Lymphomas (Non-Hodgkin's)

Description

Other Treatments

Biological response modifier therapy, also called immunotherapy, uses the body's own immune system to fight cancer using natural or laboratory-developed factors. Drugs designed for such purposes used in combination with other treatments are showing promise in trials.

Monoclonal Antibodies

Monoclonal antibodies (MAbs) are designed in the laboratory to produce the same effects as natural antibodies and are exciting new weapons in the anticancer armament. They bind to specific proteins called antigens and make them vulnerable to attack by other factors in the immune system. Lymphomas carry antigens that provoke strong immune responses and so are believed to be particularly good candidates for MAb therapy.

MAbs are called either unconjugated or conjugated, depending on how they are designed to destroy the cancer cell.

• Unconjugated monoclonal antibodies rely on a strong natural immune system. The antibody builds up at the tumor site until it is able to trigger an immune response against the cancer. A possible downside to this form is the potential development of tolerance to the antibody so that it loses its effectiveness. Rituximab is an unconjugated form and the first MAb to be approved for any cancer.
• Conjugated monoclonal antibodies are linked to a plant or bacterial toxin or radioisotope. The antibody specifically attacks the antigen on the lymphoma cell and the toxin or radioactive material from the isotope kills it.

Unconjugated MAbs (Rituximab and Others). Rituximab (Rituxan) was the first monoclonal antibody to be approved for any cancer. It is an unconjugated MAb that targets the CD-20 antigen, which is found on most B-cell lymphomas and normal mature B-cells (although not stem cells).

Rituximab is used for patients with relapsed indolent lymphomas and is proving to be very useful as first-line and maintenance therapy for patients with low-grade indolent NHL. It is also being investigated in combination with CHOP for these lymphomas.

In any case, rituximab in combination with CHOP is now considered for first-line treatment for aggressive lymphomas, with studies reporting three-year event-free survival of 53% compared to 35% with CHOP alone. To date, however, studies are not finding survival advantages for maintenance treatments of aggressive lymphomas. Rituximab is also being studied for lymphomas in the central nervous system. Combinations with other immunotherapies, such as interferon, are also promising.

The treatment has mild to moderate short-term side effects, including nausea, fever, chills, hives, dizziness, and headache. Uncommon and more serious side effects are severe allergic reactions, very low blood pressure, blood abnormalities, wheezing, infections, and sudden heart events. Fatalities associated with a first infusion of the drug occur in four to seven out of 10,000 people. Of note: HIV patients may experience more adverse effects from rituximab than with CHOP. Early studies are also investigating combinations of rituximab with conjugated MAbs, or other biologic modifiers.

Conjugated Monoclonal Antibodies with Radioimmunotherapy. Conjugated MAbs with radioimmunotherapy bind tiny amounts of radioactive materials to MAbs for delivery into the tumor. As with unconjugated MAbs, the antibodies are designed to target antigens on the surface of the malignant cells. However, the radiation enhances the effects by destroying any malignant cells in the area, whether or not they contain the target antigen.

Ibritumomab tiuxetan (Zevalin) and tositumomab (Bexxar) are the most studied. Both have produced response rates up to 80% in low-grade and follicular lymphoma, and response rates of up to 60% in lymphoma that has transformed into an intermediate or high-grade. Median duration of response is about 1 year. Between 25% and 33% of patients have achieved complete remission.

• 90Y-ibritumomab (Zevalin) is approved for patients with relapsed or persistent low-grade NHL. It is proving to be an important treatment alone or in combination with chemotherapy for a wide range of patients, including newly diagnosed patients as well as those who have relapsed or have refractory NHL. To date, studies suggest a faster response time compared to rituximab, the standard unconjugated MAb, but no differences in overall progression. Suppression of blood cell production is the most serious complication. A form of ibritumomab (Corixa) that attaches to I-131 is awaiting approval.
• Tositumomab (Bexxar) uses the radioisotope (I-131), which some advantages over the 90Y used in ibritumomab, although both target the CD-20 antibody. Overall response rates of 68% have been reported from Bexxar (with up to a third being complete responses). Duration of the responses ranged from one to 35 months. Gastrointestinal problems and flu-like symptoms can occur within two days of the infusion.

The only serious complications reported are severe allergic reactions and suppression of blood cell production, which are nearly always manageable.

Other Monoclonal Antibodies. Other MAbs are being developed that target other antigens on lymphomas. For example, epratuzumab targets CD-22 and is showing promise in early studies. Some are being studied in both conjugated and unconjugated forms and also in combination with MAbs that target different antigens.

Interferon Alpha

Interferon alpha (Intron A) is used as an antiviral drug that also has properties that are effective against some common forms of NHL, particularly low-grade, follicular NHL in advanced stages. It is usually combined with chemotherapy regimens such as CHOP that contain an anthracycline drug (usually doxorubicin). The combination is toxic, however, and outcomes are very variable. Interferon is also being studied for lymphomas in the central nervous system. It may be useful after autologous stem cell transplantation.

Side Effects. Side effects of interferon include flu-like symptoms, severe depression, irritability, weight loss, vomiting, general weakness and loss of strength, and fever. About a third of patients have a severe drop in white blood cells. About 10% of patients cannot tolerate the drug's side effects.

Vaccines

Lymphoma vaccines use the same principles as those that fight other diseases. A protein taken from a lymphoma surface cell is bound to a carrier and administered to the patient. The body's immune system perceives this substance as a foreign antigen and boosts its response not only against the vaccinated agent, but also against the look-alike lymphoma. Clinical trials are ongoing. For example, one vaccine using a protein taken from the tumor called Id-KLH is showing particular promise.

Other Agents

Antisense Oligonucleotide. Oblimersen (G3139) is called an antisense oligonucleotide. It blocks BCL-2, a protein that is genetically overexpressed in some lymphomas and prevents apoptosis (a natural process by which all cells, including cancer cells, self-destruct). To date, studies suggest it may have some activity against mantle-cell lymphoma.

Interleukin 12 (IL-12).IL-12 is a potent immune factor called a cytokine that enhances the body's ability to fight foreign invaders. Experts are investigating whether it will be useful in certain settings--such as in combination with rituximab or after stem cell transplantation.

Proteasome Inhibitors. Bortezomib (Velcade) is a proteasome inhibitor that has been approved for multiple myeloma and is being investigated for NHL. Small studies are finding some benefits for patients with low-grade and mantle-cell lymphomas.

Cyclin-Dependent Kinase Inhibitors. Flavopiridol, a drug known as a cyclin-dependent kinase inhibitor, is showing some effect in patients with mantle-cell lymphoma. This agent is designed to block enzymes that regulate cell cycles and so help block their growth.

Antibiotics for MALT. Antibiotics may cure or put into complete remission about half of mucosa-associated lymphoid tissue (MALT) cases that are caused by H. pylori infection. Those most likely to respond positively to antibiotics are those in early stages.