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 optimal results. Researchers have learned that the most effective 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. High-dose chemotherapy is one way to deliver very potent doses over a short period of time.
The treatment of AML is divided into two general phases: remission induction and consolidation/maintenance. Remission induction chemotherapy is administered to produce a complete remission in the bone marrow. Even when complete remission is achieved and no further therapy is given, over 90 percent of patients will still have a recurrence of disease in weeks or months. To prevent recurrence of leukemia, intensive therapy, called consolidation, is given immediately after recovery from remission induction therapy. Remission induction therapy and consolidation therapy are given as close together as possible. The more intensive the chemotherapy and the closer together the courses of therapy are given, 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 courses of chemotherapy or high-dose chemotherapy with autologous or allogeneic stem cell transplantation.
Stem Cell Transplant as Initial Consolidation for Acute Myeloid Leukemia
Patients with newly diagnosed AML who achieve a complete remission following induction therapy have historically been advised to receive consolidation 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 three to four courses of intensive chemotherapy delivered without stem cell support. Patients currently receive one of these consolidation treatment strategies based on attitudes toward outcomes associated with each treatment, the availability of an HLA-matched sibling stem cell donor, their physician’s bias concerning the appropriateness of each treatment option, the geographic availability of each treatment and, importantly, the age of the patient.
In 1995, a consortium of research centers published the results of a large clinical trial that compared these three treatment options to determine whether one was superior and to identify the risks associated with each treatment strategy.1 In this clinical trial, published in the New England Journal of Medicine, patients with AML who were under age 40 and had an HLA-matched sibling donor were treated with allogeneic stem cell transplantation. Patients under age 60 without an allogeneic donor were treated with either autologous stem cell 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 four years from initial treatment revealed that 55 percent of patients treated with allogeneic stem cell transplantation, 48 percent of those treated with autologous stem cell transplantation and 30 percent of patients treated with conventional-dose consolidation chemotherapy were alive without leukemia recurrence. However, there were no differences in the overall survival between the three treatment strategies because some patients who fail conventional consolidation can still be cured at the time of leukemia recurrence with either autologous or allogeneic transplant.
The side effects of all three treatment strategies were significant. Patients treated with allogeneic stem cell transplantation were more likely to die as a complication of therapy than patients treated with autologous stem cell transplantation or conventional-dose consolidation chemotherapy. The treatment-related mortality of allogeneic stem cell transplantation was 17.3 percent, compared to 9.4 percent for autologous stem cell transplantation and 7.1 percent for conventional-dose consolidation chemotherapy.
This clinical trial demonstrated that consolidation treatment of AML with allogeneic and autologous stem cell transplantation is a standard treatment option for young 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 3 treatment approaches have become safer.
At the present time the preferred consolidation treatment remains controversial.2 Current data supports the use of peripheral blood stem cells rather than bone marrow for transplantation.3 Many physicians recommend that peripheral blood stem cells should be collected after one or at the most two cycles of consolidation chemotherapy. An autologous stem cell transplant can then be substituted for the last one to two consolidation cycles of chemotherapy or held in reserve for use if the leukemia recurs. Patients should have a thorough discussion about the risks and benefits of the three types of consolidation therapy with their doctor in order to develop the best treatment plan for their situation.
Stem Cell Transplant for Induction Failures and Patients in Relapse
High-dose chemotherapy and autologous stem cell transplantation is rarely a treatment option for patients who fail remission induction therapy because the bone marrow contains many leukemia cells. Treatment for patients failing remission induction therapy is currently allogeneic stem cell transplant or additional chemotherapy or biologic therapy.
Patients with AML that relapses after an initial complete remission, however, can be cured with autologous stem cell transplant. Many centers have reported cure rates of 25 to 50 percent for patients with AML treated with autologous stem cell transplant during second remission or at the time of first relapse.4 These results are often obtained because patients elected to have their stem cells collected and stored at the time of their initial remission. Collecting stem cells at the time of relapse is much more difficult. Patients without previously stored stem cells, therefore, are often treated with allogeneic stem cell transplant, additional chemotherapy or biologic therapy.
Strategies to Improve High-Dose Chemotherapy and Autologous Stem Cell Transplant
The development of more effective cancer treatments requires that new and innovative therapies be evaluated with cancer patients. Clinical trials are studies that evaluate the effectiveness of new drugs or treatment strategies. Future progress in the treatment of AML will result from the continued evaluation of new treatments in clinical trials.
The main reason patients with AML fail treatment after autologous stem cell transplant is relapse of their leukemia. Relapse of leukemia occurs because the high-dose chemotherapy is either unable to kill all of the cancer cells in the patient and/or because leukemia cells “contaminating” the stem cells are infused back into the patient. The majority of relapses occur because all of the leukemia cells were not destroyed by the high-dose chemotherapy treatment. However, up to 10 to 15 percent of relapses may be due to infusion of leukemia-contaminated stem cells.
Doctors are performing clinical trials designed to improve the treatment of leukemia with high-dose chemotherapy. Participation in a clinical trial may offer patients access to better treatments and advance the existing knowledge about treatment of this cancer. Patients who are interested in participating in a clinical trial should discuss the risks and benefits of clinical trials with their physician. Areas of active investigation aimed at improving the treatment of AML include the following:
Treatment for minimal residual disease: Following cancer treatment, patients often achieve a complete remission (complete disappearance of the cancer). 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. Doctors refer to this as a state of “minimal residual disease”. Many doctors believe that applying additional cancer treatments when only a few cancer cells remain represents the best opportunity to prevent the cancer from returning. Immunotherapy to activate the body’s anti-cancer defense system or other agents, including monoclonal antibodies and chemotherapy drugs, can be administered over several weeks to months following high-dose chemotherapy and autologous stem cell transplantation in an attempt to eliminate any cancer cells remaining in the body or infused with the stem cells. Biologic modifiers that stimulate the immune system are being evaluated to prevent or delay relapses after autologous stem cell transplantation. Agents that are being widely tested in patients with AML include Proleukin® and Mylotarg®. One study showed that patients with AML in first relapse who received an autologous transplant following treatment with Mylotarg® had 40 percent survival.5 There were no long-term survivors in patients not treated with an autologous or allogeneic stem cell transplant. The efficacy of Proleukin® in preventing recurrences following autologous transplantation is controversial and clinical trials are still being performed. One novel approach has been to mobilize peripheral blood stem cells with Neupogen® and Proleukin® in attempts to both purge the stem cells of leukemia and to provide immune cells with the graft.6
Increased dose intensity: Since more treatment kills more cancer cells, increasing the intensity of treatment delivered to the leukemia cells is one strategy that may improve cure rates. This can be accomplished by utilizing high doses of anti-cancer therapies or by delivering multiple cycles of high-dose therapy. While increasing the intensity of treatment may kill more leukemia cells, this approach may also damage normal cells and increase the side effects of therapy.
Another approach is to deliver additional treatment directed specifically to the leukemia cells and reduce the toxicity to normal cells. Monoclonal antibodies are a treatment that can locate cancer cells and kill them directly or stimulate the immune system to kill them without harming normal cells. Dose intensity can be achieved by linking radioactive isotopes or toxins to monoclonal antibodies that target malignant cells or cells located only in the bone marrow. In this manner, cancer-killing agents are delivered primarily to cancer cells and/or the bone marrow and not in high doses to vital organs such as the liver and the lung. Monoclonal antibodies such as Mylotarg® are being evaluated as treatment to be administered during or after high-dose chemotherapy.
Cell processing: When stem cells are collected from a patient for infusion after high-dose chemotherapy, cancer cells may contaminate the stem cell collection. Although the majority of cancer relapses occurring after high-dose chemotherapy and autologous stem cell transplantation happen because the high-dose chemotherapy did not kill all of the cancer cells, it is possible that some patients may also experience a cancer recurrence from infusion of the cancer cells “contaminating” the stem cells that are being infused. 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.
Expansion of stem cells outside the body: For the past two decades, many doctors have been working on ways to get small quantities of stem cells to grow outside the body. If small quantities of “stem cells” could be increased in a culture system, as they are in the body, then many problems of collecting stem cells from bone marrow or blood could be avoided. This culture system has an added advantage of not supporting the growth of cancer cells. Thus, one could take small numbers of “stem cells”, place these cells in a culture system and grow sufficient numbers of “stem cells” suitable for transplantation that do not contain cancer cells. To learn more about techniques for removing cancer cells from the stem cell product, select Autologous Stem Sell Collection and Processing.
1 Zittoun RA, Mandelli F, Willemze, et al. Autologous or Allogeneic Bone Marrow Transplantation Compared with Intensive Chemotherapy in Acute Myelogenous Leukemia. European Organization for Research and Treatment of Cancer (EORTC) and the Gruppo Italiano Malattie Ematologiche Maligne dell’Adulto (GIMEMA) Leukemia Cooperative Groups. New England Journal of Medicine. 1995;332:217-223.
2 Nathan PC, Sung L, Crump M, et al. Consolidation Therapy with Autologous Bone Marrow Transplantation in Adults with Acute Myeloid Leukemia: A Meta-Analysis. Journal of the National Cancer Institute. 2004;96:38-45.
3 Sirohi B, Powles R, Kulkarni S, et al. Reassessing autotransplantation for Acute Myeloid Leukemia in First Remission – A Matched Pair Analysis of Autologous Marrow vs Peripheral Blood Stem Cells. Bone Marrow Transplantation. Bone Marrow Transplant. 2004;33(12):1209-14.
4 Linker CA, Autologous Stem Cell Transplantation for Acute Myeloid Leukemia. Bone Marrow Transplantation. 2003;31:731-738.
5 Sievers E, Larson R, Estey, et al. Final Report of Prolonged Disease-Free Survival in Patients with Acute Myeloid Leukemia in First Relapse with Gemtuzumab Ozogamicin Followed by Hematopoietic Stem Cell Transplantation. Proceedings from the 2002 Annual Meeting of the American Society of Hematology. Blood. 2002;100:abstract 327.
6 Schiller G, Wong S, Lowe T, et al. Transplantation of Il-2 Mobilized Autologous Peripheral Blood Progenitor Cells for Adults with Acute Myelogenous Leukemia in First Remission. Leukemia. 2001;15:757-763.
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