Acute Lymphocytic Leukemia
Acute lymphocytic leukemia is a cancer of the white blood cells known as lymphocytes.
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 breast-bone), 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 (pea-shaped 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 B-cells, 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 B-cells. 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 B-cell 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.
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
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.
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:
Symptoms in children are similar, but young children may be unable to communicate them. They include:
- 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:
- nausea and vomiting
- blurred vision
- decline in school performance
Spread to the testicles can cause painless swelling in them.
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 T-cell 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.
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
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.
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
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
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.
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
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-mer-captopurine, 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 post-remission therapy.
Adults who receive intensive chemotherapy have a 40% likelihood of long-term survival.
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 high-dose 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.
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
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 long-term 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.
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.
Patients scheduled for inpatient stays can bring their own pillows, pajamas and even food, with their doctor's approval. Temporary issuance of handicapped parking stickers are often helpful.
The presence of parents during treatment is critical. While some hospitals exclude parents during treatments, others invite them to be present. Blood can be drawn and intravenous catheters placed while children sit in their parents' laps. If at all possible, a parent should spend the night during any hospitalizations.
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.
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.
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.
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 vigilant.
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Why, Charlie Brown, Why? Videotape. Topper Books, 1990.
Marianne Vahey, M.D.
Antiangiogenic drugs —Drugs that block the formation of new blood vessels.
—Immature blood cells.
—Complete blood count, a blood test that measures red cells, white cells and platelets.
Graft versus host disease
—After bone marrow transplant, the newly transplanted white blood cells can attack the patient's own tissues.
—Chemotherapeutic drugs instilled directly into the spinal fluid, either by spinal tap or through a special reservoir.
—The number and type of chromosomes found within cells.
—The cancerous cells of ALL, immature forms of lymphocytes, white blood cells that fight infection.
—A special device surgically placed under the scalp with a direct connection to spinal fluid. Medications to treat central nervous system disease are injected into the reservoir.
—Pinpoint red spots seen on the skin with low platelet counts.
—An abnormal chromosome found in 20% of adults and 5% of children with ALL, the presence of which indicates a somewhat worse prognosis.
—Areas within the body which are relatively impermeable to medications such as chemotherapy but which can harbor cancerous cells. Some of these sites are the central nervous system, the testicles, and the eyes.
—A gland within the chest involved in the maturation of immune cells that can be invaded by T lymphocytes in T-cell ALL.
QUESTIONS TO ASK THE DOCTOR
- What type of leukemia do I or does my child have?
- What characteristics of my or my child's illness are favorable? Which are unfavorable?
- What course of therapy do you recommend?
- What medications will you use and what side effects are anticipated?
- Will I or my child need to be hospitalized for those treatments?
- Should I or my child be enrolled in a clinical trial?
- Can I continue to work or can my child go to school?
- Can I stay with my child for procedures? For hospitalizations?
- How and what should we tell our child about this illness?
- What should we tell our other children?
Table Of Contents
- Causes and symptoms
- Treatment team
- Clinical staging, treatments, and prognosis
- Alternative and complementary therapies
- ALL in remission
- Recurrent ALL
- Coping with cancer treatment
- Clinical trials
- Special concerns
- KEY TERMS
- Graft versus host disease
- Intrathecal chemotherapy
- Ommaya reservoir
- Philadelphia chromosome
- Sanctuary sites
- QUESTIONS TO ASK THE DOCTOR