Patients with indolent lymphomas that have relapsed or progressed following treatment have not been considered to be curable with standard treatment approaches. Recurrent indolent lymphomas, however, remain highly responsive to a variety of treatments and patients may survive for many years with repeated treatment.
A wide range of re-treatment options exist for relapsed indolent lymphomas. Currently available standard treatment for relapsed indolent lymphomas include single-agent chemotherapy with Fludara® or other purine analogs, combination chemotherapy, or the Rituxan® monoclonal antibody alone or in combination with chemotherapy. All of these treatments may produce complete remissions (disappearance of cancer), but none are curative. The following are all considered to be indolent lymphomas and are treated in a similar fashion.
|International Working Formulation||Revised European American Lymphoma Classification|
|Follicular Small Cleaved Cell||Follicle Center Cell (grade 1)|
|Follicular Mixed Small & Large Cell||Follicle Center Cell (grade 2)|
|Small Lymphocytic Lymphoma||Small Lymphocytic Lymphoma|
|Chronic Lymphocytic Leukemia||Chronic Lymphocytic Leukemia|
|Mantle Cell Lymphoma (mantle zone variant)|
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The following is a general overview of high-dose chemotherapy and autologous stem cell transplant for treatment of indolent lymphomas. 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.
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High-dose chemotherapy and autologous stem cell transplantation as treatment for relapsed indolent lymphoma appear to produce more frequent and longer remissions than other therapies. The duration of survival without cancer recurrence has been reported to be 40-85% 5 years following treatment with high-dose chemotherapy and autologous stem cell transplantation. The chance of dying as a complication of high-dose chemotherapy is 2-7%, which is greater than other standard treatments. The results from high-dose chemotherapy and autologous stem cell transplantation are very encouraging and suggest patients with indolent lymphoma achieve more remissions and may survive longer without recurrence than with other standard therapies. Longer follow-up is necessary to determine whether any of these patients are cured.
Several technological developments have occurred that could reduce the mortality associated with this therapy. These technological changes, combined with using this therapy earlier in a patient’s disease course, will undoubtedly be associated with lower levels of toxicity. Further evaluation of high-dose chemotherapy and autologous stem cell transplantation as treatment for patients with indolent non-Hodgkin's lymphoma is warranted.
Mantle cell lymphoma was defined as a distinct subset of non-Hodgkin's lymphoma in 1992. Mantle cell lymphoma is characterized by diffuse lymph node cancer, advanced stage of cancer at diagnosis, bone marrow involvement and lymphoma cancer cells in the blood in a quarter of patients. More than half of the patients with mantle cell lymphoma will respond to initial standard treatment, but the responses are short and patients have an average survival of less than 3 years from diagnosis. New chemotherapy agents, such as Fludara® and 2-chlorodeoxyadenosine, have anti-cancer activity, but have not improved survival. High-dose chemotherapy treatment with growth factor support produces a complete response in less that half of all patients. Rituxan® (a monoclonal antibody) produces responses in approximately 30% of patients. Interferon has also been shown to prolong remissions, but does not improve survival.
More recently, autologous and allogeneic bone marrow or blood stem cell transplants have been evaluated as treatment for mantle cell lymphoma. Allogeneic transplants are more effective for eradicating cancer cells than autologous transplants, but are associated with treatment related deaths in 40 to 50% of treated patients. In order for autologous bone marrow or blood stem cell transplants to be successful, a remission had to first be produced with the high-dose treatment, which eliminates mantle-cells from the bone marrow and blood. For patients with persistent lymphoma cells in the bone marrow or blood following high-dose treatment, autologous stem cell transplantation is not considered appropriate therapy due to the likelihood of cancer cells in the graft, which would ultimately be re-infused into the patient.
In a recent clinical study from France, the results of autologous bone marrow or blood stem cell transplants in 24 patients with mantle cell lymphoma were reported. Transplantation was performed as first-line therapy in 9 patients, as second-line therapy in 6, and as third-line therapy in 2 patients. Autologous peripheral blood stem cells were utilized in 19 patients and bone marrow was utilized in 5 patients. Eight patients were in complete remission at the time of high-dose treatment and transplantation. Seventeen patients received high-dose chemotherapy without irradiation.
After transplantation, 19 patients were in complete remission and 9 of these patients remain in remission, with an average follow-up of 34 months.
This clinical trial indicates that approximately half of patients with mantle cell lymphoma have prolonged survival following autologous transplantation compared to patients treated with standard therapies. The remissions produced by stem cell transplantation offer an opportunity to add immunological treatments like Rituxan™ after transplantation to attack remaining cancer cells and further improve outcomes. It remains to be determined if allogeneic transplants with low-dose chemotherapy and/or radiation regimens (mini-transplants) will be more effective than autologous transplants. Since allogeneic transplants are only an option for a minority of patients with mantle cell lymphoma due to older age and lack of a donor, autologous transplants will continue to be used for treatment of these patients.
The progress that has been made in the treatment of indolent lymphoma has resulted from the development of new anti-cancer therapies that have been incorporated into treatment regimens 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 indolent lymphomas.
Pre-High-Dose Chemotherapy Cytoreduction: Current pre-transplant chemotherapy regimens are used to reduce the amount of cancer prior to high-dose chemotherapy and stem cell transplantation in an attempt to induce complete remissions prior to autologous stem cell transplantation. Intensive pre-transplant treatment, however, also increases the toxicity of delivering high-dose chemotherapy and reduces the number of stem cells that can be collected to support high-dose chemotherapy. Clinical trials are ongoing to evaluate whether increased pre-transplant treatment can improve outcomes or whether it merely increases the toxicity of high-dose chemotherapy treatment. Patients treated with reinduction may also want to have their stem cells harvested before starting treatment since up to 25% will be unable to have stem cells collected after reinduction.
Cell Processing: When stem cells are collected from a patient for infusion after high-dose chemotherapy, cancer cells may contaminate the stem cell collection (graft). Although the majority of cancer relapses occurring after high-dose chemotherapy and autologous stem cell transplantation occur because the high-dose chemotherapy did not kill all of the cancer cells, it is possible that some patients may also relapse from infusion of the cancer cells "contaminating" the graft. Many techniques are being evaluated that effectively remove cancer cells from the stem cell collection. It is currently unknown whether enough cancer cells can be removed to decrease relapse rates. To learn more about techniques for removing cancer cells from the graft, select Autologous Stem Cell Collection and Processing.
Increased Dose Intensity of the High-Dose Chemotherapy Preparative Regimen: Since more treatment kills more cancer cells, increasing the intensity of treatment delivered can be accomplished by utilizing high doses of anti-cancer therapies or by delivering more than 1 cycle of high-dose treatment prior to stem cell infusion. While increasing the intensity of treatment may kill more cancer cells, this approach may also damage normal cells and increase the toxicity or side effects.
Monoclonal Antibodies: Another approach is to deliver additional treatment directed specifically to the lymphoma cells and avoid harming the normal cells. Monoclonal antibodies are a treatment that can locate cancer cells and kill them directly or stimulate the immune system to attack them. Rituxan® is the first monoclonal antibody approved for the treatment of B-cell lymphomas. It can be administered during or after high-dose chemotherapy and is being evaluated to determine whether the combination can improve cure rates. Monoclonal antibodies can also be linked to other anti-cancer toxins or radiation to deliver additional anti-cancer treatment. These strategies are being evaluated in patients with lymphoma.
Minimal Residual Disease: Following treatment with high-dose chemotherapy, more patients achieve a complete remission (complete disappearance of the cancer) than those treated with conventional doses. Unfortunately, many patients in remission still experience a relapse of their cancer. This is because not all of the cancer cells were destroyed. Doctors refer to this as a state of "minimal residual disease.” Many doctors believe that applying additional cancer treatments during the post-transplant recovery period when only a few cancer cells remain represents the best opportunity to completely eradicate the cancer and prevent the cancer from returning.
Maintenance Chemotherapy: The administration of relatively low doses of chemotherapeutic drugs after an autologous transplant could delay time to progression or prevent relapses. New drugs are constantly being evaluated in the conventional treatment of patients with lymphoma and could be used after high-dose chemotherapy with autologous stem cell support.
Vaccines: Vaccines are being actively investigated, but this therapy is currently limited by the fact that a unique vaccine has to be developed for each specific patient.
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 in the post-transplant period.
Early Aggressive Treatment: Early use of high-dose chemotherapy treatment for patients at high risk of treatment failure is an important strategy to improve cure of patients with lymphoma. Patients treated with high-dose chemotherapy and autologous stem cell transplantation as part of initial therapy have fewer side effects compared to patients who receive high-dose chemotherapy as a "treatment of last resort". Significant toxicity of high-dose chemotherapy is no greater than conventional chemotherapy when used early.