Allogenic Stem Cell Transplant for Acute Myeloid Leukemia
by Dr. C.D. Buckner updated 8/1/2017
Acute myeloid leukemia (AML) is a curable cancer 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 AML is to administer large doses of chemotherapy drugs in a short period of time. The concept is to kill leukemia 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.
The following is a general overview of allogeneic stem cell transplantation for the treatment of AML. 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 transplantation, select allogeneic stem cell transplant.
The treatment of AML is divided into two phases: remission induction and consolidation/maintenance. Remission induction chemotherapy is administered to produce a complete remission in the bone marrow. If a complete remission is achieved and no further therapy given, over 90% of patients will have a recurrence of disease in weeks to months. To prevent recurrence of leukemia, intensive therapy, called consolidation, is given as immediately after recovery from induction therapy as possible. The more intensive the treatments, the less chance the leukemia has of returning. It is very important to understand that lower doses of drugs do not work as well as higher doses of drugs. Consolidation therapy can be accomplished with multiple intensive courses of chemotherapy given close together or a single high-dose chemotherapy course with autologous or allogeneic marrow or blood stem cell transplantation.
Most transplant centers do not treat patients with AML over the age of 55-60 years, although in some centers, there has been recent interest in evaluating allogeneic transplantation following lower-dose chemotherapy in older individuals. Allogeneic or autologous stem cell transplantation should be considered as an integral component of the treatment plan for all patients 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 as Initial Consolidation:
Patients with newly diagnosed AML who achieve a complete remission following induction therapy have historically been advised to receive treatment with either high-dose chemotherapy supported by an allogeneic HLA-matched sibling stem cell transplant, high-dose chemotherapy and autologous stem cell transplant or multiple cycles of conventional-dose chemotherapy delivered without stem cell support. Patients currently receive one of these consolidation treatment strategies based on their perceptions of the outcomes associated with each treatment, the availability of an HLA-compatible sibling stem cell donor, their physician’s bias concerning the appropriateness of each treatment option and the geographic availability of each treatment.
For the past 20 years, allogeneic stem cell transplantation for consolidation therapy has been the most effective method of preventing relapses in younger patients with AML who have achieved a complete remission. Allogeneic transplantation is performed immediately after recovery from initial induction therapy and is an effective substitute for multiple cycles of intensive chemotherapy consolidation. In general, allogeneic stem cell transplants are associated with lower relapse rates, a higher rate of death from treatment and a better chance of being cured compared to autologous transplants or conventional chemotherapy.
In 1995, a consortium of research centers published the results of a large clinical trial that compared these three treatment options in order to determine whether one was superior and to identify risks associated with each treatment strategy. In this clinical trial published in the New England Journal of Medicine, patients with AML who were under age 40 and had an HLA-compatible sibling donor were treated with allogeneic marrow transplantation. Patients under age 60 without an allogeneic donor were treated with either autologous marrow transplantation or non-stem cell supported intensive chemotherapy consolidation. The patients treated with allogeneic or autologous stem cell transplantation were more likely to be cured of their disease than patients receiving conventional-dose consolidation chemotherapy. Evaluation at 4 years from initial treatment revealed that patients treated with allogeneic marrow transplantation had a 55% chance of being alive without evidence of disease recurrence and patients treated with autologous marrow transplantation had a 48% chance of being alive without evidence of disease recurrence, compared to 30% for patients treated with conventional-dose consolidation.
The side effects of all three treatment strategies were significant. Patients treated with allogeneic marrow transplantation were more likely to die as a complication of therapy than patients treated with autologous marrow transplantation or conventional-dose consolidation chemotherapy. The treatment-related mortality of allogeneic marrow transplantation was 17%, compared to 9% for autologous marrow transplantation and 7% for conventional-dose chemotherapy.
This clinical trial demonstrated that consolidation treatment of AML with allogeneic and autologous marrow transplantation are standard therapies for patients with newly diagnosed AML in complete remission because they produce superior cure rates compared to conventional consolidation chemotherapy. Since the publication of this trial, all three treatment approaches have become safer.
A similar study in children with AML demonstrated a superior outcome for children receiving allogeneic transplants from an HLA compatible family member donor, with approximately 70% being cured. In contrast to the results in adults, children receiving intensive chemotherapy have slightly better outcomes than those receiving an autologous transplant.
Allogeneic Stem Cell Transplant for Patients Failing Induction:
Allogeneic stem cell transplantation is the only treatment that can cure patients with AML who never achieve a remission with induction therapy. If a donor can be identified promptly and the allogeneic transplant performed at the first sign of induction failure, 20-30% of patients can be cured of their disease. Since 20-30% of patients do not achieve an initial remission and the majority of patients treated with conventional consolidation therapy relapse, it is probably wise that HLA typing be performed on all patients, children and adults, with AML and their family members at diagnosis.
Recent results using stem cells collected from alternative sources, such as unrelated donors and umbilical cord, suggest that at least 10-15% of patients with AML who have failed induction chemotherapy can be cured with an allogeneic transplant by this approach. Any patient who fails remission induction and does not have a suitable family member stem cell donor should have a search for an unrelated donor. Such a search should be performed at diagnosis in patients at high risk for treatment failure who do not have suitable family member donors. In order to learn more, go to stem cell donors.
Stem Cell Transplant for Relapse after a Complete Remission:
Patients with AML that relapses after an initial complete remission can be cured with an allogeneic stem cell transplant. If an allogeneic stem cell transplant is performed at the first sign of relapse or in second complete remission, approximately 20-40% of these patients can be cured, depending upon their age and donor source of stem cells.
Strategies to Improve Allogeneic Stem Cell Transplant:
The main reasons patients with leukemia fail treatment with an allogeneic 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 toxicities, infections and graft-versus-host disease. Allogeneic stem cell transplants are also limited by donor availability, since only a quarter 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: 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: Increased dose intensity directly to the leukemia cells can also be achieved by linking radioactive isotopes to monoclonal antibodies that target malignant myeloid leukemic cells or cells that are located only in the bone marrow and/or blood. 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. Forty-four patients with leukemia who had previously failed chemotherapy received high-dose chemo-radiation therapy followed by the infusion of autologous or allogeneic stem cells. In addition, they received on average twice as much radiation to the bone marrow from the isotope. Seven of 25 patients with myeloid leukemia survive 7-89 months after treatment. This technique is now being applied to patients earlier in their disease when the number of cancer cells is small and resistance to treatment has not developed.
“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 so that the patient’s immune system doesn’t attack the cancer 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 AML. 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.
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 allogeneic stem cell transplant. In some studies, these cells are combined with a biologic response modifier, such as interleukin-2, 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 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 has to begin 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.