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Acute myeloid leukemia

Acute myeloid leukemia (AML), also known as acute myelogenous leukemia, is a cancer of the myeloid line of white blood cells, characterized by the rapid proliferation of abnormal cells which accumulate in the bone marrow and interfere with the production of normal blood cells. AML is the most common acute leukemia affecting adults, and its incidence increases with age. Although AML is a relatively rare disease, accounting for approximately 1.2% of cancer deaths in the United States, its incidence is expected to increase as the population ages.

The symptoms of AML are caused by replacement of normal bone marrow with leukemic cells, resulting in a drop in red blood cells, platelets, and normal white blood cells. These symptoms include fatigue, shortness of breath, easy bruising and bleeding, and increased risk of infection. Although several risk factors for AML have been identified, the specific cause of AML remains unclear. As an acute leukemia, AML progresses rapidly and is typically fatal within weeks or months if left untreated.

Acute myeloid leukemia is a potentially curable disease; but only a minority of patients are cured with current therapy. AML is treated initially with chemotherapy aimed at inducing a remission; some patients may go on to receive a hematopoietic stem cell transplant.

Areas of active research in acute myeloid leukemia include further elucidation of the cause of AML, identification of better prognostic indicators, development of new methods of detecting residual disease after treatment, and the development of new drugs and targeted therapies.

Signs and symptoms

Most signs and symptoms of AML are due to an increased number of malignant white blood cells displacing or otherwise interfering with production of normal blood cells in the bone marrow. A lack of normal white blood cell production makes the patient susceptible to infections (while the leukemic cells themselves are derived from white blood cell precursors, they have no infection-fighting capacity). A lack of red blood cells (anemia) can cause fatigue, paleness, and shortness of breath. A lack of platelets can lead to easy bruising or bleeding with minor trauma.

The early signs of AML are often non-specific, and may be similar to those of influenza or other common illnesses. Some generalized symptoms include fever, fatigue, weight loss or loss of appetite, shortness of breath with exertion, anemia, easy bruising or bleeding, petechiae (flat, pin-head sized spots under the skin caused by bleeding), bone pain and joint pain and persistent or frequent infections.

Enlargement of the spleen may occur in AML, but it is typically mild and asymptomatic. Lymph node swelling is rare in AML, in contrast to acute lymphoblastic leukemia. The skin is involved about 10% of the time in the form of leukemia cutis. Rarely, Sweet's syndrome, a paraneoplastic inflammation of the skin, can occur with AML.

Some patients with AML may experience swelling of the gums because of infiltration of leukemic cells into the gum tissue. Rarely, the first sign of leukemia may be the development of a solid leukemic mass or tumor outside of the bone marrow, called a chloroma. Occasionally, a person may show no symptoms, and the leukemia may be discovered incidentally during a routine blood test.

Causes

A number of risk factors for developing AML have been identified, including:

"Pre-leukemic" blood disorders such as myelodysplastic or myeloproliferative syndromes can evolve into AML; the exact risk depends on the type of MDS/MPS.
Exposure to anti-cancer chemotherapy, in particular alkylating agents, can increase the risk for the subsequent development of AML. The risk is highest about 3–5 years after chemotherapy. Other chemotherapy agents, specifically epipodophyllotoxins and anthracyclines, have also been associated with treatment-related leukemia. These treatment-related leukemias are often associated with specific chromosomal abnormalities in the leukemic cells.
Ionizing radiation exposure can increase the risk of AML. Survivors of the atomic bombings of Hiroshima and Nagasaki had an increased rate of AML, as did radiologists exposed to high levels of X-rays prior to the adoption of modern radiation safety practices.
Occupational chemical exposure to benzene and other aromatic organic solvents is controversial as a cause of AML. Benzene and many of its derivatives are known to be carcinogenic in vitro. While some studies have suggested a link between occupational exposure to benzene and increased risk of AML, others have suggested that the attributable risk, if any, is slight.
Several congenital conditions may increase the risk of leukemia; the most common is probably Down syndrome, which is associated with a 10- to 18-fold increase in the risk of AML.

Diagnosis

The first clue to a diagnosis of AML is typically an abnormal result on a complete blood count. While an excess of abnormal white blood cells (leukocytosis) is a common finding, and leukemic blasts are sometimes seen, AML can also present with isolated decreases in platelets, red blood cells, or even with a low white blood cell count (leukopenia). While a presumptive diagnosis of AML can be made via examination of the peripheral blood smear when there are circulating leukemic blasts, a definitive diagnosis usually requires an adequate bone marrow aspiration and biopsy

A bone marrow examination is often performed to identify the type of abnormal blood cells; however, if there are many leukemic cells circulating in the peripheral blood, a bone marrow biopsy may not be necessary. Marrow or blood is examined via light microscopy as well as flow cytometry to diagnose the presence of leukemia, to differentiate AML from other types of leukemia (e.g. acute lymphoblastic leukemia), and to classify the subtype of disease (see below). A sample of marrow or blood is typically also tested for chromosomal translocations by routine cytogenetics or fluorescent in situ hybridization. Cytochemical stains on blood and bone marrow smears are helpful in the distinction of AML from ALL and in subclassification of AML. The combination of a myeloperoxidase or Sudan black stain and a non specific esterase stain will provide the desired information in most cases. The myeloperoxidase or Sudan black reactions are most useful in establishing the identity of AML and distinguishing from ALL. The non-specific esterase stain is used to identify a monocytic component in AMLs and to distinguish a poorly differentiated monoblastic leukemia from ALL.

The diagnosis and classification of AML can be challenging, and should be performed by a qualified hematopathologist or hematologist. In straightforward cases, the presence of certain morphologic features (such as Auer rods) or specific flow cytometry results can distinguish AML from other leukemias; however, in the absence of such features, diagnosis may be more difficult.

According to the widely used WHO criteria, the diagnosis of AML is established by demonstrating involvement of more than 20% of the blood and/or bone marrow by leukemic myeloblasts. AML must be carefully differentiated from "pre-leukemic" conditions such as myelodysplastic or myeloproliferative syndromes, which are treated differently.

Because acute promyelocytic leukemia (APL) has the highest curability and requires a unique form of treatment, it is important to quickly establish or exclude the diagnosis of this subtype of leukemia. Fluorescent in situ hybridization performed on blood or bone marrow is often used for this purpose, as it readily identifies the chromosomal translocation (t[15;17]) that characterizes APL.

Classification

The two most commonly used classification schemata for AML, are the older French-American-British (FAB) system and the newer World Health Organization (WHO) system.

French-American-British classification

The 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 its degree of maturity. This is done by examining the appearance of the malignant cells under light microscopy and/or by using cytogenetics to characterize any underlying chromosomal abnormalities. The subtypes have varying prognoses and responses to therapy. Although the WHO classification (see below) may be more useful, the FAB system is still widely used as of mid-2006.

The eight FAB subtypes are:

M0 minimally differentiated acute myeloblastic leukemia
M1 (acute myeloblastic leukemia, without maturation)
M2 (acute myeloblastic leukemia, with granulocytic maturation)
M3 (promyelocytic), or acute promyelocytic leukemia (APL)
M4 (acute myelomonocytic leukemia)
M4eo (myelomonocytic together with bone marrow eosinophilia)
M5 acute monoblastic leukemia (M5a) or acute monocytic leukemia (M5b)
M6 (acute erythroid leukemias), including erythroleukemia (M6a) and very rare pure erythroblastic leukemia (M6b)
M7 (acute megakaryoblastic leukemia)

Uncommon phenotypes of acute myeloid leukemia

The morphologic subtypes of AML include many exceedingly rare types not included in the FAB system. All of them except acute myeloid dendritic cell leukemia are included in the WHO classification (see below). The following list shows these subtypes.

World Health Organization classification

The World Health Organization (WHO) classification of acute myeloid leukemia attempts to be more clinically useful and to produce more meaningful prognostic information than the FAB criteria. Each of the WHO categories contains numerous descriptive sub-categories of interest to the hematopathologist and oncologist; however, most of the clinically significant information in the WHO schema is communicated via categorization into one of the five subtypes listed below.

The WHO subtypes of AML 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)], or translocations between chromosome 15 and 17 [t(15;17)]. 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 a prior myelodysplastic syndrome (MDS) or myeloproliferative disease (MPD) that transforms into AML. This category of AML occurs most often in elderly patients and often has a worse prognosis.
AML and MDS, therapy-related. This category includes patients who have had prior chemotherapy and/or radiation and subsequently develop AML or MDS. These leukemias may be characterized by specific chromosomal abnormalities, and often carry a worse prognosis.
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 or biphenotypic 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.

Pathophysiology

The malignant cell in AML is the myeloblast. In normal hematopoiesis, the myeloblast is an immature precursor of myeloid white blood cells; a normal myeloblast will gradually mature into a mature white blood cell. However, in AML, a single myeloblast accumulates genetic changes which "freeze" the cell in its immature state and prevent differentiation. Such a mutation alone does not cause leukemia; however, when such a "differentiation arrest" is combined with other mutations which disrupt genes controlling proliferation, the result is the uncontrolled growth of an immature clone of cells, leading to the clinical entity of AML.

Much of the diversity and heterogeneity of AML stems from the fact that leukemic transformation can occur at a number of different steps along the differentiation pathway. Modern classification schemes for AML recognize that the characteristics and behavior of the leukemic cell (and the leukemia) may depend on the stage at which differentiation was halted.

Specific cytogenetic abnormalities can be found in many patients with AML; the types of chromosomal abnormalities often have prognostic significance. The chromosomal translocations encode abnormal fusion proteins, usually transcription factors whose altered properties may cause the "differentiation arrest. For example, in acute promyelocytic leukemia, the t(15;17) translocation produces a PML-RARα fusion protein which binds to the retinoic acid receptor element in the promoters of several myeloid-specific genes and inhibits myeloid differentiation.

The clinical signs and symptoms of AML result from the fact that, as the leukemic clone of cells grows, it tends to displace or interfere with the development of normal blood cells in the bone marrow. This leads to neutropenia, anemia, and thrombocytopenia. The symptoms of AML are in turn often due to the low numbers of these normal blood elements. In rare cases, patients can develop a chloroma, or solid tumor of leukemic cells outside the bone marrow, which can cause various symptoms depending on its location.

Treatment

Treatment of AML consists primarily of chemotherapy, and is divided into two phases: induction and postremission (or consolidation) therapy. The goal of induction therapy is to achieve a complete remission by reducing the amount of leukemic cells to an undetectable level; the goal of consolidation therapy is to eliminate any residual undetectable disease and achieve a cure.

Induction

All FAB subtypes except M3 are usually given induction chemotherapy with cytarabine (ara-C) and an anthracycline (such as daunorubicin or idarubicin). Other alternatives, including high-dose ara-C alone, may also be used. Because of the toxic effects of therapy, including myelosuppression and an increased risk of infection, induction chemotherapy may not be offered to the very elderly. Induction chemotherapy usually requires a hospitalization of about 1 month to receive the chemotherapy and recover from its side effects.

Induction chemotherapy is known as "7 and 3" because the cytarabine is given as a continuous IV infusion for seven consecutive days, while the anthracycline is given for three consecutive days as an IV push. Up to 70% of patients will achieve a remission with this protocol.

The M3 subtype of AML, also known as acute promyelocytic leukemia, is almost universally treated with the drug ATRA (all-trans-retinoic acid) in addition to induction chemotherapy. Care must be taken to prevent disseminated intravascular coagulation (DIC), complicating the treatment of APL when the promyelocytes release the contents of their granules into the peripheral circulation. APL is eminently curable with well-documented treatment protocols.

The goal of the induction phase is to reach a complete remission. Complete remission does not mean that the disease has been cured; rather, it signifies that no disease can be detected with available diagnostic methods (i.e., <5% leukemic cells remain in the bone marrow). Complete remission is obtained in about 50%–75% of newly diagnosed adults, although this may vary based on the prognostic factors described above.

The durability of remission depends on the prognostic features of the original leukemia. In general, all remissions will fail without consolidation (post-remission) chemotherapy, and consolidation has become an important component of treatment.

Consolidation

Even after complete remission is achieved, leukemic cells likely remain in numbers too small to be detected with current diagnostic techniques. If no further postremission or consolidation therapy is given, almost all patients will eventually relapse. Therefore, more therapy is necessary to eliminate non-detectable disease and prevent relapse — that is, to achieve a cure.

The specific type of postremission therapy is individualized based on a patient's prognostic factors (see above) and general health. For good-prognosis leukemias (i.e. inv(16), t(8;21), and t(15;17)), patients will typically undergo an additional 3–5 courses of intensive chemotherapy, known as consolidation chemotherapy. For patients at high risk of relapse (e.g. those with high-risk cytogenetics, underlying MDS, or therapy-related AML), allogeneic stem cell transplantation is usually recommended if the patient is able to tolerate a transplant and has a suitable donor. The best postremission therapy for intermediate-risk AML (normal cytogenetics or cytogenetic changes not falling into good-risk or high-risk groups) is less clear and depends on the specific situation, including the age and overall health of the patient, the patient's personal values, and whether a suitable stem cell donor is available.

Relapsed AML

Despite aggressive therapy, however, 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, if one has not already been performed. In 2000, the monoclonal antibody-linked cytotoxic agent gemtuzumab ozogamicin (Mylotarg) was approved in the United States for patients aged more than 60 years with relapsed AML who are not candidates for high-dose chemotherapy.

Patients with relapsed AML who are not candidates for stem cell transplantion, or who have relapsed after a stem cell transplant, should be strongly considered for enrollment in a clinical trial, as conventional treatment options are limited. Agents under investigation include cytotoxic drugs such as clofarabine as well as targeted therapies such as farnesyl transferase inhibitors, decitabine, and inhibitors of MDR1 (multidrug-resistance protein). Since treatment options for relapsed AML are so limited, another option which may be offered is palliative care.

For relapsed acute promyelocytic leukemia (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.

Prognosis

Acute myeloid leukemia is a curable disease; the chance of cure for a specific patient depends on a number of prognostic factors.

Cytogenetics

The single most important prognostic factor in AML is cytogenetics, or the chromosomal structure of the leukemic cell. Certain cytogenetic abnormalities are associated with very good outcomes (for example, the (15;17) translocation in acute promyelocytic leukemia). About half of AML patients have "normal" cytogenetics; they fall into an intermediate risk group. A number of other cytogenetic abnormalities are known to associate with a poor prognosis and a high risk of relapse after treatment.

The first publication to address cytogenetics and prognosis was the MRC trial of 1998:

Risk Category	Abnormality	5-year survival	Relapse rate
Favorable	t(8;21), t(15;17), inv(16)	70%	33%
Intermediate	Normal, +8, +21, +22, del(7q), del(9q), Abnormal 11q23, all other structural or numerical changes	48%	50%
Adverse	-5, -7, del(5q), Abnormal 3q, Complex cytogenetics	15%	78%

Later, the Southwest Oncology Group and Eastern Cooperative Oncology Group, and later still, Cancer and Leukemia Group B published other, mostly overlapping lists of cytogenetics prognostication in leukemia

Antecedent MDS and prognosis

AML which arises from a pre-existing myelodysplastic syndrome or myeloproliferative disease (so-called secondary AML) has a worse prognosis, as does treatment-related AML arising after chemotherapy for another previous malignancy. Both of these entities are associated with a high rate of unfavorable cytogenetic abnormalities.

Other prognostic markers

In some studies, age >60 years and elevated lactate dehydrogenase level were also associated with poorer outcomes. As with most forms of cancer, performance status (i.e. the general physical condition and activity level of the patient) plays a major role in prognosis as well.

FLT3 internal tandem duplications (ITDs) have been shown to confer a poorer prognosis in AML. Treating these patients with more aggressive therapy, such as stem-cell transplantation in first remission, has not been shown to enhance long-term survival, so this prognostic feature is of uncertain clinical significance at this point. ITDs of FLT3 may be associated with leukostasis.

Researchers are investigating the clinical significance of c-KIT mutations in AML. These are prevalent, and clinically relevant because of the availability of tyrosine kinase inhibitors, such as imatinib and sunitinib that can block the activity of c-KIT pharmacologically.

Other genes being investigated as prognostic factors or therapeutic targets include CEBPA, BAALC, ERG, and NPM1.

Overall expectation of cure

Cure rates in clinical trials have ranged from 20–45%; however, it should be noted that clinical trials often include only younger patients and those able to tolerate aggressive therapies. The overall cure rate for all patients with AML (including the elderly and those unable to tolerate aggressive therapy) is likely lower. Cure rates for promyelocytic leukemia can be as high as 98%.

Epidemiology

Acute myeloid leukemia is a relatively rare cancer. There are approximately 10,500 new cases each year in the United States, and the incidence rate has remained stable from 1995 through 2005. AML accounts for 1.2% of all cancer deaths in the United States.

The incidence of AML increases with age; the median age at diagnosis is 63 years. AML accounts for about 90% of all acute leukemias in adults, but is rare in children. The rate of therapy-related AML (that is, AML caused by previous chemotherapy) is rising; therapy-related disease currently accounts for about 10–20% of all cases of AML. AML is slightly more common in men, with a male-to-female ratio of 1.3:1.

There is some geographic variation in the incidence of AML. In adults, the highest rates are seen in North America, Europe, and Oceania, while adult AML is rarer in Asia and Latin America. In contrast, childhood AML is less common in North America and India than in other parts of Asia. These differences may be due to population genetics, environmental factors, or a combination of the two.

A hereditary risk for AML appears to exist. There are numerous reports of multiple cases of AML developing in a family at a rate higher than predicted by chance alone. The risk of developing AML is increased threefold in first-degree relatives of patients with AML.

History

The first published description of a case of leukemia in medical literature dates to 1827, when French physician Alfred-Armand-Louis-Marie Velpeau described a 63-year-old florist who developed an illness characterized by fever, weakness, urinary stones, and substantial enlargement of the liver and spleen. Velpeau noted that the blood of this patient had a consistency "like gruel", and speculated that the appearance of the blood was due to white corpuscles. In 1845, a series of patients who died with enlarged spleens and changes in the "colors and consistencies of their blood" was reported by the Edinburgh-based pathologist J.H. Bennett; he used the term "leucocythemia" to describe this pathological condition.

The term "leukemia" was coined by Rudolf Virchow, the renowned German pathologist, in 1856. As a pioneer in the use of the light microscope in pathology, Virchow was the first to describe the abnormal excess of white blood cells in patients with the clinical syndrome described by Velpeau and Bennett. As Virchow was uncertain of the cause of the white blood cell excess, he used the purely descriptive term "leukemia" (Greek: "white blood") to refer to the condition.

Further advances in the understanding of acute myeloid leukemia occurred rapidly with the development of new technology. In 1877, Paul Ehrlich developed a technique of staining blood films which allowed him to describe in detail normal and abnormal white blood cells. Wilhelm Ebstein introduced the term "acute leukemia" in 1889 to differentiate rapidly progressive and fatal leukemias from the more indolent chronic leukemias. The term "myeloid" was coined by Neumann in 1869, as he was the first to recognize that white blood cells were made in the bone marrow (Greek: µυєλός, myelos = (bone) marrow) as opposed to the spleen. The technique of bone marrow examination to diagnose leukemia was first described in 1879 by Mosler. Finally, in 1900 the myeloblast, which is the malignant cell in AML, was characterized by Naegeli, who divided the leukemias into myeloid and lymphocytic.