Diseases related to white cells. Leukemia. Clinical manifestations

The terms acute and chronic refer to the duration of the untreated disease. Before the advent of modern chemotherapy, patients with acute leukemia usually died within weeks or months of the first manifestations of the disease. The life span of patients with chronic leukemia is now measured in years.

Leukemia primarily involves the bone marrow, but the lymph nodes and spleen may also be affected. For example, the spleen usually is enlarged in chronic myelogenous leukemia, and in chronic lymphocytic leukemia there often is enlargement of lymph nodes. Changes also take place in the leukocytes, red cells, and platelets, with consequent anemia and bleeding manifestations. The first symptoms may be weakness and an increased tendency to become fatigued because of anemia, or hemorrhages into the skin and nosebleeds, or gum bleeding due to a decrease in the number of platelets. In the acute leukemias these symptoms may be severe, the anemia may progress rapidly, and there may be fever. Chronic leukemia is more insidious in development, and the early manifestations may be overlooked until enlargementof the spleen or lymph nodes is discovered. Leukemia is recognized by examination of the blood, supplemented in most instances by examination of the bone marrow.

Acute leukemia is marked by the presence in the blood of immature cells normally not found there. In acute lymphocytic anemia (also called acute lymphoblastic leukemia), most frequently seen in children, the cells are immature forms of the lymphatic series of cells. In myeloblastic leukemia the predominant cells are the youngest recognizable precursors (myeloblasts) of the neutrophils of the blood. In a third and the least common variety, acute monocytic leukemia, the immature cells appear to be precursors of the monocytes of the blood. Myeloblastic and monocytic leukemia occur more commonly in adults and adolescents than in young children. In general, acute leukemia occurs in young persons, but no age group is exempt.

The total white cell count usually is increased but not uncommonly is normal or lower than normal (leukopenic). In such cases, abnormal immature cells may nevertheless be seen in the blood. In all forms of acute leukemia the typical cells are found in abundance in the bone marrow. “Aleukemic” leukemia refers to those instances of leukemia in which no abnormal cells are found in the blood; in these instances the leukemia is identified by examinations ofthe bone marrow.

Chronic granulocytic (myelogenous) leukemia is characterized by the appearance in the blood of large numbers of immature white cells of the granulocytic series in the stage following the myeloblast, namely, myelocytes. The spleen becomes enlarged, anemia develops, and the affected person may lose weight. The platelets may be normal or increasedin number, abnormally low values being found only in the late stages of the disease or as an unintended result of therapy. The disease is most commonly encountered in persons between the ages of 30 and 60 years. With treatment the leukocyte count falls to normal, anemia is relieved, and the size of the spleen is greatly reduced. When the leukocyte count rises again, treatment is reinstituted. Such cycles of treatment, remission, and beginning relapse with rise of leukocyte count can be repeated many times, but a stage ultimately is reached when treatment no longer is effective. The disease then often terminates in a form resembling acute leukemia (“blastic crisis”). There is considerable variation in the duration of the disease. Although in various series mean life span has been about 3 1/4 years, many affected persons live in good general condition for five to 10 years and sometimes longer.

Chronic lymphocytic leukemia differs in many ways from other forms of leukemia. It occurs most often in people over 50 years of age, and its course usually is rather benign. It is mainly characterized by an increase in the number of lymphocytes in the blood, often accompanied by more or less generalized enlargement of lymph nodes and the spleen. Affected persons may carry on for many years without treatment and without any other manifestations. There may be no anemia and no loss of weight. Life span in this disease is measured in terms of five, 10, and even 15 years, occasionally even longer. Two events mark a change in the state of relative good health. One is the development of anemia, sometimes hemolytic in type, often accompanied by some decrease in the number of platelets. The other is impairment of immune mechanisms, resulting in great susceptibility to bacterial infections.

Treatment differs according to the type of leukemia. Consequently, proper classification of the leukemia is the first step, once the diagnosis of leukemia has been made. Treatment of alltypes of leukemia reduces illness and, in acute leukemia, prolongs life.

A number of drugs are used for the treatment of leukemia and, now less frequently than before chemotherapy was available, various forms of irradiation. The therapeutic agents are all myelotoxic; i.e., they injure all the cells of the bone marrow, normal cells as well as leukemic cells. Their mode of action is through direct damage to the dividing stem cell (unspecialized cell from which specialized cells develop) or by slowing or cessation of cell division. These effects may be accomplished (1) by antimetabolites, substances that interfere with the synthesis of DNA, a constituent of the chromosomes in the cell nucleus; (2) by blocking DNA strand duplication through the binding of drugs such as the nitrogen mustards with the base groups of DNA; (3) by disruption of the mitotic spindle during cell division; or (4) by interfering with the formation or functioning of RNA, which is manufactured in the cell nucleus and plays an essential role in the production of protein and in other cell functions. Drugs with different modes of action are often combined, especially in the treatment of the acute leukemias.

Much skill and experience are needed in steering the narrow path between maximum possibledestruction of the leukemic cells and tolerable injury to the normal cells of the host. In the process of treatment anemia may increase; the body defenses, through the decrease in the number of neutrophils, may be impaired, and the platelets may be greatly reduced in number. Anemia can be treated with blood transfusions, and serious reductions in platelets can be met for a time with platelet transfusions.

Acute lymphoblastic leukemia is more successfully treated than are other forms of acute leukemia; prolonged remissions and even cures can be brought about in children with the disease. Certain drugs are used to bring about remission; if the remission is complete, the patient becomes well, and no signs of the disease are demonstrable in the blood or bone marrow; drugs other than those used to induce remission often are more useful in maintaining the remission than the remission-inducing drugs.

Acute myeloblastic leukemia and acute monocytic leukemia are less effectively treated by available drugs than is acute lymphoblastic leukemia. Nevertheless, new and aggressive forms of chemotherapy can induce lengthy remissions of the disease. Transplantation of normal bone marrow, following total irradiation of the patient to destroy all his normal bone marrow cells as well as the leukemic cells, has shown promise. With the advent of refined techniques of tissue typing, it is no longer necessary that the donor of the bone marrow be an identical twin. Marrow from histocompatible siblings (brother, sister) are effective. Best results have been obtained in patients younger than 35 years of age. When this form of treatment is successful, the patient's marrow is replaced by the donor's marrow. Although the treatment is arduous and complex, cures of acute lymphocytic and acute myelogenous forms of leukemia are now possible with bone marrow transplantation.

Chronic myelogenous leukemia is treated with a drug, busulfan, in daily doses until the leukocyte count has returned to normal. Treatment then is interrupted until the leukocyte count has risen to about 50,000 cells per cubic millimetre, when treatment is resumed. This can be repeated many times, and thus the affected person is maintained in good health for years. Not infrequently the intervals between treatments are six months in duration or longer.Busulfan, however, like other antileukemic agents, can injure the bone marrow, and other adverse effects may occur. Other drugs and X-ray therapy also have been used but are somewhat less valuable than busulfan. In suitable young patients, bone marrow transplantation has been used successfully in chronic myelogenous leukemia.

In its early stages, chronic lymphocytic leukemia seems best untreated, as long as anemia is not present or glandular enlargement is not too troublesome. None of the current treatments are curative. The high leukocyte counts in themselves are not harmful. When there is severe anemia, however, or when the platelet count is very low and bleeding manifestations are severe, adrenocorticosteroid hormones are often given.

The lymphomas are malignant tumours of lymphocytes that are usually not associated with aleukemic blood picture. Instead, enlargement of lymph nodes and/or spleen are characteristic. The lymphomas are classified into two main groups: Hodgkin's disease and non-Hodgkin's lymphoma (or lymphocytic lymphoma). Hodgkin's disease usually begins with a painless swelling of a lymph node, and it may involve lymph nodes anywhere in the body. The disease seems to begin in one lymph node and spread from there to others. Exact determination of the extent of the disease (“staging”) is important in planning its treatment. Hodgkin's disease is a potentially curable lymphoma, so details of its treatment are crucial. The early stages of the disease can be cured with radiotherapy. More-advanced stages are still curable with chemotherapy, and in some patients a combination of chemotherapy and radiotherapy is used. The staging of the disease entails a thorough medical examination, bone marrow biopsy, and X rays. The latter usually include computerized axial tomography (CAT) scanning to identify enlarged lymph nodes in the interior of the body. In many cases, surgery (laparotomy) is required to obtain for examination lymph nodes from deep within the abdomen. The goal of all these staging procedures is to enable the physician to select the therapy with the maximum curative potential.

The non-Hodgkin's lymphomas constitute a heterogeneous group that arise from either B lymphocytes or T lymphocytes. They may have an indolent course, as in the nodular well-differentiated B lymphocyte lymphomas, or the tumour may be aggressive, as in the diffuse T lymphocyte forms. Unlike Hodgkin's disease, the lymphocytic lymphomas spread through the bloodstream. Therefore, the staging procedure is not as extensive as in Hodgkin's disease. Combination chemotherapy, usually given in cycles over a period of months, is effective in certain types of diffuse lymphocytic lymphomas. Prolonged remissions with eradication of the disease are difficult to achieve in the indolent nodular lymphomas.

Another malignant disease, probably related to the above conditions, is multiple myeloma, which is characterized by a malignant overgrowth of plasma cells within the bone marrow. This severely painful disorder causes defects in the bone of the skull, the ribs, the spine, and the pelvis that ultimately result in fractures. As the bone marrow becomes more involved, anemia develops and hemorrhages occur: the number of leukocytes may be low, and abnormal myeloma or plasma cells are found in the bone marrow. This disorder is associated with a marked overproduction of immunoglobulin by the malignant plasma cell (the normal plasma cell is the source of the antibodies). The plasma cells in multiple myeloma are the progeny of a single malignant clone, and they secrete into the blood a single type of immunoglobulin molecule—a monoclonal immunoglobulin. In some cases, a component of immunoglobulin, the light chain, may be produced in excess. These light chains appear in the urine, and in multiple myeloma they are called Bence-Jones protein. A type of chronic kidney disease often develops, probably as a result of the high concentration of Bence-Jones protein in the kidney tubules; this frequently is the ultimate cause of death. In some cases the condition remains quiescent for a time, but death is inevitable. Adrenocorticosteroid hormones and chemotherapeutic agents have been used in the treatment of multiple myeloma.

Maxwell M. Wintrobe

Robert S. Schwartz