Myelodysplasia is a curable disease and the results of treatment have improved dramatically over the past 30 years. In order to have the best chance of being cured, it is important to understand the treatments available and what is necessary to achieve the best results. Researchers have learned that the best way to cure patients with myelodysplastic syndrome (MDS) is to administer large doses of chemotherapy drugs in a short period of time. The concept is to kill the abnormal cells quickly before they can develop resistance to the drugs. Allogeneic stem cell transplantation is one way to deliver very high doses of radiation and/or chemotherapy drugs over a short period of time.
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 allogeneic stem cell transplantation for treatment of MDS. 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 a general overview of the process of allogeneic stem cell transplant, select Allogeneic Stem Cell Transplant.
Allogeneic or autologous stem cell transplantation should be considered as an integral component of the treatment plan for all patients with MDS under the age of 65 years. This can only be done if HLA Testing is performed at diagnosis to determine the availability of a stem cell donor.
Allogeneic stem cell transplantation cures many patients with MDS; however, only one-third of patients will have a compatible family member donor and up to 70% of the population will have a suitable unrelated donor. When age and donor availability are taken into consideration, allogeneic transplantation is a treatment option for only a minority of patients
Allogeneic stem cell transplantation is the treatment of choice for "young" patients who have an HLA-compatible family member stem cell donor. The exact upper age limit for performing an allogeneic transplant is controversial and ranges from 45-65 years, depending on the institution performing the procedure. This is because side effects and treatment-related deaths resulting from allogeneic stem cell transplant increase with age.
An allogeneic stem cell transplant for patients under age 42 with MDS without excess blasts results in long-term disease-free survival in over 60% of patients. Disease recurrence after allogeneic transplantation is mainly seen in those patients with excess blasts at the time of transplant. However, patients without excess blasts are those who would take longer to progress to acute leukemia with standard therapy. An allogeneic marrow transplant for newly diagnosed patients with refractory anemia or refractory anemia with ringed sideroblasts has a higher early mortality rate due to treatment-related side effects and a superior long-term survival than alternative forms of therapy. Transplant related mortality worldwide ranges from 10-40%. In selecting a transplant center, it is important to obtain information about the specific results for treatment of MDS achieved at that center.
It is important to realize that the average age at diagnosis of MDS is over 65 years and most centers will not transplant patients older than 55. This is because in studies evaluating the influence of age on the outcome of transplantation for treatment of MDS, older patients have a higher transplant related mortality. Successfully transplanting older patients could dramatically increase the number of patients cured of MDS. There has been recent interest at some centers in evaluating allogeneic transplantation following lower dose chemotherapy in older individuals.
In one clinical study, 50 patients over the age of 55 with MDS were treated with allogeneic transplantation. Stem cells were obtained from HLA-matched or partially matched family members or identical twins for 44 patients and unrelated donors for 6 patients. Patients treated at the beginning of this study received cyclophosphamide chemotherapy and total body radiation and later patients received busulfan and cyclophosphamide before stem cell infusion.
Four patients (8%) died from transplant-related complications in the first three weeks. Ten patients experienced recurrence of MDS and the overall survival was approximately 35%. However, risk factors that predicted for survival with conventional treatment also predicted for survival following transplantation. Patients with advanced disease in a high-cytogenetic risk group had a higher chance of relapsing and a lower survival. Based on risk categories, patients at a low risk had a 100% survival while patients at intermediate or high risk had survivals ranging from 30 to 54%. These doctors presented evidence that there may have been improvement in outcomes over time possibly related to the shift from using cyclophosphamide and total body irradiation to busulfan and cyclophosphamide. They suggested that adjusting the blood levels of busulfan improved the results of patients receiving the busulfan cyclophosphamide regimen.
Stem cell transplantation is associated with significant toxicity in patients of all ages, but the results are encouraging in patients with favorable-risk cytogenetic features and patients prepared for transplantation with a conditioning regimen that incorporated the adjustment of busulfan blood levels.
There has been significant recent progress in the selection of compatible stem cell donors unrelated to the patient. Patients with newly diagnosed MDS who do not have a suitably matched stem cell donor are advised to have an unrelated donor search performed by the National Marrow Donor Program, which can be carried out by the center that will perform the transplant. Once a donor is identified, the patient with MDS has to go through the same decision-making as for the patient with a related donor. Older patients receiving unrelated donor stem cell transplants have a higher treatment-related mortality and the upper age limit for most transplant centers is currently 45 years of age.
Unfortunately, the majority of patients will either not have a suitable stem cell donor identified or will be over the age limit for this approach. It is important to determine as soon as possible after diagnosis whether or not a suitable stem cell donor is available. If a donor is not available, autologous stem cells can be collected if a complete remission can be achieved.
The main reasons patients with MDS fail treatment with an allogeneic stem cell transplant are cancer relapse and treatment-related mortality. Relapse occurs because the high-dose treatment is unable to kill all of the abnormal cells. Treatment-related deaths are due to regimen-related toxicities, infections and graft-versus-host disease. Allogeneic stem cell transplants are also limited by donor availability since only about one-third of patients will have an HLA-compatible family member donor. Doctors are performing clinical trials designed to improve the treatment of patients with MDS by the following approaches:
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.
Radioactive Monoclonal Antibodies: Dose intensity can also be achieved by linking cancer killing radioactive isotopes to monoclonal antibodies that target leukemia cells or cells located near leukemia cells in the bone marrow and blood. In this manner, radiation is delivered primarily to the bone marrow and not in high doses to other vital organs, such as the liver and lung. Early studies utilizing high doses of chemotherapy plus radioactive monoclonal antibodies have been successful in preventing relapses when given with allogeneic marrow transplantation.
Researchers have tested a monoclonal antibody-isotope combination that targets cancer cells in the bone marrow. Radiation from the isotope was selectively delivered to the bone marrow without toxic radiation to other normal tissues. They treated 44 patients with leukemia who had previously failed chemotherapy. All patients received the treatment regimen of chemotherapy and total body irradiation followed by the infusion of autologous or allogeneic stem cells. In addition, they then received on average twice as much radiation to the bone marrow from the isotope. This clinical trial was performed primarily to determine the optimal dose of isotope, although several patients appeared to benefit from this therapy. Three of 9 patients with lymphoid leukemia survived 23-70 months after treatment. This technique can now be applied to patients earlier in their disease when the number of cancer cells is small and resistance to treatment has not developed.
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 cancer cells immunologically. Despite this graft-versus-leukemia reaction, many patients still relapse. Clinical trials are ongoing to evaluate strategies to enhance this graft-versus-leukemia effect.
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 allogeneic stem cell 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.
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 leukemia recurrence. 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 less than a quarter of patients will have an HLA-matched family member donor, there is much ongoing research into increasing the donor pool. There has been significant progress in the use of partially matched family member donors, especially in children. At the present time, 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. Umbilical cord blood transplants have until recently been restricted to small children. Recent clinical studies suggest that cord blood can be expanded in culture and used successfully in older, heavier children and 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.