AML is a malignant disease of the bone marrow in which precursors to healthy blood cells are arrested in an early stage of development. Frequently AML develops from Myelodysplastic Syndrome (MDS). Most AML subtypes are distinguished from ot her related blood disorders by the presence of more than 20% blast cells in the bone marrow. A blast cell is an immature white blood cells. The underlying development of AML consists of a maturational arrest of bone marrow cells in the earliest stages of development.
This developmental arrest results in two disease processes. First, the production of normal blood cells markedly decreases, which results in varying degrees of anemia, thrombocytopenia (low platelets), and neutropenia (low neutrophils). Second, the rapid proliferation of these cells, along with a reduction in their ability to undergo programmed cell death (apoptosis), results in their accumulation in the bone marrow, blood, and, frequently, the spleen and liver.
AML is the most common type of acute leukemia in adults. Over the past twenty years, the studies on the development and prognosis of AML have made revolutionary progress. However, despite a revolutionary increase in the diagnosis and understanding of the disease process, improvements in patient outcomes have not paralleled the increases in basic science understanding.
The American Cancer Society concluded in its Cancer Statistics, 2013 report, that death rates have continued to decline as of 2009 for all four major cancer sites: lung, colon and rectum (colorectal), breast, and prostate. But that these drops are primarily due to reductions in smoking for lung cancer and to improvements in early detection and treatment for colorectal, breast, and prostate cancers.1
But according to the National Cancer Institute (NCI) the mortality from AML has not decreased. To the contrary, for both men and women the death rate from AML has increased for the last three decades.2 This may be partially due to the fact that treatment for other cancers using chemotherapy and radiation causes MDS and AML to develop years later. And the MDS and AML that do develop, called therapy-related MDS (t-MDS) and therapy-related AML (t-AML) are much more agressive forms of cancer.
Two-thirds of all adult AML cases cannot be cured.3 Even with aggressive treatment, the average time to death after diagnosis with AML is one year, and about 10% of patients die from the initial round of AML therapy. Thus, new strategies to promote health in people with AML are desperately needed.
AML is caused by DNA damage to cells in the bone marrow. In most cases, it's not clear what causes the DNA mutations that lead to leukemia. However, previous cancer treatments and environmental pollution both cause AML, MDS and other cancers.
Cancer is caused by cumulative DNA damage. Earlier detection of cancers has led to earlier treatment with chemotherapy and radiotherapy, which causes further DNA damage. While people are surviving longer with many cancers due to more agressive treatments, the treatments themselves cause MDS and AML to develop years later. When MDS and AML are caused by treatment of a previous cancer they are called therapy-related MDS (t-MDS) and therapy-related AML (t-AML). It is estimated that up to 20% of AML cases are caused by previous cancer treatments.3 More than 70% of patients who develop therapy-related leukemia develop t-MDS first.4
And when t-MDS/t-AML develops, it is a more aggressive form of cancer and tends to be resistant to treatment.5 The median survival in one study of t-MDS/t-AML patients was 8 months and only 10% of patients were alive after five years.6
Of those people t-AML caused by previous cancer therapy, breast cancer is the most common previous cancer. In one study, 52% of new therapy-related AML diagnoses were in women who had been previously treated for breast cancer.7 AML typically developed four years after breast cancer treatment. Up to 14% of lymphoma and Hodgkins patients who undergo autolagous bone marrow transplant develop t-MDS/t-AML as early as three years after the procedure.8 This may be due to priming chemotherapy, total body irradiation, and the extensive cellular proliferation which occurs during the transplant.
The time between the initial cancer cancer treatment and development of t-MDS/t-AML varies from approximately two years to eleven years, depending on the type of treatment used.9 While patients can be diagnosed with t-MDS/t-AML at any age, the median age at diagnosis is 61 years.10, 11
Learn more about cancer treatments and the risk of causing t-MDS/t-AML.
AML Caused by Environmental Toxins
Toxins in our environment is a known cause of MDS and AML. Exposure to the chemical benzene causes AML. Benzene is used as a solvent, and is found in petroleum products and used in the rubber industry. It is also present in cigarettes, which may explain why smokers are three times more likely to develop AML than non-smokers. Learn more about benzene and cancer.
As with therapy-related leukemia, exposure to high levels of environmental radiation is also a risk factor. People who spend long periods of time in airplanes may also be more at risk because the high altitude provides less protection against the sun's radiation. Commercial airline pilots have an increased risk of AML due to their increased radiation exposure.12
Frequently there are no symptoms at first and leukemia may be a chance finding on a blood test. When symptoms do appear, they may be vague and non-specific, similar to a flu-like illness.
- Generalised weakness and fatigue
- Anemia, and the person may appear pale, weak and tired.
- Frequent infections, fevers, chills or flu-like symptoms
- Weight loss
- Excessive or easy bruising or bleeding
- Pain in the bones and joints
- Easily becoming out of breath
- Enlarged lymph nodes, liver and/or spleen tender to the touch
- Abdominal discomfort
- Night sweats
- In men, swollen testicles
- Headaches, seizures and vomiting can occur if the spinal column is affected
Different types of leukemia develop in different ways. Acute leukemias progress rapidly, whereas in chronic leukemia, the symptoms take longer to develop and the decline is far less swift.
There are three general categories of AML treatment phases: Induction, Consolidation, and Maintenance therapies. The treatment of patients with AML includes at least one course of intensive myelosuppressive induction chemotherapy.13,14
Cytarabine (AraC) is the cornerstone of induction therapy and consolidation therapy for AML.15 A standard form of induction therapy consists of AraC (100–200 mg/m2), administered by a continuous infusion for 7 days, combined with daunorubicin, administered intravenously for 3 days (the 3+7 induction regimen).16 This therapy has been reported to induce a complete remission (CR) in 65% to 75% of patients aged 18 to 60 years.17,18,19,20 This approach results in a long-term disease-free survival of ~30%, with a treatment-related mortality (ie, the percentage of patients who died during induction) of 5% to 10%.21,22,23,24
In an effort to improve outcomes of induction therapy, some trials have included alternative anthracyclines or anthracenodiones, incorporated high-dose AraC (HDAraC), or added other agents such as purine nucleoside analogues (PNA), etoposide, fludarabine, or cladribine.25 However, presently there is no conclusive evidence to recommend one 3+7 induction regimen over another. However, the results of these studies clearly support the claim that further intensification of the induction regimen is not associated with an increased complete remission (CR) rate.26
Despite substantial progress in the treatment of newly diagnosed AML, 20% to 40% of patients do not achieve remission with the standard induction chemotherapy, and 50% to 70% of first CR patients are expected to relapse within 3 years.27, 28 The optimum strategy at the time of relapse, or for patients with the resistant disease, remains uncertain. Allogeneic stem cell transplantation has been established as the most effective form of antileukemic therapy in patients with AML in first or subsequent remission. The augmentation of the cytogenetic risk stratification by molecular prognostic markers may help define additional subgroups of AML patients who will benefit from the intensified chemotherapy; however, this approach has yet to show any overall survival benefit.
Consolidation therapy comprises treatment with additional courses of intensive chemotherapy after the patient has achieved a CR, usually with higher doses of the same drugs as were used during the induction period. The median disease-free survival for patients who received only the induction therapy is 4 to 8 months.29 However, 35% to 50% of adults aged <60 years who receive consolidation treatment survive 2 to 3 years.30, 31 High-dose AraC (2–3 g/m2) is now a standard consolidation therapy for patients aged <60 years.
Maintenance therapy, which is considered to suppress bone marrow activty less than the induction and consolidation forms of treatment, is used in patients who have previously obtained clinical remission. It is a strategy to further reduce the number of residual leukemic cells and prevent a relapse. However, its role in the routine management of AML patients is controversial and depends mainly on the intensity of the induction and consolidation therapies.32
How Successful is the Conventional Approach?
Despite the substantial progress in the treatment of newly diagnosed AML, 20% to 40% of patients still do not achieve remission with standard induction chemotherapy, and 50% to 70% of first clinical remission patients are expected to relapse over 3 years.32, 33
The prognosis for patients with AML who do not respond to first-line treatment or in those who relapse is generally poor, and optimum strategy at the time of relapse or for patients with resistant disease remains uncertain.34 Use of stem cell transplantation may be curative for a minority of patients who achieve a second CR and who have an available donor.35, 36 There is no single regimen or approach that is considered the standard of care in relapsed and refractory AML.
New drugs are being evaluates in clinical studies, including immunotoxins, monoclonal antibodies, nucleoside analogue, hypomethylating agents, farnesyltransferase inhibitors, alkylating agents, FMS-like tyrosine kinase 3 inhibitors, and multidrug-resistant modulators. However, determining the success of these treatment strategies ultimately requires well-designed clinical trials, based on stratification of the patient risk, knowledge of the individual disease, and the drug's performance status.
About Myelodysplastic Syndrome
Benzene Causes Cancer
Chemotherapy and Radiation in Oncology
MK4 Research Summary Tables