Alemtuzumab

Definition

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 seven or more days. The recommended beginning dosage for B-CLL patients is a daily dose of 3 mg of Campath administered as a two-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 (thrombopenia). 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.

Interactions

There have been no formal drug interaction studies done for alemtuzumab.

Key Terms

Alkylating agent

A chemical that alters the composition of the genetic material of rapidly dividing cells, such as cancer cells, causing selective cell death; used as a chemotherapeutic agent to treat B-CLL.

Antibody

A protective protein made by the immune system in response to an antigen, also called an immunoglobulin.

Autoimmune

An immune reaction of a patient against their own cells.

Humanization

Fusing the constant and variable framework region of one or more human immunoglobulins with the binding region of an animal immunoglobulin, done to reduce human reaction against the fusion antibody.

Monoclonal

Genetically engineered antibodies specific for one antigen.

Tumor lysis syndrome

A side effect of some immunotherapies, like monoclonal antibodies, that lyse the tumor cells, due to the toxicity of flooding the bloodstream with such a quantity of cellular contents.

Source: Gale Encyclopedia of Medicine, Published December, 2002 by the Gale Group

The Essay Author is Michelle Johnson M.S., J.D..

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