Rituximab

Rituximab is a drug that suppresses the immune system. This drug is a genetically engineered antibody that functions like the antibodies that the body produces naturally. It was the first monoclonal antibody indicated for the treatment of non-Hodgkin lymphoma (NHL). Since then, it has also been approved for the treatment of rheumatoid arthritis.

Serious side effects have been reported during or after rituximab therapy. Its suppression of the immune system increases the risk of viral and bacterial infections. Rituximab can also be toxic to the skin, gastrointestinal system, and kidneys. However, the risk and severity of many side effects is reduced if precautions are taken.

Rituximab has the brand names Rituxan and Abthera. It is co-marketed by Genentech and Biogen in the United States and by Roche in the European Union. It was approved in 1997 by the Food and Drug Administration (FDA).

Normal joint vs. joint affected by rheumatoid arthritis. Source: National Institutes of Health

Uses/Indications

Rituximab is used to treat non-Hodgkin lymphoma (NHL) and moderate to severe rheumatoid arthritis. For the treatment of NHL, rituximab is given alone or in combination with chemotherapy. Regimens with chemotherapeutic agents include in combination with anthracyclines, or in combination with cyclophosphamide (Cytoxan), vincristine (Vincasar), and prednisone (a steroid). For the treatment of rheumatoid arthritis, rituximab is used in combination with methotrexate in patients who do not respond to treatment with tumor necrosis factor (TNF) blockers such as etanercept (Enbrel).

Rituximab is used in renal transplant recipients and in the treatment of systemic lupus erythematosus (SLE), an autoimmune disorder. Rheumatoid arthritis is also classified as an autoimmune disorder.

How Rituximab is Taken

Rituximab is administered intravenously (IV). The dose is 375 mg/m² (milligrams per square meter of body surface area) in NHL. When administered as a component of Zevalin (ibritumomab tiuxetan) the dose is lowered to 250 mg/m². The number of doses and chemotherapeutic cycles used depends on the type of lymphoma.

The dose in rheumatoid arthritis is 1,000 mg given on week 1 and week 4 of treatment. Retreatment is sometimes necessary. Rituximab is infused at a rate of up to 400 mg/hour if no side effects are seen.

How Rituximab Works

NHL and rheumatoid arthritis are characterized by improper signaling and hyperactivity of the immune system. Rituximab is a monoclonal antibody that binds to a molecule (CD20) on the surface of B cells (white blood cells) of the immune system. In this way, it modulates the activity of B cells, and consequently blunts the activity of the immune system. Moreover, it can kill B cells and prevent them from proliferating.^[1]

Half-life of Rituximab

The amount of time needed to reduce circulating levels of a drug by half is called the drug's half-life. For rituximab, it is 40 hours to 16 days. The half-life depends on the dose, length of the treatment, and the amount of tumor a patient may have. Because of this long half-life, rituximab is present in the blood for 3 to 6 months after the treatment has stopped. Elimination of rituximab from the body is slower in women with rheumatoid arthritis than in men with rheumatoid arthritis, but the effectiveness in men and women is the same.

Side Effects

Rituximab can cause many side effects; some are very serious and can be fatal. The safety of rituximab is different in patients with cancer and rheumatoid arthritis because the diseases require different doses and because rituximab is used in combination with different medications.

A consequence of the immune suppression caused by rituximab is the development of bacterial and/or viral infections, which can be very serious. For example, rituximab can re-activate a hepatitis B infection which can lead to liver damage and death. In addition, rituximab has been reported to cause progressive multifocal leukoencephalopathy, or PML, in patients treated for systemic lupus. Up to 80% of people are infected with the virus that causes PML, but normally the virus stays dormant in the body and does not cause harm. When the immune system is suppressed, however, as it is by rituximab, the virus can activate and PML develops. The virus infects the brain and causes confusion, mental deterioration, loss of balance, difficulty with speaking, and loss of vision. Ultimately, PML leads to permanent disability or death. The disease has no treatment.

Many side effects occur within 24 hours of infusion. Some of these side effects include the following:

• Swelling
• Hives
• Blurred vision
• Dizziness
• Chills
• Drowsiness
• Headache
• Wheezing or trouble breathing
• Cough
• High blood pressure (hypertension)
• Heart attack
• Heart dysfunction, including cardiac arrhythmias and angina (chest pain)
• Allergic reactions

Rapid death of cancer cells due to rituximab treathment occurs within the first 12-24 hours of its infusion, and this can cause a condition called tumor lysis syndrome (TLS). The syndrome is characterized by high levels of uric acid, potassium, and phosphate, and low levels of calcium in the blood. This can lead to kidney failure, cardiac arrest, and death.

Rituximab can damage the lungs, skin, gastrointestinal tract, and kidneys. The lungs can become inflamed or infected. Painful sores, blisters, ulcers, skin peeling, and mouth blisters have been reported 1-13 weeks after treatment. Some effects of rituximab on the gastrointestinal tract include bowel obstruction or perforation (holes in the intestine), and abdominal pain. Kidney damage can be severe and includes the inability to make urine (oliguria). Kidney dysfunction is more likely to occur in patients with a very high number of cancerous cells, or after TLS.

The effects of rituximab on the fetus are not known. The risks and benefits of treatment should be considered before giving rituximab during pregnancy. Similarly, whether a nursing infant is exposed to rituximab in the breast milk is not known.

Precautions

The risk of developing the side effects can be minimized if precautions are taken. Many of the side effects, such as emergence of infections, heart complications, or gastrointestinal damage, necessitate the stopping of treatment. In patients at risk, a physician will closely follow the progress of treatment to prevent complications.

Some side effects may be avoided or minimized if caught early. Patients can be screened for hepatitis before treatment. Severe abdominal pain may be a sign of a blockage or a tear in the intestine. Blood tests detect severe deficiencies in the number of blood cells, including white blood cells. Often acetaminophen (Tylenol) and antihistamines are used during rituximab infusion to reduce the risk of developing some of the infusion reactions.

Drug Interactions

The only drug interactions reported for rituximab are those that are used therapeutically. Typically cyclophosphamide, prednisone, and vincristine are given in combination with rituximab to increase the chances of successful treatment. Methotrexate is used in combination with rituximab for the treatment of arthritis. Rituximab is unlikely to influence the metabolism of other drugs. In clinical trials, rituximab did not affect the metabolism of either methotrexate or cyclophosphamide.

Clinical Trials

Rituximab is beneficial in the treatment of both lymphoma and rheumatoid arthritis. This effectiveness justifies the use of rituximab in many patients despite the severe side effects. In NHL, rituximab delays the growth of cancerous cells, shrinks cancerous cells, and can lengthen patient survival. In rheumatoid arthritis, rituximab reduces joint pain and swelling, and in some individuals slow the progression of joint damage.

A 40-dose study in patients with relapsed or follicular lymphoma prompted the FDA to approve rituximab.^[2] In this study, 48% of the patients responded to treatment with rituximab. An analysis of 7 drug trials found that rituximab reduced the risk of death by 30%-40% and had a patient response rate of 20%.^[3] A 24-week study was performd on the effect of rituximab in combination with methotrexate in patients with rheumatoid arthritis for whom anti-tumor necrosis factor treatment was ineffective. ^[4] At least a 20% improvement in symptoms was seen in 51% of the rituximab-treated patients, compared to 18% of the placebo-treated patients. A moderate to good response was seen in 65% and 22% of the rituximab- and placebo-treated patients respectively. Rituximab improved the quality of life and the degree of disability as it decreased the progression of joint damage.

References

1. ↑ Boye J, Elter T, Engert A. An overview of the current clinical use of the anti-CD20 monoclonal antibody rituximab. Ann Oncol. 2003 Apr;14(4):520-35. Abstract | Full Text | PDF
2. ↑ McLaughlin P, Grillo-López AJ, Link BK, et al. Rituximab chimeric anti-CD20 monoclonal antibody therapy for relapsed indolent lymphoma: half of patients respond to a four-dose treatment program. J Clin Oncol. 1998 Aug;16(8):2825-33. Abstract
3. ↑ Schulz H, Bohlius J, Skoetz N, et al. Chemotherapy plus Rituximab versus chemotherapy alone for B-cell non-Hodgkin's lymphoma. Cochrane Database Syst Rev. 2007 Oct 17;(4):CD003805. Abstract
4. ↑ Cohen SB, Emery P, Greenwald MW, et al. Rituximab for rheumatoid arthritis refractory to anti-tumor necrosis factor therapy: Results of a multicenter, randomized, double-blind, placebo-controlled, phase III trial evaluating primary efficacy and safety at twenty-four weeks. Arthritis Rheum 2006;54:2793-806. Abstract | Full Text | PDF

Further Information

• Arthritis Foundation: Main Page
• BC Cancer Agency: Rituximab
• Genentech and Biogen Rituxan
• eMedicine: Lymphoma; Non-Hodgkin’s
• FDA MedWatch: Side Effect Report Form
• National Cancer Institute: FDA Approval of Rituximab