Acute Lymphocytic Leukemia
Definition
Acute lymphocytic leukemia is a cancer of the white blood cells known as lymphocytes.
Description
Leukemia is a cancer of white blood cells. In acute leukemia, the cancerous cells are immature forms called blasts that cannot properly fight infection; patients become ill in rapid fashion.
The cells that make up blood are produced in the bone marrow and the lymph system. The bone marrow is the spongy tissue found in the large bones of the body. The lymph system includes the spleen (an organ in the upper abdomen), the thymus (a small organ beneath the breastbone), and the tonsils (an organ in the throat). In addition, the lymph vessels (tiny tubes that branch like blood vessels into all parts of the body) and lymph nodes (peashaped organs that are found along the network of lymph vessels) are also part of the lymph system. The lymph is a milky fluid that contains cells. Clusters of lymph nodes are found in the neck, underarm, pelvis, abdomen, and chest.
The main types of cells found in the blood are the red blood cells (RBCs), which carry oxygen and other materials to all tissues of the body; white blood cells (WBCs), which fight infection; and the platelets, which play a part in the clotting of the blood. The white blood cells can be further subdivided into three main types: granulocytes, monocytes, and lymphocytes.
The granulocytes, as their name suggests, have particles (granules) inside them. These granules contain special proteins (enzymes) and several other substances that can break down chemicals and destroy microorganisms such as bacteria. Monocytes are the second type of white blood cell. They are also important in defending the body against pathogens. The lymphocytes form the third type of white blood cell. The two types of lymphocytes are Bcells, which make antibodies, and T-cells, which make other infection-fighting substances. Lymphocytic leukemia can arise in either B or T cells.
B-cell leukemia occurs more frequently than T-cell leukemia. It is the most common form of leukemia in children, but also occurs in adults. At diagnosis, leukemic cells can be found throughout the body, in the bloodstream, the lymph nodes, spleen, liver, occasionally in the central nervous system, and in T-cell ALL, the thymus gland.
Cancerous lymphoblasts take over the bone marrow,
reducing both the number and the effectiveness of all
types of blood cells. The cancerous cells reduce the ability
of healthy white cells to fight infection. Fewer red
cells are produced, causing anemia, and fewer platelets
increases the risk of bleeding and bruising. The presence
of the cancerous white cells in the central nervous system
can produce headaches, confusion and seizures.
The type of treatment a person receives for ALL
depends on the presence of risk factors for relapse. Children
are at standard risk if they are between ages 1 and 9,
have a total white cell count of less than 50,000 per
microliter of blood, and have B-precursor cell leukemia.
Children are at high risk if they are younger than 1 or
older than 9, if their white blood cell count exceeds
50,000 per microliter, or if they have T-cell leukemia.
Compared to children, adults are all at higher risk of
relapse at the time of diagnosis, but younger adults (less
than 25 years old) have a better prognosis.
B-cell ALL constitutes about 80% of all cases. The
cancerous cells are either early pre-B cells, the most
immature, pre-B cells, also somewhat immature, or Bcells.
These B-lineage cells contain a variety of proteins
called antigens. The presence of one of these antigens,
called CALLA for common ALL antigen, carries a
somewhat more favorable prognosis.
T-cell ALL has a less favorable prognosis than Bcell
ALL. The presence of an antigen called CD2 indicates
a more favorable prognosis.
ALL is also classified by karyotype, which is the
number and composition of a cell’s chromosomes. Normal
human cells contain 46 chromosomes. One chromosomal
abnormality often seen in ALL is a translocation,
in which a piece of one chromosome becomes attached
to a different chromosome. Different translocations carry
different prognoses. One translocation, labeled t(9;22) is
also called the Philadelphia chromosome and is found in
5% of childhood ALL and 20% of adult ALL cases. The
Philadelphia chromosome carries a somewhat less favorable
prognosis.
The number of chromosomes found in the leukemic
cells, particularly in children, also impacts prognosis.
The occurrence of more than 50 chromosomes in
leukemic cells has a very favorable prognosis. Even the
presence of one extra chromosome can be favorable.
Children whose leukemic cells have fewer than 45 chromosomes
are at highest risk of treatment failure.
Demographics
ALL is less common than AML in adults; about
1500 adults are diagnosed with ALL each year, compared
to 10,000 diagnosed with AML. About 1000 adults
die of ALL each year and the overall five-year survival
rate for adults with ALL is 58%.
About 1500 cases of ALL are diagnosed in children
under 18 each year in the United States. ALL is by far the
more common form of leukemia in children. The death
rate for children with ALL has dropped nearly 60% in the
last 30 years. The overall five-year survival rate for children
with ALL is now 80%. Still, leukemia causes more
deaths in children under 15, about 550 per year, than any
other disease.
In the United States, ALL is highest among Caucasians
and lowest among Asian-Americans. The incidence
of ALL is about 50% higher for men than for
women. Death rates in leukemia patients are highest in
African-Americans and Caucasians and lowest in Asians.
In children, the highest leukemia rates in the US
occur among those of Filipino descent; next highest are
white Hispanics, then non-Hispanic whites, and the lowest
incidence in children is in African-Americans. Survival
is higher for Caucasians than African-Americans.
The survival rate for girls is slightly higher, in part due to
the risk of relapse occurring in the testicles and in part
because boys appear to have a slightly higher risk of
bone marrow relapse.
Causes and symptoms
Causes
While specific causes for ALL are not known, there
are some known risk factors, including ionizing radiation.
Exposure to certain chemicals, particularly benzene
(used in the manufacture of plastics, rubber, and some
medicines), has also been associated with an increased
risk of developing ALL. ALL incidence in adults increases
with age.
The causes of ALL in children are also unknown.
Certain inherited genetic abnormalities, such as Down
syndrome, increase the risk. Some studies have shown
prenatal exposure to ionizing radiation increases a child’s
risk of ALL. Some contaminants of tap water, such as trihalomethanes,
chloroform, zinc, cadmium, and arsenic
are associated with an increased risk. A number of
reports suggested an increased risk of ALL among children
who lived in proximity to high voltage power lines,
but several later analyses suggested that was not true.
Studies continue in efforts to disprove or confirm this
possible connection. ALL is more common in children
who are not firstborn and among those whose mothers
took antibiotics during their pregnancies. Breastfeeding
has been found to be protective.
Symptoms
ADULTS. ALL in adults can cause any or all of the
following symptoms:
• fevers, chills, sweats
• weakness, fatigue, shortness of breath
• frequent infections
• depressed appetite, weight loss
• enlarged lymph nodes
• easy bleeding or bruising
• rash of small, flat red spots (petechiae)
• bone and joint pain
Symptoms of central nervous system involvement
include:
• headache
• nausea and vomiting
• confusion
• seizures
CHILDREN. Symptoms in children are similar, but
young children may be unable to communicate them.
They include:
• fevers
• frequent infections
• fatigue, irritability, decreased activity levels
• easy bruising or bleeding
• bone or joint pain
• a limp
• swollen belly
• enlarged lymph nodes
T-cell ALL can invade the thymus gland in the upper
chest, which can cause compression of the windpipe,
cough or shortness of breath, and superior vena cava
syndrome (compression of a large vein that causes
swelling of the head, neck, and arms).
Central nervous system involvement in children produces:
• headache
• nausea and vomiting
• blurred vision
• decline in school performance
• seizures
Spread to the testicles can cause painless swelling in
them.
Diagnosis
There are no screening tests for leukemia. The
patient’s history and physical examination raise the
physician’s suspicions, triggering orders for appropriate
tests. Pallor, swollen lymph nodes, bleeding, bruising,
pinpoint red rashes, and in children, a swollen abdomen,
will suggest the diagnosis. Testing is similar for adults
and children.
The first test is a complete blood count (CBC),
examining red cells, platelets and white cells. In early
leukemia, the total white blood cell count might be normal,
but there will usually be circulating lymphoblasts,
which is always abnormal. The red cell and platelet
counts may be low.
The abnormal CBC results trigger a referral to a
hematologist/oncologist who will perform a bone marrow
aspiration and biopsy, in which a small sample of
marrow is removed with a hollow needle inserted in the
hipbone. Although topical anesthetic will numb the skin
and bone, most patients experience brief pain during this
procedure. The sample will be examined microscopically
for evidence of lymphoblasts. The marrow will be further
studied to determine whether the lymphoblasts are of Tcell
or B-cell origin and the cells tested for chromosomal
abnormalities. A pathologist can examine the marrow and
make the diagnosis immediately. The chromosome studies
require several days to complete. The bone marrow
aspirate will be repeated occasionally during treatment to
confirm remission and to look for possible relapse.
A lumbar puncture, or spinal tap, will be performed
to rule out spread of ALL to the central nervous system. A
thin needle is inserted between two vertebrae in the lower
back, and spinal fluid removed. This fluid is examined
microscopically for the presence of lymphoblasts. Topical
anesthetics eliminate most of the discomfort of a spinal
tap, although many patients experience headaches afterwards.
Remaining flat for 30 minutes after a spinal tap
decreases the likelihood of headache.
A chest x ray will show enlargement of internal
lymph nodes or the thymus gland.
No preparation is necessary for most of the testing
done to diagnose ALL. Younger children will often
receive mild sedatives before procedures like spinal taps
and bone marrow studies. Topical anesthetic cream can
be applied an hour in advance of either a bone marrow
test or a spinal tap.
When treatment is complete, tests for minimal residual
disease can be performed. These new tests detect the
presence of lingering leukemic cells that would have
been missed by standard testing. The presence of a certain
amount of residual disease probably has an impact
on prognosis and the likelihood of relapse.
Treatment team
The treatment team consists of a hematologist/
oncologist who directs care, oncology nurses familiar
with administering chemotherapy, and often social
workers, who can address both insurance issues and psychological
support. The patient’s regular physician
should be kept informed of all cancer-related care.
Because treatment is so prolonged, most patients have
long-term intravenous catheters placed by a surgeon.
In many hospitals, a Child Life specialist will participate
in the care of children with ALL. They ensure that
children with cancer are seen, first and foremost, as children,
organizing play times, providing distraction during
scary procedures and giving parents some much-needed
respite.
Clinical staging, treatments, and prognosis
ALL does not have a formal staging system, but
treatment is different in different phases of the disease.
These phases are often divided into untreated ALL, ALL
in remission, and recurrent ALL. Conventional treatment
for ALL consists of chemotherapy for disease in the bone
marrow and treatment aimed at preventing central nervous
system disease.
ADULTS. The first phase of treatment is remission
induction. The chemotherapeutic drugs typically include
prednisone, vincristine, cytarabine, cyclophosphamide
and asparaginase. Most are given intravenously and a
few are given orally. Depending on the disease, these
drugs can achieve a complete remission in 60% to 90%
of adults. The relapse rate is higher in adults than in children.
A 50% 3-year survival has been noted in some
research series, and very aggressive treatment with multiple
drugs has produced up to a 70% survival rate.
Adverse effects of these drugs include:
• bone marrow suppression
• anemia, pallor, fatigue, shortness of breath, and angina
in older patients
• bleeding, bruising
• increased risk of infection
• hair loss (alopecia)
• mouth sores
• nausea and vomiting
• menopausal symptoms
• lower sperm counts
• tumor lysis syndrome, in which the dead cancer cells
can harm healthy organs
Treatment that is directed at preventing central nervous
system spread is called prophylactic. Because of the
blood brain barrier, a physical and chemical barrier that
prevents toxins from reaching the brain and spinal cord,
chemotherapeutic drugs do not easily reach the central
nervous system. Thus, chemotherapeutic drugs are
administered directly into spinal fluid, which circulates
around the brain and spinal cord. This is called intrathecal
chemotherapy. The drugs are given by spinal tap or
through an Ommaya reservoir, which is surgically
inserted under the scalp. This reservoir empties into the
spinal fluid around the brain.
Some patients receive prophylactic radiation therapy
to the brain, in addition to or instead of intrathecal
chemotherapy.
CHILDREN. The treatment of ALL in children represents
one of the great success stories of modern oncology.
In contrast to adults, most children with cancer enter
into research protocols, strict treatment regimens with
careful follow-up that are built on the most successful
aspects of earlier treatments. Childhood ALL now has an
80% long-term survival rate, due in large part to the
extensive and widely disseminated research on the disease.
Within the United States, research on ALL was
conducted for many years under the auspices of either
the Children’s Cancer Group or the Pediatric Oncology
Group. In 1998, recognizing the benefits of cooperation
and collaboration, these two groups joined forces with
the National Wilms’Tumor Study Group and the Intergroup
Rhabdomyosarcoma Study Group to form the
Children’s Oncology Group.
Remission induction chemotherapy for children
includes vincristine, a steroid, and asparaginase. Children
at higher risk of relapse are often given daunomycin
as well. The adverse effects of these drugs include bone
marrow suppression, risk of infection, nausea, vomiting,
hair loss, and mouth sores. Although these drugs can
reduce sperm counts, most survivors of childhood ALL
grow up to have normal fertility. The drugs can be
administered intravenously or as oral preparations. Oral
prednisone has a particularly unpleasant taste that is hard
to disguise and parents must be vigilant to ensure that
their children are taking their proper doses.
Like adults, children also receive prophylaxis against
central nervous system spread. They receive multiple
doses of intrathecal chemotherapy, with the drugs delivered
directly to the spinal fluid through a lumbar puncture
or spinal tap. Cranial radiation as central nervous system
prophylaxis for children is infrequently used. Though once
standard, brain radiation produced a high incidence of
cognitive and learning disabilities, especially among those
younger than five years old. Cranial radiation is reserved
for those children felt to be at high risk of central nervous
system disease, including those older than ten at the time
of diagnosis, those with initial white blood cell counts of
more than 50,000 per microliter, and those with T-cell
leukemia. Some high-risk children who enter remission
rapidly with induction chemotherapy receive intrathecal
chemotherapy alone, without radiation therapy.
Alternative and complementary therapies
ADULTS. Individuals with leukemia often employ
alternative or complementary therapies. Some of these
provide pain relief and improve psychological well
being. No controlled studies have yet shown that alternative
treatments offer cures for ALL, although some may
hold promise of benefit.
Patients with ALL sometimes use acupuncture,
which offers relief from generalized pain, nausea, and
vomiting. Other methods that may help with the physical
and often emotional side effects of treatment include
hypnosis, guided imagery, and yoga.
Nutritional supplements and herbs are sometimes
utilized by persons with leukemia. Coenzyme Q10 is an
antioxidant, a substance that protects cells from toxic
byproducts of metabolism. Early studies suggest,
although it is not proven, that coenzyme Q10 can
improve immune function and counteract some of the
harmful effects of chemotherapy and radiation on
healthy cells. Adverse effects of coenzyme Q10 include
headache, rash, heartburn and diarrhea. Another supplement
with potential benefit is polysaccharide K (PSK). A
few studies have shown PSK to have some benefit in
improving immunity.
Supplements that have not been proven to be of
value or are potentially dangerous to those with leukemia
include camphor, sometimes called 714-X. Green tea has
received much press for its reported abilities to enhance
the immune system and fight cancer, but studies have had
conflicting results. Some show that green tea has preventive
benefits and others show no effect. A few animal
studies suggest that growth of tumors might be slowed
by green tea, but this has not been shown in humans yet.
Hoxsey is another supplement touted as a cancer
treatment, but no studies have confirmed any benefit.
Some of its ingredients have serious adverse effects. Vitamin
megadoses have long been advocated as beneficial
in cancer, but no conclusive studies show benefit, and
they have significant potential for adverse effects, such
as diarrhea, kidney stones, iron overload, nerve damage
and liver disease.
Laetrile, or amygdalin, was once touted as a cure for
cancer and leukemia. No human or animal studies conducted
in the decades since have shown any benefit other
than relief of some pain. Laetrile can, however, cause
cyanide poisoning.
CHILDREN. Complementary and alternative treatments
are recommended less frequently for children.
Real caution must be used in administering herbal remedies
to children, whose metabolisms are very different
from those of adults. For example, jin bu hua, a traditional
Chinese medicine, can cause heart or breathing problems.
Life root and comfrey can both cause fatal liver
damage in children.
While many children are too young for formal guided
imagery, they can be distracted from the fears and
pain associated with some treatments by toys and videotapes.
Reading favorite books during scary procedures
can relieve some of their fears.
ALL in remission
ADULTS. Remission is achieved in many people
within days of beginning treatment. Treatment does not
end at that point, but rather enters into the next phases,
called consolidation and maintenance. Several different
approaches can be used in these. Some patients receive
long-term chemotherapy with drugs that might include
cytarabine, cyclophosphamide, methotrexate, 6-mercaptopurine,
vincristine, prednisone, or doxorubicin.
Other patients undergo high-dose chemotherapy or combination
chemotherapy and radiation therapy to ablate or
wipe out their own bone marrow, and then have bone
marrow or stem cell transplants. Adverse effects of bone
marrow transplant include significant risk of serious
infection and graft versus host disease (GVHD), in
which the transplanted cells fail to “recognize” the host’s
cells as self and attack the host cells. Medications to
decrease this risk include those that suppress the immune
system and steroids.
Central nervous system prophylaxis, as either
intrathecal chemotherapy or radiation therapy or both,
typically continues through at least a portion of the postremission
therapy.
Adults who receive intensive chemotherapy have a
40% likelihood of long-term survival.
CHILDREN. In children, remission induction therapy
is followed by a phase termed consolidation or intensification,
and then by a phase termed maintenance. During
intensification, children receive intermediate or highdose
methotrexate, plus some of the same drugs that are
used in induction, new drugs that do not cross-react with
those used in induction, high-dose asparaginase, or some
combination of these.
The maintenance phase of treatment for children
with ALL continues for 18 to 30 months. Daily oral mercaptopurine
and weekly oral or injected methotrexate
are given on an outpatient basis, with frequent blood tests
and examinations. Some protocols add pulses of vincristine
and prednisone during the maintenance phase.
Recurrent ALL
ADULTS. Adults who relapse after initial remission
and maintenance therapy often undergo reinduction
chemotherapy and are then referred for bone marrow or
stem cell transplant. Some receive transplants of umbilical
cord blood. Such transplants carry the risk of graft
versus host disease, but also carry the possibility of graft
versus leukemia, in which the transplanted cells attack
the residual leukemic cells. Unlike graft-versus-host
disease, graft versus leukemia is useful.
New treatments for relapsed ALL include immunotherapies
or biological response modifiers. Some reduce
adverse effects of treatment and others are used to fight
the leukemia. Some of these include cytokines, substances
that stimulate the production of blood cells after
treatment has suppressed the bone marrow, and colony-
stimulating factors, which have the same effect. Other
immunotherapies, such as monoclonal antibodies and
interferon, have not yet been shown effective against
ALL, but are still under study.
CHILDREN. The treatment and prognosis of children
who relapse depends on the timing of that relapse.
Relapse that occurs within six months is often treated
with bone marrow transplantation. Early relapse carries
the least favorable prognosis, with only 10% to 20%
chance of long-term survival. Relapse that occurs more
than a year after initial treatment is finished can be treated
with another full round of chemotherapy, and bone
marrow transplant reserved for those children who
relapse a second time. Those with such late relapses have
a 30% to 40% chance of long-term survival.
Recurrent disease may occur in a sanctuary site, or a
part of the body difficult to penetrate with chemotherapeutic
drugs. The central nervous system is the most
common site of such recurrences. Children who have an
isolated central nervous system relapse during the first
18 months of treatment have a 45% likelihood of longterm
survival. Children with central nervous system
relapse after the first 18 months of treatment have up to
an 80% chance of long-term survival. Treatment for
relapse in the central nervous system includes intrathecal
chemotherapy, and for most children, the use of radiation
therapy to the brain and spinal cord.
The testicles are the second most common site of
relapse. Early testicular relapse (within the first 18
months of treatment) carries a 40% chance of long-term
survival, and late testicular relapse carries an 85%
chance of long-term survival. Another sanctuary site is
the eye, but isolated relapse here is unusual.
Coping with cancer treatment
The treatment of ALL can be particularly draining,
not only due to adverse effects but due to its prolonged
time course. Although much of the treatment can be
given on an outpatient basis, many protocols utilize
lengthy intravenous infusions of chemotherapy and
require hospitalization.
ADULTS. To prevent nausea and vomiting, adults
can take oral anti-nausea medication an hour or so before
scheduled treatments, including intrathecal treatments.
To avoid headache, they should remain flat for at least 30
to 60 minutes after intrathecal chemotherapy. Nurses can
give instructions in mouth care if mouth sores occur and
skin care if rashes occur after radiation treatment. Books,
music, and television can provide distraction and reduce
anxiety during chemotherapy infusions.
Like adults, children can take anti-nausea drugs an
hour or so before scheduled treatments. Children, and
some adults, can apply topical anesthetic creams to sites
of bone marrow aspirates or spinal taps. Favorite stuffed
animals or blankets can be present for most procedures.
Play and fun are as important to children with cancer
as to healthy children. Items such as board games, modeling
clay, video games, dolls, and toy cars can be
enjoyed even with intravenous lines in place. Play dates
with friends should be encouraged, with proper screening
to limit exposure to contagious illnesses.
School districts are required to accommodate the special
needs of children. Children with ALL might require
shorter school days or the provision of a tutor at home.
Children who develop learning disabilities due to treatment
might require the intervention of a special education team.
Clinical trials
There are numerous clinical trials looking at novel
strategies for the treatment of ALL in adults and children.
Most oncologists consider bone marrow transplants
to be state-of-the-art in specific circumstances, and some
insurance companies agree. Many still require extensive
reviews before approving coverage for transplant.
A variety of biological agents are currently under
study. These include antibodies that react specifically
against leukemic cells, causing their death, and chemicals
that interfere with the leukemic cells’ normal DNA
function or their ability to make proteins.
Researchers are developing second and third generation
versions of established chemotherapeutic drugs, isolating
the molecular components of those drugs that
seem to be most useful in ALL and amplifying them.
Some of these drugs include 9-aminocamptothecin,
aminopterin, annamycin, Ara-G, codrycepin, decitabine,
and trimetrexate. Quinine shows promise in reducing
the incidence of drug resistance that is sometimes seen
in leukemic cells.
Locating and enrolling in clinical trials has been
made easier by listings on the Internet. A general search
under “clinical trials and leukemia” will yield several
listings. University-affiliated hospitals and oncologists
participate in many trials and can refer patients to other
sites if necessary.
Prevention
There are few preventive measures to take against
ALL. Those who work with chemicals should be cautious,
particularly around benzene. Pregnant women
should avoid exposure to ionizing radiation to reduce the
risk to their unborn children.
Special concerns
Parents of children with ALL have specific concerns
regarding the long-term consequences of treatment for
ALL, such as learning disabilities. Organizations devoted
to childhood cancer, hospital social workers, pediatric
oncologists and other parents can be important resources
when advocating for the educational needs of the child
with ALL.
When cranial radiation must be used, children have
a risk of developing secondary cancers in the central nervous
system years later. Some children are left infertile
by the treatment. Chicken pox can be lethal in children
with ALL. The introduction of the chicken pox vaccine
has reduced this risk, but parents must still be vigila
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