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In This Report

•	Highlights
•	Introduction
•	Symptoms
•	Causes
•	Risk Factors
•	Complications
•	Diagnosis
•	Prognosis
•	Treatment
•	Home Management
•	Treatment to Achieve Remiss...
•	Treatment During Remission...
•	Treatment After Relapse
•	Resources
•	References

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•	Leukemia
•	Acute lymphocytic leukemia ...

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Acute lymphocytic leukemia

Highlights

Drug Approvals

• Imatinib (Gleevec) is approved for treating Philadelphia chromosome-positive acute lymphocytic leukemia (ALL) that has not responded to treatment, or has returned after treatment.
• Dasatinib (Sprycel) is approved for patients with Philadelphia chromosome-positive ALL who are resistant to imatinib. An important 2006 New England Journal of Medicine study indicated dasatinib’s benefit in treating these patients.
• Pegaspargase (Oncaspar) is approved for treating children and adults with newly diagnosed ALL. This drug was previously approved only for patients who were allergic to L-asparaginase (Elspar). Patients can now receive pegaspargase instead of L-asparaginase as part of a combination chemotherapy regimen. With pegaspargase, patients need only 3 injections during a 20-week treatment, instead of the 21 injections required for L-asparaginase.

Investigational Drugs

Nilotinib (AMN-107), a drug that is similar to dasatinib, has shown promising results in treating patients with Philadelphia chromosome-positive ALL who are resistant to imatinib.

Treatment Research

• The chemotherapy drug 6-mercaptopurine (Purinethol) should remain a standard part of maintenance therapy for children with ALL, recommends a 2006 study in the Lancet. Researchers found that an alternative drug, 6-thioguanine (Tabloid), has risky side effects that outweigh its benefits.
• Allogeneic (donor) stem cell transplantation may be an effective treatment option for patients with Philadelphia chromosome-positive ALL who are resistant to imatinib, suggests a 2006 study in Blood.

Cranial Radiation and Stroke Risk

Children with leukemia who receive cranial (skull) radiation therapy may be at increased risk for stroke decades after their treatment ends, suggests a 2006 study in the Journal of Clinical Oncology. Researchers found that strokes could happen 10 - 20 years after treatment. Stroke occurred on average in 1 in 125 patients with leukemia compared to 1 in 500 healthy patients. Patients who received the highest doses of radiation had the greatest risk of stroke.

Introduction

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 - 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). 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), which is not covered in this report

Acute Lymphocytic Leukemia

Acute lymphocytic leukemia (ALL) is also known as acute lymphoid leukemia or acute lymphoblastic leukemia. The majority of childhood leukemias are of the ALL type. Malignancies in this disease can arise either in T-cell or B-cell lymphocytes.

• T cell ALL is diagnosed in 15% of children and adults with ALL.
• About 85% of ALL cases are of the B-cell lymphocyte lineage (often referred to as "early" or "pre" B cell lineage).

Symptoms

The symptoms of ALL may be difficult to recognize. ALL usually begins abruptly and intensely, but in some cases symptoms may develop slowly. They may be present one day, and absent the next, particularly in children. Symptoms develop when:

• There are not enough healthy mature white blood cells (leukocytes) to mount a defense against infection.
• There are not enough healthy platelets to prevent bleeding.
• The depleted oxygen-bearing red blood cells can't provide enough oxygen to organs.

Symptoms include:

• Fatigue
• Paleness -- patients may have poor coloring from anemia caused by insufficient red blood cells.
• Recurrent minor infections
• Bone pain
• Bruising -- may result from only slight injury
• Poor healing of minor cuts
• Uncontrolled bleeding -- bleeding events increase as the bone marrow fails to produce enough platelets to make a normal blood clot, a condition called thrombocytopenia.
• Small, red spots on the skin (petechiae)
• Vision changes (rare)

Causes

Between 1973 - 1990, the number of acute lymphocytic leukemia cases in children under age 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 doctors 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.

• The most common genetic injury in ALL is t(12;21), which means a translocation with a genetic shift occurred between chromosome 12 and 21. This translocation is also referred to as TEL-AML1 fusion. It occurs in about 20% of patients with ALL. 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.

Ikaros. A defective gene known as Ikaros, which regulates lymphocyte development, may play a major role in childhood ALL.

MTHFR. Methylenetetrahydrofolate reductase (MTHFR) is an enzyme involved in folate metabolism. Children with certain variations in the gene for MTHRF have a reduced risk of developing ALL. Variations in the MTHRF gene may also influence response to antifolate chemotherapy.

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.

Infections. Researchers are studying a number of viruses or other infectious substances that may trigger the leukemia, particularly in genetically susceptible children. 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. Determining 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 runoff 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 (living near power lines, video screen emissions, small appliances, cell phones) are unlikely to pose any cancer risk.

Risk Factors

ALL in Children. In 2006, experts estimated that about 3,930 cases of acute lymphocytic leukemia would be diagnosed in the U.S., with about 2,630 of them in children and adolescents younger than age 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 ages 1 - 10 years old, but the disease can strike from infancy to old age.

ALL in Adults. About 30% 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. Risk is lowest between the ages of 25 - 50.

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 and unequal access to healthcare may account for some of these differences.

Hereditary Disorders

Certain inherited disorders can increase the risk for leukemia. For example, children with Down syndrome have a 20-times greater risk of developing ALL than the general population. Other rare genetic disorders associated with increased risk include Bloom syndrome, Fanconi's anemia, ataxia-telangiectasia, neurofibromatosis, Shwachman 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 - 13 years after treatment (usually of the myeloid variety). Children under age 10 are most susceptible to acute leukemia following exposure to radiation treatments. Susceptibility decreases between the ages of 10 - 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. However, fetal exposure to diagnostic x-rays (not ultrasound) before birth increases the danger of developing ALL by the age of 15 years.

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.

Complications

Acute lymphocytic leukemia is responsible for about 1,490 deaths a year in the U.S., 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 - 85% in North America over the past 3 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 Caucasian children, but this may not be due to biological differences in the response to treatment. A 2003 study found that with equal access to effective therapy, all children can expect the same high rate of cure.
• 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 1 - 9 years old. 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 patients with the B-cell stage and T-cell types of ALL, 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 - 80% of adults with ALL can expect to achieve full remission with standard treatments and between 35 - 40% survive beyond 2 years with aggressive treatments. Younger adults with ALL have better long-term survival rates than older adults with the disease.

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 here as well as 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 for protecting bone are available.

Osteoporosis is a condition that causes progressive loss of bone density, thinning of bone tissue, and an increased risk of fractures. Osteoporosis may result from disease, dietary or hormonal deficiency, or advanced age. Regular exercise and vitamin and mineral supplements can reduce and may even reverse bone loss.

Heart Disease. Some of the treatments increase risk factors for future heart disease, including unhealthy cholesterol levels and high blood pressure. Patients with ALL should be sure to maintain a healthy lifestyle and be regularly monitored for heart risks to help reduce these effects.

Click the icon to see an image of cholesterol.

Stroke. Survivors of childhood leukemia are at increased risk of later stroke, especially if they received treatment with cranial radiation.

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. Corticosteroid 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 spinal injection 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.

Infections. Some children may be more vulnerable to infections after completing chemotherapy, although the immune system tends to improve over time. Studies 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 suggest 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. Risk for mood psychological problems may vary by treatment. A 2003 study showed that patients who received high-dose CNS radiation and methotrexate therapy had an increased risk of mood disturbances compared to those who did not receive radiation.

Recognizing this risk and getting psychologic support early is 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. A 2004 study confirmed these results, reporting that 81% of adult survivors of childhood ALL had a positive self-concept.

Effects on Caregivers

One study found that parents who take care of children with ALL develop more symptoms of post-traumatic stress disorder than their children.

Diagnosis

Laboratory tests provide the basis for diagnosing ALL.

Flow Cytometry

Flow cytometry uses light to count blood cells in a stream of fluid. It is an important tool used to diagnose leukemia, determine its progress, and tell if any disease remains after treatment. It can also determine the components and structural features of individual cells. Flow cytometry can process thousands of cells in seconds.

Complete Blood Cell Count

A complete blood cell count (CBC) is the first step in diagnosing ALL. However, blood tests do not always detect leukemia. About 10% of patients with ALL have a normal blood cell count. A CBC may show various findings, including:

• Presence of circulatory leukemic blast cells (may miss the cells on occasion)
• Presence and severity of anemia
• Count of a variety of blood cell types (a high white blood cell count indicates a more severe disease)

Click the icon to see an illustrated series detailing a complete blood cell count test.

Bone Marrow Biopsy

If blood test results are abnormal or the doctor suspects leukemia despite normal cell counts, a bone marrow aspiration and biopsy are the next steps. These are very common and safe procedures. However, because this test can produce considerable anxiety, particularly in children, parents may want to ask the doctor if sedation is appropriate for their child.

• A local anesthetic is given.
• 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. Marrow 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.

Click the icon to see an image of bone marrow removal.

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 - 100% of the marrow.

Spinal Tap

If bone marrow examination confirms ALL, a spinal tap may be performed, which uses a needle inserted into 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 quiet activities that will divert the child during that time. Parents should also be certain that the professional administering this test is highly experienced.

Click the icon to see an image of a spinal tap.

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, leukemia cells are not found in the cerebrospinal fluid.

Prognosis

Once a diagnosis of leukemia has been made, further tests are performed to check:

• Whether the cells are myeloid or lymphocytic
• Stage of maturity of the ALL B cell
• Specific markers, or immunologic features, on the surface of the cancer cell
• The genetic makeup of the cells ( cytogenetics)
• The physical characteristics of the cells ( morphology)

Determining the Cell of Origin

First, the doctors must determine the cell of origin. In other words, they want to determine if the cell 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 patients with ALL have the early precursor-B subtype, which is the least mature. It also offers the best prognosis.
• 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.

An antigen is a substance that can provoke an immune response. Typically, antigens are substances not usually found in the body.

Important antigens associated with ALL include:

• 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 (associated with a good prognosis)
• CR19
• DR

The surfaces of T-cell ALL cancer cells express several antigens as well. For example, the presence of 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
• Deciding 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 capable of checking up to 48,000 different genes in a single test, which holds promise for assessing prognosis and developing very targeted therapies in the future. Research on DNA microarray analysis continues to reveal different prognostic subgroups of ALL. As the precision, logistics, and cost effectiveness of DNA microarray assays improve, they may be used more commonly in the clinical setting.

MTHFR Variants. Methylenetetrahydrofolate reductase (MTHFR) is an enzyme involved in folate metabolism, and variations in the MTHRF gene may also influence response to antifolate chemotherapy. A 2004 study showed that patients with one of two specific variations of the MTHFR gene had a lower probability of survival following treatment with methotrexate.

Translocations. Genetic translocations (swapping of genes on chromosomes) may affect outlook. Examples include:

• 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 age 1 year. Unfortunately, anyone with t(4;11) has a poor outlook. 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 t(9;22) also indicates a poor outlook. It represents about 20% of adult cases and about only 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 in only 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 mentioned above):

• 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.

Determination of Minimal Residual Disease

Assays that test for cancerous cells are improving, allowing doctors to detect smaller and smaller amounts of hidden disease. For example, flow cytometry assays can detect 0.01% leukemic cells, and PCR assays can detect 0.001% leukemic cells. A new concept called minimal residual disease (MRD) is becoming an important prognostic factor in ALL. A more precise measure of disease response, MRD may soon replace existing measures such as "complete response" and "partial response" when assessing the effectiveness of ALL treatment. Ongoing studies of MRD in ALL may help identify patients in remission who are at risk of relapse. In addition, early therapeutic intervention based on the presence of MRD may improve outcome and prolong survival.

Drawing Conclusions from Cell Characteristics

Using the results of the tests described above, patients are classified into low-, average-, and high-risk groups. This information allows the doctor to diagnosis the type of leukemia and plan the best treatment. Each classification requires unique therapies.

Doctors 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.

Treatment

The aim of initial treatment is to get rid of the leukemia cells in the body (achieve complete remission) and have 5% of lower levels of blasts in the bone marrow.

Treatment Phases

There are typically four treatment stages for the average-risk patient with ALL:

• 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 also being used.

Supportive Treatment

Drugs Used to Prevent Infections During Treatment. Half of all patients with ALL develop fever in the early stages, especially if patients also have low levels of the white blood cells called neutrophils (a condition called neutropenia).

Blood is made of red blood cells, platelets, and various white blood cells.

Neutropenia is common in ALL and is a significant risk factor for serious infection. Of increasing concern are fungal infections, which are becoming more 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 (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.

Transfusions. Red blood cell or platelet transfusions may be needed. (Patients who may need allogeneic transplantations should not receive transfusions from potential donors.)

Home Management

A parent should call the doctor if the child has any symptoms that are out of the ordinary, including (but not limited) to:

• 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 measurement for the amount of white blood cells is an important gauge of a child's ability to fight infection.

• Counts over 1,000 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 - 1,000, the child should avoid large groups.
• If it falls between 200 - 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 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 may need reimmunization. Siblings of patients with ALL 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 common pain relievers known as nonsteroidal anti-inflammatory drugs (NSAIDs). They increase the risk for bleeding and include aspirin, ibuprofen (Motrin IB, Advil, Nuprin, Rufen), naproxen (Aleve), and 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.

Treatment to Achieve Remission

The aim of induction therapy, the first treatment phase, is to reduce the number 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.

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:

• Vincristine
• Corticosteroids (prednisone or dexamethasone) -- a 2003 study reported better survival rates with dexamethasone compared to prednisone.
• Asparaginase -- several forms are available, including L-asparaginase (Elspar) and pegaspargase (Oncaspar). In 2006, the FDA approved the use of pegaspargase in place of L-asparaginase for treating newly diagnosed ALL in children and adults. (Pegaspargase had previously been approved only for patients who were allergic to L-asparaginase.) With pegaspargase, patients will need to receive only 3 injections over a 20-week period instead of the 21 injections required for L-asparaginase.

When this regimen is used together 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 uses 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 would be vincristine, prednisone/dexamethasone, plus asparaginase, and an anthracycline (such as doxorubicin, daunorubicin, or epirubicin).

Drugs Used for Specific High-Risk Adults. Adult patients have a poorer outlook than children, and researchers are looking for more effective chemotherapy regimens. For example, cyclophosphamide-based regimens are used in adult patients with certain types of ALL. In a 2005 study, patients treated with an investigational regimen of cytabarine and high-dose mitoxantrone experienced a much higher rate of remission and survival than patients treated with the standard L-20 chemotherapy regimen of vincristine, prednisone, cyclophosphamide, and doxorubicin. Patients with the Philadelphia chromosome also benefited from the investigational treatment.

Preventing Central Nervous System Disease (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 - 70% of children without preventive (prophylactic) treatment. The brain is one of the first sites for relapsing leukemia.

CNS prophylaxis is usually:

• Administered together with induction therapy before moving to consolidation, the next standard treatment phase, particularly if there are any leukemic cells detected in the spinal fluid.
• Given through 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 and stroke.

A 2003 study reported the long-term effects of cranial or craniospinal radiation therapy during initial treatment for ALL. Among patients who achieved at least 10 years of event-free survival, those who received radiation therapy had a significantly higher risk of a second neoplasm, a slightly elevated mortality rate, and higher unemployment rate than patients who did not receive radiation therapy.

Side Effects and Complications

Side effects and complications of any chemotherapeutic regimen are common, are more severe with higher doses, and increase over the course of treatment. Toxicities can be reduced without loss of cancer-killing effects in some cases by administering the drugs for shorter duration.

Common Side Effects. Common side effects include:

• Nausea and vomiting. Drugs known as serotonin antagonists, such as ondansetron (Zofran) or granisteron (Kyril), can relieve these side effects in nearly all patients given moderate drugs and most patients who take more powerful drugs. In one study, nearly all patients who took a combination of dexamethasone (a steroid) in combination with ondansetron within 24 hours of chemotherapy experienced either a significant or complete reduction in nausea and vomiting.
• Diarrhea
• Hair loss
• Weight loss
• Depression

These side effects are nearly always temporary. Most patients are able to continue with normal activities for all but perhaps 1 or 2 days a month.

Serious Side Effects. Serious side effects can also occur and may vary depending on the specific drugs used. Infection from suppression of the immune system or from severe drops in white blood cells is a common and serious side effect. Patients should make all efforts to prevent them. The patient at high risk for infection may require very potent antibiotics and antifungal medications as well as granulocyte colony-stimulating factors or G-CSF (lenograstim, filgrastim) to stimulate the growth of infection-fighting white blood cells.

Other side effects include:

• Liver and kidney damage
• Abnormal blood clotting
• Allergic reaction
• Low blood sugar (hypoglycemia) -- a rare complication in young, thin children who are taking purine analogues such as mercaptopurine and thioguanine
• Shrinking of adrenal glands in children who take short-term, high-dose corticosteroids such as prednisolone

Long-Term Complications.

• Fatigue is very common after chemotherapy and can be significant and long-lasting.
• Combinations of intrathecal chemotherapy plus brain radiation in children can cause some serious complications, including seizures and problems in learning and concentration. Methotrexate is particularly toxic. (The effects of intrathecal chemotherapy alone on mental functioning, however, did not seem significant.) Seizures can often be treated successfully with anti-epilepsy medications.
• Late puberty. The effects of treatment in the brain can affect regions that regulate reproductive hormones, which may affect fertility later on.
• Bone loss can occur after chemotherapy, particularly with corticosteroids and after bone marrow transplantation. Drugs are available, particularly bisphosphonates, which may help reduce this risk.
• Pancreatic beta-cell damage. A 2004 study reported that children who have been off treatment for at least 1 year have a higher risk of impaired insulin response. This suggests that chemotherapy-induced beta cell damage persists after therapy has been stopped.
• Anthracyclines (doxorubicin, daunorubicin, epirubicin) have been associated with later development of heart failure. Of some encouragement, a 2000 study reported that low doses used for many ALL children may not pose a high risk to the heart. Some anthracyclines (DaunoXome, Myocet, Doxil) now come in tiny protective capsules that may reduce toxic effects.
• Mood disorders. According to a 2003 study, CNS radiation and MTX therapy were associated with an increased risk of mood disturbances (such as depression) among adult survivors of childhood ALL. This suggests that patients undergoing CNS radiation and MTX therapy may benefit from psychosocial support.

Treatment During Remission

Consolidation and maintenance therapies follow induction and first remission. The goal of consolidation and maintenance therapies is to prevent a relapse. The specific treatment choices and degree of aggressiveness after induction therapy depend on a number of factors, particularly the risk factors for relapse.

Consolidation (or Intensification) Therapy

Consolidation therapy is additional treatment that is administered after induction therapy and before maintenance therapy. This is an intense regimen that is designed to prevent the high relapse rates that occur with induction therapy alone. (The benefits of this therapy are clearer in children than in older adults, who may just be given maintenance.)

Consolidation therapy usually continues for approximately 6 months and uses 1 - 6 courses of chemotherapy, depending on risk factors for relapse.

Examples of consolidation regimens for children at standard risk:

• A limited number of courses of intermediate- or high-dose methotrexate, one of the oldest drugs used for leukemia.
• An anthracycline drug, such as daunorubicin (Cerubidine), used for reinduction followed by cyclophosphamide (Cytoxan, Neosar) 3 months after remission. These are very powerful drugs, but when used in this way toxicity is limited.

More intense regimens are used for children at high-risk for relapse.

Maintenance

The last phase of treatment is maintenance, or continuation therapy:

• Maintenance therapy typically uses weekly administration of methotrexate (usually in oral form) and daily doses of mercaptopurine. (Mercaptopurine should be given in the evening.)
• Treatment continues for between 2 - 3 years for most children with ALL (with the exception of those with mature B-cell leukemia). It is not yet clear if prolonged maintenance therapy benefits adults with ALL.
• If children were not given CNS prophylaxis before, it may be given now.

A maintenance regimen is usually less toxic and easier to tolerate than induction and consolidation. Some studies, however, indicate that overall survival could further be improved with more-aggressive maintenance therapies, including:

• Vincristine and a corticosteroid added to the standard maintenance regimen
• Longer term low-dose maintenance
• Intense regimens similar to induction (called reinduction)

Maintenance typically is ongiong until complete remission has lasted 2 - 3 years.

Investigation is ongoing to determine the best drugs and schedules to use. For example, doctors have debated whether thioguanine is a better choice than mercaptopurine (a 2006 study recommended that mercaptopurine remain the standard thiopurine drug for treating childhood ALL). Researchers are also trying to pinpoint patients who would best benefit from aggressive maintenance treatments.

Treatment After Relapse

Between 50 - 70% of children and 40 - 50% of adults who achieve complete remission after initial therapy but then suffer a relapse may be able to go into a second complete remission.

Treatment for relapse after a first remission may be standard chemotherapy or experimental drugs, or more aggressive treatments such as stem cell transplants.

The decision depends on a number of factors:

• Children who relapse 3 or more years after achieving a first complete remission have an excellent chance for a second remission without aggressive treatments.
• Those who relapse less than 6 months following initial treatment, especially while on chemotherapy, have about a 20% chance of long-term freedom from disease. In such cases, remission is possible following another course of standard chemotherapy but the duration of remission is usually less than 6 months.

Treatment decisions also rely on prior treatments and where the relapse has occurred. Relapse can occur in the bone marrow, central nervous system, or sanctuary disease sites (brain, spine, or testicles). The incidence of relapse in sanctuary sites is about 10%.

Candidates for transplantation include:

• Patients who relapse following initial remission with standard chemotherapy.
• High-risk patients in first remission who are unlikely to be cured by standard chemotherapy alone. Many adult patients may fall into this category. Studies on high-risk children have been conflicting about the value of transplants during a first remission, with a 2000 study reporting no significant advantage. A 2001 study on children with the Philadelphia chromosome, however, suggested that this approach offered a better chance for a cure.
• Patients who fail to achieve a complete remission during initial chemotherapy.

Transplantation procedures do not appear to offer any additional advantages for patients at low or standard risk.

Chemotherapy Drugs Used After Relapse

Many different drugs are used to treat ALL relapses. These drugs include vincristine, asparaginase, anthracyclines (doxorubicin, daunorubicin), cyclophosphamide, cytarabine (ara-C), and epipodophyllotoxins (etoposide, teniposide). Corticosteroids, such as prednisone or dexamethasone, may also be used.

In 2004, the FDA approved clofarabine (Clolar) for treatment of relapsed or refractory ALL in children. This drug was the first new leukemia treatment approved specifically for young patients in more than a decade. In 2005, nelarabine (Arranon) was approved to treat adults and children with relapsed or refractory T-cell acute lymphocytic leukemia (T-ALL). In 2006, the FDA approved imatinib (Gleevec) for treating patients with Philadelphia chromosome-positive ALL that has not responded to or has returned after treatment. Also in 2006, the FDA approved dasatinib (Sprycel) for patients who are not helped by imatinib.

Investigational Drugs

Tyrosine kinase inhibitors. Tyrosine kinase is a growth-stimulating protein. Tyrosine kinase inhibitor drugs block the cell signals that trigger cancer growth. Several tyrosine kinase inhibitors, including imatinib (Gleevec) and dastinib (Sprycel), have recently been approved for treating Philadelphia chromosome-positive ALL. In 2006 clinical trials, Nilotinib (AMN-107) produced excellent results in patients with Philadelphia chromosome positive ALL who are resistant to imatinib.

Monoclonal antibodies (MAbs). Used alone or in combination with chemotherapy, MAbs target specific antigens on ALL blast cells. Although MAbs have been studied primarily in the treatment of B-cell non-Hodgkin's lymphoma, drugs demonstrating benefit in preliminary trials of ALL include anti-CD20 (rituximab) and anti-CD22 (epratuzumab). Alemtuzumab (MabCampath) is also showing promise in treating relapsed or refractory T-ALL. More studies are needed to determine the best MAb regimens in ALL.

Transplantation Procedures for Acute Lymphocytic Leukemia

In order to administer high-dose chemotherapy for advanced cancer cases, stem cell transplantation procedures may be used. These procedures are based on removal and replacement of stem cells, which are produced in the bone marrow. Stem cells are the early forms for all blood cells in the body (including red, white, and immune cells). Cancer treatments harm growing cells as well as cancer cells, and so the healthy stem cells must be replaced by transplanting them from the donor into the patient.

Collecting the Stem Cells

Sources of Cells. Stem cells must first be collected either from:

• Bone marrow (bone marrow transplantation)
• Blood (peripheral blood stem cell transplantation). Evidence suggests that peripheral blood stem cell transplantation may be the superior approach. Studies report survival rates of 45% in bone marrow transplant patients compared to 65 - 70% in stem cell transplant patients, with benefits being significant in those with more severe disease.
• Fetal umbilical cord or placentas. This procedure uses donor cells but has a lower risk for immune system rejection of the cells than with a standard donor transplant. It takes longer to restore blood cells with this process, however, so at this time its use is limited to children and sometimes adults with low weight. (Some studies indicate success for adults with normal weights.)

Donor or Patient Cells. The sources of marrow or blood cells can be taken from the patient or a donor:

• If the bone marrow or stem cells are taken from a donor, the transplant is referred to as allogeneic. Allogeneic transplants from genetically matched sibling donors offer the best results in ALL. With new techniques, donor bone marrow from unrelated but immunologically similar donors is proving to work as well as those from matched siblings. This approach is still reserved for patients in second remission or beyond. A 2006 study indicated that allogeneic transplant is also a good treatment option for patients with Philadelphia chromosome-positive ALL who are resistant to imatinib (Gleevec).
• If the marrow or blood cells are taken from an identical twin, the transplant is called syngeneic.
• If the marrow or blood cells used are the patient's own, the transplant is called autologous. Autologous transplants in patients with ALL are generally not beneficial, since there is some danger that the cells used may contain tumor cells and the cancer can regrow. Treatment advances that reduce this risk, however, may make autologous transplantation feasible in patients without family donors.

The Blood Stem Cell Collection Procedure

• The donor is usually given a drug called granulocyte colony-stimulating factor, or G-CSF (filgrastim, lenograstim) to stimulate stem cell growth.
• The donor (or patient in an autologous procedure) then undergoes apheresis. With this process, the blood is withdrawn from one of the patient's veins, then passed through a machine that filters out the white cells and platelets, which contain the stem cells. The blood is returned through another vein. The entire procedure takes 3 - 4 hours but needs to be repeated several times.
• The stem cells are then frozen.

The Transplant Procedure

• The patient is given high-dose chemotherapy with or without radiation -- a treatment known as conditioning. The point is to inactivate the immune system and to kill any residual malignant cells. Drugs used are typically cyclophosphamide, carmustine, and etoposide. Alternative conditioning includes radiation with drugs.
• A few days after treatment, the patient is rescued using the stored stem cells, which are administered through a vein. This may take several hours. Patients may experience fever, chills, hives, shortness of breath, or a fall in blood pressure during the procedure.
• The patient is kept in a protected environment to minimize infection and he or she usually needs blood cell replacement and nutritional support.

Success Rates

Two- to 5-year survival rates after transplantation plus chemotherapy range from 40 - 80%. Certain patients with the Philadelphia chromosome, which carries a poor prognosis, may achieve significant success with an allogeneic bone marrow transplant from a closely matched related donor.

Side Effects and Complications

Common side effects include nausea, vomiting, fatigue, mouth sores, and loss of appetite.

The procedures themselves are fairly dangerous and carry a small risk for death. When it was first used, transplantation procedures had 10 - 25% morality rates. Now, mortality rates are below 5%. Potentially serious complications include:

• Infection resulting from a weakened immune system. This is the most common side effect and can persist for several months after the transplant. Because the stem cell procedure is done more swiftly, the risk period is shorter than with bone marrow transplantation. Many patients develop severe herpes zoster virus infections (shingles) or have a recurrence of herpes simplex virus infections (cold sores and genital herpes). Pneumonia, cytomegalovirus, and fungal infections are among the most important life-threatening infections. Fungal infections are of particular concern because they are both very serious and their incidence is increasing with advances in conditioning treatments, immunosuppression and use of potent antibiotics. The patient may require very strong antibiotics and antifungal medications as well as granulocyte colony-stimulating factors or G-CSF (lenograstim, filgrastim) to stimulate the growth of infection-fighting white blood cells.
• Graft-versus-host-disease (GVHD) is a serious attack by the patient's immune system triggered by the donated new marrow. It occurs in over half of allogeneic transplants. GVHD can results in weight loss, bacterial infections, and skin and organ problems that may persist for up to 3 years after the procedure. In some cases it is fatal. Careful matching of the donor and preventive immunosuppressive drugs, (such as corticosteroids, methotrexate, and cyclosporine), may reduce the risk for this potentially life-threatening side effect.
• Secondary cancers. There is a small long-term risk for leukemia after transplantation in young people. Use of newer chemotherapeutic drugs, however, may not pose as high a danger.
• Bleeding because of reduced platelets. This risk is highest within the first 4 weeks after bone marrow transplantation.
• Other side effects include heart, lung, and liver complications, infertility, transplant failure, muscle problems (stiffness, cramps, joint pain), frequent urination, and bladder control problems.
• Older patients should be screened for osteoporosis and hypothyroidism (underactive thyroid).

Resources

• www.leukemia-lymphoma.org -- Leukemia and Lymphoma Society
• www.cancer.org -- American Cancer Society
• www.cancer.gov -- National Cancer Institute
• www.bmtnews.org -- Blood and Marrow Transplant Information Network
• www.asco.org -- American Society of Clinical Oncology
• www.plwc.org -- People Living with Cancer
• www.aspho.org -- American Society of Pediatric Hematology/Oncology
• www.candlelighters.org -- Candlelighters Childhood Cancer Foundation
• www.clf4kids.com -- Childhood Leukemia Foundation

References

Bowers DC, Liu Y, Leisenring W, McNeil E, Stovall M, Gurney JG, et al. Late-occurring stroke among long-term survivors of childhood leukemia and brain tumors: a report from the Childhood Cancer Survivor Study. J Clin Oncol. 2006 Nov 20;24(33):5277-82.

Jabbour E, Cortes J, Kantarjian HM, Giralt S, Jones D, Jones R, et al. Allogeneic stem cell transplantation for patients with chronic myeloid leukemia and acute lymphocytic leukemia after Bcr-Abl kinase mutation-related imatinib failure. Blood. 2006 Aug 15;108(4):1421-3.

Kantarjian H, Giles F, Wunderle L, Bhalla K, O'Brien S, Wassmann B, et al. Nilotinib in imatinib-resistant CML and Philadelphia chromosome-positive ALL. N Engl J Med. 2006 Jun 15;354(24):2542-51.

Talpaz M, Shah NP, Kantarjian H, Donato N, Nicoll J, Paquette R, et al. Dasatinib in imatinib-resistant Philadelphia chromosome-positive leukemias. N Engl J Med. 2006 Jun 15;354(24):2531-41.

Vora A, Mitchell CD, Lennard L, Eden TO, Kinsey SE, Lilleyman J, et al. Toxicity and efficacy of 6-thioguanine versus 6-mercaptopurine in childhood lymphoblastic leukaemia: a randomised trial. Lancet. 2006 Oct 14;368(9544):1339-48.

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