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Rituxan® (Rituximab) Proposed Mechanism of Action

Rituxan is indicated for the treatment of patients with:

Relapsed or refractory, low-grade or follicular, CD20-positive, B-cell non-Hodgkin's lymphoma (NHL) as a single agent
Previously untreated follicular, CD20-positive, B-cell NHL in combination with CVP chemotherapy
Non-progressing (including stable disease), low-grade, CD20-positive, B-cell NHL, as a single agent, after first-line CVP chemotherapy
Previously untreated diffuse large B-cell, CD20-positive NHL in combination with CHOP or other anthracycline-based chemotherapy regimens
In combination with fludarabine and cyclophosphamide (FC) for people with previously untreated and previously treated CD20-positive chronic lymphocytic leukemia (CLL)

People with serious infections should not receive Rituxan.

WARNINGS
Rituxan can cause serious side effects that can lead to death, including:

Infusion Reactions: Serious infusion reactions can happen during the infusion or within 24 hours of receiving Rituxan. Patients must tell their doctor or get medical help right away if they get any of these symptoms: hives (itchy red welts) or rash, itching, swelling of the lips, tongue, throat, or face, sudden cough, shortness of breath, difficulty breathing or wheezing, weakness, dizziness or feel faint, palpitations (feel like your heart is racing or fluttering) chest pain.
Progressive Multifocal Leukoencephalopathy (PML): PML is a rare, serious brain infection caused by a virus. People with a weakened immune system can get PML. PML can result in death or severe disability. Patients must tell their doctor right away if they have any of the following symptoms: confusion or problems thinking, loss of balance, change in the way they walk or talk, decreased strength or weakness on one side of their body, blurred vision or loss of vision.
Tumor Lysis Syndrome (TLS): TLS is caused by the fast breakdown of cancer cells and can occur after treatment with Rituxan. TLS can cause a person to have kidney failure and the need for dialysis treatment. TLS may also cause abnormal heart rhythm.
Severe Skin and Mouth Reactions: Patients may get painful sores on the skin or in the mouth, ulcers, blisters, or peeling skin while receiving or after receiving Rituxan.

The Role of Rituxan® in Non-Hodgkin's Lymphoma

Rituxan MOA

The Immune and Lymphatic Systems

The immune system is a highly integrated network of cells, tissues, and organs that defends the body against infection and disease. This system can identify and destroy millions of foreign invaders such as bacteria, viruses, fungi and toxins, and also helps to protect the body against the growth of cancerous cells. Specialized cells called white blood cells are part of the immune system. Types of white blood cells include lymphocytes (B-cells and T-cells), and macrophages.
The lymphatic system is important to the immune system for the production and transportation of lymphocytes throughout the body, and includes a network of specialized circulatory vessels and organized structures known as lymph nodes. Lymph nodes are the sites in which B-cells and T-cells respond to invasion by foreign substances (antigens) and help prevent their spread throughout the body.

B-Cells and Non-Hodgkin's Lymphoma

Under some circumstances B-cells and T-cells can malfunction, and this can cause or contribute to the generation of malignant (cancerous) cells. These malignant cells divide uncontrollably and do not fully differentiate. The resultant blood cancers are known as lymphomas, leukemias or myelomas. Non-Hodgkin's lymphoma (NHL) is one type of blood cancer that can arise from abnormal immune cells. About 85% of Non-Hodgkin's lymphomas arise in B-cells. Therefore, an approach to combating NHL is to target B-cells.

Why Are B-cells Important?

Each mature B-cell is designed to recognize and locate one specific antigen in the body via special structures on its outer surface called B-cell receptors. B-cell receptors fit together with their matching antigen like a lock and key. The binding of an antigen to its matching B-cell receptor is the first step toward the body's production of antibodies. Antibodies are essential to help protect the body against infection and disease. They are Y-shaped proteins that are nearly identical to B-cell receptors, except that they are secreted into the bloodstream instead of remaining attached to a B-cell. Like B-cell receptors, one antibody is specific for one antigen. When an antibody finds its matching antigen, it neutralizes or marks it for destruction.
In addition to producing antibodies, B-cells exert other important influences on other types of immune cells.
Abnormally functioning B-cells can lead to or contribute to various diseases.

How Can B-Cells Be Targeted In Disease?

Research into specific proteins on B-cells has uncovered evidence that a particular protein, CD20, is expressed on the majority of mature B-cells and not on bone marrow stem cells. Greater than 90% of malignant B-cells in NHL express the CD20 antigen. Although the function of CD20 is not fully understood, data implicate a function for CD20 in regulation of the cell cycle and apoptosis (also known as cellular suicide, or programmed cell death).

Rituxan for the Treatment of CD20-Positive B-Cell Non-Hodgkin's Lymphoma

Rituxan is indicated for the treatment of patients with relapsed or refractory, low-grade or follicular, CD20-positive, B-cell non-Hodgkin's lymphoma (NHL) as a single agent; for previously untreated diffuse large B-cell, CD20-positive, NHL in combination with CHOP (cyclophosphamide, doxorubicin, vincristine and prednisone) or other anthracycline-based chemotherapy regimens; for previously untreated follicular, CD20-positive, B-cell NHL in combination with CVP (cyclophosphamide, vincristine and prednisolone) chemotherapy; and for the treatment of non-progressing (including stable disease), low-grade, CD20-positive, B-cell NHL as a single agent, after first-line CVP chemotherapy. Rituxan is also approved in combination with fludarabine and cyclophosphamide (FC) for people with previously untreated and previously treated CD20-positive chronic lymphocytic leukemia (CLL).

People with serious infections should not receive Rituxan.

Rituximab is a monoclonal antibody, which means it was designed and made by scientists to target one kind of cell. Rituximab specifically binds to the CD20 antigen on the surface of B-cells. From there, it is believed to work with the body's own immune system to attack and kill the affected B-cells. This approach can be used to target malignant B-cells in patients with NHL. While the exact mechanism is unknown, experimental evidence supports three different mechanisms play a role in the clinical activity of Rituxan. These include:
- Antibody-Dependent Cellular Cytotoxicity (ADCC) - ADCC is a process in which specific cells are coated with antibodies and targeted for destruction by specialized killer cells, such as natural killer cells and macrophages. In this situation, one part of the antibody rituximab binds to the CD20 antigen on B-cells. Another part of the same rituximab antibody binds to a receptor on specialized killer cells such as monocytes, macrophages, and natural killer cells. The killer cells then engulf the B-cell and destroy it.
- Complement-Dependent Cytotoxicity - In this scenario, the antibody rituximab binds to CD20 on B-cells, and initiates the complement system, also known as the 'complement cascade', leading to direct cell toxicity. The end result is formation of a membrane attack complex that makes a hole within the cell membrane, causing cell lysis and death.
- Apoptosis - Experimental evidence has suggested that rituximab attaches to and cross-links the CD20 antigen, activating a cascade of events that ultimately causes B-cells to commit cellular suicide, otherwise known as programmed cell death, or apoptosis.

Important Safety Information and Serious Side Effects

Rituxan can cause serious side effects that can lead to death, including: infusion reactions, tumor lysis syndrome (TLS; kidney failure due to fast breakdown of cancer cells), severe skin and mouth reactions, and progressive multifocal leukoencephalopathy (PML; a rare, serious brain infection).

Infusion Reactions: Serious infusion reactions can happen during the infusion or within 24 hours of receiving Rituxan. The doctor should give the patient medicines before their infusion of Rituxan to decrease the chance of having a severe infusion reaction. If a serious reaction occurs, the infusion may be stopped and the patient should receive medical care. Patients must tell their doctor or get medical help right away if they get any of these symptoms: hives or rash, itching, swelling of the lips, tongue, throat, or face, sudden cough, shortness of breath, difficulty breathing or wheezing, weakness, dizziness or feel faint, palpitations, or chest pain.
Tumor Lysis Sydrome (TLS): TLS is caused by the fast breakdown of cancer cells and can occur after treatment with Rituxan. TLS can cause a person to have kidney failure and the need for dialysis treatment. TLS may also cause abnormal heart rhythm. The doctor may give the patient medicines to help prevent TLS and do blood tests to check the patient for TLS.
Severe Skin and Mouth Reactions: Severe skin and mouth reactions can occur in patients who receive Rituxan.
Progressive Multifocal Leukoencephalopathy (PML): PML is a rare, serious brain infection caused by a virus. People with a weakened immune system can get PML. Patients must tell their doctor right away if they have any of the following symptoms: confusion or problems thinking, loss of balance, change in the way they walk or talk, decreased strength or weakness on one side of their body, blurred vision or loss of vision.
Rituxan has also been associated with serious and life-threatening side effects, including: the return of active hepatitis B virus infection with sudden and serious liver problems including liver failure, and death, other serious infections that can lead to death, heart problems, kidney problems, and stomach and serious bowel problems including blockage and tears in the bowel that can sometimes lead to death.
The most common side effects of Rituxan in patients with non-Hodgkin's lymphoma (NHL) include: infusion reactions, fever, chills, low white blood cells, infections, body aches, and tiredness. The most common serious side effect in NHL patients was low white blood cells.
The most common side effects of Rituxan in patients with chronic lymphocytic leukemia (CLL) were infusion reactions and low white blood cells.
Most CLL patients treated with Rituxan plus FC chemotherapy had at least one serious side effect. In clinical trials, CLL patients 70 years or older who received Rituxan with FC chemotherapy were more likely to experience severe side effects compared with younger patients who received the same treatment.
Patients should tell their doctor about any side effects that bothers them or that does not go away. These are not all of the possible side effects with Rituxan.

Patients should read the Rituxan Full Prescribing Information including Boxed WARNINGS, and the Medication Guide at www.rituxan.com.