Lymphoma

Background of Lymphoma

Lymphomas are cancers affecting the lymphatic system, the network of vessels and nodes that carry infection-fighting white cells, called lymphocytes, throughout the body.

Lymphomas are generally classified as Hodgkin's disease and non-Hodgkin's lymphoma. In both types of cancer, the lymphatic cells begin to grow abnormally. Hodgkin's disease follows a more predictable pattern, and tends to have a more limited spread. It is typically treated with radiation or chemotherapy. Non-Hodgkin's lymphomas, on the other hand, may begin in a variety of places in the body, since lymphatic tissue is present in many different organs. Treatment for non-Hodgkin's lymphoma depends on stage of the disease and may include radiation, chemotherapy or a bone-marrow transplant.

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Who is at Risk for Lymphoma?

Non-Hodgkin's lymphomas are the fifth most common type of cancer in the United States. Non-Hodgkin's lymphoma is more common in men than in women. Whites are affected more often than African-Americans or Asian-Americans.

Although some types of non-Hodgkin's lymphoma are among the most common childhood cancers, over 95 percent of non-Hodgkin's lymphoma cases occur in adults. The average age at diagnosis is in the 60s. The increasing average age of the American population is expected to contribute to an increase in non-Hodgkin's lymphoma cases during the next few years.

The American Cancer Society estimates that in 2005 about 7,350 new cases of Hodgkin disease will be diagnosed in the U.S. The disease is more common in early adulthood (age 15 to 40, usually 25 to 30) and late adulthood (after age 55).

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Hutchinson Center Lymphoma Research

Overview of Lymphoma Research at the Hutchinson Center

Hutchinson Center researchers, in collaboration with colleagues at the University of Washington, are developing highly effective, less-toxic therapies for patients with lymphoma. Several of these treatments are currently available to patients enrolled at clinical trials at the Seattle Cancer Care Alliance and collaborating institutions.

Our researchers are world leaders in bone-marrow and stem-cell transplantation for the treatment of both Hodgkin's and non-Hodgkin's lymphomas. Typically, patients who undergo these procedures first receive high doses of chemotherapy and radiation followed by an infusion of healthy stem cells to reconstitute their immune system.

Hutchinson Center researchers and colleagues have developed several modifications that make the transplant procedure more easily tolerated by older or less medically fit patients:

• Our researchers have played a key role in the development and testing of antibodies that target the delivery of radiation and chemotherapy directly the immune-system cells in which lymphoma develops.
• Our researchers have found that patients with relapsed follicular lymphoma who were treated with radioactive antibodies followed by a transplant with their own stem cells (known as an autologous stem-cell transplant) had a five-year overall survival rate of 67 percent. In comparison, patients who received total-body irradiation plus chemotherapy or chemotherapy alone followed by transplant had an overall survival rate of 53 percent.
• Hutchinson Center researchers pioneered development of the "mini-transplant." The procedure involves a minimal dose of radiation and is typically administered entirely on an outpatient basis.

Other research aims to improve non-transplant options for lymphoma patients, including:

• Researchers are investigating new medications that may allow patients with incurable, slow-growing forms of leukemia to control their disease with long-term drug therapy that has few side effects.
• Preliminary clinical trials have shown that a type of combination chemotherapy known as CHOP (consisting of cyclophosphamide, doxorubicin, vincristine and prednisone), followed by treatment with a radioactively-tagged antibody that targets B lymphocytes (cells that give rise to lymphoma), induced remission in 98 percent of patients. Greater than 80 percent of patients remain disease-free more than two years after treatment.

Delivering targeted, less toxic treatment to lymphoma's most vulnerable victims

One of cancer's cruelest ironies is that it mostly strikes older people, a group that is least physically able to cope with the side effects of treatment.

This can be especially challenging for doctors who treat immune-system cancers like lymphoma, which often require heavy rounds of radiation and chemotherapy followed by a stem-cell transplant to knock the disease into remission. But oncologists like Dr. Ajay Gopal, an assistant professor of medicine at the University of Washington and an assistant member in the Clinical Research Division, are discovering that some of these lifesaving options can be delivered with a gentler touch.

Using antibodies that deliver a blast of radiation directly to cancer cells and drug regimens with fewer side effects, Gopal and colleagues hope to improve the quality of life for lymphoma patients young and old. This newer generation of therapies also benefits those whose disease has relapsed after initial therapy, another group less physically fit to withstand the side effects of treatment.

Gopal and colleagues found that patients with relapsed follicular lymphoma who were treated with radioactive antibodies followed by a transplant with their own stem cells (known as an autologous stem-cell transplant) had a five-year overall survival rate of 67 percent. In comparison, patients who received total-body irradiation plus chemotherapy or chemotherapy alone followed by transplant had an overall survival rate of 53 percent. What's more, patients in the antibody group were nearly three times less likely to die from treatment-related complications.

In a recent pilot study of 16 patients, Gopal and colleagues achieved overall three-year survival rates of 93 percent for relapsed mantle-cell lymphoma using the radioactive antibodies followed by chemotherapy and an autologous transplant. Disease-free survival during that time period was 61 percent, and no patients died from treatment-related complications.

On another research front, Gopal is developing more easily tolerated chemo regimens for patients who have relapsed lymphomas.

"If a patient's disease returns after chemotherapy, some are treated with a different chemotherapy regimen followed by an autologous transplant," he said. "That second chemo regimen is often very intense and typically must be given in the hospital. We're trying to develop a regimen using a new generation of drugs that we hope will be just as effective but much gentler," he said. This therapy is currently being tested in a clinical trial through the Puget Sound Oncology Consortium.

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Using the immune system to improve stem-cell transplant outcomes

A new treatment developed at the Hutchinson Center offers new hope for patients with lymphoma, multiple myeloma and a number of other cancers. The procedure combines a high-dose stem-cell transplant using the patient's own stem cells, followed by a nonmyeloablative transplant, also known as a mini-transplant, using stem cells from a matched sibling. The approach appears to increase survival and reduce toxicity compared to conventional transplants.

Dr. David Maloney, lead researcher, explains that success relies on the cancer-fighting properties of the sibling-donated stem cells. The process has also been successfully used for the treatment of leukemia and renal-cell cancer.

Harnessing the immense power of the body's own immune system to combat lymphomas and myeloma and other cancers has long been the goal of Maloney's laboratory team. A core area of his research is the development of monoclonal antibodies. These immune system components are engineered to recognize and bind to specific proteins on the surface of cancer cells. Such antibodies can be designed to attack cancer cells by themselves or they can be used to deliver cancer-killing doses of chemotherapy or radiation.

In addition, the team is investigating a variety of treatment regimens based on nonmyeloablative transplants, in which the patient undergoes low-dose therapy that does not ablate, or wipe, out the bone marrow, as in a conventional stem-cell or bone-marrow transplant. Ultimately the patient experiences both substantially reduced side effects and a more vigorous graft-vs.-tumor (GVT) effect to extend remissions. GVT is when the donor marrow recognizes the tumor cells and destroys them.

In support of these therapeutic strategies the Maloney laboratory is seeking a better understanding of how the immune system reconstructs itself after stem-cell transplantation to improve the efficiency and effectiveness of stem-cell transplantation for lymphomas, myelomas and other blood-based cancers.

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High-dose chemotherapy regimens for children increase survival rates

Childhood lymphoma tends to occur in an aggressive form that paradoxically is more curable than lymphomas in adults. Unlike the survival rates for lymphoma in adults, the newer high-dose chemotherapy regimens have pushed survival rates for children to between 70 and 90 percent, with chemotherapy protocols for Hodgkin's lymphoma exceeding 90 percent survival rates.

Dr. Julie Park is a pediatric hematologist/oncologist at Children's Hospital and Regional Medical Center whose clinical research focuses on both newly diagnosed and relapsed children with non-Hodgkin lymphoma, and lymphoblastic and Burkitt's and large-cell lymphomas.

The short-duration, high-dose chemotherapy regimens in children carry added risks of infertility, particularly for boys, a higher risk of a secondary malignancy and some risk of cardiac effects. Park is testing new therapies in a continual effort to improve effectiveness of treatment regimens while reducing both short- and long-term side effects.

Dr. Debra Friedman is a pediatric hematologist/oncologist at Children's Hospital and Regional Medical Center whose research focuses on the design and implementation of treatment for children and adolescents with newly diagnosed, recurrent and refractory Hodgkin disease, as well as the biology of the disease. In addition, she is on the steering committee of the Children's Oncology Group, a national clinical-trials organization, where she leads lymphoma research efforts in the areas of initial therapy, supportive care and late effects. She is a lead investigator for a Clinical Oncology Group Phase III study that is evaluating different chemotherapy regimens given with or without radiation therapy to compare how well they work in treating children with newly diagnosed Hodgkin disease. She also leads a study examining health outcomes for pediatric Hodgkin disease.

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Novel approaches in lymphoma treatment

It is unusual for one researcher to take a therapy approach from basic-cell science, to laboratory testing and then pursue it all the way from preclinical to clinical trials. But that is just the path Dr. Oliver Press has taken to developing targeted therapies for lymphomas and other cancers of the immune system.

In one example of this unique approach, Press's team developed a radioimmunotherapy that uses immune system components to deliver a lethal dose of radiation specifically to tumor cells while sparing the nearby tissue.

One of the challenges of treating non-Hodgkin's lymphoma is that the cancer can be concentrated in different parts of the body, making it difficult to deliver enough tumor-killing chemotherapy or radiation without damaging toxic effects to healthy tissues.

Press' research team develops and tests molecules called monoclonal antibodies that recognize and bind to proteins on the surface of specific immune system cells, called B lymphocytes. When the antibodies latch onto the B cell the normal process of cell growth and differentiation is disrupted resulting in cell death. In collaboration with Dr. Pat Stayton in the University of Washington Department of Bioengineering, Press' team has used genetic engineering to design more lethal antibody conjugates, which are antibodies combined with a toxin, such as chemotherapy or radioactive isotopes.

In one of the most successful new treatments for non-Hodgkin's lymphoma, Press' team in collaboration with Drs. Irwin Bernstein, Dana Matthews, Fred Appelbaum, and Janet Eary used a targeted antibody combined with a radioactive isotope. The antibody preferentially binds to the cancer cells concentrating the radiation dose to the tumor. In clinical trials using such antibodies 90 to 95 percent of B cell lymphoma patients treated experienced complete shrinkage of the tumor.

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Mini-transplants offer new hope to patients

Dr. Rainer Storb's clinical research team has successfully developed a radically different approach to bone-marrow transplantation that opens up the possibility of a cure for many more people. Because this new treatment, called the mini-transplant or nonmyeloablative stem-cell transplant, does not wipe out bone marrow, patients experience minimal toxicity. The procedure offers new hope for older or otherwise medically unfit patients who cannot withstand the rigors of a conventional transplant. The mini-transplant involves minimal doses of radiation, meaning that patients do not lose their hair or experience severe nausea or other side effects, and typically can be performed without a hospital stay.

Storb's team initially published results of an international study involving 46 patients with an average age of 56 years who underwent the new procedure. The study demonstrated that the new mini-transplant might offer hope to more patients with leukemia and nonmalignant blood disorders than ever before. Two-thirds of the study participants — patients who previously would have had little chance of a cure — had survived more than a year.

To date, more than 660 patients have received mini-transplants at the Hutchinson Center and a dozen other institutions. The longest survivor is more than six years post-transplant. The procedure eventually may be offered to a wide range of patients, offering an easier, lower-cost therapy for people with leukemia, myeloma, lymphoma, sickle-cell anemia and autoimmune diseases.

Storb and colleagues are now exploring the potential of the mini-transplant to treat solid tumors, such as kidney cancer.

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Articles Related to Lymphoma and Lymphoma Information

• Full Recovery After Cell Transplantation for Treating Leukemia or Lymphoma Can Take 3-5 Years
  
  
• Precision punch to lymphoma — Ajay Gopal and colleagues use antibodies to deliver targeted, less toxic treatment to lymphoma’s most vulnerable victims
  
  
• New hope on the horizon for lymphoma — Preliminary study of treatment for follicular lymphoma offers patients the possibility of a longer cancer-free life
  
  
• Mini-transplants for those over 50: Success! — Storb/McSweeney study says outpatient treatment combination of low radiation, potent drugs works for older patients

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