Acute Myeloid Leukemia Consolidation
The treatment of acute myeloid leukemia (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 immediately after recovery from remission induction therapy. These treatments are given as closely 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.
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The following is a general overview of the treatment of the consolidation treatment options for acute myeloid leukemia. 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.
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Consolidation Therapy for Acute Myeloid Leukemia
Patients with newly diagnosed AML who achieve a complete remission following remission 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 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-matched sibling stem cell donor, their physician’s bias concerning the appropriateness of each treatment option, and the geographic availability of each treatment.
Despite the initial choice of consolidation therapy, it is important to determine the availability of a marrow or stem cell donor as soon as possible following the initial diagnosis of AML. This allows for an immediate transplant if remission induction is a failure and defines therapeutic options once a remission is achieved.
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 the 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-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 conventional-dose chemotherapy consolidation. The patients treated with allogeneic or autologous stem cell transplantation were more likely to be cured of their disease than the patients receiving conventional-dose consolidation chemotherapy. Evaluation at 4 years from initial treatment revealed that patients treated with allogeneic stem cell transplantation had a 55% chance of being alive without evidence of disease recurrence and patients treated with autologous stem cell transplantation had a 48% chance of being alive without evidence of disease recurrence, compared to only 30% for patients treated with conventional-dose consolidation chemotherapy.
The side effects of all three treatment strategies were significant. Patients treated with an allogeneic stem cell transplantation were more likely to die as a complication of therapy than patients treated with an autologous stem cell transplantation or conventional-dose consolidation chemotherapy. The treatment-related mortality of allogeneic stem cell transplantation was 17.3%, compared to 9.4% for autologous stem cell transplantation and 7.1% for conventional-dose consolidation chemotherapy.
This clinical trial demonstrated that consolidation treatment of AML with allogeneic and autologous stem cell 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 due to advances in the treatment and supportive care.
Patients who achieve a complete response receive consolidation therapy with one or more courses of chemotherapy. Frequently, only one consolidation course is given, which compromises the intensity of consolidation treatment, thereby resulting in lower cure rates. In general, patients with a translocation of chromosome 8 to chromosome 21 have a better outcome than other patients with AML. For the “good-risk” patients with potentially curable leukemia, i.e. those with the 8:21 translocation, a reduction in the amount of consolidation therapy can unnecessarily reduce the chance for cure.
Physicians affiliated with the Leukemia Group B have recently reported the results of several clinical trials in which patients received one or three cycles of high-dose cytarabine consolidation after achieving complete remission. Fifty patients under the age of 61 with AML and the 8:21 translocation were evaluated and compared based on whether they received one or three or more cycles of consolidation therapy.
Sixty-two percent of patients receiving one cycle of consolidation therapy experienced recurrent leukemia, compared to 19% of patients receiving three cycles or more. Of patients assigned to one cycle of consolidation therapy, only 41% survived, compared to 75% of patients receiving three or more cycles of consolidation therapy.
This clinical study clearly demonstrates that the intensity of consolidation treatment affects survival in younger patients with good-risk AML as defined by the 8:21 translocation. However, whether or not older patients benefit from more intensive treatment is less clear because side effects may outweigh the benefits of aggressive treatment.
The other unknown is whether or not patients would derive similar benefit from one cycle of high-dose chemotherapy supported by autologous peripheral blood stem cells. For patients who are unlikely to agree to or who would poorly tolerate multiple cycles of intensive consolidation chemotherapy, an autologous or allogeneic bone marrow or blood stem cell transplantation should be considered.
Risks and Benefits of an Allogeneic Stem Cell Transplant
If an allogeneic stem cell transplant is performed as consolidation, patients may proceed directly to the transplant following remission induction, as there does not appear to be an advantage to receiving chemotherapy in addition to that related to the transplant itself. In essence, the transplant is the consolidation treatment. Additional chemotherapy not related to the transplant procedure for consolidation before the allogeneic transplant may increase toxicity without preventing relapses.
Patients with a suitable stem cell donor who should consider an allogeneic transplant as consolidation immediately after remission induction include patients with normal cytogenetics or adverse cytogenetic abnormalities, patients who require more than one induction cycle to achieve a remission, and patients who refuse to undergo the 3-4 cycles of consolidation and maintenance required for adequate control of disease with conventional chemotherapy alone.
Some patients with a suitable stem cell donor may consider delaying allogeneic transplant until first relapse. Patients over the age of 50-60, depending on other risk factors and general condition, patients with acute promyelocytic leukemia, and patients with “good” cytogenetic abnormalities (t8-22 and inverted 16) who can tolerate all prescribed consolidation therapy may not need to expose themselves to the immediate risk of an allogeneic stem cell transplant.
For patients who choose to have a stem cell transplant only if they relapse, it is important that it be performed at the very first sign of relapse. This requires bone marrow examinations every 4-6 weeks for the first 2 years after diagnosis. This strategy offers the best chance to catch the leukemia early when treatment will be more effective.
Consolidation chemotherapy typically consists of 3 to 4 cycles of cytarabine given in high doses over 5 days in conjunction with additional chemotherapy drugs such as etoposide, daunomycin or idarubicin. Remission duration has been correlated with the dose of cytarabine and the number of cycles administered. In general, the more intensive the consolidation, the higher the cure rate.
The administration of consolidation chemotherapy interferes with the production of blood cells by the bone marrow, resulting in low white cell counts in the blood. There is usually a delay of one to two weeks after the administration of chemotherapy before the bone marrow resumes function, leaving patients with low blood counts for days or weeks. During this time, patients are often hospitalized and given antibiotics and observed for infections. Neupogen® and Leukine® are growth factors that hasten the recovery of white blood cells after the administration of chemotherapy.
For example, one clinical trial evaluated the effects of Neupogen® on the recovery of white blood cells in 194 patients with AML undergoing 2 courses of intensive consolidation therapy after achieving a complete remission. They found that the duration of time with extremely low blood cell counts was reduced from 19 to 12 days in patients receiving Neupogen®, which was associated with a reduction in hospitalization by 3 days after the first course and by 5 days after the second course. Patients receiving Neupogen® also received less intravenous antibiotics and less treatment for fungal infections. There were no differences, however, in infections, early deaths or survival.
Consolidation chemotherapy is typically associated with 14-21 days of myelosuppression similar to induction for each of 3-4 courses. For patients who are unwilling or unable to undergo the complex and intensive chemotherapy required for consolidation therapy, either an autologous or allogeneic transplant may be considered, since these treatments condense the therapy and produce results that are equivalent or superior to the best chemotherapy regimens.
The average age at the time of diagnosis for patients with AML is over 65 years. This is 10-15 years older than the average age of patients entered on clinical trials that have defined optimal current treatment for patients with AML. In general, only about one-third of patients older than age 60 tolerate the intensive chemotherapy required to achieve optimal results. However, it is probably not age itself, but the higher frequency of other organ dysfunction present in older individuals that leads to increased toxicity. In addition to the impaired capacity to recover from intensive treatments, older patients with AML frequently have a leukemia that arises from more primitive myeloid cells, which is more difficult to eradicate because there are no normal cells left to repopulate the bone marrow.
Patients over 60 with AML and no other major medical problem appear to benefit from intensive consolidation treatment. All studies have shown that the same dose response that is observed in younger individuals is also observed in older individuals. Both Neupogen® and Leukine® are white blood cell growth factors currently approved by the Food and Drug Administration to facilitate white blood cell production and may especially be of benefit to older patients with AML.
Strategies to Improve Post-Remission Therapy
While significant progress has been made in the treatment of leukemia, many patients still succumb to leukemia and the complications of treatment and better treatment strategies are still needed. Future progress in the treatment of leukemia will result from continued participation in appropriate clinical studies. Currently, there are several areas of active exploration aimed at improving the treatment of leukemia.
Supportive Care: Supportive care refers to treatments designed to prevent and control the side effects of cancer and its treatment. Side effects not only cause patients discomfort, but also may prevent the optimal delivery of therapy at its planned dose and schedule. In order to achieve optimal outcomes from treatment and improve quality of life, it is imperative that side effects resulting from cancer and its treatment are appropriately managed. For more information, go to managing side effects.
Stem Cell Transplant: High-dose chemotherapy and autologous or allogeneic stem cell transplantation is currently a superior consolidation treatment option for many patients. To learn about new developments with these therapies, go to strategies to improve Allogeneic Stem Cell Transplant or Autologous Stem Cell Transplant.
New Consolidation Chemotherapy Regimens: Development of new multi-drug chemotherapy treatment regimens that incorporate new or additional anti-cancer therapies for use as treatment is an active area of clinical research. New anti-cancer therapies that are being evaluated in combination with consolidation chemotherapy include the following:
Multiple Drug Resistance Inhibitors: Patients with AML fail to achieve a remission or relapse because of chemotherapy drug resistance that can be present at the time of diagnosis or are induced by treatment. Several drugs are being tested to determine if they will overcome or prevent the development of multiple drug resistance in AML as part of remission induction strategies.
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 tested alone or in combination with chemotherapy in clinical studies. Interleukin-2 is currently being evaluated as a maintenance agent after consolidation therapy. Newer biologic agents are in the developmental phase.
Treatment for Minimal Residual Disease: Following post-remission treatment, patients typically achieve a complete remission (complete disappearance of the cancer). Unfortunately, many patients in remission still experience a relapse of leukemia. This is because not all the leukemia cells were destroyed. Doctors refer to this as a state of “minimal residual disease.” Many doctors believe that applying additional treatments when only a few leukemia cells remain represents the best opportunity to prevent the leukemia from returning. Immunotherapy to activate the body’s anti-cancer defense system or other agents including monoclonal antibodies, biologic response modifiers and chemotherapy drugs can be administered over several weeks to months in an attempt to eliminate any leukemia cells remaining in the body.