慢性淋巴细胞白血病治疗新药alemtuzumab

慢性淋巴细胞白血病是常见于成人的血液系统疾病,alemtuzumab作为一种作用机制独特的新颖单克隆抗体,对源于B和T细胞的各种恶性肿瘤具有很好的治疗作用。

Alemtuzumab: A Place in Therapy for Treatment of Multiple Sclerosis

Alemtuzumab is a humanized mononclonal antibody known to cause rapid depletion of B-and T-cell lymphocytes. Subsequent repletion of these lymphocytes leads to changes in adaptive immunity. Alemtuzumab is approved by the United States Food and Drug Administration (FDA) for the treatment of B-cell lymphocytic leukemia but has been investigated off-label in recent years for treatment of autoimmune diseases, including multiple sclerosis (MS). In MS treatment, alemtuzumab is administered as pulsed therapy, given once daily initially for 5 consecutive days and then for 3 consecutive days at 12-month intervals. Alemtuzumab has recently been compared to interferon beta 1-a in one phase II and two phase III trials in patients with relapsing-remitting MS. Results from the studies show alemtuzumab compared to interferon beta 1-a is associated with a greater reduction in the risk of sustained accumulation of disability and is more effective in reducing disease relapse rates. The treatment of MS continues to be a healthcare challenge due to the modest clinical benefit and adverse effect profiles of available disease modifying treatment options. Available data suggest alemtuzumab may offer better efficacy outcomes compared to traditional disease modifying therapies in patients with MS. However, the agent has not been compared to other new disease modifying medications that have been recently introduced.

FDA授予MS治疗药alemtuzumab快通道审批资格

FDA授予Genzyme公司的多发性硬化症（MS）药物alemtuzumab（Ⅰ）快通道审批资格，该公司董事长兼首席执行官HenriTermeer称（Ⅰ）是治疗MS的一种潜在的，具有创新意义的药物，Genzyme将与FDA共同努力以加快该计划的审查过程。

Effect of Alemtuzumab on Intestinal Intraepithelial Lymphocytes and Intestinal Barrier Function in Cynomolgus Model

Background：Alemtuzumab has been used in organ transplantation and a variety of hematologic malignancies （especially for the treatment of B-cell chronic lymphocytic leukemia）.However,serious infectious complications frequently occur after treatment.The reason for increased infections postalemtuzumab treatment is unknown at this stage.We explore the effect ofalemtuzumab on intestinal intraepithelial lymphocytes （IELs） and intestinal barrier function in cynomolgus model to explain the reason of infection following alemtuzumab treatment.Methods：Twelve male cynomolguses were randomly assigned to either a treatment or control group.The treatment group received alemtuzumab （3 mg/kg,intravenous injection） while the control group received the same volume of physiological saline.Intestinal IELs were isolated from the control group and the treatment group （on day 9,35,and 70 after treatment） for counting and flow cytometric analysis.Moreover,intestinal permeability was monitored by enzymatic spectrophotometric technique and enzyme-linked immunosorbent assay.Results：The numbers of IELs were decreased significantly on day 9 after treatment compared with the control group （0.35 ± 0.07 × 10^8 and 1.35 ± 0.09 × 10^8,respectively; P 〈 0.05） and were not fully restored until day 70 after treatment.There were significant differences among four groups considering IELs subtypes.In addition,the proportion ofapoptotic IELs after alemtuzumab treatment was significantly higher than in the control group （22.01 ± 3.67 and 6.01 ± 1.42,respectively; P 〈 0.05）.Moreover,the concentration of D-lactate and endotoxin was also increased significantly on day 9 after treatment.Conclusions：Alemtuzumab treatment depletes lymphocytes in the peripheral blood and intestine of cynomolgus model.The induction of apoptosis is an important mechanism of lymphocyte depletion after alemtuzumab treatment.Notably,intestinal barrier function may be disrupted after alemtuzumab treatment.

Alemtuzumab induction therapy in highly sensitized kidney transplant recipients

Background Immunosuppression for immunologically high-risk kidney transplant patients usually involves antithymocyte globulin induction with triple drug maintenance therapy. Alemtuzumab, a humanized anti-CD52 antibody, was expected to be a promising induction therapy agent for kidney transplantation. However, currently no consensus is available about its efficacy and safety. This study aimed to evaluate the efficacy and safety of alemtuzumab as immune induction therapy in highly sensitized kidney transplant recipients.Methods In this prospective, open-label, randomized, controlled trial, we enrolled 23 highly immunological risk patients （panel reactive antibody 〉20%）. They were divided into two groups： alemtuzumab group （trial group） and anti-thymocyte globulin （ATG） group （control group）. Patients in the alemtuzumab group received intravenous alemtuzumab （15 mg） as a single dose before reperfusion. At the 24th hour post-operation, another dosage of alemtuzumab （15 mg） was given. The control group received a bolus of rabbit ATG （9 mg/kg）, which was given 2 hours before kidney transplantation and lasted until the removal of vascular clamps when the anastomoses were completed. Maintenance immunosuppression in both groups comprised standard triple therapy consisting of tacrolimus, prednisone, and mycophenolate mofetil （MMF）. Acute rejection （AR） and infection episodes were recorded, and kidney function was monitored during a 2-year follow-up. X2 test, ttest and Kaplan-Meier analysis were performed with SPSS17.0 software.Results Median follow-up was 338 days. In both the alemtuzumab group and ATG group, creatinine and blood urea nitrogen values in surviving recipients were similar （P 〉0.05）. White blood cell counts were significantly reduced in the alemtuzumab group for the most time points up to 6 months （P 〈0.05）. One patient receiving alemtuzumab died for acute myocardial infarction at the 65th day post-operation. Two ATG patients died for severe pulmonary infection or cardiac and pulmonary failure. Cumulative 2-year graft survival rate was 90.9% in the alemtuzumab group and 81.8% in ATG group （P 〉0.05） respectively. There was one graft failure in the alemtuzumab group and two graft failures in ATG group, with all graft failures at tributed to rejection episodes. The alemtuzumab group had a 2-year cumulative freedom from rejection rate of 81.8%, compared with 72.7% for the ATG group （P 〉0.05）.Conclusion Alemtuzumab induction therapy for highly sensitized kidney transplant recipients is an effective and safe protocol yielding an acceptable acute rejection rate.

Efficacy and safety of induction therapy with alemtuzumab in kidney transplantation： a meta-analysis

Background Alemtuzumab, a humanized CD52 monoclonal antibody, with its profound lymphocyte depletion property, was expected to be a promising induction therapy agent for kidney transplantation （KTx）. However, currently no consensus is available about its efficacy and safety. The aim of this meta-analysis was to make a profound review and an objective appraisal of this issue. Methods Relevant papers were searched, essentially in the PubMed database and the Cochrane library. After a thorough review, randomized controlled trials （RCTs） comparing the outcome of KTx using alemtuzumab induction therapy （test group） with a control group were collected according to the inclusion criteria. Data of general characteristic of studies and major outcomes of Ktx were extracted and meta-analyses were performed with RevMan 4.2 software. The odds ratio （OR） with a 95% confidence intervals （Co was the principle measurement of effect. Results Five RCTs were included. The chi square test showed no significant between-study heterogeneity, thus fixed effect model was employed. Sub-group analysis with studies including alemtuzumab induction followed by a tacrolimus-based immunosuppressive regimen showed that the acute rejection rate （ARR） was lower relative to the control （OR=0.59, 95% CI 0.34-1.01, P=0.05）. However, meta-analysis with all included studies revealed that neither ARR nor patient/graff survival rates differ significantly between the test and the control group, but the cytomegalovirus （CMV） infection rate was higher in the test group （OR 2.50, 95% CI 1.22-5.12, P=0.01）. A great number of the test group recipients safely remained on a regimen that was steroid-free and with a reduced dose of conventional immunosuppressive drugs. Conclusions Alemtuzumab induction therapy for KTx was an effective and safe protocol in the tested follow-up period. Steroid avoidance and a dose reduction of conventional immunosuppressive drugs after alemtuzumab induction therapy may have clinical importance. However, high quality RCTs with larger population and longer follow-up are needed for a more accurate and objective appraisal of this novel protocol.

The response of intestinal stem cells and epithelium after alemtuzumab administration

Qiurong Li1,Qiang Zhang1,Chenyang Wang1,Shaojun Jiang2,Ning Li1,Jieshou Li1 Intestinal stem cells may have important roles in the maintenance of epithelial integrity during tissue repair.Alemtuzumab is a humanized anti-CD52 lymphocytic antibody that is increasingly being used to induce immunosuppression;intestinal barrier function is impaired during treatment with alemtuzumab.We investigated the response of intestinal stem cells to epithelial damage resulting from alemtuzumab treatment.Intestinal epithelial cell loss and abnormal Paneth cell morphology were found following a single dose of alemtuzumab.The animals receiving alemtuzumab exhibited increased apoptosis in the villi 3 days after alemtuzumab treatment and in the crypt on day 9,but apoptosis was scarce on day 35.We assessed expression of Musashi-1-and Lgr5-positive stem cells following alemtuzumab treatment.Increased numbers of cells staining positive for both Musashi-1 and Lgr5 were found in the stem cell zone after alemtuzumab treatment for 3 and 9 days.These data indicated that the epithelial cells were injured following alemtuzumab treatment,with the associated expansion of intestinal stem cells.After alemtuzumab treatment for 35 days,the numbers of intestinal epithelial cells and intestinal stem cells returned to normal.This study suggests that alemtuzumab treatment induced the increase in stem cells,resulting in the availability of more enterocytes for repair.

多发性硬化症治疗药Alemtuzumab的Ⅲ期临床试验获阳性结果

赛诺菲公司的下属公司Genzyme近日宣布,Genzyme公司和拜耳公司共同开发的人源单克隆抗体alemtuzumab的一项名为CARE-MSⅡ的Ⅲ期临床研究获得阳性结果,两项主要考察指标达到预期。

多发性硬化症治疗药Alemtuzumab的Ⅲ期临床研究又获新数据

本刊曾在2011年第11期上刊登过一则有关多发性硬化症（MS）治疗药——抗CD52单抗alemtu—zumab（专利名：Lemtrada^TM）的Ⅲ期临床研究获得阳性结果的报道。Genzyme公司近日在第64届美国神经病学学会（AAN）年会上公布了本品在该项名为CARE—MSII的Ⅲ期临床研究中的最新数据。

alemtuzumab是治疗慢性淋巴细胞白血病的一线药物

英国研究者Hillmen P等开展了一项随机试验来评价在治疗慢性淋巴细胞白血病（CLL）患者时，与chlorambucil相比，静脉内给予alemtuzumab的有效性和安全性。患者接受alemtuzumab（30mg每周3次，连续12周）治疗，或chlorambucil（40mg／m^2每28天，连续12个月）。主要疗效指标为无疾病进展生存期（PFS），次要疗效指标包括总体有效率（ORR）、完全缓解（CR），到采取替代疗法的时间、安全性及总体生存率。

重型再生障碍性贫血的治疗与造血干细胞移植

重型再生障碍性贫血(SAA)是由多种病因导致的重度骨髓造血功能衰竭综合征,临床以严重的贫血、感染、出血为主要特征。SAA发病机制复杂,至今尚未完全明了。SAA起病急,病情重,病情进展快,目前随着对SAA的深入研究以及诊疗水平的提高,对于其治疗策略也发生了改变。从经典的免疫抑制治疗,即主要以抗胸腺细胞球蛋白和环孢素为基础的治疗方案,到血小板生成素受体激动剂的应用及以异基因造血干细胞移植等为基础的联合治疗方案,均不同程度促进SAA患者的造血功能重建,极大改善其生存及预后,成为当下SAA治疗的研究热点。本文结合国内外文献对SAA治疗的新进展进行综述。

大颗粒淋巴细胞白血病

大颗粒淋巴细胞(LGL)白血病是一种少见的克隆性淋巴组织增殖性疾病。WHO分类将其区分为三种不同类型:T细胞大颗粒淋巴细胞白血病(T-LGL),NK-细胞的慢性淋巴增殖性疾病(CLPD-NK)和侵袭性NK细胞白血病。虽细胞起源不同,但T-LGL与CLPD-NK在临床表现和治疗方面很相似,多数患者无症状不需要治疗,当出现明显的血细胞减少时,首先考虑免疫抑制治疗。相反,侵袭性NK细胞白血病和罕见的CD56+侵袭性T-LGL白血病呈暴发性病程,发病年龄更早,需要较强的联合化疗序贯异基因造血干细胞移植。该类疾病相对稀少,故指导治疗的临床试验亦少。本文对该病的发病机制、诊断、治疗和预后进行了综述。

再生障碍性贫血的治疗进展

重型再生障碍性贫血（SAA）是威胁生命的严重疾病,病死率高,随着造血干细胞移植等治疗的开展,这部分患者生存率已得到极大的提高.SAA一旦诊断需立即开始治疗.对于非输血依赖的非SAA患者,可选择观察和支持治疗.年轻（小于40岁）有同胞全相合供者的SAA患者首选造血干细胞移植,没有条件的患者首选免疫抑制治疗.免疫抑制治疗国外一线推荐马抗胸腺细胞球蛋白（ATG）;国内相关研究表明兔ATG和猪抗淋巴细胞免疫球蛋白（ALG）都可作为一线治疗,血液学缓解率可达60％～70％.复发、难治的SAA患者,可考虑无关供者骨髓移植、第2次ATG治疗或阿伦单抗治疗.间充质干细胞治疗、促血小板生成素受体（c-MPL）拮抗剂艾曲波帕及左旋咪唑在难治性及复发的SAA患者中也表现出了一定的疗效,期待进一步的临床研究.

Risk factors and outcomes of delayed graft function in renal transplant recipients receiving a steroid sparing immunosuppression protocol

AIM To analyse the risk factors and outcomes of delayed graft function(DGF) in patients receiving a steroid sparing protocol. METHODS Four hundred and twenty-seven recipients of deceased donor kidney transplants were studied of which 135(31.6%) experienced DGF. All patients received monoclonal antibody induction with a tacrolimus based, steroid sparing immunosuppression protocol.RESULTS Five year patient survival was 87.2% and 94.9% in the DGF and primary graft function(PGF) group respectively, P = 0.047. Allograft survival was 77.9% and 90.2% in the DGF and PGF group respectively, P < 0.001. Overall rejection free survival was no different between the DGF and PGF groups with a 1 and 5 year rejection free survival in the DGF group of 77.7% and 67.8% compared with 81.3% and 75.3% in the PGF group, P = 0.19. Patients with DGF who received IL2 receptor antibody induction were at significantly higher risk of rejection in the early post-transplant period than the group with DGF who received alemtuzumab induction. On multivariate analysis, risk factors for DGF were male recipients, recipients of black ethnicity, circulatory death donation, preformed DSA, increasing cold ischaemic time, older donor age and dialysis vintage.CONCLUSION Alemtuzumab induction may be of benefit in preventing early rejection episodes associated with DGF. Prospective trials are required to determine optimal immunotherapy protocols for patients at high risk of DGF.

Hemophagocytic lymphohistiocytosis: Recent progress in the pathogenesis, diagnosis and treatment

Hemophagocytic lymphohistiocytosis(HLH) is a hyperinflammatory syndrome that develops as a primary(familial/hereditary) or secondary(non-familial/hereditary) disease characterized in the majority of the cases by hereditary or acquired impaired cytotoxic T-cell(CTL) and natural killer responses. The molecular mechanisms underlying impaired immune homeostasis have been clarified, particularly for primary diseases. Familial HLH(familial hemophagocytic lymphohistiocytosis type 2-5, Chediak-Higashi syndrome, Griscelli syndrome type 2, Hermansky-Pudlak syndrome type 2) develops due to a defect in lytic granule exocytosis, impairment of(signaling lymphocytic activation molecule)-associated protein, which plays a key role in CTL activity [e.g., X-linked lymphoproliferative syndrome(XLP) 1], or impairment of X-linked inhibitor of apoptosis, a potent regulator of lymphocyte homeostasis(e.g., XLP2). The development of primary HLH is often triggered by infections, but not in all. Secondary HLH develops in association with infection, autoimmune diseases/rheumatological conditions and malignancy. The molecular mechanisms involved in secondary HLH cases remain unknown and the pathophysiology is not the same as primary HLH. For either primary or secondary HLH cases, immunosuppressive therapy should be given to control the hypercytokinemia with steroids, cyclosporine A, or intravenous immune globulin, and if primary HLH is diagnosed, immunochemotherapy with a regimen containing etoposide or anti-thymocyte globulin should be started. Thereafter, allogeneic hematopoietic stem-cell transplantation is recommended for primary HLH or secondary refractory disease(especially EBVHLH).

氟达拉滨耐药的慢性淋巴细胞白血病治疗进展

对嘌呤类药物发生耐药为慢性淋巴细胞白血病(CLL)患者预后差的特征。虽然近年来免疫化疗联合应用如氟达拉滨(Fludarabine,Flu)、环磷酰胺(CTX)和利妥昔单抗(rituximab)已导致初治患者反应率达95%和无失败生存率增加,但因为缺乏治疗反应和对Flu耐药许多慢淋患者仍不能治愈。补救治疗的策略包括含阿来组单抗(alemtuzumab)的方案、靶向药物和异基因造血干细胞移植(allo-SCT)。单药alemtuzumab治疗Flu耐药的CLL患者反应率高达40%,但反应并不持久,中数生存期约1-2年。耐Flu-CLL患者亦可采用alemtuzumab与Flu、CTX和/或利妥昔单抗,或其他药物如雷利度胺(lenalidomide)、flavopiridol和靶向药物联用进行补救性治疗。包括alemtuzumab和/或利妥昔的免疫化疗方案和allo-SCT或可改善该病的预后,但对新的、更有效的治疗仍需要继续研究。

Antibody induction therapy in adult kidney transplantation: A controversy continues

Antibody induction therapy is frequently used as an adjunct to the maintenance immunosuppression in adult kidney transplant recipients. Published data support antibody induction in patients with immunologic risk to reduce the incidence of acute rejection(AR) and graft loss from rejection. However, the choice of antibody remains controversial as the clinical studies were carried out on patients of different immunologic risk and in the context of varying maintenance regimens. Antibody selection should be guided by a comprehensive assessment of immunologic risk, patient comorbidities, financial burden as well as the maintenance immunosuppressives. Lymphocyte-depleting antibody(thymoglobulin, ATGAM or alemtuzumab) is usually recommended for those with high risk of rejection, although it increases the risk of infection and malignancy. For low risk patients, interleukin-2 receptor antibody(basiliximab or daclizumab) reduces the incidence of AR without much adverse effects, making its balance favorable in mostpatients. It should also be used in the high risk patients with other medical comorbidities that preclude usage of lymphocyte-depleting antibody safely. There are many patients with very low risk, who may be induced with intravenous steroids without any antibody, as long as combined potent immunosuppressives are kept as maintenance. In these patients, benefits with antibody induction may be too small to outweigh its adverse effects and financial cost. Rituximab can be used in desensitization protocols for ABO and/or HLA incompatible transplants. There are emerging data suggesting that alemtuzumab induction be more successful than other antibody for promoting less intensive maintenance protocols, such as steroid withdrawal, tacrolimus monotherapy or lower doses of tacrolimus and mycophenolic acid. However, the long-term efficacy and safety of these unconventional strategies remains unknown.