Leukemia.

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Leukemia.
I

INTRODUCTION

Leukemia, any of several types of cancers that affect blood cells, including oxygen-carrying red cells; certain infection-fighting white cells, such as granulocytes,
macrophages and lymphocytes; and platelets, which aid in blood clotting. According to the American Cancer Society, leukemia is the sixth leading cause of cancer
deaths among men and the seventh leading cause of cancer deaths among women. Each year in the United States about 31,000 new cases of leukemia are diagnosed
and the disease causes an estimated 22,000 deaths. It accounts for about one-third of all cancers in children under age 15.
Blood cells are made in the bone marrow, the spongy tissue in the center of bones. A leukemia begins when an immature blood cell in the marrow, known as a
progenitor cell, becomes cancerous, dividing uncontrollably and overriding the body's normal restrictions on cell division. Over time, the marrow becomes crowded with
cancerous cells, all of them descendants of the first abnormal cell. The malignant cells may also accumulate in a patient's lymph nodes, spleen, and elsewhere. At the
time of diagnosis, up to a trillion leukemic cells may be present in the body.
The mass of leukemic cells in the marrow suppresses the production of healthy blood cells, giving rise to the symptoms typical of leukemia. Pale skin, fatigue, and
shortness of breath are signs of anemia, a decrease in the concentration of red cells in the blood. Nose bleeds, gum bleeding, a tendency to bruise easily, and pinheadsized red spots on the skin reflect the decrease in the concentration of platelets in the blood. A lack of functional white cells makes patients with leukemia prone to
infection.
Leukemia was first described by European physicians during the mid-19th century. During autopsies, physicians noted cases of profoundly elevated white cell
counts--today we know that many of these white cells were nonfunctional leukemic cells--and very low red cell counts. For this reason, the condition was referred to as
weisses blut (German for "white blood"). Later, the term leukemia (Greek leukos, "white"; haima, "blood") was applied to the disease.

II

TYPES OF LEUKEMIA

The leukemias are classified by two principal characteristics: the lineage of blood cell that becomes cancerous, and how rapidly the disease progresses. A leukemia is
classified as myelocytic or myelogenous if the malignant cells have descended from the progenitors of red cells, granulocytes, macrophages, or platelets. If the leukemic
cells have descended from a lymphocyte precursor cell, the leukemia is referred to as lymphocytic.
Myelocytic or lymphocytic leukemia can be acute or chronic, terms that refer to the patient's life expectancy if the disease remains untreated. Acute leukemias develop
rapidly, and without prompt treatment, the suppression of normal blood cell production is so severe that death occurs in a matter of weeks. In the chronic leukemias,
patients may survive for several years or more without treatment because the effects of leukemic cells on the structure and function of the marrow develop more slowly
and are less severe. In chronic myelocytic leukemia, for example, the leukemic cells can often complete their development and become functional blood cells. In chronic
lymphocytic leukemia, the leukemic lymphocytes do not function normally, but in many cases the abnormal cells do not severely inhibit normal blood cell development.
The four major forms of leukemia--acute myelocytic, chronic myelocytic, acute lymphocytic, and chronic lymphocytic--can be further subcategorized based on the
appearance of the malignant cells, the presence of characteristic molecules on their surface, or their stage of development. For example, hairy-cell leukemia is an
uncommon type of chronic lymphocytic leukemia in which the malignant cells have fine, hairlike projections on their surface.
Myelocytic leukemia--both acute and chronic forms--can occur at any age, but more than 90 percent of cases occur in adults, and the risk of developing the disease
increases dramatically after the age of 50. Acute myelocytic leukemia is the most common form of leukemia in the United States, with 12,000 new cases diagnosed each
year. About 4,600 new cases of chronic myelocytic leukemia are diagnosed each year.
Chronic lymphocytic leukemia occurs rarely before the age of 45 and increases in incidence with each succeeding decade. Acute lymphocytic leukemia, by contrast, can
occur at any age, but about half the cases occur in children under the age of 19, with the peak incidence occurring at about 4 years of age. In the United States,
chronic lymphocytic leukemia accounts for about 9,700 new cases of leukemia each year, and acute lymphocytic leukemia, for about 4,000 new cases.

III

CAUSES

In most cases of leukemia, the cause is unknown, but physicians have identified four known causes of certain types of leukemia. Intensive radiation exposure or
moderately intense exposure for long periods (see Radiation Effects, Biological) increases the risk of acute and chronic myelocytic leukemia and acute lymphocytic
leukemia, but not chronic lymphocytic leukemia. The high rate of leukemia among Japanese survivors of the atomic bomb detonations at Hiroshima and Nagasaki at the
end of World War II dramatically demonstrated the role of high-dose radiation in causing leukemia.
Exposure to certain chemicals can also cause leukemia. Workers exposed to benzene over long periods have an increased risk of developing acute myelocytic leukemia.
Tobacco smoking appears to increase the incidence of this form of leukemia. Chemotherapy drugs used to treat breast cancer, ovarian cancer, lymphomas, and certain
other cancers also increase a patient's risk of later developing acute myelocytic leukemia.
Two viruses, human T-cell leukemia viruses (HTLV) I and II, are known to cause T-cell leukemia, a very rare form of lymphocytic leukemia, in humans. However, only a
small percentage of people who are infected with these viruses develop cancer. Although virus-related leukemia is rare in humans, it is quite common in other animal
species, such as cats, chickens, and mice.
Genetic factors may also contribute to the development of leukemia. Some inherited conditions, such as Down syndrome, increase a person's risk of developing
leukemia. In addition, scientists have identified rare clusters of leukemia in several members of the same family, presumably due to an inherited genetic mutation.

IV

DIAGNOSIS

Bone marrow biopsy and blood cell tests are the primary techniques used to diagnose leukemia. In a bone marrow biopsy, cells are collected through a hollow needle
inserted into the outer edge of a hipbone, or a small cylinder of bone containing marrow is removed with a special needle. The marrow sample is examined with a
microscope for the presence of leukemic cells.
Blood tests that monitor blood cell counts--the number of cells of different types in the blood--can also reveal abnormalities characteristic of various forms of leukemia.
Patients with acute leukemias nearly always have decreased red cell and platelet counts. In some patients, white cell counts are also very low. In others, a large number
of leukemic cells enter the blood from the bone marrow, making white cell counts very high. However, physicians can examine these cells under the microscope to
determine that they are abnormal, leukemic cells, not healthy white cells, and that the elevated white cell count is not due to another cause, such as infection.
Patients with chronic leukemias usually have slightly decreased red cell counts. Platelet counts are usually normal or mildly increased in patients with chronic myelocytic

leukemia, and normal or mildly decreased in chronic lymphocytic leukemia. Nearly all chronic leukemia patients have increased white cell counts. In chronic myelocytic
leukemia, some of these leukemic white cells are capable of functioning as normal cells do by fighting infectious microbes. Hence, infection is no more common than in a
healthy individual. In chronic lymphocytic leukemia the blood contains large numbers of malignant lymphocytes that do not function normally. Normal lymphocytes
coexist but are suppressed, and the inability to respond to microbes with specific antibody production may increase the frequency and severity of infection in some
patients.
Additional tests, such as staining of cells with various chemical dyes to help doctors examine their appearance, analysis of molecules on the surface of the cells, and
analysis of the cells' genetic material, are performed on leukemic cells collected from the marrow or blood. These tests help doctors determine the subcategory of
leukemia, which, in turn, may affect a patient's prognosis and the approach to treatment. Tests such as chest X rays and examination of the spinal fluid for leukemic
cells can help doctors determine how far the disease has spread.

V

TREATMENT

Treatment of leukemia depends on the type and extent of the disease and is tailored to each individual patient. In general, chemotherapy--the use of drugs that kill
rapidly dividing cells--is the mainstay of treatment for both acute and chronic leukemias. In acute leukemias, chemotherapy is very intensive and uses several drugs,
either simultaneously or sequentially, in order to kill as many leukemic cells as possible. Antibiotics and transfusions of red cells and platelets help sustain patients whose
blood counts are dangerously low because they are receiving intensive chemotherapy.
Sometimes radiation is used to shrink collections of leukemic cells that accumulate in various parts of the body, such as on the lining of the brain and spinal cord in
acute lymphocytic leukemia, or within lymph nodes in chronic lymphocytic leukemia. If left untreated, collections of cells on the lining of the brain and spinal cord can
cause headache, blurred vision, and confusion, and elsewhere in the body can cause swelling and tenderness of the affected area.
Particularly in young patients, if doctors determine that chemotherapy alone is not likely to be successful or if patients relapse after chemotherapy, allogeneic
(genetically different) stem cell transplantation may be performed. In this procedure, very intensive total body radiation or very high doses of chemotherapy or both are
used. The chemotherapy and radiation are designed to destroy all the leukemic cells in a patient's body; however, this treatment also destroys the blood-forming
system in the patient's bone marrow. For this reason, healthy stem cells, the cells in bone marrow that enable long-term formation of blood, must then be infused into a
patient to replenish the blood-forming system. The stem cells must come from an immunologically matched donor, usually a sibling, but if a sibling match is unavailable,
occasionally an unrelated donor may be sought. The latter can be identified from a database of volunteer donors. These databases can be searched for a person with an
identical or very close tissue type match. Formerly, stem cells could only be transplanted from the bone marrow of the donor. The procedure was known as bone
marrow transplantation. Recent advances now make it possible to recover stem cells from blood, or from the placenta and umbilical cord blood ("cord blood") after
delivery of a newborn, making the transplant procedure much simpler and less risky for the donor. Cord-blood stem cells are frozen, kept in a "bank," and can be used
later for a patient in need. The number of stem cells in these samples may be insufficient for larger adults and are used most commonly for children or smaller adults
who require a transplant and are in need of a matched, unrelated donor.
An unexpected effect of allogeneic stem cell transplantation is what is known as graft-versus-leukemia effect. The immune cells of the donor recognize minor tissue type
antigens (the proteins that produce antibodies) that do not match the recipient's. These donor immune cells attack the recipient's tissues, including both leukemia cells
and normal tissues. The attack against the recipient's normal tissues is referred to as graft-versus-host disease. This attack can be acute or chronic, and very mild or
very severe. It is a serious, unwanted complication of allogeneic stem cell transplantation. Graft-versus-leukemia-cells, on the other hand, is a desirable effect and is
responsible in part for some of the beneficial effects of transplantation, especially in patients who received transplants to treat acute or chronic myelocytic leukemia.
Transplantation is most effective in children and young adults; in older adults it is often too hazardous a procedure to apply. An approach called non-myeloablative stem
cell transplantation is being tested in older patients. Here very mild pretreatment with chemotherapy or irradiation is used, while anti-immune therapy is relied on to
prevent the recipient's immune system from rejecting the donor's stem cells. The graft-versus-leukemia effect is relied on as a substitute for the very intensive therapy
given before a standard transplant for leukemia.
Immunotherapy is a promising new approach to treating leukemia. In this technique, highly specific molecules known as monoclonal antibodies are manufactured in the
laboratory to target molecules on the surface of leukemic cells. The antibodies themselves may kill the leukemic cells, or a radioactive substance or cell toxin attached to
the antibodies may kill the leukemic cells, when injected intravenously into a patient. This method provides a convenient means of delivering the radioactive or toxic
substance directly to leukemic cells, where it may kill these cells with minimal effect on healthy cells.
The goal in treating acute leukemias is to kill enough leukemic cells to produce a remission, meaning that the production of healthy blood cells is no longer suppressed,
blood cell counts return to normal, and the patient's symptoms diminish. At that stage, further therapy is used to try to prolong remission or achieve a cure. About 80
percent of children with acute lymphocytic leukemia are cured. Cure rates in acute myelocytic leukemia are estimated to be about 40 percent in children but are much
lower in adults depending on their age. Since most patients are over 65 years when they develop the disease, cures are infrequent.
In the chronic leukemias, cures are very infrequent, but today's chemotherapy regimens have increased the average survival in these patients from about three years
to more than six years. Chronic lymphocytic leukemia in its most indolent form may not require treatment and may not progress or be a serious health consequence for
the patient. In patients with active or progressive disease, several new drugs and types of monoclonal antibodies are available to treat the disease. In chronic
myelocytic leukemia, a dramatic advance in therapy involves the introduction of a drug that specifically targets the leukemia-causing change in the marrow cell. The
introduction of this treatment has been projected to increase survival to more than a decade on average. Young patients with the disease who have an appropriate
stem cell donor can be cured with stem cell transplantation.

Contributed By:
Marshall A. Lichtman
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