82 Leukemia

Leukemia, commonly known as cancer of the blood, describes a group of malignant disorders that arise in the blood-forming cells. The bone marrow, where the cells of the blood are made, malfunctions to pro­duce abnormal white cells {leukemic cells) in an un­controlled manner to the detriment of all the other essential blood cells.

Hematopoiesis

Blood cell formation, known as hematopoiesis, starts in the bone marrow, the spongy interior of the large bones, with a pool of immature or undifferentiated cells known as pluripotent stem cells, which contain the characteristics of all the major blood cell lines. These cells divide, either producing themselves ex­actly or producing more specialized cells that contain the characteristics of only one of the two major cell lines: One of these two specialized cells, known as the mixed myeloid progenitor cell, consists of the progeni­tor cells to the red blood cells, the monocytes and granulocytes (white cells), and the platelets. The other, the lymphoid stem cell, produces the lympho­cytes that make up about 30 percent of the circulating white blood cells. The two types of lymphocytes - T cells and B cells - have different functions: The T cells attack and destroy virus-infected cells, foreign tissue, and cancer cells; B cells produce antibodies, which are proteins that help destroy infectious agents.

The production process is continual through divi­sion and differentiation, with cell characteristics be­coming increasingly defined with each division. The result is that cells are “committed” to evolution into one specific cell type, and thus, as mature cells, they are released into the bloodstream at a rate consistent with the body’s needs and the death of old cells. The exception is the lymphocytes: These are allowed to leave the bone marrow as immature cells, but they mature in the lymph system (thymus, spleen, lymph nodes, and so forth) before entering the bloodstream. In normal health, immature stem cells or blasts are present in the circulating blood only in very small numbers, and healthy bone marrow does not contain more than 5 percent of the total cell population.

From 6 weeks until about 6 to 7 months in utero, liver and the spleen are the main organs involved in blood formation. Thereafter, the bone marrow takes over. In infants, practically all the bones are in­volved, but in adults the production is limited to the vertebrae, ribs, sternum, skull, sacrum, pelvis, and the proximal ends of the femur. Because the entire blood cell formation, growth, maintenance, destruc­tion, and replacement cycle is most efficiently orga­nized, it follows that any abnormal reproduction of any type of cell will disrupt the blood cell balance and, in the absence of a self-regulating mechanism, will affect the body’s general health.

Every day at least 200 billion red cells, 10 billion white cells, and over 400 billion platelets are pro­duced in the marrow. The averagel life-span of the cells varies according to the cell type, and ranges from 1 to 2 days for white cells, to about 7 days for platelets, to 120 days for red cells. In normal circulat­ing blood there are approximately 1,000 red cells to each white cell. But in leukemia, the normal produc­tion of blood cells fails. In all but its rarest form, one or more of the types of white blood cells reproduces abnormally and creates useless, immature blast cells or poorly developed cells of inferior quality.

Classificatioii of the Leukemias

Leukemia types are classified according to the type of white cell that is affected. The two main types of the disease are myeloid (also called granulocytic or myelogenous) and lymphatic (or lymphocytic). These two main types are derived from the two major cell lines: the mixed myeloid progenitor cell line, which produces the white blood cell monocytes or granulo­cytes; and the lymphoid cell line, which gives rise to the lymphocytes. These are further subdivided into acute (progressing rapidly) and chronic (progressing slowly). In the acute form, there is abnormal growth of immature or blast cells whereas in chronic leuke­mia, more mature cells proliferate, although abnor­mal immature cells may also be present. The follow­ing are the diseases that mainly arise:

1. Acute myeloid leukemia (AML), also called acute myelogenous leukemia, acute myelocytic leu­kemia, acute Hiyeloblastic leukemia, and acute granulocytic leukemia, is synonymous with the group known as acute nonlymphocytic leukemia (ANLL), which includes some of the rar6r subtypes of the disease (e.g., monocytic leukemia). AML in­volves the neutrophils (one of the granulocytes) that stem from the myeloid progenitor cell line.

2. Chronic myeloid leukemia (CML), also called chronic myelogenous leukemia, chronic myelocytic leukemia, and chronic granulocytic leukemia (CGL), produces excessive numbers of granulocytes that ac­cumulate in the bone marrow and blood stream.

3. Acute lymphoblastic leukemia (ALL), also known as acute lymphocytic leukemia and acute lymphatic leukemia, arises as a result of abnormal immature lymphocytes, which proliferate in the bone marrow and the bloodstream and affect the lymphocytes (the B cells and T cells) stemming from the lymphoid cell line.

4. Chronic lymphocytic leukemia (CLL), also known as chronic lymphatic leukemia and chronic lymphogenous leukemia, produces an abnormal in­crease in lymphocytes that lack their infection­fighting ability. It is the major type of a group of diseases known as lymphoproliferative disorders, which includes such rarer forms of leukemia as hairy cell leukemia and adult T cell leukemia.

Distribution and Incidence

Leukemia occurs worldwide and represents just over 5 percent of all cancers. The disease does not present in a regular pattern, and its comparative rarity helps to explain its irregularity. Leukemia can strike anyone, at any time, and at any age. The difficulties in collecting statistics relating to leuke­mia in populations throughout the world are due not only to the different methods of reporting cases and identifying the true leukemia cell-type specificity, but also to the variable standards and access to medi­cal care. Comparing the incidence of leukemia and other cancers on a worldwide basis can therefore present problems.

The specific types of leukemia are very different in their age patterns and presentation:

1. Acute myeloid leukemia (AML) is the major form ofleukemia. Its rate of incidence increases with age, yet it also occurs in early infancy and in those in their early 20s. With a mean estimated presentation at around the age of 40 years, the disease affects both sexes equally.

2. Chronic myeloid leukemia (CML) is considered an “adult” leukemia, attacking those in the 30- to 50-year age bracket, although it also presents in the older age groups. It, too, has an equal rate of inci­dence in males and females.

3. Acute lymphoblastic leukemia (ALL) is often referred to as “childhood leukemia” for the reason that it accounts for 85 percent of leukemia in chil­dren and only 15 percent of cases in adults.

4. Chronic lymphocytic leukemia (CLL) is primar­ily a disease of the elderly; it rarely presents in anyone below the age of 40. It is more common in males than females, with a male/female ratio of 2:1.

The estimated incidence of all cases ofleukemia in the developed countries of the world is 10 per 100,000 of population, the most common now being CLL including the lymphoproliferative disorders, followed by AML and its subgroups, then CML, and lastly ALL. Incidence rates vary in some countries of the world and among some ethnic groups, but no variation is of great significance. The male/female incidence ratio is about 1.7:1.

Etiology

The etiology of leukemia is at present unknown. The basic question is what causes a healthy cell to change to become malignant and to proliferate in that state. The consensus of opinion is that the dis­ease results from the interaction of a number of factors, including environmental agents, and investi­gations are being pursued on the following:

1. Genetic factors, involving chromosomal abnor­malities and changes.

2. Disorders of the immune system (the body’s de­fense system against infection).

3. Exposure to ionizing radiation from a single large dose or from repeated small doses.

4. Chemicals that suppress bone marrow function.

5. Infection - viruses: Retroviruses are known to cause leukemia and Ijrmphomas in certain animal species but not in humans, although recently a type of RNA virus has been isolated from patients with adult T cell leukemia known as human T cell leukemia virus HTLVl.

Epidemiology

As the cause of leukemia remains obscure, epide­miology has assumed an importance in two direc­tions: first, the incidence, age, and sex differences in the various forms of the disease related to their geographic presentation, and second, the hunt for etiologic clues.

One of the first epidemiology studies on leukemia was by W.

Toward the close of the nineteenth century, a small number of cases of leukemia in its acute form were reported in Europe, and attention was focused on this new form of the disease, particularly in Amer­ica. George Dock of the University of Michigan was a leading investigator of the complicated aspects of acute leukemia and its rapid onset. The literature, which Dock reviewed extensively in 1903, regarded infection and “some microscopic germ” as suspects.

The infective theory of acute leukemia was fur­ther discussed in a 1917 publication in the British Journal of Children’s Diseases by G. Ward, who had collected a series of 1,457 cases of leukemia. This work added to the knowledge of the age-sex distribu­tion of the disease and suggested that although acute leukemia resembled an infectious disease in many respects (e.g., the feverlike symptoms it caused), there was little evidence to suggest that it was by nature infectious or that it was hereditary.

Leukemia tends to present in an irregular pat­tern, evidenced by the number of “clusters” of cases that are regularly reported, clusters being defined as more cases of the disease than would be expected to occur in a specific area. The first report of a cluster of leukemia cases came from Paris in 1922, where four patients living within a short distance of one an­other were diagnosed with acute leukemia in a pe­riod of 7 weeks. It was the commonly held view that the cause was the water from a canal in the area. In this event, as with most clusters, the pattern was of normal or less than normal incidence of the disease both before and after the appearance of the cluster of cases.

Because of the sudden presentation of clusters of the disease, investigations are often launched to find a cause. The identification of possible contributory factors within the environment is one approach, al­though the prime concentration is on what influ­ences the basic cells and genes to change and begin the malignant process. The most established etio­logic factor in human leukemias is ionizing radia­tion. The atom bombs dropped on Hiroshima and Nagasaki in 1945, for example, brought a rise in the incidence of leukemia, which began about 3 years after the atomic attack and reached a peak at 6 years, but then slowly declined to a normal inci­dence of the disease at 20 years. On investigation it was found that the greatest incidence was among those closest to the explosion, whereas at 2,000 me­ters or more the risk of leukemia was no greater than among unirradiated people.

Altogether some 250 cases of leukemia occurred between 1946 and 1965 in the 183,000 people exposed to radiation in Hiroshima and Nagasaki. From this information it followed that only a small proportion of those irradiated developed leukemia, and this led to the suggestion of individual suscepti­bility. Later, public concern about nuclear power causing leukemia was heightened by the number of clusters of cases of the disease reported in areas surrounding nuclear power stations. Indeed many questions have been raised on this issue, particu­larly because childhood cases appear to be more prominent in these reported clusters. The pattern — which became apparent in the aftermath of the attacks on Hiroshima and Nagasaki - seems to emerge in these clusters as well; for if nuclear power stations are emitting radiation, relatively few people are actually affected - again raising the etiologic question of possible susceptibility.

The issue of genetic susceptibility was studied by Frederick Gunz, a distinguished research physician at Sydney Hospital in Australia, whose biological approach to epidemiology resulted in his publica­tions in 1974 and 1975 on the genetics of human leukemia. Gunz concluded that evidence from family studies reinforced the theory of a genetic basis in some people for chronic lymphatic leukemia in par­ticular. Gunz also reported that certain chemicals, notably benzene along with viruses, were identified as triggering factors in some animal leukemias, but evidence for such a conclusion in human leukemia remained elusive.

A major epidemiology study embracing a popula­tion base of some 20 million people was started in 1984 in England and Wales, at the University of Leeds, by the Leukaemia Research Fund. This com­puterized program with diagnostic check controls will be of major importance in assessing current trends in the presentation of the disease.

Clinical Manifestations and Pathology

Some of the first symptoms of acute leukemia are similar to those of common infectious illness. All the leukemias share common signs and symptoms aris­ing from the infiltration of the bone marrow, with leukemic cells replacing the normal tissues. The lack of red cells causes fatigue and anemia, the lack of normal white cells results in infections and fever, and the lack of platelets produces bleeding and bruising. The lymph nodes, spleen, and liver may become en­larged as they are infiltrated with leukemic cells. Bone or joint pains are associated symptoms, and purpura is often present. Although the basic features of the leukemias are common, marked differences exist between the acute and chronic leukemias in their mode of presentation. In the acute leukemias, influenza-type symptoms and fever (present for only days or weeks) signal the sudden and rapid progress of the acute form of the disease. Weakness, exhaus­tion, enlargement of the lymph nodes, abnormal bleeding (from the gums for example), and a tendency to bruise easily are some of the chief symptoms.

By contrast, the symptoms of chronic leukemias are generally far more subtle. It is not uncommon for the disease to be discovered accidentally when a blood test is carried out for an unrelated reason. The most common symptoms are loss of energy, tired­ness, fever, night sweats, and loss of appetite. There may also be enlargement of the liver and spleen and the lymph nodes.

Leukemia can be diagnosed only by microscopic examination of the blood and the bone marrow. A blood test may show low hemoglobin, low levels of normal white cells, and a low platelet count; and leukemic blast cells may be present. A bone marrow biopsy will confirm the diagnosis of leukemia and the predominant cell type involved, which will en­able the leukemia to be correctly classified.

Treatment

The remedies for leukemia in the nineteenth cen­tury were few, and none was useful in controlling the disease for any length of time. In the first 50 years following its recognition (Bennett 1845), leukemia was generally accepted as a chronic disease, and the limited therapeutics in the armory of the general physician were applied. Quinine was used for com­bating fever; morphine and opium, for diarrhea; iron, for anemia; iodine, for external use as an antibacterial; and arsenic. In 1786, Thomas Fowler of York, England, introduced a solution of arsenic trioxide for the cure of agues, remittent fevers, and headaches. In addition, it became a general tonic for animals and humans alike, and in 1865 a German physician prescribed this solution in the treatment of a woman with chronic myeloid leukemia. The patient became temporarily restored to health, and as a result, arsenic became the first agent of some beneficial use in the treatment of certain forms of leukemia, causing a shrinkage of the enlarged spleen and lymph nodes and a reduction in the leuke­mic cells.

The discovery in 1895 of X-rays by Wilhelm Rontgen soon led to X-ray therapy Ofleukemias with results similar to those produced by arsenic. How­ever, X-ray therapy had a greater advantage be­cause it was discovered to have the ability to prevent cell division and to inhibit cell growth. On the other hand, patients could eventually become resistant to treatment with X-rays. Thus William Osler com­mented in 1914 that he had not seen any striking permanent improvement in patients who had under­gone X-ray therapy, and C. E. Forkner of Cornell University, New York, writing on the etiology of leukemia in 1938, stated that although much could be done to add to the comfort of patients with chronic forms of leukemia, acute leukemia did not respond to any form of therapy.

In 1946, two American research groups reported on nitrogen mustard therapy, which arose from the poisonous mustard gas research study initiated dur­ing World War II. It was found that the chemical analogues of the gas could cause depression of the blood cells, and that some patients in cases of leuke­mia and lymphoma who had become resistant to X- ray therapy responded to treatment with this agent. This new treatment triggered intensive efforts to find less toxic and more specific therapeutic agents. The result was the introduction of chemotherapy. The aim of all treatment of leukemia is to achieve a prolonged remission of the disease, a state in which all clinical signs of abnormal blood cells disappear and the normal balance of less than 5 percent of blasts in the bone marrow is restored.

Chemotherapy is the form of induction therapy used to effect a remission. A variety of drugs are used to attack the leukemic cells in diverse ways, and they are often given in combination to enhance the efficacy of treatment. However, as these drugs can affect both the leukemic and normal cells, their doses and the sequence of their use must be con­trolled with great care. Usually combinations of drugs belonging to different groups of chemical com­pounds are used to attack leukemic cells at different stages of their growth to prevent leukemic cells from becoming resistant to the therapy.

Radiotherapy by deep X-irradiation may also be given; and in certain instances it is used to attack leukemic cells that may accumulate in certain areas of the body - for example, in the central nervous system, the testis, and the eye - and for which che­motherapy is less effective. The treatment and choice of drugs differ for each of the main types of the disease. The slowly progressing chronic leuke­mias are less responsive to the currently available therapies than are the acute leukemias, although in nearly all cases modern therapy can effect remis­sion. The next stage is to keep the patient in remis­sion through a second level of treatment known as consolidation therapy, to be followed by maintenance therapy, which aims to destroy any remaining or undetected leukemic cells. Antibiotics are available to treat infections, to which the immunosuppressed patient has an increased susceptibility. Complete re­mission does not always mean cure because some residual leukemic cells may still be present and re­main undetected even by means of microscopic ex­amination and will multiply over a period of time. If leukemic cell growth recurs, treatment is restarted to achieve a second remission. Survival rates differ for each type of leukemia. The most encouraging results are achieved in children with acute lympho­blastic leukemia; over half of those diagnosed are now long-term survivors.

A further form of treatment in suitable cases is bone marrow transplantation. This new therapy in­volves high-dose chemotherapy and total body irra­diation followed by an infusion of bone marrow from either a suitable donor (an allogeneic transplant) or from the patient’s own marrow taken and stored during remission (an autograft transplant). Apart from suitable donor availability, a major complica­tion at present is graft-versus-host disease resulting from the reaction of the infused marrow with the recipient and, in autologous transplant, the risk of residual disease still being present in the marrow. This form of therapy has been responsible for the control of the disease in cases where other means would not have been successful.

History and Geography

Leukemia was identified as a new disease in 1845 by two independent observers. John Hughes Bennett, lecturer in clinical medicine and pathologist to the Royal Infirmary at Edinburgh, published his obser­vations in the Edinburgh Medical Journal of Octo­ber 1845, a month before Rudolph Virchow pub­lished his findings under the title Weisses Blut. Two years later, Virchow named the disease leukemia, Greek for “white blood,” and Bennett in 1851 called it Ieucocythemia, Greek for “white cell blood.” Both men, who were keen observers and in the early stages of what were to become distinguished careers in medicine, made their observations at the autopsy table. However, it is unlikely that the disease was new in 1845, for there had been earlier reports of what was described as peculiar conditions of the blood, pus in the blood, and “milky” blood, with some symptoms compatible with those of leukemia. David Craigie in Edinburgh and Alexandre Donne in Paris, among others, were physicians who in the decade previously were alert to something odd in the condition of the blood of certain patients.

The microscope at that time was a crude instru­ment, and there was no satisfactory means of illumi­nating the specimens being observed. In fact, what is remarkable is that the disease was recognized at all, when one considers its rarity, on the one hand, and the continual epidemics of infectious diseases as well as chronic ailments of the last century which occu­pied the medical profession, on the other. But after recognition, reports of suspected or actual cases of leukemia began to appear in the literature, slowly revealing its worldwide distribution. Case reports from Europe and America also indicated the ineffec­tual nature of any known therapy.

Two breakthroughs occurred in the last half of the nineteenth century. The first was the discovery by Emst Neumann in 1868 of the importance of the bone marrow in the formation of blood; a year later, he published his report on the changes in the bone marrow in leukemia, which introduced the term myelogenous leukemia. The second came in 1877, when Paul Ehrlich, a medical student at the time, developed a stain that permitted the cells to be clearly defined. By then, the microscope had been improved, and the new technique of staining en­abled features of the blood to be studied that had hitherto been unseen or unsuspected.

Thus began a new era in hematology, but it was to be nearly 70 years before any progress was to be made in the treatment of leukemia. This began with the realization that folic acid was important to blood cell formation, and that its lack caused anemia and, significantly, a decrease in the white cells. Ensuing experiments showed that some preparations contain­ing folic acid inhibited growth of experimental tu­mors, whereas other observations indicated that it might stimulate the growth of leukemic cells. This led a group of researchers in the United States to develop a series of new drugs that were designed as antagonists of folic acid for trial in the treatment of human cancers. Aminopterin was one of these new drugs and was used with much success in the treat­ment of acute leukemia by Sidney Farber and his group at Boston Children’s Hospital in the late 1940s. Much research followed in a quest for new and more successful drugs to combat leukemia, with the result that by the late 1980s there was an estab­lished armamentarium of drugs used mostly in com­bination to achieve a remission and to maintain it.

Leukemia is a disease of major interest in both hematology and cancer research where much prog­ress has been and is still being made, measured in terms of patient survival. Moreover, the outstanding “problem areas” of research are now more clearly defined and recognized, and current research efforts (in both pure and applied settings) within the fields of cell and molecular biology, immunology, cytogenet­ics, and virology are directed toward investigating such problems as the following:

1. Application of molecular mechanisms in therapy to destroy leukemic cells

2. Role of viruses in influencing the development of the disease

3. Nature of environmental triggers of leukemia

4. How to achieve earlier recognition of leukemia

5. How to understand the scientific basis for remis­sion and thus how it can be maintained

6. How to eliminate residual disease

It is hoped that improved therapy for both adult and childhood cases will result from these complex and concentrated research efforts and that survival rates will be increased even more. Virchow wrote the following in 1858: “I do not wish by any means to infer that the disease in question [leukemia] is abso­lutely incurable; I hope on the contrary that for it too remedies will at length be discovered.” Today there is optimism that Virchow’s hope will be realized.

Gordon J. Piller

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