Back-Up for Lymphoma
New agents work from a variety of angles.

By Roxanne Nelson

When a routine tuberculosis skin test in 1993 came back positive, Jared Silberman was puzzled. Follow-up tests showed no signs of tuberculosis, but instead revealed he had stage 4 non-Hodgkin’s lymphoma (NHL), which meant this cancer of the lymph system was throughout at least one organ or tissue in addition to the lymph nodes.

Silberman, of Washington, D.C., completed the standard six-month treatment of CHOP (cyclophosphamide‚ doxorubicin‚ vincristine and prednisone) and radiation. Because his cancer was advanced, chemotherapy was followed by autologous bone marrow transplant. The then 42-year-old went into remission and stayed that way before being diagnosed with NHL again in 2003.

After a decade’s worth of research and drug development since his first diagnosis, Silberman found a wider range of treatment options the second time around for what his doctors said was not a relapse of his previous NHL. “I had four infusions of Rituxan without any side effects,” says Silberman, who is now on maintenance Rituxan® (rituximab) therapy three times a year to keep his disease in remission.

NHL encompasses a group of cancers of the lymphoid system that are divided into two major categories based on the type of immune cell (lymphocyte) from which it arises. B-cell lymphoma—about 80 to 85 percent of all NHL cases in the United States—arises from B lymphocytes, while T-cell lymphoma arises from T lymphoctyes and makes up about 15 percent of cases. B-cell lymphoma is further divided into aggressive lymphomas, including diffuse large B-cell lymphoma and mantle cell lymphoma, and slow-growing indolent lymphomas, including follicular lymphoma and marginal zone lymphoma. T-cell lymphoma is divided into more than 10 subtypes, including mycosis fungoides (a lymphoma of the skin) and nasal T-cell lymphoma.

Lymphoma experts say a better understanding of the molecular defects in lymphoma have led researchers to rethink the way they use both old and newer drugs while at the same time designing new ones with more specific mechanisms of action. The more than 55,000 Americans diagnosed with NHL each year can look not only to Food and Drug Administration-approved treatments, such as Rituxan, Bexxar® (tositumomab), Zevalin® (ibritumomab tiuxetan) and Ontak® (denileukin diftitox), but also promising new agents being tested in clinical trials.

Reworking Rituxan

In 1997, Rituxan became the first genetically engineered monoclonal antibody to be approved in the United States for low-grade follicular B-cell NHL. The drug targets the CD20 receptor found on the surface of normal and malignant B cells. This type of therapy is an effective way of targeting specific cancer cells with a low degree of toxicity to normal cells. Like Silberman, many patients do not experience serious adverse effects from Rituxan.

Rituxan’s success in patients with follicular B-cell lymphoma whose disease recurred after initial chemotherapy led researchers to test its use as first-line therapy. The use of Rituxan has grown significantly since 1997 and it has now become an essential part of treatment for not only low-grade but also more aggressive B-cell lymphomas.

George Weiner, MD, director of the Holden Comprehensive Cancer Center at the University of Iowa, says Rituxan is increasingly being used in combination with chemotherapy, including CHOP. A number of large phase III studies showed that adding Rituxan to standard chemotherapy significantly increased survival in older patients with diffuse large B-cell lymphoma.

“Rituxan has become a standard part of treatment one way or another for essentially all B-cell lymphomas,” Dr. Weiner says. “You could look at just about any chemotherapy combination that has been used to treat B-cell lymphoma, and it has been evaluated with Rituxan.”

One study reported that patients who received Rituxan with CHOP had a 39 percent improvement in cancer-free survival compared with patients who received CHOP alone. Oncologists now routinely add Rituxan to chemotherapy for newly diagnosed patients with aggressive B-cell lymphoma. The FDA is currently reviewing an additional indication of Rituxan for this type of NHL.
An important issue regarding the optimal use of Rituxan is the question of maintenance therapy to keep the disease in remission. Maintenance Rituxan therapy is primarily used in patients with follicular B-cell lymphoma, which tends to relapse even years after treatment. Recent phase III studies found that giving Rituxan every few months for up to two years increases the probability of keeping the lymphoma in remission. “We’re still working to figure out how Rituxan should be used in the course of therapy and the relative role of up-front versus maintenance therapy,” Dr. Weiner says.

Emerging Antibodies

While the reasons are unclear, many patients with B-cell lymphoma eventually become resistant to Rituxan. Attempts have been made to re-target CD20 in order to overcome Rituxan resistance and allow a second response. Currently in clinical trials are two next-generation antibodies, HuMax-CD20 and ocrelizumab, which are designed to have an ability to kill B-lymphoma cells.
In an early-phase study of patients with relapsed or refractory low-grade follicular B-cell NHL, HuMax-CD20 showed activity in up to two thirds of 37 evaluable patients, including nine patients whose disease had recurred after prior therapy with Rituxan. Ocrelizumab appears to have an increased ability to kill B-lymphoma cells. Trials of the new agent in B-cell lymphoma are ongoing in Europe.

In addition, monoclonal antibodies Bexxar and Zevalin can be effective, because unlike Rituxan, the drugs contain a radioactive isotope that delivers radiation directly to cancerous B cells. Like Rituxan, Bexxar and Zevalin are only effective in patients with B-cell lymphoma.

“This is an exciting time in the area of lymphoma because there are many new therapies being tried and tested,” says Stephen Ansell, MD, PhD, associate professor of medicine at the Mayo Clinic College of Medicine.

Several monoclonal antibodies being tested against lymphoma target the CD30 antigen. CD30 is primarily expressed in patients with Hodgkin’s disease or anaplastic large-cell lymphoma, and early studies have found success in CD30-positive lymphoma. Dr. Ansell recently completed a phase I/II trial of the antibody MDX-060 and found the drug to be well tolerated. Even though the study was not looking at efficacy, Dr. Ansell says that of 29 patients, one patient with relapsed CD30-positive lymphoma achieved remission and two others had their tumors shrink by at least 30 percent (a partial response).

SGN-30, another new anti-CD30 antibody, induced death of malignant cells in preclinical studies, says John Leonard, MD, clinical director of the Center for Lymphoma and Myeloma at Weill Medical College of Cornell University. “We are now in phase II trials for Hodgkin’s disease and anaplastic large-cell lymphoma. Safety and tolerability are good, and we’ve seen some evidence of tumor shrinkage.” SGN-30 has also shown benefit in patients with relapsed CD30-expressing anaplastic lymphoma of the skin.

Dr. Leonard speculates SGN-30 will most likely be used in combination with chemotherapy for Hodgkin’s disease and anaplastic large-cell lymphoma and possibly as a single agent for patients with relapsed disease.

Targeting the Proteasome

Velcade® (bortezomib), an FDA-approved drug for multiple myeloma, inhibits activity of the proteasome, a crucial cellular structure that acts as the cell’s garbage disposal, destroying damaged proteins. Disruption of the activity of the proteasome promotes death of cancer cells. In recent studies, Velcade caused a partial response in about half of patients with mantle cell lymphoma, a rare and difficult-to-treat type of B-cell lymphoma.

The FDA recently granted Velcade fast-track status for relapsed and refractory mantle cell lymphoma. Mantle cell lymphoma, more commonly seen in older males, is difficult to put into remission even with the use of Rituxan and CHOP. Currently, many patients receive high-dose chemotherapy and bone marrow/stem cell transplant.

Harnessing the Immune Response

Lisa Taverna, of Bethesda, Maryland, received Rituxan after her low-grade follicular lymphoma diagnosis in January 2005. After four doses, her disease had regressed by 70 percent. “I had a very quick response to Rituxan,” she says. “Within about three weeks, I could already tell that the enlarged lymph nodes were shrinking.”

Because Taverna’s lymphoma responded to Rituxan, she was eligible for a phase III trial with a vaccine called FavId to determine if the vaccine given after Rituxan is better than Rituxan alone. Though vaccines are typically thought of as preventive medicine, these lymphoma vaccines contain a specific protein present on the patient’s tumor cell that stimulates an immune response, and early trials found FavId to be safe and effective in patients with B-cell NHL. Although Taverna is unaware of whether she is receiving the vaccine or placebo, she says her disease has remained in remission.

Favorable responses have also been seen with a vaccine immune stimulant called PF-3512676 (formerly ProMuneTM), which is currently being evaluated in relapsed lymphoma and other tumor types, such as lung and kidney cancer.

Finding Other Active Agents

Activation of certain genes can cause cancer cell death or halt cancer cell growth. A class of experimental drugs called histone deacetylase (HDAC) inhibitors cause DNA molecules to be loosely bound to proteins called histones, resulting in increased gene expressions and potential anti-tumor effects. Vorinostat (also called SAHA) is being tested in solid tumors and hematological malignancies. By altering the mechanisms that allow tumor growth, vorinostat produced anti-tumor activity and was well tolerated in early trials.

“One patient with transformed large-cell lymphoma had a remission for over a year, and another had a partial remission that lasted six months,” says Owen O’Connor, MD, PhD, a medical oncologist at Memorial Sloan-Kettering Cancer Center who co-authored a 2003 report of a phase I vorinostat trial. A phase II study showed tumor regression in eight of 33 patients with mycosis fungoides. The FDA has granted fast-track status to the new agent for cutaneous T-cell lymphoma.

Already approved for advanced colorectal cancer, Avastin® (bevacizumab) has also proven effective in treating lymphoma. For patients with relapsed aggressive NHL, experts say more chemotherapy would not be able to cure the disease. Avastin is a targeted agent that is directed to the vascular endothelial growth factor (VEGF), which is found at high levels in patients with aggressive NHL. A study of Avastin as a single agent in this group of patients found that of 43 patients, two had a partial response and eight experienced stabilization of their disease. Another trial is planned that will combine Avastin with CHOP and Rituxan as first-line therapy in diffuse B-cell NHL.

Although lymphoma patients can find treatment success with currently approved agents, doctors are hopeful the many new agents in early- and late-phase testing will mean more options for patients diagnosed with lymphoma. “It’s right to be optimistic. I think we have newer and better tools down the road,” says Dr. Weiner. “We don’t know if they’ll be better than Rituxan, but there is laboratory reason to think they may offer some advantages.”