Acute lymphoblastic leukemia (ALL) 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 ALL 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 treatment of ALL. 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 transplantation, select Allogeneic Stem Cell Transplant.
The treatment of ALL is divided into two phases: remission induction and post-remission or consolidation/maintenance therapy. 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 leukemia in weeks to months. To prevent recurrence of leukemia, intensive post-remission therapy is given as soon as possible after recovery from induction therapy. 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. Post-remission therapy can be accomplished with multiple intensive chemotherapy treatments given close together or a single high-dose chemotherapy treatment followed by autologous or allogeneic stem cell transplantation.
Most transplant centers do not treat patients with ALL over the age of 55-65 years, although there has been recent interest in some centers 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 is only possible if HLA testing is performed at diagnosis to determine the availability of a stem cell donor.
It is important to understand that HLA typing is not routinely performed at the time of diagnosis for children with ALL, with the exception of certain patients at high risk of treatment failure. This is because the majority of patients are cured with chemotherapy and HLA typing can be performed at the time of leukemia recurrence.
Allogeneic Stem Cell Transplant as Post-Remission Therapy
Currently, 70-80% of children with ALL are cured with conventional multi-drug combination chemotherapy. The current trends are to decrease the intensity of treatment for those easily cured and increase the intensity for those not being cured. Currently, the role of allogeneic stem cell transplantation as post-remission therapy for children with ALL is limited to a relatively small number of children who are less likely to be cured with conventional chemotherapy (high-risk groups) and for children who experience a recurrence after initial treatment.
Children who should be considered for an allogeneic transplant in first remission rather than intensive consolidation chemotherapy include those with Burkitt’s type leukemia and those found to have the Philadelphia chromosome present in their leukemic cells on cytogenetic analysis. In a recent clinical trial, 81% of young adults and children with Philadelphia Chromosome-positive ALL were alive and free of leukemia 3 years after allogeneic stem cell transplantation from an HLA-compatible sibling. Infants with abnormalities in chromosome 11or 23 in their leukemia cells who develop leukemia in the first year of life should also be considered. Recent and ongoing studies may identify other patients with risk factors that predict for failure of conventional post-remission chemotherapy consolidation and maintenance, making allogeneic stem cell transplantation a reasonable option.
For the past 20 years, allogeneic stem cell transplantation has been the most effective method of preventing relapses in younger patients with adult ALL who have achieved a complete remission following induction therapy. Allogeneic stem cell transplantation is performed immediately after recovery from initial induction therapy and is an effective substitute for multiple cycles of intensive post-remission chemotherapy consolidation and maintenance. 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 stem cell transplants or conventional chemotherapy.
Until recently, few direct comparisons of allogeneic stem cell transplantation to conventional post-remission chemotherapy or autologous stem cell transplantation have been performed. Several clinical studies have suggested that approximately 50% of adults treated with allogeneic stem cell transplantation in first remission could be cured. This was confirmed by investigators in France who performed a large clinical study that directly compared allogeneic stem cell transplantation to conventional post-remission chemotherapy in adult patients 15-40 years of age with ALL in first complete remission. Almost 50% of patients treated with allogeneic stem cell transplantation were alive without cancer recurrence 5 years from treatment, compared to only 32% of patients treated with conventional post-remission chemotherapy and 39% of patients treated with autologous stem cell transplantation.
In another clinical study, researchers from England and Israel treated over 1,200 patients with conventional chemotherapy, allogeneic transplantation, or autologous transplantation. The researchers directly compared the results of 170 patients treated with allogeneic transplantation with the results of patients treated with conventional chemotherapy or autologous transplantation. The five-year disease-free survival rate for patients treated with allogeneic transplant was 54%, compared with only 34% for patients treated with conventional chemotherapy or autologous transplantation. The relapse rate following allogeneic transplantation was 23%, compared to 61% for patients treated with conventional chemotherapy or autologous transplantation.
For adults with ALL, it is important to identify at the time of diagnosis those patients who are likely to fail conventional chemotherapy in order to plan for an allogeneic stem cell transplant. The following risk factors have been associated with a higher chance of relapse for patients who achieve an initial complete remission: longer than 4 weeks to achieve a complete remission, age over 35 years, white blood cell count over 30,000 and non B or T cell leukemias (null cell phenotype). In one large clinical study, 62% patients treated with standard chemotherapy who had no adverse risk factors appeared cured 5 years from treatment, compared to 33%, 22% and 11% for patients with one, two or three risk factors, respectively. Only 1 in 4 patients over age 15 are in the good risk group. Other clinical studies have identified the presence of the Philadelphia chromosome as a poor prognostic feature and T-cell leukemia with mediastinal adenopathy as a good prognostic feature. In one study reported by the French doctors, 39% of patients with 1 or more adverse risk feature were cured with allogeneic stem cell transplantation, compared to only 14% with standard chemotherapy.
Patients over the age of 50 (depending on risk factors and general condition) and patients with a low white blood cell count who achieve a complete remission with one course of chemotherapy are advised to have an allogeneic transplant only if they relapse. To detect early relapse requires bone marrow examinations at frequent intervals (every 4-6 weeks) for the first 2 years after diagnosis.
Allogeneic Stem Cell Transplantation for Patients Failing Induction
Allogeneic stem cell transplantation is the best available therapy for children with ALL who fail induction therapy (do not achieve a remission following treatment). If a donor can be identified promptly, and the allogeneic transplant performed as soon as treatment failure is recognized, up to 50% of children can probably be cured of their disease. Patients at high-risk for not achieving a remission or for relapsing after remission induction should have HLA typing performed at diagnosis. Patients not responding well to induction therapy should have HLA typing performed as soon as possible.
More recently, there has been considerable success in using unrelated individuals as bone marrow or blood stem cell donors. Unrelated stem cells are obtained by a computerized search of umbilical cord blood banks and unrelated bone marrow donors facilitated by the National Marrow Donor Program (NMDP), which is sponsored by the National Institutes of Health. This search is initiated by the transplant center that will provide treatment. Recent results of unrelated donor and umbilical cord blood suggests that 20% or more of patients with childhood ALL can be cured by this approach. Any child with ALL who fails remission induction and does not have a suitable family member donor should have a search for an unrelated donor or compatible umbilical cord blood.
Allogeneic stem cell transplantation is also the best available therapy for adults with ALL who fail induction therapy. If a donor can be identified promptly, and the allogeneic transplant performed as soon as the leukemia recurs, 20-40% of patients can probably be cured of their disease. Patients at high-risk for not achieving a remission or for relapsing after remission induction should have HLA typing performed at diagnosis. Patients not responding well to induction therapy should have HLA typing performed as soon as possible.
Recent results of unrelated donor and umbilical cord blood suggests that 10-20% or more of young patients with ALL can be cured by this approach. Any patient who fails remission induction and does not have a suitable family member donor should have a search for an unrelated donor.
Allogeneic Stem Cell Transplantation for Relapsed Acute Lymphoblastic Leukemia
Allogeneic stem cell transplantation is the best available therapy for patients who relapse after a complete remission. Approximately half of children and 20-30% of adults transplanted in second complete remission appear cured. Recent results using stem cells from unrelated donors and umbilical cord blood suggests that 20% or more of patients with ALL who relapse after a complete remission can be cured by this approach.
Investigators from Memorial Sloan Kettering Cancer Center reported the results of a clinical study that compared allogeneic stem cell transplantation to conventional chemotherapy treatment in children with ALL in second complete remission. All patients participating in this clinical study were under 18 years of age and had an HLA-matched sibling stem cell donor. At 5 years from initiation of treatment, 62% of patients treated with allogeneic stem cell transplantation were alive without cancer recurrence, compared to only 26% of patients treated with conventional chemotherapy. The reason for the higher cure rate was mostly due to the ability of allogeneic stem cell transplantation to prevent cancer recurrence. Sixty-seven percent of patients treated with conventional chemotherapy experienced recurrence of leukemia, compared to only 19% of patients treated with allogeneic stem cell transplantation. Most importantly, all patients, regardless of risk factors, had superior outcomes when treated with allogeneic stem cell transplantation. Patients who had failed initial treatment with chemotherapy regimens using more than 5 drugs or anthracyclines, patients with elevated white blood counts, and patients that took a prolonged time to achieve an initial clinical remission all were more likely to be cured with allogeneic stem cell transplantation than conventional chemotherapy.
Strategies to Improve Allogeneic Stem Cell Transplantation
The main reasons patients with ALL fail treatment with an allogeneic stem cell transplant is relapse and fatal side effects of treatment. Relapse of leukemia occurs because the high-dose treatment is unable to kill all of the cancer cells. Treatment-related deaths are due to side effects of treatment, including infections and graft-versus-host disease. Allogeneic stem cell transplants are also limited by donor availability since less than a quarter of patients will have an HLA-compatible family member donor. Doctors are performing clinical studies designed to improve the treatment of patients with ALL 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.
Increase 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. This strategy can be used in children since they tolerate increased doses of chemotherapy and radiation therapy.
Increased Doses of Chemotherapy or Radiation: The strategy of increasing the dose of chemotherapy and total body irradiation is applicable only to children, as toxicities of this approach are too high in adults.
Over a number of years, researchers at the City of Hope National Medical Center treated 23 patients with Philadelphia chromosome-positive ALL with high-dose etoposide chemotherapy and total-body radiation therapy. These patients then received allogeneic stem cell transplantation, using stem cells that were donated by a sibling. The results showed that 30% of these patients died of treatment-related complications. However, treatment outcomes appeared to be improved in patients who were treated after 1992 due to improvements in treatment and supportive care. Overall, 65% of patients were alive and free of disease after 3 years. Of those patients treated after 1992, 81% were alive and free of disease three years following treatment.
These findings suggest that recent improvements in supportive care, such as more effective prevention and treatment of infections, have resulted in better outcomes for patients with ALL undergoing stem cell transplantation. For patients with Philadelphia chromosome-positive ALL, high-dose chemotherapy with an allogeneic stem cell transplantation appears to be more effective than standard-dose chemotherapy.
Researchers at the International Bone Marrow Transplant Registry sought to determine whether the use of chemotherapy alone before an allogeneic SCT is as effective as the use of both chemotherapy and radiation therapy. They compared the outcomes of 627 children with ALL who underwent an allogeneic SCT after being treated with either A) a chemotherapy drug called cyclophosphamide plus total-body radiation therapy or B) a combination of chemotherapy consisting of cyclophosphamide and busulfan, without radiation therapy. These children had various stages of cancer, but most were in their second remission. The results showed that 3-year survival rates were 55% for those who received chemotherapy combined with radiation therapy, compared with 40% for those who received the combination chemotherapy. The risk of relapse (recurrence, or return of the cancer) was similar in the two groups; however, more children who were treated with the busulfan chemotherapy died from complications related to the SCT. Long-term complications were not reported. The researchers concluded that children with ALL who received chemotherapy plus total-body radiation therapy had an increased survival time over those who received the combination chemotherapy without radiation therapy.
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.
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.
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