Leukemia ( Acute Lymphatic Leukemia)

Acute lymphocytic leukemia

Highlights

Acute Lymphocytic Leukemia (ALL)

There are four major types of leukemia. ALL is the most common type of leukemia diagnosed in children, and the least common type diagnosed in adults. About 5,200 people are diagnosed with ALL each year. Children account for two-thirds of these cases. In general, children with ALL have a better prognosis than adults. Most children with ALL can be cured of this cancer.

Symptoms and Diagnosis

Symptoms of ALL include fatigue, pale skin, recurrent infections, bone pain, bruising, and small red spots under the skin. Doctors use various tests, including blood counts and bone marrow biopsies, to diagnose ALL.

Treatment

ALL is treated with chemotherapy and, sometimes, radiation. Children receive different types of chemotherapy regimens than adults. Patients with advanced cancer that has not responded to these treatments may need a stem cell transplant.

Infection Prevention

Both chemotherapy and transplantation increase the risk for infection. Patients must take serious precautions to avoid exposure to germs. Ways to prevent infection include:

Practice good hygiene including regular handwashing and dental care (brushing, flossing) Avoid crowds, especially during cold and flu season Eat only well-cooked foods (no raw fruits or vegetables) Boil tap water before drinking it Do not keep fresh flowers or plants in your house as they may carry mold Make sure you are up to date with vaccinations. Children may need to be reimmunized 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 of these blast cells 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 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) and others are called 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). 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 bacteria and other foreign particles), eosinophils (which trigger allergies and also react to 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 substances (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

Understanding 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 10 years of life, after which it atrophies (shrinks). Lymphatic vessels begin as tiny tubes and lead to larger lymphatic ducts and branches. 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. Both leukemia and lymphomas (Hodgkins disease and non-Hodgkins lymphomas) are cancers of lymphocytes. The difference is that leukemia starts in the bone marrow while lymphomas originate in lymph nodes and then spread to the bone marrow or other organs. Causes

The causes of the disease are not known, but researchers believe that ALL develops from a combination of genetic, biologic, and environmental factors.

Genetic Translocations

Up to 65% of leukemias contain genetic rearrangements, called translocations, in which some of the genetic material (genes) on a chromosome may be shuffled or swapped between a pair of chromosomes.

The most common genetic translocation in ALL is the Philadelphia (Ph) chromosome where DNA is swapped between chromosomes 9 and 22 [t(9:22)]. It occurs in about 20 - 30% of adults and 3 - 5% of children with ALL. Another common translocation in ALL is t(12;21), which is referred to as TELAML1 fusion. It occurs in about 20% of patients with ALL. Researchers believe that this translocation may occur during fetal development in some patients. Risk Factors

Age

ALL in Children. ALL is the most common type of cancer diagnosed in children. ALL accounts for about 75% of cases of childhood leukemia. Each year, about 3,600 American children and adolescents are diagnosed with ALL.

ALL can strike children of all ages, but is most likely to occur when children are 2 - 4 years of age. It is slightly more common in boys than in girls.

ALL in Adults. ALL is the least common type of leukemia among adults. About 1 in 3 cases of ALL occur in adults.

Race and Ethnicity

Caucasian and Hispanic children have a higher risk for ALL than AfricanAmerican children.

Hereditary Disorders

ALL does not appear to run in families. But certain inherited genetic disorders may increase risk. For example, children with Down syndrome have a 20times greater risk of developing ALL than the general population. Other rare genetic disorders associated with increased risk include Klinefelter syndrome, Bloom syndrome, Fanconi anemia, ataxia-telangiectasia, neurofibromatosis, Shwachman syndrome, IgA deficiency, and congenital X-linked agammaglobulinemia.

Radiation and Chemical Exposure

Previous cancer treatment with high doses of radiation or chemotherapy can increase the risk for developing ALL. Prenatal exposure to x-rays may also increase risk in children. Lower levels of radiation (living near power lines, video screen emissions, small appliances, cell phones) are unlikely to pose any cancer risk.

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 Fever without known cause Bone pain Abdominal swelling 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) Diagnosis

ALL is diagnosed based on various tests.

Physical Examination

The doctor will examine a patient for signs of enlarged lymph nodes or enlarged liver or spleen. The doctor will also look for any signs of bruising or bleeding.

Blood Tests

A complete blood cell count (CBC), which checks for numbers of white cells, red blood cells, and platelets, is the first step in diagnosing ALL. Patients with ALL generally have a higher than normal white blood count and lower than normal red blood cell and platelet counts.

Click the icon to see an illustrated series detailing a complete blood cell count test. Blood tests are also performed to evaluate liver, kidney, and blood clotting status and to check for levels of certain minerals and proteins.

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 rotate the needle to obtain a 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 of 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 (lumbar puncture) 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 performing this test is 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.

Tests Performed after Diagnosis

Once a diagnosis of leukemia has been made, further tests are performed on the bone marrow cells:

Cytochemistry, flow cytometry, immunocytochemistry, and immunophenotyping tests are used to to identify and classify specific types of leukemia. For example, cytochemistry distinguishes lymphocytic leukemia cells from myeloid leukemia cells. Immunophenotyping shows if ALL cells are T cells or B cells based on the antigen located on the surface of the cell. Cytogenetics and fluorescent in situ hybridization (FISH) are used for genetic analysis. Cytogenetic testing can detect translocations (such as Philadelphia chromosome) and other genetic abnormalities. FISH is used to identify specific changes within chromosomes. Genetic variations may help determine response to treatment.

An antigen is a substance that can provoke an immune response. Typically, antigens are substances not normally present in the body. Cell Classification

The results of cytogenetic, flow cytometry, immunophenotyping, and other tests can help provide information on types and subtypes of ALL cells. The particular subtype of cell can aid in determining prognosis and treatment.

An older classification system called the French-American-British (FAB) classification grouped ALL into L1, L2, and L3 subtypes. A newer classification system classifies ALL B cells or T cells based on their stage of maturity.

B-Cell ALL Subtype Classfication:

Early Pre-B Common ALL Pre-B ALL Mature B-cell ALL (Also called Burkitt leukemia) T-Cell ALL Subtype Classifcation:

Pre-T ALL Mature T-cell ALL Prognosis

Acute lymphocytic leukemia is responsible for about 1,400 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.

According to the American Cancer Society, certain factors can help determine prognosis:

Age. Younger patients (especially those younger than age 50) have a better prognosis than older patients. Initial white blood cell (WBC) count. People diagnosed with a WBC count below 50,000 tend to do better than people with higher WBC counts. ALL subtype. The subtype of T cell or B cell affects prognosis. For example, patients with T-cell ALL tend to have a better prognosis than those with mature B-cell ALL (Burkitt leukemia.) Chromosome translocations. People who have Philadelphia chromosomepositive ALL tend to have a poorer prognosis, although new treatments are helping many of these patients achieve remission. Response to chemotherapy. Patients who achieve complete remission (disappearance of signs and symptoms of cancer) within 4 - 5 weeks of starting treatment tend to have a better prognosis than those who take longer. Patients who do not achieve remission at any time have a poor prognosis. Evidence of minimal residual disease (presence of leukemia cells in the bone marrow) may also affect prognosis. Other factors, such as central nervous system involvement or recurrence, may also indicate a poorer prognosis.

Outlook in Children with ALL. More than 95% of children with ALL attain remission.

Certain children are at higher risk for a poor outcome than others:

Infants and children age 10 years and older tend to have a poorer outcome than young children (ages 1 - 9 years). Some studies indicate a better prognosis for girls than boys. This may be partly due to boys risks for testicular cancer. Survival rates for African-American and Hispanic children are lower than Caucasian and Asian children, but this may be due to poorer access to treatment. Responding well to early treatment is a good sign regardless of the risk category. Other positive predictors include:

Less than 5% of cells being blasts after 7 - 14 days of treatment Less than 1,000 blasts per microliter on peripheral smear after 7 days Outlook in Adults with ALL. Adults tend to have a more severe condition than children, even if they are carrying the same ALL genes. Still, 60 - 80% of adults with ALL can expect to achieve full remission with standard treatments, and 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.

Treatment

Treatment Phases

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

Induction therapy in order to achieve a first remission Central nervous system prophylaxis (preventive treatment), usually given

along with induction therapy Consolidation, intensive therapy to prevent relapse after remission has been achieved Maintenance treatment, lower intensity therapy given for several years 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 longterm 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, common in ALL, is a significant risk factor for serious infection. Doctors are increasingly concerned about 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.)

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

Both children and adults typically start with a 3-drug regimen. Imatinib (Gleevec) or dasatanib (Sprycel) may be added for patients with Philadelphia chromosome-positive ALL.

For children, the standard drugs are:

Vincristine (Oncovin), a vinca alkaloid drug Prednisone or dexamethasone. These drugs are corticosteroids. Dexamethasone may be more effective than prednisone, but it increases the risk for infections and other serious side effects. Asparaginase. Generally provided as pegaspargase (Oncaspar) in place of Lasparaginase (Elspar) for treating newly diagnosed ALL in children. With pegaspargase, patients need only 3 injections over a 20-week period instead of the 21 injections required for L-asparaginase. For adults, the standard drugs are:

Vincristine Prednisone Anthracycline drug, such as such as doxorubicin, daunorubicin, or epirubicin. Some adult chemotherapy regimens also add on an asparaginase drug or cyclophosphamide (Cytoxan). Preventing Central Nervous System Disease (CNS Prophylaxis)

The induction chemotherapy described above does not penetrate the bloodbrain barrier sufficiently to destroy leukemic cells in the brain. 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 50 - 70% of children who don't receive prophylactic preventive treatment. The brain is one of the first sites for relapsing leukemia.

For children, CNS prophylaxis uses intrathecal chemotherapy, in which a drug is injected directly into the spinal fluid. Intrathecal chemotherapy is given with methotrexate alone or a combination of methotrexate, cytarabine, and hydrocortisone.

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, may significantly reduce the risk for mental impairment. Cranial radiation is also associated with increased risks for stroke and secondary cancers.

Adult CNS prophylaxis is performed in one of three ways:

Cranial radiation plus intrathecal chemotherapy with methotrexate High-dose systemic infusion of methotrexate plus intrathecal methotrexate without cranial radiation Intrathecal methotrexate chemotherapy alone Evidence of Remission after Induction Treatment

Survival in acute leukemia depends on complete remission. Although 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 shorter the time to remission the better the outlook:

A complete remission usually occurs within the first 4 weeks. Patients who show low disease levels within 7 - 14 days have an excellent outlook, particularly if they have favorable genetic factors, and may need lessintensive treatments afterward. Patients with high disease levels at 14 days or who require more than 4 weeks to achieve remission are at higher risk for relapse and most likely need more aggressive treatment. Side Effects and Complications

Side effects and complications of any chemotherapeutic regimen and radiation therapy are common, are more severe with higher doses, and increase over the course of treatment. Administering drugs for shorter duration can sometimes reduce toxicities without affecting the drugs' cancerkilling effects.

Common Side Effects. Typical side effects include:

Nausea and vomiting. Drugs known as serotonin antagonists, such as ondansetron (Zofran) or granisteron (Kyril), can relieve these side effects. Diarrhea Hair loss Weight loss Depression 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 infection. The patient at high risk for infection may need 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. Patients should make all efforts to minimize exposure to bacteria and viruses.