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Acute Lymphocytic Leukemia

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Acute lymphocytic leukemia (ALL) is also known as acute lymphoid leukemia or acute lymphoblastic leukemia. Nearly 75% of childhood leukemias are of the ALL type. Malignancies in this disease can arise either in the T?cells or B?cells lymphocytes.
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Acute Lymphocytic Leukemia
Acute Lymphocytic Leukemia
WHAT IS ACUTE LYMPHOCYTIC LEUKEMIA?
The word leukemia literally means "white blood" and is used to describe a variety of cancers that begin in the
blood?forming cells of the bone marrow.
White blood cells (leukocytes) evolve from immature cells referred to as blasts. Malignancy in these blasts is the source
of leukemias, which generally progresses as follows:
Normally, blasts constitute 5% or less of healthy bone marrow. In leukemia, however, these blasts remain

abnormally immature and multiply continuously, eventually constituting between 30% and 100% of the bone
marrow.
Eventually these malignant blast cells fill up the bone marrow and prevent production of healthy red cells,

platelets, and mature white cells (leukocytes).
They spill out of the marrow into the bloodstream and lymph system and can travel to the brain and spinal cord (the
central nervous system). As the number of normal cells decline, dangerous symptoms develop, which, if untreated,
become lethal.
Leukemias are divided into two major types:
Acute (which progresses quickly with many immature white cells).

Chronic (which progresses more slowly and has more mature white cells).

Some blasts are called lymphoblasts (which become mature cells called lymphocytes) or myeloblasts (which mature to
myeloid cells). [For a description of these cells see Box Blood Cell Lines and Lymph System.] Acute leukemias are in
turn subdivided into two classifications according to whether the malignant blasts are lymphocytes or myeloid:
Acute lymphocytic leukemia (ALL), which is the subject of this report.

Acute myeloid leukemia (AML).

Acute Lymphocytic Leukemia
Acute lymphocytic leukemia (ALL) is also known as acute lymphoid leukemia or acute lymphoblastic leukemia. Nearly
75% of childhood leukemias are of the ALL type. Malignancies in this disease can arise either in the T?cells or B?cells
lymphocytes.
T?cell ALL is diagnosed in 15% of children and adults with ALL.

Between 80% and 85% of ALL cases, however, are of the B?cell lymphocyte lineage (often referred to as

"early" or "pre" B cell lineage).
Blood Cell Lines and the Lymph System
Blood Cell Lines
In adults, blood cells are produced by the bone marrow, the spongy material filling the body's bones. The
bone marrow produces two blood cell groups, myeloid and lymphoid.
Myeloid Cell Line. The myeloid cell line includes the following:
Immature cells called

erythrocytes that later develop into red blood cells.
Blood clotting cells (

platelets).
Some white blood cells, including

macrophages (which act as scavengers for foreign particles),
eosinophils (which trigger allergies and also defend against parasites), and neutrophils (the main
defenders against bacterial infections).
Lymphoid Cell Line. The lymphoid cell line includes the lymphocytes, which are the body's primary
infection fighters. Among other vital functions, certain lymphocytes are responsible for producing
antibodies, factors that can target and attack specific foreign agents (antigens).
Lymphocytes develop in the thymus gland or bone marrow and are therefore categorized as either
B?cells (bone marrow?derived cells) or T?cells (thymus gland?derived cells).
Lymphocytes and the Lymph System
1

Acute Lymphocytic Leukemia
To understand how acute lymphocytic leukemia (ALL) arises requires knowledge of lymphocytic
development and function:
B?cells

develop and mature in their final form (known as differentiation) in the bone marrow.
T?cells

also start out in the bone marrow but differentiate and mature in the thymus gland,
located beneath the breastbone. This small gland is active mostly in the fetal stage through the
first ten years of life, after which it atrophies (shrinks).
B?cell and T?cell lymphocytes leave these organs through the bloodstream, which eventually

branches out into the tiny blood vessels called capillaries.
Once they leave the capillaries, some lymphocytes migrate into the surrounding tissues. A

proportion of these lymphocytes (along with fluid, proteins, and other substances) then enters
the lymphatic vessels.
Lymphatic vessels begin as tiny, blind?ended tubes and lead to larger lymphatic ducts and

branches until they drain into two ducts in the neck, where the fluid re?enters the bloodstream.
Along the way, the fluid passes through

lymph nodes, which are oval structures composed of
lymph vessels, connective tissue, and white blood cells. Here, the lymphocytes are either
filtered out or are added to the contents of the node.
WHAT ARE THE SYMPTOMS OF ACUTE LYMPHOCYTIC LEUKEMIA?
Acute lymphocytic leukemia may be difficult to recognize. Symptoms develop under the following conditions:
When there are insufficient healthy mature white blood cells (leukocytes) to mount a defense against infection.

When there are not enough healthy platelets to prevent bleeding.

When the depleted oxygen?bearing red blood cells are unable to provide enough oxygen to organs.

ALL often begins abruptly and intensely, but symptoms may also develop slowly over time. They may be present one
day and absent the next, particularly in children. They include the following:
Patients with ALL may tire easily and have poor coloring from anemia caused by insufficient red blood cells.

Recurrent minor infections.

Bone pain.

Bruising, poor healing of minor cuts, or uncontrolled bleeding. Such symptoms may result from only slight

injury. Such bleeding events increase as the bone marrow fails to produce sufficient platelets to make a normal
blood clot (a condition called thrombocytopenia).
Small, red spots on the skin known as petechiae. They may form as a result of bleeding due to

thrombocytopenia.
Vision changes (rare). In rare cases, leukemia affects the eye, causing worsening vision or other visual

symptoms.
WHAT CAUSES ACUTE LYMPHOCYTIC LEUKEMIA?
Between 1973 and 1990, the number of acute lymphocytic leukemia cases in children under 15 rose by 27%. The
causes of the disease are not known, but experts believe that ALL develops from a combination of genetic, biologic,
and environmental factors.
Genetic Factors
Advances in genetic technologies have allowed identification of a number of mutations associated with ALL. Missing
or defective genes that suppress tumors are responsible for some of these cases. Identifying specific genetic groups is
allowing physicians to determine how aggressive a specific case is and eventually could provide targets for developing
highly specific treatments.
Translocations. Up to 65% of leukemias contain genetic rearrangements, called translocations, in which some of the
genetic material (genes) on a chromosome may be altered, or shuffled, between a pair of chromosomes.
For example, the most common genetic injury in ALL is t(12;21), which means a translocation with a genetic

shift between chromosome 12 and 21. It is also referred to as TEL?AML1 fusion and occurs in approximately
20% of ALL patients. Researchers believe that this translocation may occur during fetal development in some
patients.
About 20% of adults and about 5% of children with ALL have a genetic abnormality called the Philadelphia

(Ph) chromosome (t(9;22)).
Another important chromosome translocation is t(4;11) involving the MLL gene, also called HRX or ALL?1.

It tends to occur in infants with leukemia.
[For more information see Genetic Abnormalities under How Are Characteristics of Acute Lymphocytic Leukemia
Cells Used for Determining a Prognosis?]
2

Acute Lymphocytic Leukemia
Ikaros. A defective gene known as Ikaros, which regulates lymphocyte development, may play a major role in
childhood ALL.
Environmental Factors
Radiation. Exposure to repeated or high doses of ionizing radiation, which includes x?rays and gamma rays, has long
been known to increase the chances of developing leukemia. Specifically, radiation for certain cancer treatments is a
known cause of future leukemia.
Infectious Agents. Researchers are studying a number of viruses or other infectious agents that may trigger the
leukemia, particularly in genetically susceptible children. One researcher suggests, in fact, that a cluster of leukemia
cases reported near a nuclear plant may not be due to radiation, as widely believed, but to increased exposure to viruses
or infectious organisms brought in by a migrant work force. This is supported by clusters of ALL observed in different
small geographical areas where inward migration rates were high.
Special viruses called retroviruses, or RNA tumor viruses, cause leukemia in animals. The first of these viruses
associated with human leukemia was human thymic leukemia virus ?1 (HTLV?1), which may be responsible for some
cases of adult acute T?cell leukemia. A strong viral or infectious suspect for ALL, however, has not yet emerged.
Chemicals. To determine whether exposure to specific chemicals causes or increases the risk for leukemia is a daunting
challenge. About 75,000 synthetic chemicals were introduced in the first half of the century. In addition, investigators
must study the emissions from cars, the pesticides in foods and in neighborhoods, and the runoffs in drinking water.
Electromagnetic Fields. Some studies have reported an association between leukemia and high levels of
electromagnetic radiation (EMR), although this is controversial. Lower levels of radiation (e.g., living near power lines,
video screen emissions, small appliances, cell phones) are unlikely to pose any cancer risk.
WHO GETS ACUTE LYMPHOCYTIC LEUKEMIA?
ALL in Children. About 3,600 cases of acute lymphocytic leukemia are expected to be diagnosed in 2003, with about
2,200 of them in children and young people under 20. Until recently, most studies listed it as the most common
childhood cancer. (Some recent evidence suggests that cancers in the central nervous system may be surpassing ALL in
children.) The disease typically develops in children between one and 10 years old, but the disease can strike from
infancy to old age.
ALL in Adults. About 20% of ALL cases occur in adults. Adults who develop ALL are usually male and over 50 years
old, with the highest risk being above age 70.
Ethnicity and ALL
Caucasian and Asian children have a much higher risk for ALL than African?American children, although
African?American and Hispanic children who develop it do not appear to fare as well. Socioeconomic factors do not
appear to completely explain this difference.
Hereditary Disorders
Certain inherited disorders can increase the risk for leukemia. For example, children with Down's syndrome have a
20?fold greater risk of developing acute leukemia than the general population. Other rare genetic disorders associated
with increased risk include Bloom syndrome, Fanconi's anemia, ataxia?telangiectasia, neurofibromatosis, Schwachman
syndrome, IgA deficiency, and congenital X?linked agammaglobulinemia.
People Exposed to Radiation
Children treated with radiation and chemotherapy for Hodgkin's disease are at higher risk for acute leukemia within 2 to
13 years after treatment (usually of the myeloid variety). Children under 10 are most susceptible to acute leukemia
following exposure to radiation treatments. Susceptibility decreases between the ages of 10 and 19 then increases
slowly again through age 50. After 50, a person is again at high risk of developing acute leukemia following ionizing
radiation.
Most people who are not treated for cancer have low exposure to radiation, so radiation from other sources is not a
significant cause of leukemia. The following are some situations that may increase risk from radiation:
Fetal exposure to diagnostic x?rays (not ultrasound) before birth increases the danger of developing ALL by

the age of 15 years.
One study of children who lived near a nuclear waste processing plant in France found an increased risk for

leukemia, particularly if they ate local fish.
3

Acute Lymphocytic Leukemia
Reports of increased incidence in leukemia in peacekeepers and military personnel who were stationed in

Bosnia have sparked investigation of certain weapons that use depleted uranium, which were employed in the
Balkan wars. Military officials say the risk is unlikely, but more research is needed.
Indoor radon also does not appear to increase the risk for leukemia. (Radon does increase the risk for lung cancer,
however, particularly in smokers).
People Highly Exposed to Toxic Chemicals
Decades of research show that those who work in the petroleum industry (where benzene is derived) have a two to
threefold increased risk of developing leukemia (most often acute myeloid). Others who may be at some risk for
leukemia and lymphomas include painters, agricultural workers, distillers, dye users, furniture finishers, and rubber
workers.
People Exposed to Electromagnetic Fields
Because people's exposure to electromagnetic fields varies widely over the course of time, it is very difficult to
determine any risk. The following are some observations from studies on determining who, if anyone, might be at risk
for leukemia from exposure to electromagnetic fields:
Evidence is mixed on any risk for living near high?power electrical lines. A 2001 study reported a small

increase in risk for people living near high?voltage cables. Others have found no evidence of risk. In any case,
the risk is still very small.
One 2000 study suggested that people living in homes with wiring at very high current levels had a risk for

ALL that was about 20% above average.
Most studies have found that exposure to low?energy waves from household appliances does not increase the

risk of childhood ALL.
A 2000 study of workers highly exposed to wireless communication devices found no risk for leukemia or

other cancers.
A major study is under way to determine if there is any association between magnetic field exposure and survival in
children with ALL.
HOW SERIOUS IS ACUTE LYMPHOCYTIC LEUKEMIA?
Acute lymphocytic leukemia is responsible for about 1,400 deaths a year, and it can progress quickly if untreated.
However ALL is one of the most curable cancers and survival rates are now at an all?time high. Both the oldest and
very young age groups tend to have lower survival rates, usually because the leukemia that develops in these patient
groups tends to have genetic features that produce a more severe condition.
Outlook in Children with ALL. Survival rates in children with cancer, and leukemia in particular, have increased from
53% to 85% in North America over the past three decades.
Certain children are at higher risk for a poor outcome than others:
African?American and Hispanic children appear to have a poorer outcome than Non?Hispanic Caucasian

children. Research is underway to determine whether social and economic differences or other factors are
primarily responsible.
Survival rates in boys tend to be lower than in girls. The reason for this is not known, although it may be

partially due to the boys' higher risks for less favorable genetic profiles and for T?cell ALL.
Survival rates in infants are improving but they are still poor. The best results are in children ages one to nine.

Older children may require more aggressive treatment.
The prognosis may vary depending on other risk factors as well, including the subtype of the cancer, how high

the white blood count is, degree of organ involvement, and genetic background.
Although children with precursor?B and early precursor?B tend to have a better prognosis than ALL patients

with the B?cell stage and T?cell, advances in treatment are improving the outlook for patients with all these
latter types.
Responding well to early treatment is a good sign regardless of the risk category.
Outlook in Adults with ALL. Adults tend to have a more severe condition than children, even if they are carrying the
same ALL genes. Between 60% and 80% of adults with ALL can expect to achieve full remission with standard
treatments and between 35% and 40% survive beyond two years with aggressive treatments. Younger adults with ALL
have better long?term survival rates than older adults with the disease.
4

Acute Lymphocytic Leukemia
Long?Term Physical Effects of Treatments
The intense treatments required by ALL can have serious short? and long?term side effects. Some long?term
complications of particular concern are discussed below. They are also discussed in the section on treatments.
Fatigue and General Feelings of Ill Health. Long?term effects of the disease and its treatments may include fatigue and
general aches and pains, which can have a negative impact on daily life.
Osteoporosis. Loss of bone density (osteoporosis) is a side effect of corticosteroids. Patients or their parents should
discuss approaches to reduce this risk. Many therapies of protecting bone are available.
Heart Disease. Some of the treatments increase risk factors for future heart disease, including unhealthy cholesterol
levels and high blood pressure. ALL survivors should be sure to maintain a healthy lifestyle and be regularly monitored
for heart risks to help reduce these effects.
Obesity. Children treated for ALL are at higher risk for obesity, possibly because the treatments trigger an earlier than
normal occurrence in childhood weight gain. Corticosteroids, drugs used in treatments, also increase appetite, which
contributes to the problem. One study indicated, however, that lifestyle factors, such as adopting a pattern of reduced
physical activity during treatment, plays the major role in this complication.
Impaired Mental and Neurologic Functioning. Cranial radiation and drugs used in chemotherapy, especially specific
corticosteroids and intrathecal treatments may impair mental functioning and cause neurologic problems, such as
movement problems. Advances in cranial radiation may reduce the neurologic and mental risks from this treatment, but
it can occur with many other treatments as well. Of particular interest was a 2001 report suggesting that
methylphenidate (Ritalin) may improve mental performance in children.
Infections. Some children may be more vulnerable to infections for some time after completing chemotherapy, although
the immune system tends to improve over time. Studies now suggest that young survivors of leukemia have an
increased risk for measles, mumps, and rubella (MMR), even if they have been previously vaccinated. Children, then,
may need reimmunization.
Impaired Physical Growth. Cranial radiation can result in impaired growth.
Infertility. Chemotherapy, cranial radiation, or both can impair fertility in male and female patients.
Secondary Cancer. Rarely secondary cancers, most often leukemia (generally acute myeloid leukemia), can later
develop.
Psychologic and Mental Consequences
Studies are finding that survivors of childhood leukemia tend to have more psychological problems, including stress,
depression, anger, and confusion, than their physically healthy siblings. As adults, they are also more likely to be
unemployed or working part time. Recognizing this risk and getting psychologic support early may be important and
helpful. Nevertheless, in one 2002 study, young survivors reported satisfaction with life, a sense of purpose, and an
ability to cope because of their experiences with cancer.
Effects on Caregivers
Parents also suffer, and one study found that they developed more symptoms of post?traumatic stress disorder than
their children. Mothers and fathers suffer equally.
HOW IS ACUTE LYMPHOCYTIC LEUKEMIA DIAGNOSED?
Laboratory tests provide the basis for diagnosing ALL.
Flow Cytometry
Flow cytometry is an important diagnostic technique in leukemia that uses complex fluids, laser optics, and computers.
It is most often used to count blood cells but it can also determine the components and structural features of cells. It can
process thousands of cells in seconds and take measurements of a single cell. Advanced techniques using flow
cytometry employ fluorescent light that is scattered by cells and revealed by lasers. The features of the scattered light
allow experts to detect many characteristics of the cells. It is important in leukemia for diagnosing patients, for
providing information on their prognosis, and for identifying residual disease after treatments.
5

Acute Lymphocytic Leukemia
Complete Blood Cell Count
A complete blood cell count is the first step in diagnosing ALL. This test will often show various findings, including
the following:
The presence of circulatory leukemic blast cells.

The presence and severity of anemia.

The count of a variety of blood cell types. (A high white blood cell count indicates a more severe disease.)

These tests will not always show the presence of leukemic cells.

Blood tests do not always detect leukemia, and about 10% of patients with ALL have a normal blood cell count.
Bone Marrow Biopsy
If the results of the blood tests are abnormal or the physician suspects leukemia despite normal cell counts, a bone
marrow aspiration and biopsy are the next steps.
A local anesthetic is given. (This is a very common and safe procedure. However, because this test can

produce considerable anxiety, particularly in children, parents may want to ask the physician if sedation is
appropriate for their child.)
A needle is inserted into the bone, usually the rear hipbone. There may be brief pressure or pain. A small

amount of marrow is withdrawn. (It looks like blood.)
A larger needle is then inserted into the same place and pushed down to the bone. The health professional will

wiggle the needle from side to side to loosen a larger specimen for the biopsy. The patient will feel some
pressure.
The sample is then taken to the lab to be analyzed. All the results are completed within a couple of days.

Normal bone marrow contains 5% or less blast cells (the immature cells that ordinarily develop into healthy blood
cells). In leukemia, abnormal blasts constitute between 30% and 100% of the marrow.
Spinal Tap
If bone marrow examination confirms ALL, a spinal tap may be performed, which uses a needle inserted in to the spinal
canal. The patient feels some pressure and usually must lie flat for about an hour afterward to prevent severe headache.
This can be difficult, particularly for children, so parents should plan reading or other quit activities that will divert the
child during that time. Parents should also be certain that the professional administering this test is highly experienced.
A sample of cerebrospinal fluid with leukemia cells is a sign that the disease has spread to the central nervous system.
In most cases of childhood ALL, leukemic cells are not found in the cerebrospinal fluid.
HOW ARE CHARACTERISTICS OF ACUTE LYMPHOCYTIC LEUKEMIA CELLS USED
FOR DETERMINING A PROGNOSIS?

Once a diagnosis of leukemia has been made, further tests are performed to assess the following properties:
Whether the cells are myeloid or lymphocytic (i.e. the cell of origin).

Stage of maturity of the ALL B?cell.

Their

immunologic features (the specific markers on the surface of the cancer cell that respond to antigens).
Their

cytogenetics (the genetic makeup of the cells).
Their

morphology (their physical characteristics).
Determining the Cell of Origin
First, the physician must determine the cell of origin (whether it is myeloid or lymphocytic). One method is to measure
an enzyme called terminal deoxynucleotidyl transferase (TdT).
About 95% of all ALL types (except the subtype B?cell) have elevated TdT.

Only about 20% of cases of acute myeloid leukemia (AML) express TdT, however, so its use in determining

the cell line is limited.
B?Cell Maturity
The stage of maturity of the leukemic B?cell helps determine prognosis. There are three stages:
Early precursor?B. Approximately 80% of ALL patients have the early precursor?B subtype, which is the

least mature. It also offers the best prognosis.
6

Acute Lymphocytic Leukemia
Precursor?B. This is the intermediate stage.

B?cell. This is the mature cell and ALL in this stage is identical to Burkitt's non?Hodgkin's lymphoma. It is

therefore treated differently from other ALL cases.
Immunological Markers
A series of tests are used to determine the immunologic pattern of the leukemia cell (how it can be expected to interact
with the immune system).
On the surface of malignant ALL cells are markers for certain antigens (molecules that set off a targeted attack by the
immune system using antibodies). Such antigens are proving to be very helpful in predicting outcome.
Important ones include the following:
CD10, more frequently referred to as cALLa (common ALL antigen). This antigen occurs in about half of all

ALL cases and in about 80% of ALL B?precursor patients. It is associated with a good prognosis.
CD95. Likewise, the presence of CD95 has a positive influence.

CR19.

DR.

The surfaces of T?cell ALL cancer cells express several antigens as well. For example the presence one of these, CD2,
suggests a favorable prognosis.
Testing for Genetic Abnormalities
Genetic tests are useful for a number of important criteria:
Diagnosing a specific ALL subtype.

Designing appropriate treatment.

Gauging prognosis.

Monitoring patients throughout treatment and beyond.

Cytogenetics is a technique that researchers use to determine specific genetic abnormalities, which are found in nearly
65% of all leukemias. Detecting these genetic defects is helpful in making a full diagnosis of ALL and in planning the
most appropriate therapy. Specific technologies called microarray chips are now capable of checking up to 48,000
different genes in a single experiment, which holds promise for assessing prognosis and developing very targeted
therapies in the future.
Translocations. Genetic translocations (defective alterations of genetic arrangements) may affect outlook. [For more
details on translocations, see Genetic Factors, under What Causes Acute Lymphocytic Leukemia?] Examples include
the following:
Patients with the t(12;21) genetic translocation (also referred to as TEL?AML1 fusion) have an excellent

prognosis.
Patients who carry the defective gene called ETV6 often respond well to chemotherapy.

The t(4;11), sometimes referred to as MLL, is the most common translocation in children under one year.

Unfortunately, it carries a poor outlook in anyone who carries it. A 2001 study suggested that this genetic
variant may actually be a unique leukemia and require treatments that differ from standard ALL.
The Philadelphia translocation also t(9;22) indicates a poor outlook. It represents about 20% of adult cases and

only about 5% of childhood cases.
The t(1;19) location occurs in about 5% of ALL childhood cases and requires aggressive treatment.

Ploidy. Ploidy refers to the number of chromosomes. Additional copies (hyperdiploidy) or absence of copies
(hypodiploidy) of chromosomes affect prognosis. For example, in children hyperdiploidy is associated with a more
favorable outcome and hypodiploidy with a poorer outcome. (Hypodiploidy occurs only in 1% of children with ALL.)
Morphology
The morphology of a cell includes its physical characteristics, such as shape and structure. To determine the
morphology of the leukemia cells, samples of the bone marrow are taken and particular contents of the cells are stained
with a dye. They are then examined under a microscope.
Acute lymphocytic leukemia cells are grouped according to the French?American?British (FAB) classification system
into three ALL morphologic types. (It should be noted that this system is subjective and is now used to complement
other diagnostic tests as mentioned above):
7

Acute Lymphocytic Leukemia
L1 cells.

These are small blasts with scant amounts of cytoplasm (the substance in a cell between its membrane
and nucleus). L1 cells usually contain a round nucleus and there is little variation among them. L1 represents
the most common ALL morphology and offers the best prognosis. It occurs in about 85% of children and 30%
of adults with ALL.
L2 cells.

These cells are larger than L1 and have more abundant cytoplasm. They vary significantly among
each other and have an irregularly shaped nucleus. L2 morphology conveys a poorer prognosis than L1,
although the two cells' types are treated similarly. Subtype L2 is the most common morphologic type in ALL
adults; 64% of adults with ALL have this subtype compared with only 15% of children.
L3 cells.

These are uncommon. They resemble another malignancy called Burkitt's lymphoma and their
treatments are now the same.
Drawing Conclusions from Cell Characteristics
Using the results of the tests described above, patients are classified into low?, average?, and high?risk groups, which
have unique therapies. This information allows the doctor to diagnosis the type of leukemia and plan the best treatment.
Physicians attempt to make a prognosis and determine an optimal treatment plan by assessing all the cell characteristics
plus the white blood cell count. As examples:
Patients who have an L1 or L2 morphology, a white blood cell count of less than 15,000 mm3, a t(12;21)

genetic translocation, and a cALLa?positive antigen marker have an excellent outlook.
On the other hand, patients who have an L2 morphology, a white blood cell count greater than 30,000 mm3,

and who lack the cALLa marker have a poorer prognosis and require more aggressive treatment.
WHAT ARE THE GENERAL GUIDELINES FOR TREATING ACUTE LYMPHOCYTIC
LEUKEMIA?

The aim of the initial treatment phase is to achieve complete remission, in which there is no evidence of leukemia in the
body, and in which the bone marrow has 5% or lower levels of blasts.
Treatment Phases
There are typically four treatment stages for the average?risk ALL patient, both children and adults.
Induction therapy and usually central nervous system prophylaxis (preventive treatment) to achieve a first

remission.
Consolidation and maintenance to prevent relapse after remission.

Specific Treatments Used in ALL
The following are specific treatments used for ALL:
Chemotherapy is the primary treatment for each stage.

Radiation to the brain and spinal cord is also administered in some cases.

A bone marrow transplant is often recommended for relapsed ALL or in cases that cannot be induced into

remission (refractory disease). It is also sometimes considered after remission is achieved for certain high?risk
ALL types. The timing of bone marrow transplantation can be controversial, particularly after a first remission,
although it has produced excellent long?term survival rates in appropriate patients.
New drugs known as biological therapies are currently being investigated.

Supportive Treatment
Drugs Used to Prevent Infections during Treatment. Half of all ALL patients develop fever in the early stages,
especially if patients also have neutropenia (low levels of the white blood cells called neutrophils). Neutropenia is
common in ALL and is a significant risk factor for serious infection. Of increasing concern are fungal infections, which
are becoming common in these patients, particularly after transplant procedures.
Antibiotics and Antifungal Medications.

The use and timing of antibiotics and antifungal medications depend
on the particular organisms and severity of the infection. In some cases of neutropenia, patients may need
preventive antibiotics.
Granulocyte Colony?Stimulating Factor.

Granulocyte colony?stimulating factor (e.g. lenograstim, filgrastim)
is often given to patients who receive chemotherapy in order to stimulate the growth of infection?fighting
white blood cells. This helps prevent neutropenia.
Intravenous Fluids. Patients may also need to receive intravenous fluids and be treated for fluid imbalances, which can
cause abnormal levels of sodium, potassium, calcium, and uric acid. Such treatments might include sodium bicarbonate,
allopurinol, and aluminum hydroxide or calcium carbonate.
8

Acute Lymphocytic Leukemia
Transfusions. Red blood cell or platelet transfusions may be needed. (Patients who may have allogeneic
transplantations should not receive transfusions from potential donors.)
HOW IS A CHILD WITH ACUTE LYMPHOCYTIC LEUKEMIA MANAGED AT HOME?
A parent should call the doctor if the child has any symptoms that are out of the ordinary, including (but not limited) to
the following:
Any fever of 101°F or higher.

Any signs of a flu or cold.

Shortness of breath.

Severe diarrhea.

Blood in the urine or stools.

Trouble urinating.

Home Management for Preventing Infection
Tracking Neutrophils. Parents should track their child's absolute neutrophil count. This the measurement for the amount
of white blood cells, and is an important gauge of a child's ability to fight infection.
Counts over 1,000, for instance, usually provide sufficient protection so that children can engage in normal

activities, including school and other functions where they are exposed to other children.
If the count is between 500 and 1000, the child should avoid large groups.

If it falls between 200 and 500 the child should stay at home and should see only healthy visitors who have

washed their hands vigorously.
Neutrophil counts below 200 indicate that the child is at high risk for infection and should have no visitors.

Maintaining Strict Hygiene. Children with ALL and anyone exposed to them, not only friends and family members but
also doctors and nurses, should maintain strict hygiene:
Frequent hand washing with antibacterial soap is particularly essential.

Everyone should wash their hands before and after meals, after being outside, before preparing food, and after

going to the bathroom.
When visiting the doctor, a parent should ask about a side entrance or areas where the ALL patient will not be

exposed to other sick children.
Vaccinations. Studies now suggest that young survivors of leukemia have an increased risk for measles, mumps, and
rubella (MMR), even if they have been previously vaccinated. Children, then, may need reimmunization. Siblings of
ALL patients who require polio vaccinations should be given the killed virus (IPV), not the live polio vaccination
(OPV).
Other Precautions
Use a soft toothbrush when counts are low to prevent gum bleeding.

Avoid the common pain relievers known as nonsteroidal anti?inflammatory agents (NSAIDs). They increase

the risk for bleeding and include ibuprofen (Advil, NSAIDs include aspirin, ibuprofen (Motrin IB, Advil,
Nuprin, Rufen), naproxen (Aleve), ketoprofen (Actron, Orudis KT).
Some of the drugs used for leukemia cause extreme sun sensitivity. Children should wear sunblock and be covered with
sun?protective clothing when going outside in order to avoid sunburn, which can cause skin infection.
WHAT ARE THE TREATMENTS TO ACHIEVE A FIRST REMISSION?
The aim of induction therapy, the first phase, is to reduce the body's burden of leukemia cells to undetectable levels.
The general guidelines for induction therapy are as follows:
Patients are given intensive chemotherapy that uses powerful multi?drug regimens. (Infants require special

regimens not discussed here.)
For both children and adults, some of these therapies are administered orally, others intravenously.

Hospitalization is usually necessary at some point to help prevent infection and to administer blood products.

However, much of this therapy can be given on an outpatient basis.
After the first cycle of induction, bone marrow tests are done to determine if the patient is in remission.

Another bone marrow test is sometimes done about a week later to confirm the first results.

A bone marrow transplant is considered for patients who do not respond at all to induction treatment.

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Acute Lymphocytic Leukemia
Drugs Used for Induction Chemotherapy
Drugs Used for Standard or Low?Risk Patients. A three?drug regimen is typically used for standard or low?risk
patients. (A fourth drug, such as cyclophosphamide, may be added for adult patients.) Examples of drugs used in
regimens for children include the following:
Vincristine.

A corticosteroid (prednisone or dexamethasone). Of note: a 2003 study reported better survival rates with

dexamethasone compared to prednisone.
Asparaginase. (Several forms are available. Investigation on a potent form called

E?coli asparaginase
(Asparaginase medac) is promising for preventing relapse, particularly second relapses, but this agent is very
toxic and increases the risk for blood clots.)
When this regimen is used in conjunction with CNS prophylaxis, remission rates of greater than 95% have been
achieved in children. In a 2001 study, researchers reported that the most effective regimen for many children may
employ dexamethasone after the first month with a longer duration for asparaginase (30 rather than the standard 20
weeks).
Drugs Used for High?Risk Children. A four or five?drug regimen is used for many high?risk children. An example of
a four?drug regimen follows:
Vincristine, prednisone/dexamethasone, plus asparaginase, and an anthracycline (e.g., doxorubicin,

daunorubicin, epirubicin).
Drugs Used for Specific High?Risk Adults. Adult patients have a poorer outlook than children do, and investigators and
looking for more effective chemotherapy regimens. For example, cyclophosphamide?based regimens are used in
certain adult patients with particular genetic translocations or who have T?cell ALL.
Central Nervous System (CNS Prophylaxis)
CNS prophylaxis is critical for preventing disease that has spread to the brain, spine, and testes (called sanctuary
disease sites). Although only 3% of children with ALL have evidence of leukemia in the central nervous system (CNS)
at the time of diagnosis, leukemia will spread to this region in between 50% and 70% of children without preventive
(prophylactic) treatment. The brain is one of the first sites for relapsing leukemia.
CNS prophylaxis involves the following:
It is often administered in conjunction with induction therapy before moving to consolidation, the next

standard treatment phase, particularly if there are any leukemic cells detected in the spinal fluid.
It often employs

intrathecal chemotherapy, in which a drug is injected directly into the spinal fluid. The drugs
used are either methotrexate alone or a combination of methotrexate, hydrocortisone, and cytarabine.
(Induction chemotherapy does not penetrate the blood?brain barrier sufficiently to destroy leukemic cells in
the brain.)
In some cases, methotrexate, with or without other drugs, is given as systemic (widespread) therapy at the

same time as intrathecal chemotherapy. The addition of this treatment is effective in preventing relapse in the
central nervous system and can substitute for radiation to the skull.
Cranial Radiation Therapy. Some high?risk children also receive radiation to the skull (cranial irradiation), radiation to
the spine, or both at the same time. This combination can be very toxic and can cause later learning problems. It is
generally used only in children who have evidence of the disease in the central nervous system at the time of diagnosis.
Later complications can include learning and neurologic problems. Using lower?dose units of radiation, however, is
proving to be effective and to significantly reduce the risk for mental impairment. Cranial radiation is also associated
with later risk factors for heart disease.
Indications for Remission after Induction Treatment
Survival in acute leukemia depends on complete remission. Although is not always clear?cut, remission
is indicated by the following:
All signs and symptoms of leukemia disappear.

There are no abnormal cells in the blood, bone marrow, and cerebrospinal fluid.

The percentage of blast cells in the bone marrow is less than 5%.

Blood platelet count returns to normal.

Induction can produce extremely rapid results and the faster the time to remission the better the outlook:
10

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