Acute Myelocytic Leukemia

Background

Acute myeloid leukemia (AML) consists of a group of malignant disorders characterized

by the replacement of normal bone marrow with abnormal, primitive hematopoietic cells.
If untreated, the disorder uniformly results in death, usually from infection or
bleeding. Although the cure rate has improved, treatments are associated with notable
morbidity and mortality.

Pathophysiology

Acute leukemia is believed to begin in a single somatic hematopoietic progenitor that

transforms to a cell incapable of normal differentiation. Acute myeloid leukemia is a very
heterogeneous disease from a molecular standpoint; oncogenic transformation into a
leukemic stem cell may occur at different stages of normal hematopoietic cellular
maturation, from the most primitive hematopoietic stem cell to later stages, including
myeloid/monocytoid progenitor cells and promyelocytes. This determines which subtype
of acute myeloid leukemia results, often with very different behavior and growth
characteristics.

As opposed to acute lymphoblastic leukemia (ALL), acute myeloid leukemia is most

commonly associated with the development of fusion genes resulting from chromosome
translocations. Many translocations are characteristic of a particular subtype of acute
leukemia and often convey additional prognostic information to the clinician. Although
many patients have only a single cytogenetic abnormality, multiple genetic mutations are
often required for the complete leukemic transformation.

Many of the leukemic cells no longer possess the normal property of apoptosis, or
programmed cell death. As a result, they have a prolonged life span and are capable of
unrestricted clonal proliferation. Because transformed cells lack normal regulatory and
growth constraints, they have favorable competitive advantage over normal
hematopoietic cells. The result is the accumulation of abnormal cells with qualitative
defects. A major cause of morbidity and mortality is the deficiency of normally
functioning mature hematopoietic cells rather than the number of malignant cells.

Splenomegaly due to leukemic infiltration further contributes to pancytopenia by

sequestering and destroying circulating erythrocytes and platelets. As the disease
progresses, signs and symptoms of anemia, thrombocytopenia, and neutropenia increase.

Leukemic cells may infiltrate other bodily tissues, causing many clinically significant
complications including CNS involvement, pulmonary dysfunction, or skin and gingival
infiltration.

Frequency

International:

Although leukemia has been reported in children worldwide, the incidence rate widely
varies. In the United States and other highly industrialized countries, acute myeloid
leukemia accounts for about 15% of childhood leukemia. In other areas, such as Turkey,
nearly one half of children diagnosed with leukemia have acute myeloid leukemia.
Childhood leukemia (other than Burkitt type) is less common in Africa, but the ratio of
acute myeloid leukemia to ALL is roughly 1:1. Likewise, the incidence of acute myeloid
leukemia in Asia is significantly higher than more developed parts of the world, nearly
equal to that of ALL as reported by Bhatia and Neglia.2
Mortality/Morbidity

The long-term survival rate for pediatric patients with acute myeloid leukemia is nearly
55%. Acute myeloid leukemia accounts for about 35% of childhood deaths from
leukemia. Mortality is a consequence of resistant progressive disease or treatment-related
toxicity.

Race

Minor geographic variations are observed in the incidences of the different subtypes of
acute myeloid leukemia. However, ALL is more common in white children than in black
children, whereas acute myeloid leukemia affects all races nearly equally. The incidence
of one subtype, acute promyelocytic leukemia (APL), is slightly increased in the Hispanic
pediatric population. Areas of the world where rates of acute myeloid leukemia are higher
than average include Shanghai, New Zealand, and parts of Japan.

Sex

Male and female distributions are nearly equal at all ages.

Age

Acute myeloid leukemia is diagnosed in persons of all ages, ranging from the newborns
to the elderly. In the first year of life, acute myeloid leukemia accounts for nearly one
third of all newly diagnosed leukemias. For the rest of the first decade of life, ALL is
more common than acute myeloid leukemia by a ratio of 4:1. The incidence of these
diseases is roughly equal during adolescence, and the incidence of acute myeloid
leukemia increases in adulthood.

History

Symptoms of acute myeloid leukemia (AML) can be divided into those caused by a
deficiency of normally functioning cells, those due to the proliferation and infiltration of
the abnormal leukemic cell population, and constitutional symptoms.

• Symptoms due to a deficiency of normally functioning cells

o Cytopenias
o Anemia: This common finding is characterized by pallor, fatigue,
tachycardia, and headache. The major pathophysiologic mechanism is
related to decreased production in the infiltrated bone marrow. Bleeding,
hemolysis, and sequestration and destruction in an enlarged spleen or liver
may all contribute to anemia.
o Hemorrhage due to thrombocytopenia: This is in part due to decreased
production of megakaryocytes in the bone marrow. The most common
findings are easy bruising, petechiae, epistaxis, gingival bleeding, and,
sometimes, GI or CNS hemorrhage. The patient with disseminated
intravascular coagulation might also have symptoms of hemorrhage or
thrombosis, including painful swelling and sharp, colored demarcation of
an extremity.

o Fever: This is a common presenting complaint in patients with acute

leukemia. In this context, fever should always be attributed to infection.
Depending on the site of infection, symptoms may vary. Symptoms may
be pulmonary (eg, cough, dyspnea, hypoxia, chest pain), as in patients
with pneumonias; neurologic (eg, lethargy, emesis, headache), as in
patients with meningitis; or other (eg, pain or changes in bladder and
bowel function due to colitis or urinary tract infection).
• Symptoms due to the proliferation and infiltration of the abnormal leukemic cell
mass and infiltrative disease
o The most common extramedullary infiltration due to leukemic cells occurs
in the reticuloendothelial system. This infiltration may manifest as
adenopathy, hepatomegaly, or splenomegaly.
o In rare cases, a mediastinal mass may cause symptoms of respiratory
insufficiency or superior vena cava syndrome.
o Abdominal masses may cause pain or obstruct the GI or urogenital tracts.
Nodules of myeloblasts, called chloromas, can be found in the skin, CNS
or any other organ.
o Monoblastic leukemia is often associated with gingival hyperplasia and
CNS infiltration.

Gingival hyperplasia in a patient with monoblastic

leukemia.

• Constitutional and miscellaneous symptoms

o Fever: Unexplained persistent fevers are sometimes the only presenting

symptom of patients with leukemia. Weight loss and cachexia are unusual
findings in children with leukemia but not in adults. These effects can
result from increased catabolic nutritional state combined with decreased
caloric intake from anorexia.
o Orthopedic symptoms: Bone pain is less common in patients with acute
myelocytic leukemia than in patients with acute lymphoblastic leukemia
(ALL). Its cause may be periosteal elevation due to leukemic cell
infiltrates or bone infarctions. On occasion, weakened bony cortex permits
pathologic fractures of the extremity, which result in pain and decreased
mobility, or vertebral compression fractures after minimal trauma. Such
compression fractures cause back pain and dysfunction of the lower
extremity (eg, weakness, loss of bladder and bowel function).
o CNS involvement
 Although this is uncommon at initial diagnosis, it can appear at any
time during follow-up and is associated with various findings.
 The most common signs and symptoms are related to elevated
intracranial pressure; they include headache, nausea and emesis,
lethargy, irritability, and visual complaints.
 Involvement of the cranial nerves, most often the facial nerve
(resulting in Bell palsy) and the abducens nerve (resulting in
esotropia), may appear as an isolated finding or in combination
with other manifestations.
 In addition to infiltration and proliferation of leukemic cells with
mass effect, intracranial hemorrhage and CNS infections can cause
similar devastating CNS complications.
 Spinal lesions are rare. However, in acute myeloid leukemia, blast
cells periodically form large aggregates called chloromas or
granulocytic sarcomas that lead to epidural compression.
  Extreme leukocytosis with WBC counts of more than 200 X 109/L
(>200,000 cells/μL) is often associated with hyperviscosity,
intracerebral leukostasis, and intracerebral hemorrhage early in the
course of the disease.
o Ocular manifestations: In rare cases, leukemic cells infiltrate all parts of
the eye. The retina and iris are the sites most commonly affected. Iritis
often causes photophobia, pain, and increased lacrimation, whereas, retinal
involvement is often accompanied by hemorrhage and can lead to a loss of
vision.

Physical

• Pancytopenia
o Pallor with tachycardia is observed to different degrees proportional to the
severity of anemia. With severe anemia, patients may have lethargy, a
heart murmur, and signs of congestive heart failure.
o Bleeding manifestations are most commonly observed in the skin and
include petechiae, purpuric lesions, and ecchymoses.
o GI bleeding may indicate erosions or perforation.
o Signs of infection include fever, gingivitis, hypotension, or respiratory
distress, depending on the site of infection.
• Signs of leukemic infiltration and proliferation
o Adenopathy, at times generalized, is less common in acute myeloid
leukemia than in ALL.
o Splenomegaly is sometimes massive, particularly in young children.
o Pronounced organomegaly occasionally result in respiratory
embarrassment in infants due to decreased diaphragmatic excursion.
o CNS findings include lethargy, cranial nerve dysfunction (particularly
esotropia and facial palsy), and papilledema.
o Typhlitis can lead to acute pain in the lower quadrants that mimic signs of
appendicitis.
o Signs of perforation include hypotension, abdominal distension, and
decreased bowel sounds. Clinical deterioration is rapid if the condition is
not recognized.
o Skin nodules are occasionally found in patients with acute myeloid
leukemia. They are typically firm, raised, and often bluish-purple in color.

Causes

Although the cause of acute myeloid leukemia is unknown in most patients, several
factors are associated with its development. Despite these correlations, most people
exposed to the same factors do not develop leukemia. This pattern suggests that these
factors trigger the malignant transformation of cells, perhaps due to the action of one or
more oncogenes or tumor suppressor genes. Defects in DNA repair mechanisms also
contribute to the development of acute myeloid leukemia.

• Radiation exposure
o A great deal of evidence has implicated radiation in leukemogenesis in
many patients, as evidenced in Japan after the atomic explosions at
Hiroshima and Nagasaki. Although young children had the high risk of
developing ALL, teens and adults were most likely to contract acute
myeloid leukemia. Most of the leukemias arose within the first 5 years
after exposure, although some developed as much as 15 years after
exposure.
 o Reports of increased risk of leukemia among patients who live near
nuclear plants are under investigation, but data are lacking. Likewise,
early reports that exposure to strong electromagnetic fields is a risk factor
for acute leukemia have not been corroborated.
• Exposure to toxins and drugs
o Exposure to toxic chemicals that cause damage to bone marrow, such as
benzene and toluene used in the leather, shoe, and dry cleaning industries,
is associated with leukemia in adults. Direct evidence of this effect in
children has not been established. Exposure to pesticides has been noted to
increase the risk of acute myeloid leukemia.
o A compelling association has been observed after treatment with
antineoplastic cytotoxic agents, particularly alkylating agents such as
procarbazine, the nitrosoureas, cyclophosphamide, melphalan, and, most
recently, the epipodophyllotoxins etoposide and teniposide. Patients
receiving these agents to treat malignancies (eg, Hodgkin Disease) have a
significantly increased risk of developing a preleukemic syndrome that
ultimately transforms into overt acute myeloid leukemia, especially if the
agents are administered with radiation therapy.
• Genetic factors and syndromes
o Children with Down syndrome (trisomy 21) have a 15-fold increased risk
of developing leukemia, most commonly acute megakaryoblastic
leukemia, compared with the general population. The risk of
megakaryoblastic leukemia in Down syndrome is approximately 400 times
greater than the rest of the population. Children with Down syndrome who
have transient myeloproliferative syndrome as neonates, a condition often
indistinguishable from acute leukemia, also have a high risk of developing
acute leukemia in subsequent years.
o Patients with inherited disorders, such as Shwachman-Diamond syndrome,
Bloom syndrome, or Diamond-Blackfan anemia, Fanconi anemia,
dyskeratosis congenita, Kostmann syndrome, also have an elevated risk of
developing leukemia. Although statistics vary, about 10% of patients with
Fanconi anemia, 5-10% of patients with Shwachman-Diamond
syndrome, and 1 in 6 patients with Bloom syndrome develop leukemia.
The risk of acute myeloid leukemia in patients with dyskeratosis congenita
is nearly 200 times the normal population. These syndromes share features
of poor DNA repair that are believed to predispose affected individuals to
leukemogenic stimuli. Children with neurofibromatosis type I also appear
to be at increased risk for developing acute myeloid leukemia.
o Although most cases are diagnosed after a relatively brief duration of
symptoms, some patients may present with myelodysplasia. This relatively
indolent disorder is characterized by slowly progressive anemia or
thrombocytopenia. This disorder can be present for many months or even
years before it ultimately converts to acute myeloid leukemia.