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Introduction

Leukemia is a malignancy (cancer) of the blood cells which causes abnormal proliferation of
blood cells within the bone marrow. It involves the production of abnormal white blood cells,
which are responsible for fighting infections. These abnormal cells do not function in the same
way as normal white blood cells. The leukemia cells continue to grow and divide, eventually
crowding out the normal blood cells. The end result is that it becomes difficult for the body to
fight infections, control bleeding, and transport oxygen.
Leukemia is classified based on how quickly the disease develops and the type of abnormal cells
being produced. It is termed an acute leukemia if it develops rapidly. This results in large
numbers of leukemia cells accumulating very quickly in the blood and bone marrow, leading to
symptoms such as tiredness, easy bruising, and susceptibility to infections. Acute leukemia
requires fast and aggressive treatment. Chronic leukemia develops slowly over time. These type
of leukemia may not cause specific symptoms at the beginning of their course. However, if left
untreated, the cells may eventually grow to high numbers, as in the acute form causing similar
symptoms.
Leukemia is further classified as myeloid or lymphoid, depending upon the type of white blood
cell that makes up the leukemia cells. Normal blood cells develop from stem cells that have the
potential to become many cell types (Multipotential Stem Cells). Myeloid stem cells mature in
the bone marrow and become immature white cells called myeloid blasts. These myeloid blasts
further mature to become either red blood cells, platelets, or certain kinds of white blood cells.
Lymphoid stem cells mature in the bone marrow to become lymphoid blasts. The lymphoid
blasts develop further into T or B lymphocytes which are special types of white blood cells.
Myeloid leukemia is made up of cells that arise from myeloid stem cells, while lymphoid
leukemia arises from lymphoid stem cells. In order to choose the right treatment for leukemia, it
is important to know the type of cell involved.

Types of Leukemia

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Leukemia is classified into four major types. These are Acute Lymphocytic Leukemia (ALL),
Chronic Lymphocytic Leukemia (CLL), Acute Myeloid Leukemia (AML), and Chronic Myeloid
Leukemia (CML).
Acute Lymphocytic Leukemia (ALL) is the most common type of leukemia in children, but it
can also affect adults. In this type of leukemia, the immature lymphoid cells grow rapidly in the
blood.
Acute Myeloid Leukemia (AML) involves the rapid growth of myeloid cells. It occurs in both
adults and children.
Chronic Lymphocytic Leukemia (CLL) is a slow-growing cancer of lymphoid cells that usually
affects people over 55 years of age. It almost never occurs in children or adolescents.
Chronic Myeloid Leukemia (CML) primarily affects adults.

Less common types of leukemia include:

Hairy cell leukemia is an uncommon type of chronic leukemia.

Chronic myelomonocytic leukemia (CMML) is another type of chronic leukemia that


develops from myeloid cells.

Juvenile myelomonocytic leukemia (JMML) is a type of myeloid leukemia that usually


occurs in children under 6 years of age.

Large granular lymphocytic leukemia (LGL leukemia) is a type of chronic leukemia that
develops from lymphoid cells. It can be slow or fast-growing.

Acute promeylocytic leukemia (APL) is a subtype of AML

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Acute lymphocytic leukemia (ALL)


This is a blood cancer that results when abnormal white blood cells (leukemia
cells) accumulate in the bone marrow.
ALL progresses rapidly, replacing healthy cells that produce functional
lymphocytes with leukemia cells that can't mature properly. The leukemia cells are
carried in the bloodstream to other organs and tissues, including the brain, liver,
lymph nodes and testes, where they continue to grow and divide. The growing,
dividing and spreading of these leukemia cells may result in a number of possible
symptoms.
ALL is typically associated with having more B lymphatic cells than T cells. B and
T cells play active roles in preventing the body from infections and germs and
destroying cells that have already become infected. B cells particularly help
prevent germs from infecting the body while T cells destroy the infected cells.
ALL can occur at any age, but acute lymphocytic leukemia incidences occur most
frequently in people under the age of 15 or over the age of 45. Although ALL
makes up the largest percentage of leukemia diagnoses in children under the age of
15 (specifically between the ages of two to four), it is rare for adults to develop this
disease.

Acute myeloid leukemia (AML)


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This is a fast-growing form of cancer of the blood and bone marrow.


AML is the most common type of acute leukemia. It occurs when the bone marrow
begins to make blasts, cells that have not yet completely matured. These blasts
normally develop into white blood cells. However, in AML, these cells do not
develop and are unable to ward off infections.
In AML, the bone marrow may also make abnormal red blood cells and platelets.
The number of these abnormal cells increases rapidly, and the abnormal (leukemia)
cells begin to crowd out the normal white blood cells, red blood cells and platelets
that the body needs.
One of the main things that differentiates AML from the other main forms of
leukemia is that it has eight different subtypes, which are based on the cell that the
leukemia developed from. The types of acute myelogenous leukemia include:
Myeloblastic (M0) - on special analysis
Myeloblastic (M1) - without maturation
Myeloblastic (M2) - with maturation
Promyeloctic (M3)
Myelomonocytic (M4)
Monocytic (M5)
Erythroleukemia (M6)
Megakaryocytic (M7)

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Chronic lymphocytic leukemia (CLL)


This is a typically slow-growing cancer which begins in lymphocytes in the bone marrow and
extends into the blood. It can also spread to lymph nodes and organs such as the liver and spleen.
CLL develops when too many abnormal lymphocytes grow, crowding out normal blood cells and
making it difficult for the body to fight infection.
The term "chronic" means that the disease develops slowly. The abnormal lymphocytes take
longer to develop and multiply. A disease like CLL, therefore, may take several years before it
becomes serious. Comparatively, the progression of acute lymphocytic leukemia (ALL) is very
quick. ALL may advance in a much shorter period.

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Chronic myeloid leukemia (CML)


This is a form of cancer that affects the bone marrow and blood. It begins in the blood-forming
cells of the bone marrow and then, over time, spreads to the blood. Eventually, the disease
spreads to other areas of the body.
Typically, being categorized as chronic indicates that this type of leukemia spreads and grows
slowly. However, CML can change from slow progressing into a rapidly growing, acute form
of leukemia that can spread to almost any organ in the body.
Unlike the three other main types of leukemia, CML has a significant difference that sets it apart
from the rest. It has been shown that CML is associated with an abnormal chromosome known as
the Philadelphia chromosome (Ph chromosome).
Chromosomes are structures in cells that contain genes, which give instructions to the cells. The
Ph chromosome is an abnormality that occurs when a piece of chromosome 22 breaks off and
attaches to the end of chromosome 9, which also breaks off and attaches to chromosome 22.
The breaks in both chromosomes cause the BCR and ABL genes, which combine to create the
cancer gene. The link between the Ph chromosome and CML was discovered around 1960.

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Causes of leukemia
The exact cause of leukemia is not known, but it is thought to involve a combination of genetic
and environmental factors. Leukemia cells have acquired mutations in their DNA that cause them
to grow abnormally and lose functions of typical white blood cells. It is not clear what causes
these mutations to occur. One type of change in the cells' DNA that is common in leukemia is
known as a chromosome translocation. In this process, a portion of one chromosome breaks off
and attaches to a different chromosome. One translocation seen in almost all cases of CML and
sometimes in other types of leukemia is an exchange of DNA between chromosomes 9 and 22,
which leads to what is known as the Philadelphia chromosome. This creates an oncogene
(cancer-promoting gene) known as BCR-ABL. This change in DNA is not inherited but occurs
sometime in the life of the affected individual.
Most cases of leukemia are not believed to be hereditary, but certain genetic mutations and
conditions can be passed along to offspring that increase the chances of developing leukemia. A
condition known as Li-Fraumeni syndrome is characterized by an inherited mutation in
a tumor suppressor gene known as TP53, and individuals with this condition have an increased
risk of leukemia and other cancers. Other hereditary conditions that can increase the risk of
developing leukemia include Down syndrome, neurofibromatosis type 1 and Noonan syndrome.

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Leukemia Risk Factors


A risk factor is any attribute, characteristic or exposure of an individual that increases the
likelihood of developing a disease or injury. There are several risk factors that contribute towards
developing leukemia.

Exposure to radiation is known to increase the risk of developing AML, CML, or ALL.
Also, increases in leukemia were observed in people surviving atomic bombs.

Radiation therapy for cancer can also increase the risk of leukemia.

Exposure to benzene, used commonly in the chemical industry, increases the risk of
leukemia.

Cigarette smoking is known to increase the risk of developing AML.

Genetic conditions such as Down's syndrome and Li-Fraumeni syndrome can increase the
risk of developing leukemia.

Blood disorders known as myelodysplastic syndromes confer an increased risk of


developing AML.

Human T-cell leukemia virus type 1 (HTLV-1) is a virus that causes a rare type of
leukemia.

Certain chemotherapy drugs for cancer can increase the risk for AML or ALL.

It is important to note that having risk factors does not mean that a person will definitely get
leukemia, and most people with risk factors will not develop the disease. Likewise, not everyone
who develops leukemia has an identifiable risk factor.

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Symptoms and Signs

The symptoms and signs of leukemia depend upon the type of leukemia. Slow-growing or
chronic leukemia may not cause any symptoms at the outset, while aggressive or rapidly growing
leukemia may lead to severe symptoms. The symptoms of leukemia arise from a loss of function
of the normal blood cells or from accumulation of the abnormal cells in the body.
Signs and symptoms of leukemia typically include the following:

Fevers

Night sweats

Swollen lymph nodes that are usually painless (Lymphadenopathy)

Feelings of fatigue, tiredness (Anemia)

Easy bleeding or bruising, causing bluish or purplish patches on the skin or tiny red spots
on the skin, or recurring nosebleeds

Frequent infections

Bone or joint pain

Weight loss that is otherwise unexplained, or loss of appetite

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Enlargement of the spleen or liver, which can lead to abdominal pain or swelling
(Hepatomegaly and Splenomegaly)

Red spots on the skin (petechiae)

If leukemia cells have infiltrated the brain, symptoms such as headaches, seizures, confusion,
loss of muscle control, and vomiting can occur.

Diagnosis

In addition to a medical history (asking about symptoms and risk factors) and a physical exam to
look for signs of leukemia (Lymphadenopathy, Splenomegaly), the diagnosis of leukemia
typically involves laboratory studies of a blood sample. Abnormal numbers of blood cells may
suggest a diagnosis of leukemia, and the blood sample may also be examined under the
microscope to see if the cells appear abnormal.
A sample of the bone marrow may also be obtained to establish the diagnosis. For a bone marrow
aspirate, a long, thin needle is used to withdraw a sample of bone marrow from the hip bone,
under local anesthesia. A bone marrow biopsy involves insertion of a thick, hollow needle into
the hip bone to remove a sample of the bone marrow, using local anesthesia.
Cells from the blood and bone marrow are further tested if leukemia cells are present. These
additional tests look for genetic alterations and expression of certain cell surface markers by the
cancer cells (immunophenotyping). The results of these tests are used to help determine the
precise classification of the leukemia and to decide on optimal treatment.
Other tests that may be useful include a chest X-ray to determine if there are enlarged lymph
nodes or other signs of disease and a lumbar puncture to remove a sample of cerebrospinal fluid
to determine if the leukemia cells have infiltrated the membranes and space surrounding the
brain and spinal cord.
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Imaging tests such as MRI and CT scanning can also be useful for some patients to determine the
extent of disease.

Treatment

There are a number of different medical approaches to the treatment of leukemia. Treatment will
typically depend upon the type of leukemia, the patient's age and health status, as well as whether
or not the leukemia cells have spread to the cerebrospinal fluid. The genetic changes or specific
characteristics of the leukemia cells as determined in the laboratory can also determine the type
of treatment that may be most appropriate.
Watchful waiting may be an option for some people with a chronic leukemia who do not have
symptoms. This involves close monitoring of the disease so that treatment can begin when
symptoms develop. Watchful waiting allows the patient to avoid or postpone the side effects of
treatment. The risk of waiting is that it may eliminate the possibility of controlling the leukemia
before it worsens.
Treatments for leukemia include chemotherapy, radiation therapy, Interferon therapy, and stem
cell transplant. Combinations of these treatments may be used. Surgical removal of the spleen
can be a part of treatment if the spleen is enlarged.
Acute leukemia needs to be treated when it is diagnosed, with the goal of inducing a
remission (absence of leukemia cells in the body). After remission is achieved, therapy may be
given to prevent a relapse of the leukemia. This is called consolidation or maintenance therapy.
Acute leukemia can often be cured with treatment.

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Chronic leukemia are unlikely to be cured with treatment, but treatments are often able to control
the cancer and manage symptoms. Some people with chronic leukemia may be candidates for
stem cell transplantation, which does offer a chance for cure.

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Interferon Therapy
Interferons are a class of proteins that are released by virus-infected cells. They help normal cells
to make antiviral proteins. Interferons also help the body to reduce leukemia cell proliferation
(growth and reproduction), while strengthening the body's immune response.
Interferon-alpha (INF-a) is a type of interferon that frequently is used to treat leukemia.
In addition, based on a patient's response to INF-a, a physician can better predict the anticipated
length of survival.
Interferon-alpha can be given by a number of method, that is, by injection into a vein, into a
muscle, or under the skin. Subcutaneous (under the skin) injection is the customary route.
INF-a usually is offered to all newly diagnosed patients who are not candidates for stem cell
transplantation.
Often IFN-a is started at a low dose (e.g. 3 MIU daily), with gradual increases over time.
Unfortunately, though, this drug is not without side effects.
Possible IFN-related complaints include fevers, chills, muscle aches, bone pain, headaches,
concentration difficulties, fatigue, nausea, vomiting, and general flu-like symptoms when starting
the drug.
Such symptoms usually last for 1 to 2 weeks, but may be lessened by drugs such as
acetaminophen. Side effects recur if the INF-a dosage is increased, but they are temporary and
usually improve after INF-a therapy is completed.

Chemotherapy
Chemotherapy is the administration of drugs that kill rapidly dividing cells such as leukemia or
other cancer cells. Chemotherapy may be taken orally in pill or tablet form, or it may be
delivered via a catheter or intravenous line directly into the bloodstream. Combination
chemotherapy is usually given, which involves a combination of more than one drug. The drugs
are given in cycles with rest periods in between.

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Sometimes, chemotherapy drugs for leukemia are delivered directly to the cerebrospinal fluid
(known as intrathecal chemotherapy). Intrathecal chemotherapy is given in addition to other
types of chemotherapy and can be used to treat leukemia in the brain or spinal cord or, in some
cases, to prevent spread of leukemia to the brain and spinal cord. An Ommaya reservoir is a
special catheter placed under the scalp for the delivery of chemotherapy medications. This is
used for children and some adult patients as a way to avoid injections into the cerebrospinal
fluid.
Side effects of chemotherapy depend on the particular drugs taken and the dosage or regimen.
Some side effects from chemotherapy drugs include hair loss, nausea, vomiting, mouth sores,
loss of appetite, tiredness, easy bruising or bleeding, and an increased chance of infection due to
the destruction of white blood cells. There are medications available to help manage the side
effects of chemotherapy.
Some adult men and women who receive chemotherapy sustain damage to the ovaries or testes,
resulting in infertility. Most children who receive chemotherapy for leukemia will have
normal fertility as adults, but depending on the drugs and dosages used, some may
have infertility as adults.

Radiation therapy
Radiation therapy uses high energy radiation to target cancer cells. Radiation therapy may be
used in the treatment of leukemia that has spread to the brain, or it may be used to target the
spleen or other areas where leukemia cells have accumulated.
Radiation therapy also causes side effects, but they are not likely to be permanent. Side effects
depend on the location of the body that is irradiated. For example, radiation to the abdomen can
cause nausea, vomiting, and diarrhea. With any radiation therapy, the skin in the area being
treated may become red, dry, and tender. Generalized tiredness is also common while undergoing
radiation therapy.

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Stem cell transplant


In stem cell transplantation, high doses of chemotherapy and/or radiation are given to destroy
leukemia cells along with normal bone marrow. Then, transplant stem cells are delivered by an
intravenous infusion. The stem cells travel to the bone marrow and begin producing new blood
cells. Stem cells may come from the patient or from a donor.
Autologous stem cell transplantation refers to the situation in which the patient's own stem cells
are removed and treated to destroy leukemia cells. They are then returned to the body after the
bone marrow and leukemia cells have been destroyed.
An allogeneic stem cells transplant refers to stem cells transplanted from a donor. These may be
from a relative or an unrelated donor. A syngeneic stem cell transplant uses stem cells taken from
a healthy identical twin of the patient.
Stem cells may be removed (harvested) in different ways. Typically, they are taken from the
blood. They can also be harvested from the bone marrow or from umbilical cord blood.
Stem cell transplantation is done in a hospital, and it is necessary to remain in the hospital for
several weeks. Risks of the procedure include infections and bleeding due to the depletion of
normal blood cells. A risk of stem cell transplant with donor cells is known as graft-versus-host
disease (GVHD). In GVHD, the donor white blood cells react against the patient's normal
tissues. GVHD can be mild or very severe, and often affects the liver, skin, or digestive tract.
GVHD can occur at any time after the transplant, even years later. Steroids or medications that
suppress the immune response may be used to treat this complication.

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Supportive treatments

Because many of the treatments for leukemia deplete normal blood cells, increasing the risk for
bleeding and infection, supportive treatments may be needed to help prevent these complications
of treatment. Supportive treatments may also be needed to help minimize and manage unpleasant
side effects of medical or radiation therapy.
Types of supportive and preventive treatments that can be used for patients undergoing treatment
for leukemia include the following:

Blood or platelet transfusions

Anti-nausea medications

Antibiotics or antiviral medications to treat or prevent infections

White blood cell growth factors to stimulate white blood cell production (G-CSF and
GM-CSF

Red cell growth factors to stimulate red blood cell production

Intravenous injections of immunoglobulins to help fight infection

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Complications

Many of the challenges of leukemia relate to the depletion of normal blood cells as well as the
side effects of treatments as described in the previous section, such as frequent infections,
bleeding, and GVHD in recipients of stem cell transplants. Weight loss and anemia are further
complications of leukemia and its treatment. Complications of any leukemia also include a
relapse or a progression of the disease after a remission has been achieved with treatment.
Other complications of leukemia relate to the specific type of leukemia. For example, in 3%-5%
of cases of CLL, the cells change characteristics and transform into an aggressive lymphoma.
This is known as a Richter transformation. Autoimmune hemolytic anemic, in the body attacks
and destroys red blood cells, is another potential complication of CLL. People with CLL are also
more likely to develop second cancers and other blood disorders and blood cancers.
Tumor lysis syndrome is a condition caused by the rapid death of cancer cells when treated. It
can occur in almost any type of cancer, and it is seen with some cases of leukemia, particularly
when large numbers of leukemia cells are present such as with AML or ALL. The rapid
destruction of the leukemia cells leads to the release of large amounts of phosphate, which
further causes metabolic abnormalities and can lead to kidney failure.
Children who receive therapy for ALL may experience late adverse effects including central
nervous system (CNS) impairment, slowing of growth, infertility, cataracts, and an increased risk
for other cancers. The incidence of these late effects varies depending upon the age at treatment
and the type and strength of therapies.

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Prognosis

The prognosis of leukemia depends upon the type of leukemia that is present and the age and
health status of the patient. Mortality (death) rates for leukemia are higher in the elderly than in
younger adults and children. In many cases, leukemia can be managed or cured with treatments
available today. In particular, childhood ALL has a very high five-year survival rate.
Modern treatments have led to a greater than fourfold increase since 1960 in five-year survival
rates for leukemia. For the time period from 2004-2010, five-year survival rates for different
types of leukemia were approximately:

CML: 60%

CLL: 84%

AML: 25% overall, 66% for children and teens younger than 15

ALL: 70% overall, 92% for children and teens younger than 15, and 93% for children
younger than 5

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Prevention

Most people who develop leukemia do not have a known risk factor, and it is generally not
possible to prevent leukemia. Certain risk factors, such as exposure to radiation or benzene, may
be minimized, but this does not guarantee prevention of leukemia.

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Research being conducted leukemia

Leukemia is an active area of biomedical research. Ongoing studies are examining the risk
factors and causes of leukemia, as well as examining new and improved treatment options.
Clinical trials are studies that examine new drugs or new combinations of drugs and existing
treatments. Trials are under way to test new targeted therapy, biological therapy, and
chemotherapy regimens. Patients should discuss their situation and care with their doctor if they
are interested in being part of a clinical trial.

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at:

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Accessed

October 11, 2015.


2. Medical News Today. Leukemia: Causes, Symptoms and Treatments. 2015. Available at:
http://www.medicalnewstoday.com/articles/142595.php?page=2. Accessed October 11, 2015.

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3. Emedicine.medscape.com. Leukemias: Background, Pathophysiology, Epidemiology. 2015.


Available at: http://emedicine.medscape.com/article/1201870-overview. Accessed October 11,
2015.
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