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MabCampath(阿仑单抗 Alemtuzumab)infusion

新药编辑:新特药 更新时间:2015-05-03

Campath(欧洲商品名:MabCampath)是第一个对烷化剂或福达华治疗无效的患者仍具有显着疗效的药物。根据一项国际II期临床研究结果显示,经其它药物治疗复发或难治的CLL患者用Campath治疗后可使其生存期显着延长1倍以上。目前,有关专家正致力于研究该药的新用法及联合用药,如研究与福达华等联合应用的疗效。
Campath是CD52抗体,可与表面携带CD52抗原的细胞相结合从而启动细胞破坏过程。通过这一方式,Campath可以清除外周血、骨髓及其它累及器官的淋巴细胞。由于T淋巴细胞同样携带CD52抗原,Campath已被成功地应用于前T细胞性白血病(T-PLL)及外周T细胞淋巴瘤的治疗。作为对福达华的补充,Campath在非清髓性移植中也发挥着重要作用。

目前,已有越来越多的肿瘤专家在早期治疗中选择Campath。

CAMPATH®(阿仑单抗)注射静脉使用

最初美国批准:2001

生产商:Genzyme公司
 
适应症
CAMPATH是1的CD52导向杀伤抗体作为单剂用于治疗B细胞慢性淋巴细胞白血病(B-CLL)。

剂量和用法
超过2小时的静脉输液管理。
升级推荐剂量为30毫克/天每周三次12周。
Premedicate口服抗组胺药和对乙酰氨基酚剂量前。
 
剂型和优势
30毫克/ 1毫升单用小瓶。
 
禁忌
没有。
 
注意事项:
血象:

获得全血细胞计数(CBC)和血小板计数在治疗及CD4细胞计数在治疗后每周一班,直至恢复到≥200个细胞/微升。
停止对自身免疫性疾病或严重的血液学不良反应。

感染:
CAMPATH导致严重的和长期的淋巴细胞和增加感染的风险。如果发生严重感染,隐瞒,直到感染治疗解析。
不要管理活病毒疫苗,最近收到CAMPATH的患者。

不良反应
最常见的不良反应(≥10%):血细胞减少,输液反应,巨细胞病毒(CMV)和其他感染,恶心,呕吐,腹泻,失眠。

日期:08/2009

Alemtuzumab is sold as Campath in the United States. Alemtuzumab is a humanized monoclonal antibody that selectively binds to CD52 (a protein found on the surface of normal and malignant B and T cells) that is used to reduce the numbers of circulating malignant cells of patients who have B-cell chronic lymphocytic leukemia (B-CLL).

Purpose

Alemtuzumab is a monoclonal antibody used to treat B-CLL, one of the most prevalent forms of adult chronic leukemia. It specifically binds CD52, a protein found on the surface of essentially all B and T cells of the immune system. By binding the CD52 protein on the malignant B cells, the antibody targets it for removal from the circulation. Scientists believe that alemtuzumab triggers antibody-mediated lysis of the B cells, a method that the immune system uses to eliminate foreign cells.

Alemtuzumab has been approved by the FDA for treatment of refractory B-CLL. For a patient's disease to be classified as refractory, both alkylating agents and fludarabine treatment must have been tried and failed. Thus, this drug gives patients who have tried all approved treatments for B-CLL another option. As most patients with B-CLL are in stage III or IV by the time both alkylating agents and fludarabine have been tried, the experience with alemtuzumab treatment are primarily with those stages of the disease. In clinical trials, about 30% of patients had a partial response to the drug, with 2% of these being complete responses.

This antibody has been tested with limited success in the treatment of non-Hodgkin's lymphoma (NHL) and for the preparation of patients with various immune cell malignancies for bone marrow transplantation. There is also a clinical trial ongoing to test the ability of this antibody to prevent rejection in kidney transplantation.

Description

Alemtuzumab is produced in the laboratory using genetically engineered single clones of B cells. Like all antibodies, it is a Y-shaped molecule can bind one particular substance, the antigen for that monoclonal antibody. For alemtuzumab, the antigen is CD52, a protein found on the surface of normal and malignant B and T cells as well as other cells of the immune and male reproductive systems. Alemtuzumab is a humanized antibody, meaning that the regions that bind CD52, located on the tips of the Y branches, are derived from rat antibodies, but the rest of the antibody is human sequence. The presence of the human sequences helps to reduce the immune response by the patient against the antibody itself, a problem seen when complete mouse antibodies are used for cancer therapies. The human sequences also help to ensure that the various cell-destroying mechanisms of the human immune system are properly triggered with binding of the antibody.

Alemtuzumab was approved in May of 2001 for the treatment of refractory B-CLL. It is approved for use alone but clinical trials have tested the ability of the antibody to be used in combination with the purine analogs pentostatin, fludarabine, and cladribine, and rituximab, a monoclonal antibody specific for the CD20 antigen, another protein found on the surface of B cells.

Recommended Dosage

This antibody should be administered in a gradually escalating pattern at the start of treatment and any time administration is interrupted for 7 or more days. The recommended beginning dosage for B-CLL patients is a daily dose of 3 mg of Campath administered as a 2-hour IV infusion. Once this amount is tolerated, the dose is increased to 10 mg per day. After tolerating this dose, it can be increased to 30 mg, administered three days a week. Acetominophen and diphenhydramine hydrochoride are given thirty to sixty minutes before the infusion to help reduce side effects.

Additionally, patients generally receive anti-infective medication before treatment to help minimize the serious opportunistic infections that can result from this treatment. Specifically, trimethoprim/sulfamethoxazole (to prevent bacterial infections) and famciclovir (to prevent viral infections) were used during the clinical trial to decrease infections, although they were not eliminated.

Precautions

Blood studies should be done on a weekly basis while patients are receiving the alemtuzumab treatment. Vaccination during the treatment session is not recommended, given the T cell depletion that occurs during treatment. Furthermore, given that antibodies like alumtuzumab can pass through the placenta to the developing fetus and in breast milk, use during pregnancy and breastfeeding is not recommended unless clearly needed.

Side Effects

A severe side effect of alemtuzumab treatment is the possible depletion of one or more types of blood cells. Because CD52 is expressed on a patient's normal B and T cells, as well as on the surface of the abnormal B cells, the treatment eliminates both normal and cancerous cells. The treatment also seems to trigger autoimmune reactions against various other blood cells. This results in severe reduction of the many circulating blood cells including red blood cells (anemia), white blood cells (neutropenia), and clotting cells (thrombocytopenia). These conditions are treated with blood transfusions. The great majority of patients treated exhibit some type of blood cell depletion.

A second serious side effect of this drug is the prevalence of opportunistic infections that occurs during the treatment. Serious, and sometimes fatal bacterial, viral, fungal, and protozoan infections have been reported. Treatments to prevent pneumonia and herpes infections reduce, but do not eliminate these infections.

The majority of other side effects occur after or during the first infusion of the drug. Some common side effects of this drug include fever and chills, nausea and vomiting, diarrhea, shortness of breath, skin rash, and unusual fatigue. This drug can also cause low blood pressure (hypotension).

In patients with high tumor burden (a large number of circulating malignant B cells) this drug can cause a side effect called tumor lysis syndrome. Thought to be due to the release of the lysed cells' contents into the blood stream, it can cause a misbalance of urea, uric acid, phosphate, potassium, and calcium in the urine and blood. Patients at risk for this side effect must keep hydrated and can be given allopurinol before infusion.
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Campath Improves Blood Cell Counts In Myelodysplastic Syndromes Patients

A recent study showed that treatment with the drug Campath resulted in improvement of blood cell counts in some myelodysplastic syndromes patients.

In myelodysplastic syndromes (MDS) patients, symptoms such as low blood cell counts and progression of disease can often be linked to problems with the immune system.

Horse antithymocyte globulin and cyclosporine are drugs that keep the immune system in check (also referred to as immunosuppressive therapy). They have been shown to be effective at improving blood cell counts and reducing the need for blood transfusions.  However, if given for extended periods, these treatments can cause severe toxicity in the kidneys.

Recent studies have shown that the drug Campath (alemtuzumab), produced by the biotechnology company Genzyme, is able to keep the immune system in check better than other treatments like horse antithymocyte globulin. It also effectively treats diseases that involve low blood cell levels caused by the immune system.

For these reasons, the study authors hypothesized that Campath may have potential for the treatment of MDS.

For their study, the researchers recruited 32 patients with MDS and low blood cell levels. The patients were chosen based on criteria indicating the patients’ likelihood of responding to immunosuppressive therapy.

The patients received an initial test dose of 1 mg of Campath. After the initial test dose, patients received 10 mg of Campath for 10 days.

Researchers saw an improvement of blood cell levels or a complete response in 21 patients (68 percent).  Of the patients with lower-risk MDS, 77 percent responded to treatment, and 57 percent of higher-risk MDS patients responded to treatment.

According to Dr. Elaine Sloand, a researcher at the National Institutes of Health and lead author on the study, high-risk MDS patients did not respond to suppression of the immune system. “[High-risk MDS patients] may have a different type of disease since MDS is heterogeneous and likely represents multiple diseases,” she explained.

Of the patients who showed a response, 11 percent responded by three months, 18 percent by six months, and 56 percent by 12 months.

Of the 25 patients who were dependent on red blood cell transfusions before the Campath treatment, 10 achieved transfusion independence at three months.

Of nine patients who responded to treatment and were able to be evaluated after one year, seven were transfusion-independent.

One major complication with Campath is the occurrence of infections that take advantage of the weakened immune system.  For this reason, patients also received preventative treatments and were monitored closely.

Of the 32 patients, 13 contracted infections during the course of treatment.  Each of these infections was easily resolved.

All patients had low white blood cells 24 hours after the first infusion, which continued for up to two years.  Low platelet levels were seen in 12 patients, but this problem resolved within three months.

The study authors suggested that Campath may be effective in a larger population of MDS patients than horse antithymocyte globulin due to the increased response rate and its decreased kidney toxicity.

Dr. Sloand added that “It is too early to tell whether Campath is superior to the combination of horse antithymocyte globulin and cyclosporine. However, it is much more immunosuppressive for a longer period of time. We intend to continue the study to answer these questions.  One would expect that Campath would produce longer remissions, but we still don’t know that for sure.”

 

Campath(alemtuzumab)作用于存在于B和T淋巴细胞上的CD52抗原,从而破坏淋巴细胞

美一公司的抗白血病新药获FDA批准

美国Millennium制药公司于本周一宣布,该公司与Ilex Oncology公司合作研制的抗白血病药物Campath(alemtuzumab)已经获得美国食品和药品管理局(FDA)的批准。
尽管在临床试验中有患者因使用Campath而死亡,但FDA仍批准该药可用于那些烷化剂和氟达拉宾无效的B细胞性慢性淋巴细胞性白血病治疗。
Campath是一种人源性单克隆抗体,主要作用于存在于B和T淋巴细胞上的CD52抗原,从而破坏淋巴细胞。
Campath是第一个也是目前唯一获准用于治疗慢性B-细胞淋巴细胞白血病(B-CLL)的人源化单克隆抗体。本品靶向癌淋巴细胞和非癌淋巴细胞表面的CD52抗原,而不靶向那些能够成熟分化成新的健康的淋巴细胞的细胞。这种活性被称为造血细胞的选择性,即对正常的血液成份如中性粒细胞、红细胞和血小板的前体没有影响。一旦Campath与淋巴细胞表面的 CD52抗原结合,就会通过各种不同的机制选择性杀灭肿瘤细胞。这些不同的作用机制还包括注射Campath后,恶性淋巴细胞从血液、脾脏以及骨髓的清除。虽然Campath对清除积聚在淋巴结和结外物质的恶性淋巴细胞有一些作用,但是它对清除骨髓恶性淋巴细胞的作用是最强的,从而使机体更新健康的淋巴细胞。

Campath输注有关的最常见的不良反应为寒战、发热、恶心、呕吐和高血压。血液学毒性包括全血细胞减少/骨髓再生不良、贫血、血小板减少症和中性粒细胞减少症,需要进行定时监测。感染性不良反应包括败血症、肺炎以及巨细胞病毒(CMV)、念珠菌病、曲霉病和毛霉菌病等机会性感染。Campath在活动性系统性感染患者、潜在的免疫缺陷患者或已知的1型过敏症患者或对Campath或其他任何成份过敏的患者中禁用。

尽管Campath临床研究中存在30%的死亡率(约半数是治疗相关性死亡,包括血液毒性反应如骨髓增生低下)以及较高的感染率,但是该药总有效率可达到33%,平均有效持续时间为7个月。在2个小规模临床试验中,其有效率分别为21%和29%,平均有效持续时间分别为7和11个月。

在2000年的晚些时候,FDA顾问委员会投票表决,以14票对1票建议加快Campath批准应用,这将允许药物一边在随访研究中搞清未明的问题,一边上市。但是,必须在包装盒上注明应警惕药物的血液毒性、输注反应和治疗相关的感染。

最近该药品已提请欧洲联盟批准以MabCampath的名称在欧盟市场上市,预计在今年下半年可获欧盟的最终批准。

Millennium制药公司称,作为单独用药或联合治疗,Campath正被考虑用于血液肿瘤包括外周和皮肤T细胞淋巴瘤、自体免疫性疾病如多发性硬化的治疗和器官移植排异反应的治疗。
德国Schering AG公司治疗癌症的氟达拉滨新型口服制剂,Fludara Oral(Ⅰ)已在其第一个市场英国上市,用于B细胞慢性淋巴细胞性白血病(CLL)的二线治疗。静脉注射用氟达拉滨是在烷化剂以后治疗B细胞CLL的金标准二线药,如病人不能上医院去接受静脉注射,则(Ⅰ)是有用的。
在此期间,因FDA顾问委员会于去年年底支持Campath(alemtuzumab),Sche-ring公司的CLL专利业务不久将得到进一步扩大。用烷化剂和氟达拉滨治疗无效的病人可用Campath治疗。

该药用于CLL的申报文件正在接受EMEA评审。

另外,Schering已获得Climodien(地诺孕素+雌二醇戊酸酯)的荷兰销售许可证。Climodien是治疗绝经后症状的持续性复合激素替代治疗药。预期今年年底前通过相互承认程序也可获得其余欧盟国家的许可证。
减少器官移植排异新技术Campath

伦敦消息,英国剑桥大学卡恩教授最近透露,他和同事开发出一种可减少器官移植排异的新技术,在30名患者身上进行试验获得了良好效果。
植入患者体内的新器官会被患者免疫系统认为是“异物”而遭到排异。为了防止这种情况,医生们在手术中经常同时采用多种药物,对患者免疫系统进行抑制。但这些抑制免疫药物通常副作用较大,并有可能增加患者得癌症和脆骨症等疾病的危险。
英国《独立报》27日报道说,卡恩教授等研究出的新技术,需要在患者手术前向其体内注入一种名为“坎帕斯”(CAMPATH)的人工合成抗体。该抗体可暂时清除血液中的淋巴细胞,使免疫系统处于失效状态。这使得器官植入患者体内后,不会马上遭到患者免疫系统的排异。免疫系统在一、两个月的逐渐恢复中,会把被移植器官“误认为”是患者体内原有的组成部分。<br>
研究人员用新技术对30名接受肾脏移植的患者进行试验后发现,新技术能将被移植器官遭排斥的可能性降低约50%。另外,采用新技术后患者可只服用一种药物,而药剂量只有原来的一半左右。

(FDA)美國食品藥物管理局 2001年5月批准上市

德國Schering AG公司治療癌症的氟達拉濱新型口服制劑,用于B細胞慢性淋巴細胞性白血病(CLL)的二線治療。靜脈注射用氟達拉濱是在烷化劑以后治療B細胞CLL的金標准二線藥。

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