What is leukemia?

Causes and Symptoms

The blood is essential for all the physiological processes of the body. It is composed of red cells called erythrocytes, white cells called leukocytes, and platelets, each of which has distinct functions. Erythrocytes, which contain hemoglobin, are essential for the transport of oxygen from the lungs to all the cells and organs of the body. Leukocytes are important for protecting the body against infection by bacteria, viruses, and other parasites. Platelets play a role in the formation of blood clots; therefore, these cells are critical in the process of wound healing. Blood cell development, or hematopoiesis, begins in the
bone marrow with immature stem cells that can produce all three types of blood cells. Under the influence of special molecules called growth factors, these stem cells divide rapidly and form blast cells that become one of the three blood cell types. After several further divisions, these blast cells ultimately mature into fully functional erythrocytes, leukocytes, and platelets. In a healthy individual, the number of each type of blood cell remains relatively constant. Thus, the rate of new cell production is approximately equivalent to the rate of old cell destruction and removal.

Mature leukocytes are the key players in defending the body against infection. There are three types of leukocytes: monocytes, granulocytes, and lymphocytes. In leukemia, leukocytes multiply at an increased rate, resulting in an abnormally high number of white cells, a significant proportion of which are immature cells. All forms of leukemia are characterized by this abnormally regulated growth; therefore, leukemia is a cancer, even though tumor masses do not form. The cancerous cells live longer than the normal leukocytes and accumulate first in the bone marrow and then in the blood. Since these abnormal cells crowd the bone marrow, normal hematopoiesis cannot be maintained in a person with leukemia. The patient will usually become weak as a result of the lack of oxygen-carrying red cells and susceptible to bleeding because of a lack of platelets. The abnormal leukocytes do not function effectively in defending the body against infection, and they prevent normal leukocytes from developing; therefore, the patient is immunologically compromised. In addition, once the abnormal cells accumulate in the blood, they may hinder the functioning of other organs, such as the liver, kidney, lungs, and spleen.

It has become clear that leukemia, which was first recognized in 1845, is actually a pathology that comprises more than one disease. Leukemia has been divided into four main types, based on the type of leukocyte that is affected and the maturity of the leukocytes observed in the blood and the bone marrow. Both lymphocytes and granulocytes can be affected. When the cells are mainly immature blasts, the leukemia is termed acute, and when the cells are mostly mature, the leukemia is termed chronic. Therefore, the four types of leukemia are acute lymphocytic (ALL), acute granulocytic (AGL), chronic lymphocytic (CLL), and chronic granulocytic (CGL). The granulocytic leukemias are also known as myologenous leukemias (AML, CML) or nonlymphoid leukemias (ANLL, CNLL). These are the main types of leukemia, although there are additional rarer forms. These four forms of leukemia account for about 5 percent of the cancer cases in the United States. The incidence of acute and chronic forms is approximately equivalent, but specific forms are more common at different stages of life. The major form in children is ALL; after puberty, there is a higher incidence of AGL. The chronic forms of leukemia occur in the adult population after the fourth or fifth decade of life, and men are twice as likely to be affected as women.

The causes of leukemia are still not completely understood, but scientists have put together many pieces of the puzzle. It is known that several environmental factors increase the risk of developing leukemia. Among these are exposure to radiation, chemicals such as chloramphenicol and benzene, and possibly viruses. In addition, there is a significant genetic component to this disease. Siblings of patients with leukemia have a higher risk of developing the disease, and chromosomal changes have been found in the cells of most patients, although they disappear when the patient is in remission. For example, the genetic basis of certain forms of CML is an exchange of information (translocation) between chromosome 22 and chromosome 9; the shortened chromosome 22 is referred to as the Philadelphia chromosome. These different “causes” can be linked by understanding how oncogenes function. Every person, as part of his or her genetic makeup, has several oncogenes that are capable of causing cancer. In the healthy person, these oncogenes function in a carefully regulated manner to control cell growth. After exposure to an environmental or genetic influence that causes chromosome abnormalities, however, these oncogenes may become activated or deregulated so that uncontrolled cell growth occurs, resulting in the abnormally high number of cells seen in leukemia. The translocation associated with the Philadelphia chromosome results in abnormal expression of an oncogene encoding an enzyme that regulates cell division.

Leukemia is often difficult to diagnose in the early stages because the symptoms are similar to more common or less serious diseases. “Flulike” symptoms, sometimes accompanied by fever, may be the earliest evidence of acute leukemia; in children, the first symptoms may be less pronounced. The symptoms quickly become more pronounced as white cells accumulate in the lymph nodes, spleen, and liver, causing these organs to become enlarged. Fatigue, paleness, weight loss, repeated infections, and an increased susceptibility to bleeding and bruising are associated with leukemia. As the disease progresses, the fatigue and bleeding increase, various skin disorders develop, and the joints become painfully swollen. If untreated, the afflicted individual will die within a few months. Chronic leukemia has a more gradual progression and may be present for years before symptoms develop. When symptoms are present, they may be vague feelings of fatigue, fever, or loss of energy. There may be enlarged lymph nodes in the neck and armpits and a feeling of fullness in the abdomen because of an increase in the size of the spleen as much as tenfold. Loss of appetite and sweating at night may be initial symptoms. Often, chronic leukemia eventually leads to a syndrome resembling acute leukemia, which is ultimately fatal.

If these symptoms are present, a doctor will diagnose the presence of leukemia in two stages. First, blood will be drawn and a blood smear will be analyzed microscopically. This may indicate that there are fewer erythrocytes, leukocytes, and platelets than normal, and abnormal cells may be visible. A blood smear, however, may show only slight abnormalities, and the number of leukemic cells in the blood may not correspond to the extent of the disease in the bone marrow. This requires that the bone marrow itself be examined by means of a bone marrow biopsy. Bone marrow tissue can be obtained by inserting a needle into a bone such as the hip and aspirating a small sample of cells. This bone marrow biopsy, which is done under local anesthetic on an outpatient basis, is the definitive test for leukemia. Visual examination of the marrow usually reveals the presence of many abnormal cells, and this finding is often confirmed with biochemical and immunological tests. After a positive diagnosis, a doctor will also examine the cerebrospinal fluid to see if leukemic cells have invaded the central nervous system.

Treatment and Therapy

The treatment and life expectancy for leukemic patients varies significantly for each of the four types of leukemia. Treatment is designed to destroy all the abnormal cells and produce a complete remission, which is defined as the phase of recovery when the symptoms of the disease disappear and no abnormal cells can be observed in the blood or bone marrow. Unfortunately, a complete remission may be only temporary, since a small number of abnormal cells may still exist even though they are not observed under the microscope. These can, with time, multiply and repopulate the marrow, causing a relapse of the disease. With repeated relapses, the response to therapy becomes poorer and the durations of the remissions that follow become shorter. It is generally believed, however, that a remission that lasts five years in ALL, eight years in AGL, or twelve years in CGL may be permanent. Therefore, the goal of leukemia research is to develop ways to prolong remission.

By the time acute leukemia has been diagnosed, abnormal cells have often spread throughout the bone marrow and into several organs; therefore, surgery and radiation are usually not effective. Treatment programs include chemotherapy or bone marrow transplants or both.

Chemotherapy
is usually divided into several phases. In the first, or induction, phase, combinations of drugs are given to destroy all detectable abnormal cells and therefore induce a clinical remission. Vincristine, methotrexate, 6-mercaptopurine, L-asparaginase, daunorubicin, prednisone, and cytosine arabinoside are among the drugs that are used. Combinations that selectively kill more leukemic cells than they do normal cells are available for the treatment of ALL; however, in AGL no selective agents are available, resulting in the destruction of equal numbers of diseased and healthy cells. An alternative strategy does not rely on destroying the abnormal cells but instead seeks to induce immature leukemic cells to develop further. Once the cells are mature, they will no longer divide and will eventually die in the same way that a normal leukocyte does. Drugs such as cytarabine and retinoic acid have been tested, but the results are inconclusive.

Although the induction phase achieves clinical remission in more than 80 percent of patients, a second phase, called consolidation therapy, is essential to prevent relapse. Different combinations of anticancer drugs are used to kill any remaining cancer cells that were resistant to the drugs in the induction phase. Once the patient is in remission, higher doses of chemotherapy can be tolerated, and sometimes additional intensive treatments are given to reduce further the number of leukemic cells so that they will be unable to repopulate the tissues. During these phases of treatment, patients must be hospitalized. The destruction of their normal leukocytes along with the leukemic cells makes them very susceptible to infection. Their low numbers of surviving erythrocytes and platelets increase the probability of internal bleeding, and transfusions are often necessary. The dosages of chemotherapeutic agents must be carefully calculated to kill as many leukemic cells as possible without destroying so many normal cells that they cannot repopulate the marrow. In general, children handle intensive chemotherapy better than adults.

Following the induction and consolidation phases, maintenance therapy is sometimes used. In ALL, maintenance therapy is given for two to three years; however, its benefit in other forms of leukemia is a matter of controversy.

A second form of therapy is sometimes indicated for patients who have not responded to chemotherapy or are likely to relapse.
Bone marrow transplantation has been increasingly used in leukemic patients to replace diseased marrow with normally functioning stem cells. In this procedure, the patient is treated with intensive chemotherapy and whole-body irradiation to destroy all leukemic and normal cells. Then a small amount of marrow from a normal donor is infused. The donor can be the patient himself, if the marrow was removed during a previous remission, or an immunologically matched donor, who is usually a sibling. If a sibling is not available, it may be possible to find a matched donor from the National Marrow Donor Program, which has on file approximately ten million donors. Marrow is removed from the donor, broken up into small pieces, and given to the patient intravenously. The stem cells from the transplanted marrow circulate in the blood, enter the bones, and multiply. The first signs that the transplant is functioning normally occur in two to four weeks as the numbers of circulating granulocytes and platelets in the patient’s blood increase. Eventually, in a successful transplant, the bone marrow cavity will be repopulated with normal cells.

Bone marrow transplantation is a dangerous procedure that requires highly trained caregivers. During this process, the patient is completely vulnerable to infection, since there is no functional immune system. The patient is placed in an isolation unit with special food-handling procedures. There is little chance that the patient will reject the transplanted marrow, because the immune system of the patient is suppressed. A larger problem remains, however, because it is possible for immune cells that existed in the donor’s marrow to reject the tissues and organs of the patient. This
graft-versus-host disease (GVHD) affects between 50 and 70 percent of bone marrow transplant patients. Even though the donor is immunologically matched, the match is not perfect, and the recently transplanted cells regard the cells in their new host as a “foreign” threat. Twenty percent of the patients who develop GVHD will die; therefore, drugs such as cyclophosphamide and cyclosporine, which suppress the immune system, are usually given to minimize this response. GVHD is not a problem if the donor is the patient. In 2012, the drug Prochymal was approved for use in children with GVHD; it was the stem-cell drug approved for usage. Since the availability of matching bone marrow cells is exceeded by the need, recent studies have involved the testing of hematopoietic umbilical cord cells from unrelated donors. The incidence of relapse as well as GVHD was similar to that when using matched bone marrow cells, suggesting that cord blood cells have the potential to serve as an alternative to conventional transplants.

Aggressive chemotherapy and bone marrow transplantation have dramatically increased the number of long-lasting remissions. For those who survive the therapy, it appears that, in ALL, approximately 40 percent of adults may be cured of the leukemia. The outlook for permanent remission is 10 to 20 percent in AGL and 65 percent for CGL patients. Statistics for chronic lymphocytic leukemia have been difficult to predict, because individual cases that have been similarly treated have had very different outcomes. The average lifespan after a diagnosis of CLL is three to four years; however, some patients live longer than fifteen years.

Perspective and Prospects

As the number of deaths from infectious disease has decreased, cancer has become the second most common cause of disease-related death. It is estimated that one of three people in the United States will develop a form of cancer and that the disease will kill one of five people. The search for causes and treatments of various cancers is perhaps the most active area of biological research today. Multiple lines of experimentation are being pursued, and significant advances have been made.

Leukemia is one of the cancers that scientists understand fairly well, but many unanswered questions remain. Leukemia research can be divided into two broad approaches. In the first, the researcher seeks to modify and improve the current methods for treatment: chemotherapy and bone marrow transplantation. In the second, an effort is being made to understand more about the disease itself, with the hope that completely different strategies for treatment might present themselves.

The risks involved in current therapy for leukemia have been discussed in the previous section. Treatment schedules, individually designed for each patient, will add to the understanding of how other physiological characteristics affect treatment outcome. Significant advances in reducing the risk of GVHD are likely to come quickly. In marrow transplants in which the donor is the patient, research is in progress to improve ways to screen out abnormal cells, even if they are present at very low levels, before they are infused back into the patient. In addition, for transplants in which the donor is not the patient, techniques that remove the harmful components of the bone marrow are being developed. Bone marrow cells can be partially purified, resulting in an enriched population of stem cells. Administering these to the leukemic patient should greatly reduce the risk of GVHD. Since bone marrow can be stored easily, the day may come when healthy people will store a bone marrow stem cell sample in case they contract a disease that would require a transplant.

Basic research in leukemia focuses on a simple question, “Why are leukemic cells different from normal cells?” This question is asked from a variety of perspectives in the fields of immunology, cell biology, and genetics. Immunologists are looking for markers on the surfaces of leukemic cells that would distinguish them from their normal counterparts. If such markers are found, it should be possible to target leukemic cells for destruction by using monoclonal antibodies attached to drugs. These “smart drugs” would be able to home in on the diseased cells, leaving normal cells untouched or only slightly affected. This would be a great advance for leukemia treatment, since much of the risk for the leukemic patient following chemotherapy or bone marrow transplant involves susceptibility to infection because the normal immune cells have been destroyed. Similarly, it may be possible to “teach” the patient’s immune system to destroy abnormal cells that it had previously ignored. Similar forms of immunotherapy have shown promise in treating forms of cancer such as melanoma.

Cell biologists are seeking to understand the normal hematopoietic process so that they can determine which steps of the process go awry in leukemia. Some of the growth factors involved in hematopoiesis have been identified, but it appears that the process is quite complex, and as yet scientists do not have a clear picture of normal hematopoiesis. When the understanding of the normal process becomes more complete, it may be possible to localize the defect in a leukemic patient and provide the missing growth factors. This might allow abnormal immature cells to complete the developmental process and relieve the symptoms of disease.

Geneticists are studying the chromosomal changes that underlie the onset of leukemia. As the oncogenes that are involved are identified, the reasons for their activation will also be determined. Once the effects of these genetic abnormalities are understood, it may be possible to intervene by genetically engineering stem cells so that they can develop normally.

These areas of research will likely converge to provide the leukemia treatments of the future. Leukemia is a cancer for which there is already a significant cure rate. It is not unreasonable to expect that this rate will approach 100 percent in the near future.

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