Acute Myeloid Leukemia: Overview and Treatment
Medically reviewed by Dr. C.H. Weaver M.D. Medical Editor (08/2018)
Acute myeloid leukemia (AML) is a cancer of the bone marrow and blood characterized by the rapid uncontrolled growth of immature white blood cells known as myelocytes. The disease is more common in adults than in children, with the average age at diagnosis being more than 65 years. However, diagnostic procedures and treatment of children and adults are similar.
In order to understand the best treatment options available for AML, patients should know the classification or histologic subtype of the cancer and the results of analyses of chromosomes determined by cytogenetic examination. These are tests performed on a sample of the patient’s bone marrow. AML is frequently associated with abnormal chromosomes of the leukemia cells. Knowing the specific chromosomal abnormalities associated with leukemia is important for determining specific treatments and outcomes.
Cytogenetics in Adult AML
The following table reports the outcomes of treatment according to whether favorable or unfavorable cytogenetics were present in patients with AML treated with standard intensive chemotherapy. The table illustrates the importance of cytogenetic analyses in adults.
Cytogenetics in Childhood AML
Changes in chromosomes in leukemia cells can be identified in 80% of children with AML. These distinct chromosomal changes detected on cytogenetic examination are often associated with different outcomes of treatment. With current treatment, 30-50% of children with AML are cured. It is important to identify those children who can be cured with standard treatments and those who should receive more individualized treatment. The distinct type of chromosomal abnormality present at diagnosis has been shown to help identify patients with a “good” or “bad” outcome.
In one Pediatric Oncology Group study, outcomes of 478 children with AML were reported. They found that children with an inverted 16th chromosome had a survival rate without relapse of 58%, those with a translocation of chromosomes 8 and 21 had a survival rate without relapse of 45% and patients with no chromosomal abnormalities had a survival rate without relapse of 45%. Children with translocation of chromosomes 15 and 17 had a survival rate without relapse of 20% and children with 11q23 abnormalities had a survival rate of 24%.
This study shows that children with AML who have “bad” chromosomal changes should not be treated with standard chemotherapy, but instead should be entered into clinical trials evaluating new therapies or be treated with a stem cell transplant.
Molecular Monitoring of Minimal Residual Disease
Patients with leukemia containing cytogenetic abnormalities can often be tested after treatment for the detection of small numbers of leukemia cells that cannot be detected under the microscope. The technique used is called polymerase chain reaction (PCR). PCR can detect very small numbers of leukemia cells, thereby indicating the need for more treatment, as small numbers of leukemia cells inevitably lead to a relapse. PCR is useful for the monitoring of treatment results of both children and adults with AML.
The treatment of AML occurs in 2 phases. All histologic subtypes are currently treated the same way except for acute promyelocytic leukemia (M3 subtype).
The initial treatment phase of AML is called remission induction and the goal of remission induction therapy is to achieve a complete remission or disappearance of all detectable leukemia cells. After a complete remission is achieved, the second phase of treatment, post-remission therapy, begins. Post-remission therapy is necessary because, although there may be no detectable cancer cells after remission induction, undetectable leukemia cells still exist and the leukemia will return without additional post-remission therapy. Post-remission therapy is often referred to as consolidation.
Acute Myeloid Leukemia Induction
The treatment of acute myeloid leukemia (AML) has improved dramatically over the past 30 years. Because of the development of more dose intensive chemotherapy and improvements in supportive care, many patients with AML are now cured. 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.
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.
Researchers have learned that the best way to cure patients with AML is to administer large doses of chemotherapeutic agents in a short period of time. The concept is to kill leukemia cells within 6 months before resistance to the drugs occurs. Therapy is divided into two phases:
- Remission induction: Induction chemotherapy is administered to produce a complete remission in the bone marrow, which is defined as less than 5% “blasts” in the bone marrow sample and a return to normal blood counts.
- Post-remission consolidation/maintenance: Once a remission is achieved it must be "consolidated" with additional intensive therapy or the leukemia is likely to recur.
Remission Induction Therapy
During remission induction therapy, patients are given large doses of chemotherapy over a period of 5-7 days. These chemotherapy drugs kill leukemia cells and normal bone marrow cells. The major side effects of these drugs are related to toxicities of rapidly growing cells in the body, i.e., normal bone marrow, skin and the gastrointestinal tract. Each drug also has specific side effects for other organs.
Standard remission induction therapy currently consists of 3 days of an anthracycline and 7 days of cytarabine. Following induction, patients typically require 2-3 weeks for bone marrow blood cell production to recover. During this time, patients often require blood and platelet transfusions to maintain red blood cell and platelet levels. In order to reduce the risk of infection, antibiotics and blood cell growth factors that stimulate the bone marrow to produce normal white blood cells are often given during this period of time. Neupogen® and Leukine® are white blood cell growth factors currently approved by the Food and Drug Administration to facilitate white blood cell production. After 2-3 weeks, blood counts will begin to recover and often return to normal. A bone marrow examination is repeated to see if a remission has been achieved.
For patients in remission, the consolidation therapy will begin. If patients have not achieved a remission, another induction course of treatment will be given immediately. However, for patients with an HLA-compatible marrow donor, consideration should be given to having an immediate allogeneic stem cell transplant without receiving a second course of induction therapy. This will depend on chances of achieving a remission with a second cycle of chemotherapy. However, even if a remission is achieved with a second cycle of chemotherapy, remission duration is often very short despite consolidation.
For patients with acute promyelocytic leukemia (M3), all-trans-retinoic acid, Vesanoid®, may be included in the remission induction regimen. Patients with acute promyelocytic leukemia typically receive Vesanoid® at some time during their treatment course. There are ongoing clinical trials to determine the optimal time to administer this drug.
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, consolidation therapy is initiated immediately after recovery from induction therapy. These treatments 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 for patients to understand that lower doses of drugs do not work as well as higher doses of drugs.
Acute Myeloid Leukemia Consolidation
If a complete remission is achieved following remission induction therapy 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. In general 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.
Consolidation can be achieved 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.
The results of a clinical trial evaluating consolidation has been 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 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 Remission Induction
New Drug Development: All new drugs for the treatment of patients with AML are tested first in patients with relapsed or refractory disease. When they are found to be effective, they are then evaluated in remission induction regimens.
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.
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:
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.