Overview
Small Lymphocytic Lymphoma/Chronic Lymphocytic Leukemia (SLL/CLL) is considered a very indolent or slowly growing cancer, occurring predominantly in older individuals. Because the cancer grows slowly, it is very hard to cure with traditional cancer chemotherapy or radiation therapy treatments, which only destroy rapidly growing cells. Although curing patients is very difficult, patients may live a very long time with their disease. In fact, the average patient with SLL/CLL lives 6-10 years from diagnosis.
A variety of factors ultimately influence a patient’s decision to receive treatment of cancer. The purpose of receiving cancer treatment may be to improve symptoms through local control of the cancer, increase a patient’s chance of cure, or prolong a patient’s survival. The potential benefits of receiving cancer treatment must be carefully balanced with the potential risks of receiving cancer treatment.
The following is a general overview of the treatment of SLL/CLL with allogeneic stem cell transplantation. Circumstances unique to your situation and prognostic factors of your cancer may ultimately influence how these general treatment principles are applied. The information on this Web site is intended to help educate you about your treatment options and to facilitate a mutual or shared decision-making process with your treating cancer physician.
Most new treatments are developed in clinical trials. Clinical trials are studies that evaluate the effectiveness of new drugs or treatment strategies. The development of more effective cancer treatments requires that new and innovative therapies be evaluated with cancer patients. Participation in a clinical trial may offer access to better treatments and advance the existing knowledge about treatment of this cancer. Clinical trials are available for most stages of cancer. Patients who are interested in participating in a clinical trial should discuss the risks and benefits of clinical trials with their physician. To ensure that you are receiving the optimal treatment of your cancer, it is important to stay informed and follow the cancer news in order to learn about new treatments and the results of clinical trials.
For patients under the age of 50-60 with SLL/CLL, allogeneic stem cell transplantation may be a treatment option. For a general overview of the process of allogeneic stem cell transplant, select allogeneic stem cell transplant.
Allogeneic Stem Cell Transplantation for SLL/CLL
Allogeneic stem cell transplantation is the only therapeutic strategy that is potentially curative for patients with SLL/CLL. Until ten years ago, SLL/CLL had been considered an incurable slowly growing cancer of the elderly requiring chemotherapy only to treat symptoms or delay disease progression. In parallel with the growing evidence of safety and effectiveness of stem cell transplantation for the treatment of other leukemias, there was emerging interest in using this approach to treat younger patients with SLL/CLL. About 40% of patients with SLL/CLL are younger than 60 years and about 10% are younger than 50 years at the time of the diagnosis.
In spite of several new drugs (Fludara® or Leustatin®) and new drug combinations (such as cyclophosphamide plus Fludara®), or monoclonal antibodies (Rituxan® or Campath-1H), there is no current evidence that any of these strategies can cure patients with SLL/CLL. The average duration of survival for younger patients with SLL/CLL remains around 5 years from the initiation of therapy. The most useful predictor for decreased survival is the history of prior treatment. Patients with SLL/CLL who fail any kind of therapy (cancer returns or progresses after treatment) have an average life expectancy of 30 months. Patients who are refractory to treatment with chemotherapy have an average survival of only 9 months. These outcomes have resulted in consideration of more aggressive and potentially curative approaches, such as stem cell transplantation. Two transplantation strategies have been evaluated for patients with SLL/CLL: autologous stem cell transplantation and allogeneic stem cell transplantation. For more information on autologous transplantation, go to autologous stem cell transplant.
Allogeneic stem cell transplantation has two main advantages. One advantage is that the stem cells collected from a donor are free of leukemia. The other advantage is that the donor lymphocytes facilitate the killing of SLL/CLL cells by an immunologic graft-versus-leukemia effect. These two features of an allogeneic stem cell transplant act in concert with high doses of chemotherapy and irradiation to contribute to the cure of some patients with SLL/CLL. Currently, more than 200 patients with SLL/CLL have received allogeneic bone marrow or blood stem cell transplants. The main disadvantage of an allogeneic stem cell transplant is the side effects, which may result in death in up to 30% of patients. This is mainly due to complications related to graft-versus-host disease. Leukemia recurrence is unusual and 45-65% or patients survive beyond 3 years from treatment and may be cured.
Strategies to Improve Treatment with Allogeneic Stem Cell Transplantation
The progress that has been made in the treatment of SLL/CLL has resulted from the development of new anti-cancer therapies, the use of autologous and allogeneic stem cell transplants, and the performance of clinical trials. Future progress will result from continued participation in appropriate clinical trials. Currently, there are several areas of active exploration aimed at improving the treatment of SLL/CLL with allogeneic stem cell transplantation.
Use of Peripheral Blood Stem Cells: Stem cells may be collected from a number of sites in the body, including the bone marrow and the peripheral blood. Physicians at The Fred Hutchinson Cancer Center, City of Hope, and Stanford University performed a randomized clinical trial comparing allogeneic bone marrow transplantation (BMT) to peripheral blood stem cell (PBSC) transplantation in patients with leukemia and lymphoma. The results of this study were presented at the American Society of Hematology Annual Meeting in New Orleans.
Patients receiving PBSC experienced more rapid recovery from treatment than patients receiving BMT. White blood cell counts recovered 5 days earlier and platelets recovered 8 days earlier. There were more deaths in patients receiving bone marrow due to lung complications, infections and cancer recurrence. This occurred predominantly in patients with more advanced cancers. There was no difference in the incidence of acute graft-versus-host disease and there was an increase in the incidence of chronic graft-versus-host disease of approximately 10% in patients receiving PBSC. Although, the follow-up period for this study is too short to make definite conclusions about the incidence and severity of chronic graft versus host disease, the physicians concluded that allogeneic peripheral blood stem cells were superior to bone marrow stem cells.
Enhancement of Immunity after Stem Cell Transplants: Allogeneic stem cell transplants are more effective in preventing relapses than autologous transplants because the donor cells recognize the cancer as foreign and kill the cancer cells immunologically. Despite this graft-versus-leukemia reaction, many patients still relapse. There are clinical trials that attempt to enhance this graft-versus-leukemia effect in an attempt to reduce the number of relapses.
Biological Modifier Therapy: Biologic response modifiers are naturally occurring or synthesized substances that direct, facilitate or enhance the body’s normal immune defenses. Biologic response modifiers include interferons, interleukins and monoclonal antibodies. In an attempt to improve survival rates, these and other agents are being evaluated following treatment with an allogeneic stem cell transplant.
Donor White Blood Cell Infusions: In patients who do not have graft-versus-host disease following an allogeneic stem cell transplant, further infusions of white blood cells from the donor are being evaluated to prevent or treat relapses after the transplant. In some studies, these cells are combined with a biologic response modifier, such as Proleukin®, to further enhance the graft-versus-leukemia reaction.
Lymphocytes are white blood cells that are part of the body’s immune system and are capable of destroying cancer cells. Doctors have been trying for several years to use lymphocytes (a type of white blood cell) reactive specifically against cancer cells as a form of treatment. For many reasons, this has been a difficult goal to achieve. First, billions of lymphocytes are needed in order to have a therapeutic effect because it takes several lymphocytes to kill a single cancer cell. Thus, in order for lymphocyte infusions to be practical therapy, extremely large numbers of specific immune lymphocytes need to be produced. Getting lymphocytes to grow and multiply in culture systems outside the body has been difficult. Second, the lymphocytes grown in culture have to be specifically reactive to the cancer cell that has to be killed. Lymphocytes normally attack and kill a variety of foreign invaders, but each lymphocyte is specific and only kills one target and no other. Third, the immune lymphocytes must survive and not be destroyed when infused into a patient with cancer.
Recently, doctors in Holland have been able to grow and expand lymphocytes outside the body that kill leukemia cells without damaging normal cells. When they infused these lymphocytes into a patient with leukemia, the patient achieved a complete disappearance of leukemia. This may represent the first time expanded T lymphocytes have been shown to have a beneficial anti-cancer effect when infused into a patient.
Unfortunately, the use of donor lymphocytes can also be associated with the development of graft-versus-host disease. Several recent studies suggest that the risk for developing graft-versus-host disease may be decreased if a specific type of lymphocyte, the CD8 lymphocyte, is removed. Until now, there has not been an effective and efficient way to remove, or deplete, these CD8 cells from the other donor lymphocytes. Just recently, European researchers presenting at the European Group for Blood and Marrow Transplantation meeting in Austria reported the use of a new technique to deplete the CD8 lymphocytes from the donor cells that are to be infused into the patient.
Researchers treated 9 patients who experienced a recurrence of leukemia after undergoing high-dose therapy and an allogeneic stem cell transplantation. The researchers collected lymphocytes from the respective donors. They were able to deplete 98 to 100% of the CD8 lymphocytes from the donor lymphocyte samples, while still retaining 75% of the other lymphocytes needed to treat the recurrent leukemia. The donor CD8-depleted lymphocytes were then infused into the corresponding patients. Only 1 of the 9 patients developed graft-versus-host disease, a number much lower than would usually occur if CD8 lymphocytes were not depleted from the infusion.
These researchers concluded that the depletion of CD8 lymphocytes from the other donor lymphocytes by high-density microsphere separation appears to be effective. Furthermore, the CD8-depleted donor lymphocyte infusion appeared to decrease the incidence of graft-versus-host disease, while preserving the therapy’s anti-leukemia effect.
Neupogen® Versus Donor Leukocyte Infusion: The use of Neupogen® may help provoke an immune reaction against leukemia cells as effectively as would an infusion of donor white blood cells. The use of donor white blood cells can be associated with 2 complications: 1) graft-versus-host disease and 2) some of the tissue in the patient’s bone marrow can be damaged by the donor’s white blood cells. For these reasons, the availability of a biologic therapy that can help stimulate white blood cell production is a welcome advance in treatment. Neupogen® is a type of growth factor called a granulocyte colony-stimulating factor that, when injected under the skin, causes white blood cell counts (particularly granulocytes) to increase dramatically. Researchers in Nebraska conducted a clinical study to determine whether the use of Neupogen® would be as effective as infusions of donor white blood cells in treating recurrent leukemia.
Researchers used Neupogen® to help increase white blood cell counts in 14 patients who suffered a recurrence after undergoing high-dose therapy and an allogeneic stem cell transplant for CML or AML. The results showed that 43% of patients had a complete response to the therapy. However, 43% also developed chronic graft-versus-host disease. Fifteen months after treatment, 73% of the patients were alive and 43% had no signs or symptoms of disease.
While some of the positive effects observed in this study may have been due to discontinuation of the immunosuppressive therapy, it appears that the use of Neupogen® may be a good and safe initial approach to treating patients who have a recurrence of AML or CML after high-dose therapy and an allogeneic stem cell transplant. Should this strategy fail, patients could then receive an infusion of donor white blood cells. Researchers believe this treatment strategy may be effective in CLL, as well as other leukemias.
Graft Manipulation: For many years, it has been known that the removal of lymphocytes from the graft (collected cells) could prevent or ameliorate the graft-versus-host reaction. However, when T-cells are removed from the graft, there is an increase in graft failure and relapse rates. Many clinical trials are currently underway to determine the optimal cellular composition of the graft to ensure engraftment without graft-versus-host disease and without an increase in relapse. These studies have been made easier by the development of blood stem cell transplants, which allow for the collection and processing of large numbers of stem cells from the peripheral blood.
Increase in the use of Donors other than HLA-Matched Siblings: Since only a quarter of patients will have an HLA-matched family member donor, there is much ongoing research aimed at increasing the number of available donors. There has been significant progress in the use of partially matched family member donors, especially in children. Currently, an HLA-compatible unrelated donor can be found for approximately 70% of patients; however, the search must be initiated early enough in the disease course to be of benefit. There is also increasing definition of the degree of mismatching that can be tolerated in unrelated donors, especially in children. The use of umbilical cord blood is expanding and will increase the unrelated donor pool. Until recently, umbilical cord blood transplants have been restricted to children. Recent clinical studies suggest that umbilical cord blood can be expanded in culture and used successfully in adults.
“Mini-transplants”: Traditionally, the high-dose radiation and chemotherapy regimens used in allogeneic stem cell transplants are very toxic and involve complete destruction of the bone marrow. Recently, several transplant centers have evaluated less toxic regimens, including lower doses of chemotherapy, radiation and/or biologic therapy prior to an allogeneic transplant. The concept of a mini-transplant is two-fold. The less toxic regimens utilizing lower doses of chemotherapy, radiation therapy and/or biologic therapy kill some cancer cells and suppress the patient’s immune system so that it won’t attack the donor cells. Once the donor cells are infused into the patient, they can recognize the patient’s cancer cells as foreign and mount an attack against the cancer.
Several small clinical trials have demonstrated that successful eradication of leukemia cells can be achieved with (“mini-transplants”). This represents a potential new approach for safer treatment of a large variety of cancers currently treated with allogeneic stem cell transplantation, including multiple myeloma. The technique of mini-transplants has now been expanded to include the use of unrelated HLA-matched donors and has the potential to make this therapy more widely applicable. This is important for elderly patients, as their age often excludes them from being able to receive the high dose of treatment typically used in allogeneic stem cell transplantation.
Early Aggressive Treatment: Early use of allogeneic stem cell transplantation for patients at high risk of treatment failure could be an important strategy to improve cure of patients with SLL/CLL. Patients who have not been heavily pretreated typically experience fewer complications from an allogeneic transplant. Younger patients who are likely to experience a cancer recurrence following chemotherapy may benefit from initial treatment with a stem cell transplant.
Increased Dose Intensity: Since more treatment kills more cancer cells, increasing the intensity of treatment delivered to the leukemia cells by utilizing high doses of anti-cancer therapies is one strategy to improve cure rates. The strategy of increasing the dose of chemotherapy and total body irradiation, however, is applicable only to children, as toxicities of this approach are too high in adults.
Monoclonal Antibodies: Another approach is to deliver additional treatment directed specifically to the leukemia cells and avoid harming the normal cells. This is an attractive approach since there are now a variety of monoclonal antibodies that are specific for B cell lymphomas and leukemias. Some antibodies will kill lymphoma cells directly like Rituxan® or are linked to toxins or radioactive isotopes that kill cancer cells.
Physicians at the Dana-Farber Cancer Institute have linked antibodies to a toxic substance called ricin (immunotoxin). The antibody, therefore, delivers cancer cell killing ricin directly to the cancer. The potential advantages of this approach are that the treatment selectively identifies cancer cells and can kill cancer cells resistant to chemotherapy. Forty-nine patients with B-cell non-Hodgkin’s lymphoma were treated with the immunotoxin approximately 3 months after transplant. There were no severe toxicities from the treatment. The 4-year survival was 72%, and 56% of patients survived without cancer recurrence. This study is important because it demonstrates that an immunotoxin can be given without severe toxicities. However, further improvement in treatment is needed since there were continued relapses despite the administration of the immunotoxin.
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