Acute myeloid leukemia overview

# Overview
Acute myeloid leukemia (AML) 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. This leukemia arises from myeloblasts, which are hematologic white cells that are normally involved in hematopoiesis. Acute myeloid leukemia may be classified according to the French-American-British (FAB) classification and World Health Organization (WHO). Acute myeloid leukemia must be differentiated from other diseases such as: acute lymphoblastic leukemia, chronic myeloid leukemia, agranulocytosis, aplastic anemia and lymphoma. In 2015, the incidence of acute myeloid leukemia was approximately 6.5 per 100,000 individuals with a case-fatality rate of approximately 50% in the United States. The incidence of acute myeloid leukemia increases with age. Common risk factors in the development of acute myeloid leukemia are myelodysplastic syndromes, aplastic anemia, myelofibrosis and paroxysmal nocturnal hemoglobinuria. Common complications include infections, disseminated intravascular coagulation, and hemorrhage. Symptoms of acute myeloid leukemia include fever, fatigue, weight loss and loss of appetite. Physical examination findings of acute myeloid leukemia include anemia, fever, pallor, Leukemia cutis, bruising, petechiae, ecchymosis and tachycardia. Laboratory findings consistent with the diagnosis of acute myeloid leukemia include leukocytosis, thrombocytopenia, anemia and leucopenia. If a lung infection is suspected, a chest x-ray may be helpful in the diagnosis. The mainstay therapy is chemotherapy and usually includes a combination of daunorubicin, cytarabine and etoposide or mitoxantrone and anabolic steroids. Supportive care includes intravenous nutrition, antimicrobial therapy, and replacement of blood products.

# Historical Perspective
In the 17th and 18th centuries, scientists first discovered blood cells, which are the malignant cells in acute myeloid leukemia. In the 19th century, the first case of acute leukemia was discovered. In the 20th century, chemotherapy was introduced for the treatment of acute leukemia. The 21st century witnessed advancements in the understanding of disease biology, and targeted therapies for acute myeloid leukemia were introduced to the market.

# Classification
There are 3 classifications systems for acute myeloid leukemia. These classifications include the  French-American-British (FAB), the World Health Organization (WHO) , and the European LeukemiaNet (ELN). The original classification was the  French-American-British (FAB) , and the most recent classification was the 2017 European LeukemiaNet (ELN).

# Pathophysiology
Normal hematopoiesis involves the production of blood cells, and this normal physiologic process is dysregulated in acute myeloid leukemia. The pathophysiology of acute myeloid leukemia involves multiple mechanisms, including altered signal transduction and autonomous proliferation, differentiation blockade, evasion of apoptosis, and self-renewal. The pathophysiology of acute promyelocytic leukemia specifically involves a fusion protein that results from a translocation between chromosomes 15 and 17.

# Causes
The causes of acute myeloid leukemia are broad and include benzene exposure, radiation, alkylating agents, topoisomerase II inhibitors, and specific gene mutations. Each of these risk factors carries a defined probability of progression to acute myeloid leukemia. Overall, most cases of acute myeloid leukemia are sporadic rather than inherited.

# Differentiating Acute Myeloid Leukemia from Other Diseases
The differential diagnosis of acute myeloid leukemia includes a variety of other hematologic malignancies, specifically acute promyelocytic leukemia (APL), acute lymphoblastic leukemia (ALL), chronic myeloid leukemia (CML), and chronic lymphocytic leukemia (CLL). Each of these conditions has distinct causes and therapies. There is some overlap between the causes and laboratory abnormalities amongst these diseases.

# Epidemiology and Demographics
In 2015, the incidence of acute myeloid leukemia was approximately 6.5 per 100,000 individuals with a case-fatality rate of approximately 50% in the United States. The incidence of acute myeloid leukemia increases with age; the median age at diagnosis is 63 years. Males are more commonly affected with acute myeloid leukemia than women. The male to female ratio is approximately 1.3 to 1.

# Risk Factors
Common risk factors in the development of acute myeloid leukemia are advanced age, benzene exposure, prior myelodysplastic syndrome, germline mutations, and other conditions like aplastic anemia.

# Screening
There are currently no guidelines for screening for acute myeloid leukemia. Monitoring of the complete blood count is done routinely.

# Natural History, Complications, and Prognosis
The natural history of acute myeloid leukemia involves the commencement of symptoms including fatigue, bleeding, and infection. Some patients will also present with disseminated intravascular coagulation, in which bleeding and thrombosis occurs simultaneously. Complications of acute myeloid leukemia include infection, hemorrhage, venous thromboembolism, and therapy-related complications. The prognosis of acute myeloid leukemia is largely based upon on the European LeukemiaNet (ELN) classification system.

# Diagnosis

## History and Symptoms
Important components of the history of acute myeloid leukemia include assessment of pre-existing hematologic conditions, exposure to prior chemotherapy or radiation, occupational exposures, and congenital disorders. Symptoms include fever, fatigue, infections, and bleeding. These symptoms are a result of impaired normal blood cell production.

## Physical Examination
Common physical examination findings of acute myeloid leukemia include anemia, fever, pallor, leukemia cutis, bruising, petechiae, ecchymosis, tachycardia. Neurologic symptoms can also occur, but these are more rare.

## Laboratory Findings
The laboratory abnormalities in acute myeloid leukemia can be broadly divided into abnormalities of the complete blood count, abnormalities of serum chemestries, and abnormalities of the coagulation system. The complete blood count usually shows anemia, thrombocytopenia, leukopenia, and elevated blast count. The serum chemistries can show findings consistent with tumor lysis syndrome, which includes increased potassium, increased uric acid, increased phosphate, decreased calcium, and increased lactate dehydrogenase. In the acute promyelocytic leukemia sub-category of acute myeloid leukemia, the coagulation profile usually shows elevated prothrombin time, elevated partial thromboplastin time, elevated thrombin time, elevated reptilase time, and low fibrinogen. This combination of coagulation parameters accounts for high hemorrhagic risk, especially in patients with acute promyelocytic leukemia.

## Electrocardiogram
Electrocardiogram is useful for assessment of QT interval prior to starting treatment with ivosidenib and arsenic trioxide. It is also useful for assessing anthracycline chemotherapy-induced arrhythmias.

## Chest X-Ray
Chest x-rays are useful for the diagnosis and evaluation of various aspects of acute myeloid leukemia management, including differentiation syndrome, infection, volume overload, and venous catheter placement.

## CT
Abdominal and chest CT scans may be helpful in the diagnosis of acute myeloid leukemia. Findings on CT scans suggestive of acute myeloid leukemia or myeloid sarcoma include enlarged lymph nodes, hepatosplenomegaly, splanchnic venous thrombosis, and pulmonary embolism.

## MRI
Brain MRIs are helpful in the detection of thrombotic events, such as ischemic stroke, in patients with acute myeloid leukemia and especially acute promyelocytic leukemia. An abdominal MRI is helpful in the detection of mesenteric thrombosis in these patients.

## Other Diagnostic Studies
Other diagnostic studies for acute myeloid leukemia include cytochemistry, flow cytometry, immunohistochemistry, PCR and biopsy.

# Medical Therapy
The mainstay therapy from acute myeloid leukemia is induction chemotherapy, which usually includes a combination of an anthracycline and cytarabine. Induction chemotherapy sometimes includes etoposide. The decision about consolidation therapy depends on the risk assessment of acute leukemia. Relapsed acute myeloid leukemia is treated with a variety of other chemotherapeutics. Novel FDA-approved agents include midostaurin, enasidenib, CPX-351, gemtuzumab ozogamicin, and ivosidenib. Supportive care measures include transfusions and hydration.

# Surgery
Surgery is not the first-line treatment option for patients with acute myeloid leukemia.

# Primary Prevention
There is no established method for primary prevention of acute myeloid leukemia.

# Secondary Prevention
There is no established method for secondary prevention of acute myeloid leukemia.

# Cost-effectiveness of Therapy
A limited number of cost-effective studies have been done. For the acute promyelocytic leukemia sub-type of acute myeloid leukemia, these studies showed that all-trans retinoic acid-based therapy is more cost-effective than chemotherapy.