血脂的相关性。结果：①研 究组空腹血糖、餐后2 h 血糖、糖化血红蛋白、BMI均明显高于对照组,差异具有统计学意义（P<0.05）;②研究组TC、TG、LDL-C 均明显高于对照组,HDL-C明显低于对照组,差异具有统计学意义（P<0.05）;③研究组IL-2、IFN-r明显低于对照组,差异具有统 计学意义（P<0.05）;IL-6 明显高于对照组,差异具有统计学意义（P<0.05）;④研究组的NK 细胞数量、CD4+/ CD3+、CD4+/ CD8+、 CD56++CD4+/ CD3+均低于对照组的（P<0.05）;CD8+/ CD3+、CD18+/ CD8+、CD19+/ CD3+均高于对照组的（P<0.05）;两组CD28+/ CD8+差异无统计学意义（P＞0.05）。⑤NK 细胞数量与TC、TG、LDL-C水平均呈负相关（r=-0.527、-0.598、-0.485）,NK 细胞数量与 HDL-C 水平呈正相关（r=0.528）。结论：NK 细胞在妊娠期糖尿病孕妇中数量减少,活性也降低,可能与参与免疫反应的NK细胞 不同表型细胞含量发生变化,导致血脂调节失衡,引发高血脂症的过程有关。     

Phase I Trial: Cirmtuzumab Inhibits ROR1 Signaling and Stemness Signatures in Patients with Chronic Lymphocytic Leukemia

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苏尼替尼治疗46例慢性粒细胞白血病的临床分析

目的比较和评价苏尼替尼治疗慢性粒细胞白血病（CML）的临床效果。方法回顾分析近7年来收治我院的46例CML患者的临床诊疗资料,统计其完全缓解（CR）率、生存期及影响因素。结果完全缓解35例,占总病例数的76.09%;部分缓解7例,占15.22%;未缓解4例,占8.69%。统计至2010年12月,五年存活26例,五年生存率56.52%。结论苏尼替尼是早期治疗CML的有效手段,能较为明显的缓解病情,减少并发症的发生率,提高患者的生存率,治疗过程中仍需要患者及其家属的密切配合。     

A Multicenter Phase I/II Study of Obatoclax Mesylate Administered as a 3- or 24-Hour Infusion in Older Patients with Previously Untreated Acute Myeloid Leukemia

Purpose

An open-label phase I/II study of single-agent obatoclax determined a maximum tolerated dose (MTD) and schedule, safety, and efficacy in older patients (≥70 yr) with untreated acute myeloid leukemia (AML).

Experimental Design

Phase I evaluated the safety of obatoclax infused for 3 hours on 3 consecutive days (3 h×3 d) in 2-week cycles. Initial obatoclax dose was 30 mg/day (3 h×3 d; n = 3). Obatoclax was increased to 45 mg/day (3 h×3 d) if ≤1 patient had a dose-limiting toxicity (DLT) and decreased to 20 mg/day (3 h×3 d) if DLT occurred in ≥2 patients. In the phase II study, 12 patients were randomized to receive obatoclax at the dose identified during phase I (3 h×3 d) or 60 mg/day administered by continuous infusion over 24 hours for 3 days (24 h×3 d) to determine the morphologic complete response rate.

Results

In phase I, two of three patients receiving obatoclax 30 mg/day (3 h×3 d) experienced grade 3 neurologic DLTs (confusion, ataxia, and somnolence). Obatoclax was decreased to 20 mg/day (3 h×3 d). In phase II, no clinically relevant safety differences were observed between the 20 mg/day (3 h×3 d; n = 7) and 60 mg/day (24 h×3 d; n = 5) arms. Neurologic and psychiatric adverse events were most common and were generally transient and reversible. Complete response was not achieved in any patient.

Conclusions

Obatoclax 20 mg/day was the MTD (3 h×3 d) in older patients with AML. In the schedules tested, single-agent obatoclax was not associated with an objective response. Evaluation in additional subgroups or in combination with other chemotherapy modalities may be considered for future study.

Trial Registration

ClinicalTrials.gov {"type":"clinical-trial","attrs":{"text":"NCT00684918","term_id":"NCT00684918"}}NCT00684918     

大剂量阿糖胞苷治疗儿童急性髓系白血病的耐受性研究

目的:探讨儿童急性髓系白血病对于大剂量阿糖胞苷的耐受性,为临床用药提供指导.方法:从我院2007年1月～2011年1月收治的儿童急性髓系白血病患者中选取40例,将其作为临床研究对象,随机分成A、B两组,每组均20例患者.两组都给予大剂量阿糖胞苷,A组患者给予体表面积3 g/m2用量;B组患者给予体表面积2 g/m2用量.一周后,分别观察两组急性髓系白血病儿童的治疗效果、神经系统毒性和副作用.结果:治疗一周后,A组患者贫血例数2例(10.00％)较B组患者贫血例数8例(40.00％)少,A组患者所表现的神经毒性头疼、嗜睡、淡漠及惊厥方面较B组患者严重,A组患者所表现的副作用眼球震颤、轮替运动障碍、共济失调均较B组患者严重.结论:大剂量阿糖胞苷虽具有更好的疗效,基本耐受但其不良反应相对严重.     

臭椿酮抑制急性骨髓性白血病细胞恶性生物学行为的研究

为了探讨臭椿酮(ailanthone,AIL)对急性骨髓性白血病(acute myelogenous leukemia,AML)细胞恶性生物学行为的影响,用不同浓度(0.2、0.4、0.8、1.6、3.2μmol·L^-1)的AIL处理对数生长期的HL-60细胞,将miR-449a mimic质粒、mimic对照质粒、miR-449a inhibitor质粒、inhibitor对照质粒分别转染至未经任何处理的HL-60细胞,并用1.0μmol·L^-1浓度的AIL处理细胞24 h。采用CCK-8法检测细胞增殖水平,细胞划痕实验检测细胞迁移水平,Transwell小室法检测细胞侵袭水平,Annexin V-FITC/PI双染法检测细胞凋亡水平,qRT-PCR法检测miR-449a mRNA表达水平,Western blot法检测磷脂酰肌醇3-激酶(PI3K)、磷酸化PI3K(p-PI3K)、蛋白激酶B(AKT)、磷酸化AKT(p-AKT)蛋白表达水平。结果显示,AIL干预后HL-60细胞增殖抑制率、凋亡率升高,细胞迁移率及细胞侵袭数降低(P<...     

A Novel Application of Furazolidone: Anti-Leukemic Activity in Acute Myeloid Leukemia

Acute myeloid leukemia (AML) is the most common malignant myeloid disorder of progenitor cells in myeloid hematopoiesis and exemplifies a genetically heterogeneous disease. The patients with AML also show a heterogeneous response to therapy. Although all-trans retinoic acid (ATRA) has been successfully introduced to treat acute promyelocytic leukemia (APL), it is rather ineffective in non-APL AML. In our present study, 1200 off-patent marketed drugs and natural compounds that have been approved by the Food and Drug Administration (FDA) were screened for anti-leukemia activity using the retrovirus transduction/transformation assay (RTTA). Furazolidone (FZD) was shown to inhibit bone marrow transformation mediated by several leukemia fusion proteins, including AML1-ETO. Furazolidone has been used in the treatment of certain bacterial and protozoan infections in human and animals for more than sixty years. We investigated the anti-leukemic activity of FZD in a series of AML cells. FZD displayed potent antiproliferative properties at submicromolar concentrations and induced apoptosis in AML cell lines. Importantly, FZD treatment of certain AML cells induced myeloid cell differentiation by morphology and flow cytometry for CD11b expression. Furthermore, FZD treatment resulted in increased stability of tumor suppressor p53 protein in AML cells. Our in vitro results suggest furazolidone as a novel therapeutic strategy in AML patients.     

SHIP1在急性髓细胞白血病患者中的表达及对人白血病细胞凋亡的影响研究

目的:探讨含SH2结构域的肌醇1(SHIP1)在急性髓细胞白血病患者中的表达及对人白血病细胞凋亡的影响。方法:采用Western blot检测收集的急性髓细胞白血病患者骨髓中SHIP1的表达。人白血病细胞U937转染SHIP1过表达载体(pEGFP-SHIP1组)及对照空载体(pEGFP组),同时设置对照组,对照组细胞不转染载体,其他步骤同pEGFP-SHIP1组和pEGFP组。流式细胞仪检测48 h的细胞凋亡情况,Western blot检测48 h细胞中SHIP1、Bcl-2、Bax、Akt、p-Akt的表达。结果:急性髓细胞白血病患者骨髓中SHIP1表达明显低于正常人(P0.05)。pEGFP-SHIP1组细胞中SHIP1、Bax表达和凋亡率均明显高于pEGFP组及对照组(P0.01),Bcl-2、p-Akt表达均明显低于对照组(P0.01)。结论:SHIP1在急性髓细胞白血病患者骨髓中表达下调,其可能通过Akt信号促进人白血病细胞凋亡。