Allo: CML
Overview
The diagnosis of chronic myeloid leukemia (CML) is made in approximately 20% of affected individuals by detecting a high white blood cell count on routine blood testing. These patients are usually without symptoms and often have difficulty understanding the serious nature of their disease since they do not feel ill. It is very important for such patients to understand that drastic treatment may be indicated despite the lack of symptoms. Allogeneic stem cell transplantation can eradicate the leukemia and all other therapies are aimed at controlling the growth of abnormal cells and attempting to delay the progression of leukemia from a chronic phase to a blastic phase resembling acute myeloid leukemia. Treatment can also prevent some of the signs and symptoms of the disease, such as an enlarged spleen, fatigue and weight loss. At the time of initial diagnosis, most patients are in what is called the chronic phase of chronic myeloid leukemia. The natural evolution of the disease is to progress to an accelerated phase and ultimately, into a blastic or acute leukemia phase.
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 allogeneic stem cell transplantation for treatment of CML. 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.
Results of Allogeneic Stem Cell Transplantation
Allogeneic stem cell transplantation is currently the treatment of choice for "young" patients who have an HLA-compatible family member. The exact upper age limit for performing an allogeneic transplant in early chronic phase is controversial, with ranges from 45-65 years depending on the institution performing the procedure. This is because treatment-related deaths increase with age. In general, older patients are often advised to have the transplant performed only after disease progression or at least until interferon or Gleevec® treatment has been proven to be ineffective; whereas younger patients are encouraged to have the transplant performed within the first year of diagnosis. Extensive analyses of transplant results have documented the adverse effects of delay on outcome. Patients who delay the transplant can have progression of their disease to an accelerated phase or blastic phase, which results in poor outcomes from transplantation. In addition, patients who are transplanted in late chronic phase have increased mortality from the transplant procedure. The following presents some aspects of this dilemma.
Transplants from HLA-Matched Siblings
Effect of Phase of Disease on Transplant Results:
• Chronic Phase: Patients transplanted in chronic phase have a less than 10% chance of dying of the treatment in the first year and a 5-year survival of 80-90%.
• Accelerated Phase: Patients transplanted in accelerated phase have a 5-year survival of approximately 45% with transplant-related complications causing increased mortality.
• Blastic Phase: Patients transplanted in blastic phase have a 5-year survival of approximately 15%, with the major cause of failure being recurrent leukemia.
Transplants from Unrelated Donors
There has been significant recent progress in the selection of HLA-compatible unrelated donors. Patients with newly diagnosed CML who do not have a suitably matched related donor are advised to have an unrelated donor search performed by the National Marrow Donor Program. This can be carried out by the center that will perform the transplant. Once a donor is identified, the patient with CML has to go through the same decision making as a patient with a related donor and the results are similar. However, older patients receiving unrelated donor transplants have a higher treatment-related mortality and the upper age limit for most transplant centers is 45 years. There is also a marked difference in outcomes depending on the center performing the transplant.
In a recent evaluation of transplant results from unrelated donors for patients with CML in chronic phase, the survival at 5 years was 57% for all patients. Survival was adversely affected by an interval from diagnosis to transplant of one year or more, the degree of HLA matching, obesity, and age over 50 years. For patients who were 50 years of age or under and received a transplant from an HLA-matched donor, the survival at 5 years was 74%. More recently, transplanted patients in this good-risk group had a survival of 87%. These outcomes are similar to those achieved from HLA-matched family members.
Effects of Delay in Chronic Phase on Transplant Results
Patients transplanted from an HLA-matched sibling in chronic phase within one year of diagnosis have a 5-year survival of 85%, while those transplanted between 1 and 2 years from diagnosis have a survival of 78%. Patients transplanted in chronic phase more than 2 years from diagnosis have a survival of 50% because of increased mortality resulting from complications of the transplant.
Effects of Age on Transplant Results for Patients with CML in CP
The effects of age on transplant results in patients with CML in chronic phase have been extensively evaluated. It is important to realize that the average age at diagnosis of CML is 67 years and most centers will not transplant patients older than 55 years. Successfully transplanting older patients could dramatically increase the number of patients cured of CML and some transplant centers are actively investigating transplants in older individuals. In a clinical study evaluating the influence of age on the outcome of transplantation for treatment of CML in chronic phase, no patients under 20 years of age died. Patients 30-40, 40-50 and 50-60 years old were 1.24, 2.30 and 2.5 times more likely to die from complications of the transplant, respectively. Patients over 40 years had a significant increase in the risk of dying from complications of the transplant compared to younger individuals. Thus, patients under the age of 40 had a 5-year survival of 85%, compared to 65-70% for patients over 40 years of age.
Strategies to Improve Treatment
The main reasons patients with leukemia fail treatment with an allogeneic stem cell transplant are relapse and treatment-related mortality. Relapse of leukemia occurs because the high-dose treatment is unable to kill all of the cancer cells. Treatment-related deaths are due to regimen related side effects, 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 leukemia by the following approaches:
Use of Peripheral Blood Stem Cells Rather than Bone Marrow: 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 to peripheral blood stem cell 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 peripheral blood stem cells experienced more rapid recovery from treatment than patients receiving bone marrow transplants. 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 peripheral blood stem cells. 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: Delivering anti-cancer therapy directly to leukemia cells can be achieved by linking radioactive isotopes to monoclonal antibodies that target myeloid leukemic cells or cells that are located only in the bone marrow. In this manner, radiation is delivered primarily to the bone marrow and not in high doses to vital organs, such as the liver and lung. Early studies utilizing high doses of chemotherapy plus radioactive monoclonal antibodies have been highly successful in preventing relapses when given with allogeneic stem cell transplantation.
Researchers have tested a monoclonal antibody-isotope combination that targets bone marrow cells. 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. Seven of 25 patients with myeloid leukemia survive 7-89 months after treatment and 3 of 9 patients with lymphoid leukemia survive 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. There are clinical trials that attempt 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, 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. They 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. They have now infused these lymphocytes into a patient with leukemia who had relapsed after an allogeneic bone marrow transplant. Following infusion of the lymphocytes, this patient achieved a complete disappearance of leukemia. This technique can potentially be used against a variety of cancers and offer a less toxic and more specific approach to cancer therapy.
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 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. The results showed that all patients with CML had a complete response to treatment.
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, especially for those with CML.
Graft Manipulation: For many years, researchers have known that the removal of lymphocytes from the graft 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 one-third of patients will have an HLA-matched family member donor, there is much ongoing research into 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 if the search is begun 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 children. Recent clinical studies suggest that umbilical cord blood can be expanded in culture and used successfully in adults.
"Mini-allografts": Traditionally, the 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 for preparation of patients prior to an allogeneic transplant. The concept is to produce sufficient immunosuppression to receive a graft of donor stem cells and then induce the graft to fight the leukemia by the infusion of donor lymphocytes. The cancer is attacked both immunologically and by the chemotherapy drugs.
Several small clinical trials have demonstrated that successful eradication of leukemia cells can be achieved with ("mini-allografts"). This represents a potential new approach for safer treatment of a large variety of cancers currently treated with allogeneic stem cell transplantation, including acute myeloid leukemia. The technique of mini-allografts has now been expanded to include the use of unrelated HLA matched donors and has the potential to make this therapy more widely applicable.
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.
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