Acute myeloid leukemia
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Acute myelogenous leukemia (AML), also known as acute myeloid leukemia, is a cancer of the myeloid line of blood cells. The median age of patients with AML is 70; it is rare among children.
Myeloid leukemias are characterized as "acute" or "chronic" based on how quickly they progress if not treated. Chronic myelogenous leukemia (CML) is often without symptoms and can remain dormant for years before transforming into a blast crisis, which is markedly similar to AML.
Pathophysiology
Specific chromosomal abnormalities are seen in patients with some forms of AML. These chromosomal abnormalities tend to disrupt genes that encode for transcription factors needed for myeloid stem cells to differentiate into specific blood components. Without differentiation occurring, these myeloid precursor cells fill the bone marrow and spill out into the blood. The overpopulation of the bone marrow with myeloid precursors also results in suppression of normal marrow stem cells, giving rise to the symptoms of anemia (lack of red blood cells), thrombocytopenia (lack of platelets), and neutropenia (lack of neutrophils).Subtypes
World Health Organization (WHO) classification
The World Health Organization (WHO) classification of acute myeloid leukemia (AML) attempts to be more applicable and produce more meaningful prognostic information then the older French-American-British (FAB) criteria, described below.The WHO criteria are:
- AML with characteristic genetic abnormalities, which includes AML with translocations between chromosome 8 and 21 [t(8;21)], inversions in chromosome 16 [inv(16)] and translocations between chromosome 15 and 17 [t(15;17)] (which causes acute promyelocytic leukemia (APL)). Patients with AML in this category generally have a high rate of remission and a better prognosis compared to other types of AML.
- AML with multilineage dysplasia. This category includes patients who have had prior myelodysplastic syndrome (MDS) or a myeloproliferative diseases (MPD) that transforms into AML. This category of AML occurs primarily in elderly patients
- AML and MDS, therapy related. This category includes patients who have had prior chemotherapy and/or radiation and subsequently develop AML or MDS.
- AML not otherwise categorized. Includes subtypes of AML that do not fall into the above categories.
- Acute leukemias of ambiguous lineage. Acute leukemias of ambiguous lineage (also known as mixed phenotype acute leukemia) occur when the leukemic cells can not be classified as either myeloid or lymphoid cells or where both types of cells are present.
French-American-British (FAB) classification
The older French-American-British (FAB) classification system divided AML into 8 subtypes, M0 through to M7 based on the type of cell from which the leukemia developed and degree of maturity. This is done by examining the appearance of the malignant cells under light microscopy or cytogenetically by characterization of the underlying chromosomal abnormality. Each subtype is characterised by a particular pattern of chromosomal translocations and have varying prognoses and responses to therapy. Although the WHO classification is more useful, the FAB system is still in use.The eight different subtypes are:
- M0 (undifferentiated AML)
- M1 (myeloblastic, immature)
- M2 (myeloblastic, mature)
- M3 (promyelocytic), or acute promyelocytic leukemia (APL)
- M4 (myelomonocytic)
- M4eo (myelomonocytic together with bone marrow's eosinophil)
- M5 monoblastic(M5a) or monocytic(M5b)
- M6 (erythrocytic) (Erythroleukemia)
- M7 (megakaryoblastic)
Symptoms
Most signs and symptoms of AML are due to the increased numbers of malignant white blood cells and the displacement of normal blood cells from the marrow. A lack of normal blood cell production in the bone marrow makes the patient susceptible to infections due to the lack of normal immune cells, chiefly the so-called neutrophils. The early signs of AML may be similar to those of influenza or other common illnesses, and often have many different signs and symptoms. Some generalized symptoms include:- Fever
- Fatigue
- Weight loss or loss of appetite
- Shortness of breath (dyspnea)
- Anemia
- Easy bruising or bleeding
- Petechiae - flat, pin-head sized spots under the skin caused by bleeding
- Bone pain and joint pain
- Persistent infections
Occasionally, a person may show no symptoms and the leukemia is discovered during a routine blood test. Usually, the symptoms of AML appear within a few weeks and experience sudden onset of illness.
Diagnosis
Patients with AML usually present with symptoms such as fatigue, bleeding, infection, prompting medical attention. An abnormal blood test reading will then result in further testing in a hospital with a hematologist to determine AML. Most patients with AML will experience a high count of malignant white blood cells, and low counts of red blood cells and platelets.A bone marrow aspiration or biopsy is then conducted to identify the type of abnormal blood cells and determine the best treatment plan for the patient. The marrow is taken from the back of the hipbone. Marrow sample aliquots are sent to different test as part of a multidisciplinary process required to establish an accurate diagnosis. Smears are prepared and stained e.g. with Giemsa dye and will give a fair idea of the subtype of leukemia. Labeling live cells with monoclonal antibodies and subsequent analysis in a flow cytometer allows for speedy and accurate diagnosis of AML and for beginning of chemotherapy. Test for molecular changes in turn allow the doctors to establish a prognostic profile of the given patient.
The presence of Auer rods can distinguish AML from other lymphomas.
Because acute promyelocytic leukemia has the highest curability and has a unique form of treatment, it is important to establish or exclude the diagnosis of this subtype of leukemia. This is done by a microscopic (so-called FISH) test, which allows the doctors to demonstrate that the AML is caused by an exchange in chromosomal material between chromosomes 15 and 17 (a so-called balanced translocation, or t(15;17)).
Causes
There is ongoing research into the causes of acute myelogenous leukaemia; however, it is not known for sure what causes it.It is thought that in very rare cases, excessive exposure to harmful chemicals such as benzene and radiation such as atomic bomb explosions may trigger abnormal DNA mutations, resulting in leukemia. Patients who have received previous treatment with certain drugs (alkylating agents) are also at higher risk of developing AML.
Because of inherited genetic defects, some individuals are born with an abnormal immune system, which causes them to be at higher risk of developing leukemia.
Treatment
Chemotherapeutic treatment is divided into two phases: induction and postremission therapy. In all FAB subtypes except M3, the usual initial treatment includes cytarabine (ara-C) and an anthracycline (such as daunorubicin or idarubicin). Because of the toxic effects of therapy (from myelosuppression and increased risk of infection), induction chemotherapy is generally not offered to the very elderly.Complete remission is obtained in about 50%-75% of newly diagnosed adults. The bone marrow is examined for malignant cells following induction chemotherapy. Complete remission does not mean that the disease has been cured; rather, it signifies that no disease can be detected (i.e., <5% leukemic blasts in the bone marrow).
Once complete remission is achieved, more therapy is necessary to eliminate nondetectable disease to prevent relapse of disease and achieve a cure. Postremission therapy can include more intensive chemotherapy, known as consolidation chemotherapy, or bone marrow transplant. However, despite aggressive therapy, only 20%-30% of patients enjoy long-term disease-free survival. For patients with relapsed AML, the only proven potentially curative therapy is a stem cell transplant. In 2000, Mylotarg (gemtuzumab zogamicin) was approved in the United States for patients aged more than 60 years with relapsed AML who are not good candidates for high-dose chemotherapy.
The M3 subtype, also known as acute promyelocytic leukemia, is almost universally treated by the drug ATRA (all-trans-retinoic acid). For relapsed APL, arsenic trioxide has been tested in trials and approved by the Food and Drug Administration. Like ATRA, arsenic trioxide does not work with other subtypes of AML.
For many AML cases with so-called balanced translocations, doctors can now accurately monitor the effect of chemotherapy with molecular assays (PCR [polymerase chain reaction] tests). Often, these quantitative PCR assays have the sensitivity to detect one leukemic cell in 100,000 normal ones. Such data allow the doctors to better evaluate the effect of therapy and to foresee relapses of the disease long before they can be diagnosed by other methods or even felt by the patients.
External links
For more information, see:- [National Cancer Institute (NCI) PDQ statement on AML for health professionals]
- [Association of Cancer Online Resource (ACOR) Leukemia Links]
- [Blood & Marrow Transplant Information Network]
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