Lymphomas (Non-Hodgkin's)

Description

Transplantation

In order to administer high-dose chemotherapy for advanced cancer cases, stem cell transplantation procedures may be used. Stem cell procedures have proven to produce long-term survival and even cures in some patients with aggressive (intermediate and high-grade) non-Hodgkin's lymphomas. These procedures are based on removal and replacement of stem cells, which are produced in the bone marrow. Stem cells are the early forms for all blood cells in the body (including red, white, and immune cells). Cancer treatments harm growing cells as well as cancer cells, and so the healthy stem cells must be replaced by transplanting them from the donor into the patient.

Collecting the Stem Cells

Sources of Cells. Stem cells must first be collected in one of the following ways:

• Directly from blood (peripheral blood stem cell transplantation).
• From bone marrow (bone marrow transplantation).
• From umbilical cords or placentas. This procedure uses donor cells, but has a lower risk for immune system rejection of the cells than with a standard donor transplant. It takes longer to restore blood cells with this process, however, so at this time its use is limited to children and sometimes adults with low weight. (A small 2001 study on adults suggested it might also be useful for adults with normal weights.)

Some current evidence suggests that the stem cell and bone marrow procedures produce similar benefits in terms of response rates and duration of remission. However, in a 2002 study stem cell transplantation was associated with better overall survival rates. It also seems to be superior in terms of cost, quality of life, and the need for less supportive care, so is the procedure discussed here.

Donor or Patient Cells. The marrow or blood stem cells can be taken from the patient (autologous) or from a matched donor (allogeneic):

• In an autologous transplant, the marrow or blood cells used for replacement are taken from the patient. There is some danger, however, that the cells used may contain tumor cells and the cancer can regrow and cure rates are unlikely. It is unclear if this approach improves survival compared to standard chemotherapy for newly diagnosed disease. However, it clearly has benefit in the treatment of some forms of relapsed non-Hodgkin's lymphomas. There is also a higher risk for leukemia. (This risk is lower in peripheral stem cells transplants than in bone marrow transplants.)
• In an allogeneic transplant, bone marrow or stem cells are taken from a donor. Siblings are the best donors. Relapse rates can be very low with this approach and cure may be possible in some cases. However, it is highly toxic and donor and recipient must be matched as closely as possible to avoid rejection by the immune system, a serious complication called graft-versus-host disease. Advances in techniques are reducing the toxicities associated with this approach.

The Blood Stem Cell Collection Procedure.

• The donor is usually given a drug called granulocyte colony-stimulating factor, or G-CSF (filgrastim, lenograstim, pegfilgrastim) to stimulate stem cell growth.
• The patient (or donor in an allogeneic procedure) then undergoes apheresis. With this process the blood is withdrawn from one of the patients veins, then passes through a machine that filters out the white cells and platelets, which contain the stem cells. The blood is returned through another vein. The entire procedure takes three to four hours but needs to be repeated several times.
• The stem cells are treated to remove contaminants and then are frozen to keep them alive until the patient is ready to receive them back.

Blood is the only fluid tissue in the body. Blood transports oxygen and nutrients to body tissues, and returns waste and carbon dioxide. Blood distributes nearly everything that is carried from one area in the body to another place within the body. For instance, hormones are transported from the endocrine organs to their target organs. Blood helps maintain body temperature and normal pH levels in body tissues. The protective functions of blood include clot formation and the prevention of infection.

The Transplantation Procedure

• Allogeneic transplants are preceded by chemotherapy treatment known as conditioning. The point of this treatment is to inactivate the immune system and to kill any residual malignant cells. It is extremely toxic since it also destroys non-malignant marrow cells. Agents used are typically cyclophosphamide, carmustine, and etoposide. Alternative conditioning to reduce toxicity includes total-body radiation plus one agent. Monoclonal antibodies, such as rituximab, are promising agents, since they have low toxicity and may add benefits for all stages of transplantation.
• A few days after treatment, the patient is rescued using the stored stem cells, which are administered through a vein. This may take several hours. Patients may experience fever, chills, hives, shortness of breath, or a fall in blood pressure during the procedure.
• The patient may be treated with granulocyte colony-stimulating factor after chemotherapy. The goal is to stimulate the growth of infection-fighting white blood cells. (Adding another substance, thrombopoietin, may prove to enhance stem cell production.)
• The patients are kept in a protected environment to minimize infection. Allogeneic patients may need blood cell replacement, nutritional support, and agents to treat graft-versus host disease. They usually can leave the hospital within three to five weeks.

Candidates and Success Rates

Candidates. These procedures are typically used for patients with relapsed aggressive lymphoma who are still sensitive to the effects of chemotherapy. The procedures are not effective for patients whose tumors are not responsive to drugs. (One study did suggest that certain primary (non-relapsed) lymphomas initially unresponsive to a first round of chemotherapy but who respond to a second round may benefit from combination of high-dose chemotherapy and radiation followed by transplantation.) It is also being investigated as first-line therapy for patients with aggressive lymphomas, although at this time evidence does not support its use.

Success Rates. Success rates vary depending on many factors. The following are survival rates reported by a few 2000 and 2001 studies of patients with different lymphomas:

• In patients with refractory or relapsed intermediate grade NHL who received autologous transplantation, five-year survival rates averaged 34%.
• In a study of allogeneic bone marrow transplantation, 58% of patients with late-stage low-grade lymphoma had survived after an average of 29 months.
• Patients with anaplastic large-cell lymphoma were treated with autologous stem cell transplantation with intensified chemotherapy as first line-therapy. Survival rates were 87% at five and more years afterward. (Survival was much lower with other lymphomas.)
• Patients with diffuse aggressive NHL who did not achieve a first remission but who are still sensitive to chemotherapy achieved a five-year survival rate of up to 37% after autologous stem cell transplantation.
• In one study, 35% of patients with an initial poor prognosis were still alive five years after an allogeneic stem cell transplantation, although mortality probability from the treatment itself was very high (48%).

Side Effects and Complications

Common side effects include nausea, vomiting, fatigue, mouth sores, and loss of appetite.

The procedures themselves are fairly dangerous and carry a small risk for death. When it was first used, transplantation procedures had 10% to 25% morality rates. Now mortality rates are below 5%. Potentially serious complications are the following:

• Infection resulting from a weakened immune system. This is the most common side effect and can persist for several months after the transplant. Because the stem cell procedure is done more swiftly, the risk period is shorter than with bone marrow transplantation. Many patients develop severe herpes zoster virus infections (shingles) or have a recurrence of herpes simplex virus infections (cold sores and genital herpes). Pneumonia, cytomegalovirus, aspergillus (a type of fungus), and Pneumocystis carinii (a protozoan) are among the most important life-threatening infections.
• Graft-versus-host disease (GVHD) is a serious attack by the patient's immune system triggered by the donated new marrow in allogeneic transplants. Acute GVHD occurs in over half of allogeneic transplants, usually within 90 days. Its severity ranges from very mild symptoms to a life-threatening condition (more often in older patients). In some cases, it can become chronic, which usually develops after the third month following the transplant but may not develop for a year or more. GVHD can causes gastrointestinal problems, severe skin reactions, hair loss, mouth and throat ulcers, and liver damage. Careful matching of the donor and preventive immunosuppressive drugs, such as corticosteroids, methotrexate, and cyclosporine (Sandimmune), may reduce the risk. T-lymphocyte depletion is another approach for preventing GVHD, which involved reducing the number T-cells infused with the stem cells.
• Secondary cancers. There is a small long-term risk for leukemia after transplantation in young people. Use of newer chemotherapeutic agents, however, may not pose as high a danger as older treatments.
• Bleeding because of reduced platelets. This risk is highest within the first four weeks after BMT.
• Infertility.
• Organ complications to the liver, heart, kidney, or lungs.
• Failure of the transplant. The marrow graft may fail or new marrow cells may not grow.