by Dr. C.H. Weaver M.D. 3/2019
High-dose chemotherapy should be considered an integral component of the overall treatment strategy of all high grade/aggressive non-Hodgkin’s lymphomas in patients up to the age of 70. Consideration of its role in the treatment of a specific patient should be planned at initial diagnosis because high-dose chemotherapy cures more patients than conventional-dose chemotherapy in many situations.
All high grade/aggressive lymphomas classified according the IWF or REAL system are listed below. The information presented in this section is applicable to all lymphomas in the table.
Autologous Stem Cell Transplant as Initial Treatment
High-dose chemotherapy can be incorporated into the initial treatment regimen or delivered to patients in complete remission after induction chemotherapy. For patients whose cancer is in complete remission after treatment with an aggressive multi-drug “leukemia type” chemotherapy regimen, the benefit of additional treatment with high-dose chemotherapy and stem cell transplantation is unknown. Patients in complete remission but at high risk of relapse may want to consider high-dose chemotherapy as additional treatment or have stem cells harvested and stored for use if the lymphoma relapses.
Patients in complete remission after treatment with conventional 3-4 drug “lymphoma type” chemotherapy regimens have a higher risk of cancer relapse and have received additional treatment with high-dose chemotherapy and stem cell transplantation in clinical trials to determine whether additional treatment can improve the chance of cure. Small numbers of patients have been treated with high-dose chemotherapy and stem cell transplantation in first remission and the chance of cure has been reported to be 70-90%. This appears to represent a substantial improvement over standard lymphoma treatments.
Resistant or recurrent high-grade or highly aggressive lymphomas are still curable, however there is no standard treatment. Conventional chemotherapy salvage regimens are able to produce a remission in a minority of patients. High-dose chemotherapy and autologous or allogeneic stem cell transplantation is probably the best “salvage” treatment, but may be difficult to perform.
In order to perform an autologous stem cell transplant, the patient must have previously collected and stored stem cells or be able to achieve a second remission. In order to perform an allogeneic stem cell transplant, a suitable stem cell donor must be identified. HLA typing for donor identification is time consuming and only 30-40% of patients will have a suitable stem cell donor identified.
High-dose chemotherapy and autologous or allogeneic stem cell transplantation has been reported to cure approximately 15% of patients with resistant lymphoma and 20%-30% of patients with Burkitt’s lymphoma still sensitive to treatment with chemotherapy.
Strategies to Improve Autologous Stem Cell Transplantation
It is useful to think of high-dose chemotherapy as a sequence of events. Improving the cure rates associated with high-dose chemotherapy may result from intervening in one or more points in this sequence. The conventional sequence of delivering high-dose chemotherapy starts with reinduction chemotherapy followed by collection of stem cells. The next step is treatment with the high-dose chemotherapy preparative regimen, followed by infusion of the previously collected stem cells and then the post-transplant recovery period.
Progress in the treatment of lymphoma with high-dose chemotherapy and autologous stem cell transplantation will result from continued participation in appropriate clinical trials. Currently, there are several areas of active exploration aimed at improving high-dose chemotherapy treatment of lymphoma.
Pre-High-Dose Chemotherapy Cytoreduction: Current chemotherapy reinduction regimens utilizing conventional doses are used to reduce the amount of cancer prior to high-dose chemotherapy and induce complete remissions in a minority of patients. Most patients are not in complete remission at the time of high-dose chemotherapy and autologous stem cell transplantation. Intensive pre-transplant treatment with reinduction chemotherapy, 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 be present in the stem cell collection. Although the majority of cancer relapses 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 collected stem cells. 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 stem cell collection, select Autologous Stem Cell Collection and Processing.
Increased Dose Intensity of the High-Dose Chemotherapy 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 supported by stem cells. 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 tested in patients with lymphoma.
Minimal Residual Disease: More patients achieve a complete remission following treatment with high-dose chemotherapy than treatment with conventional doses. Unfortunately, many patients who achieve a remission still experience a relapse of their cancer. This is because not all of the cancer cells were destroyed by treatment and may not have been detected. 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 prevent the cancer from returning.
Maintenance Chemotherapy: The administration of relatively low doses of chemotherapeutic drugs after an autologous transplant could delay time to cancer 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 currently is 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 a recurrence following treatment 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.