Chronic myelogenous leukemia.
Primarily considered all "adult" leukemia because it usually occurs in individuals between 30 and 50 years old, CML shows no real partiality toward any age group or gender - striking even the very old and the very young, with a fairly equal rate of incidence in in both males and females.
WHAT IT IS
Chronic Myelogenous Leukemia is a malignant disorder involving the production of mature white cells formed in the bone marrow, which results in the abnormal accumulation of these cells in both the bone marrow and the bloodstream.
Perhaps CML can be best understood by first becoming familiar with the functions, composition and normal cell growth activity of healthy blood, and with some general information which is common to all forms of leukemia.
Blood Functions and Composition
The blood is a vital organ which supplies oxygen, food and other essential nutrients, hormones and chemicals to cells throughout the body. It serves as one of the body's most effective defenses against infection, and it also assists in the removal of toxins and other waste materials.
Whole blood is made up of many components, with each component performing a specific role in the blood's overall functions. The three main blood elements involved in leukemia are the red cells, clotting cells and white cells which are formed in the bone marrow and lymph nodes and circulate through the bloodstream in a clear fluid plasma:
Red Blood Cells (Erythrocytes) contain hemoglobin, an iron-rich protein which picks up oxygen as the blood passes through the lungs, transports it, and releases it to organs and tissues throughout the body. A shortage of these red blood cells, a condition known as anemia, can cause weakness, dizziness, shortness of breath, headaches and irritability.
Clotting Cell (Platelets) are tiny disc-shaped cells which help prevent abnormal or excessive bleeding by forming clots. A deficiency of platelets can cause bleeding of the mucous membranes or other tissues, such as the skin. Unexplained or excessive bruising is characteristic of a platelet deficiency.
White Blood Cells (Leukocytes) play a major role in defending the body against disease-producing bacteria, viruses and fungi. There are three main types of leukocytes, with each type performing a specific infection-fighting function;
* Monocytes defend the body against bacterial infection.
* Granulocytes represent about 60 percent of all circulating white blood cells. Granulocytes (which are sometimes also referred to as neutrophils) combat infection by rapidly increasing in number, engulfing and destroying foreign substances, and then quickly returning to their original preinfection count.
* Lymphocytes consist of two types of cells which combine forces to create a complex interaction to regulate the immune response. T-cells attack virus-infected and malignant cells. B-cells produce and release antibodies, or protein substances, which bind to infectious agents and help prevent them from doing damage to the body.
A deficiency in any type of normal white blood cell may result in an increased susceptibility to infections.
Blood Cell Growth
The blood, like all human tissues and organs, is composed primarily of cells which are developed enough to perform efficiently. The red, white and clotting cells enter the bloodstream after the maturation process called hematopoiesis, which begins with the production of immature cells in the blood-forming tissue of the bone marrow, spleen or lymph nodes. Actually, only a small percentage of cells are produced in the spleen and lymph nodes. The majority of cells, including most of those involved in CML, originate and mature in the bone marrow - the spongy meshwork interior which fills the cavities of the large bones.
Blood cells grow in the same general manner as all other human cells. Tissues or organs of the body contain a pool of immature, or undifferentiated, cells known as stem cells. These cells begin to divide and mature until they become fully developed, or differentiated, cells.
The original cells involved in blood cell production are called pluripotent stem cells, meaning that they contain the characteristics of all the different cell types which make up the major blood cell lines. One of these lines is known as the myeloid fine which gives rise to the white cell called monocytes and granulocytes. Another is the lymphoid line which gives rise to lymphocytes. As cells mature, they are released into the bloodstream to replace those which have become old and worn out.
Blood cells are not released from the bone marrow until they are "mature enough" to perform efficiently. Normally, immature cells or "blasts" are not present in the bloodstream. A relatively small amount of these immature cells are contained in the bone marrow, still involved in the growth process. However, "blasts" should never constitute more than five percent of the bone marrow cells.
The entire blood cell reproduction, growth, maintenance, and destruction cycle is really a highly efficient and orderly process. The abnormal and excessive reproduction of any type of cell obviously disrupts the delicate blood cell balance necessary to sustain the body's general well-being.
Leukemia affects the production of white blood cells, causing them to reproduce uncontrollably, crowding out existing healthy cells. These abnormal white cells "over-populate" the bone marrow - often with immature, nonfunctioning blasts - and spill over into the bloodstream. Hence the term leukemia, which is derived from the Greek, and literally means "white blood."
The bone marrow becomes severely impaired and is unable to maintain production of sufficient levels of red blood cells and platelets, while white cell production becomes so rapid that these cells do not reach the level of maturity necessary to perform their infection-fighting functions.
Leukemic cells infiltrate all the major organs of the body, sometimes causing these organs to malfunction or fail. The kidneys may become impaired. The liver may become enlarged, as may the spleen - particularly characteristic of CML - causing it to become overactive, a condition known as hypersplenism. Normally, the spleen acts as a filter for the blood, screening out aging red cells and platelets. When the spleen becomes enlarged, it can actually start doing its job too well, removing perfectly healthy red cells and platelets - further reducing the number of these already decreased cells.
As leukemia progresses, the entire blood system becomes flooded with useless, immature blast cells. If this disease is left untreated, a person with leukemia becomes increasingly susceptible to fatigue, excessive bleeding and infections until, finally, the body becomes virtually defenseless - making every minor injury or infection very serious.
Leukemia, itself, rarely kills. People may die, instead, from internal bleeding which would have been prevented by the platelets. Or, more often, they may die from infections which may start with a minor virus or bacteria, and which would have ordinarily been quickly wiped out by healthy white blood cells.
The exact course leukemia takes, and the speed with which it takes that course, varies with the type and age of the white cells initially affected.
There are two major types of leukemia: lymphocytic leukemia which involves lymphoid committed cells which form and mature in the lymphatic system, and myelogenous leukemia which affects myeloid committed cells which form and mature in the bone marrow. In medical terminology, the root "myelo" always refers to bone marrow.
Each of these types can occur in either the acute or chronic form. The acute form affects young cells still involved in the growth process which divide quickly and hasten the progress of the disease. The chronic form involves more mature cells which have stopped dividing or do so at a relatively slow rate.
Chronic myelogenous or granulocytic leukemia specifically involves the over-production of granulocytes which evolve from the myeloid "committed" cell. Since granulocytes are among the most mature white cells produced in the bone marrow, CML is considered to be a slowly-progressing disease. It does progress, however, and - if left undiagnosed or untreated - will reach its advanced leukemic stage, with far too much discomfort and in far too little time.
The remainder of this brochure, therefore, will deal only with CML - its symptoms, diagnosis, course and treatment.
CML is a difficult disease to diagnose early in the course of the disease. The major difficulty in detecting CML in its early stages is that often people are without symptoms. It is not uncommon for the disease to be discovered accidentally during a routine physical examination or blood test.
When symptoms do appear they usually manifest in very subtle and varied forms of general malaise. Most common are complaints attributable to anemia, with its accompanying feelings of weakness, fatigue, dizziness, headaches and irritability.
The spleen often becomes enlarged causing a sensation of fullness, or a lump, in the upper-left portion of the stomach. Sometimes patients complain of becoming easily satiated and having little or no appetite. A more frequent symptom, however, is that of unexplained weight loss one which occurs with no real change in dietary habits. Although uncommon, some patients experience pain in the area of the spleen or in the bones.
Other symptoms can include excessive perspiration, night sweats, an increase in infections, frequent high-grade or chronic low-grade fevers and, occasionally, an attack of gout.
Excessive bleeding is usually symptomatic of the acute leukemias or other blood disorders. Likewise, CML patients may have problems with excessive bleeding after a minor injury or surgical procedure, or abnormal or unexplained skin bruises. Some women may also experience unusually heavy menstrual periods.
Since the symptoms outlined above are similar to those of many common ailments and serious diseases, an accurate diagnosis of CML can only be made by the microscopic examination of the blood and bone marrow.
Often CML is first suspected by a patient's internist or general practitioner. The patient may or may not complain of any symptoms. However, a physical examination will often indicate that the spleen is enlarged, and preliminary blood tests will show an elevated white count and a depressed red count, signaling that the patient is anemic. At this point, a hematologist or oncologist - specialists in the diagnosis and treatment of malignant blood diseases and their related disorders - should be called in to perform further tests on the patient's blood and bone marrow.
Microscopic examination of additional blood samples will indicate which cells make up the elevated white count. The blood of a patient with CML will show a whole spectrum of granulocytes - ranging from the most mature cells to those immature blasts which normally are not present in the circulating blood.
A tentative diagnosis can usually be made at this point. In order to confirm this diagnosis, however, a sample of the bone marrow tissue must be obtained so these marrow cells can be examined and their chromosomal makeup analyzed. In certain cases a molecular analysis called the Southern blot will be done.
In an exceptional situation, where a patient lives a great distance from a hospital or medical center with the facilities to perform bone marrow examinations, there is one additional diagnostic tool which is helpful in confirming suspicions of CML. This is a blood cell stain test which can be performed on a sample taken from the circulating blood.
However, this test does not result in a totally reliable confirmation of the diagnosis. Nor is it as accurate as those performed on the bone marrow. It should be used only when it is impossible to have a bone marrow test performed.
Obtaining a bone marrow sample is a relatively uncomplicated procedure. Samples are usually taken from the blood-making marrow of the iliac bone located in the rear hip area. Alternatively, the sternum bone may be used. A localized section of the skin and the underlying bone is anesthetized, a small syringe-type needle is inserted into the bone, and a tiny amount of marrow is withdrawn through the syringe. The bone marrow cells are then closely examined under a microscope.
The bone marrow sample is also used in the final diagnostic test for CML: a chromosomal analysis to confirm the presence of a specific cell abnormality in which there is a translocation (or swap) of parts and genetic information between one of the chromosomes in pair 9 and one in pair 22. This defect is known as the "Philadelphia Chromosome" because it was first identified at the University of Pennsylvania School of Medicine in Philadelphia. Findings indicate that, although this defect is genetic, it is not an inherited trait and is a result rather than a cause of CML. Although the exact cause of this chromosomal defect is still unknown, it is now clear that the Philadelphia chromosome translocation produces a change in the hereditary material (DNA) in the cell which results in a growth stimulatory signal in the CML cells. This causes the high white cell count and splenic enlargement seen in CML.
Only after the results of the blood tests, bone marrow examination and chromosomal analysis are reviewed can a positive CML diagnosis be made.
The course of CML can be divided into three separate phases: initial or "chronic," accelerated, and transformation or "blast crisis,"with each of these stages having its own distinct effect on the quality of life the patient can expect to maintain.
A patient can live for years, relatively symptom-free, in the initial stage. During this time, CML is easily controlled by mild chemotherapeutic drugs which are taken orally. Although these drugs produce few, if any, side effects, they do not induce durable remissions. Interferon, another treatment given subcutaneously, produces durable remissions in 25 percent of individuals. The patient usually feels quite well. The white cell count is kept within or near the normal range, and the spleen shrinks back to its original size. Hospitalization is unnecessary and clinical visits are infrequent. The patient can engage in all normal family work and social activities. This chronic phase lasts an average of three years, although it can last up to ten years or longer.
Usually after a period of years, CML begins to accelerate and becomes resistant to the simple treatment used in the initial phase. The white cell count becomes slightly elevated and symptoms gradually reappear.
Even though the doses of chemotherapy are increased, the white cell count continues to rise. The patient begins to experience symptoms on a continual basis and normal activity becomes curtailed.
Optional or experimental treatments are often tried during this stage in an effort to reverse the progress of the disease. If the acceleration does continue, however, this phase is marked by a gradual deterioration of the patient's well-being and by increased experimentation with types and/or doses of therapy, which requires frequent clinic or laboratory visits.
The length of the accelerated state can vary. However, it is always a relatively short period of time before the disease undergoes transformation, and converts to its acute form. During this phase, CML becomes almost totally resistant to chemotherapy. Leukemic cells reproduce more rapidly and at a progressively immature stage. The bone marrow becomes so overburdened with blasts that it literally releases billions of these useless cells into the bloodstream. This is known as "blast crisis." The white count becomes extremely elevated and, as these blasts infiltrate the spleen, it may again become massively enlarged.
Depending upon the type of cells involved in blast crisis, aggressive chemotherapy may again reverse the disease. Unfortunately, most remissions are only partial and of short duration.
For most patients, the onset of transformation inevitably means closer hospital supervision. Some patients may require blood transfusions or antibiotic treatment to help fight infections. However, much can be done to support the CML patient, and pain or other physical suffering is rarely a problem.
Since CML is often diagnosed when a patient is still without symptoms, actual treatment may be postponed until the white cell count rises above the normal range, at which point symptoms will appear. Once treatment does begin, it is aimed at alleviating any discomfort associated with these symptoms. There are two treatments which may delay the progression of the disease from the chronic phase to the blastic transformation: interferon therapy and allogeneic bone marrow transplantation. If interferon does not produce a major cytogenetic remission (reduction of the Philadelphia chromosome to below 30 percent), then a search for a bone marrow transplantation donor should be undertaken (related or unrelated donors can now be used). This therapy is curative in 50 percent of the patients treated overall but only 30 percent of patients with CML have a donor. Patients who are over 50 years of age or who have other medical problems may not be eligible for this therapy. In any event, an attempt should be made to assess interferon resistant patients for allogeneic bone marrow transplantation during the first year to determine if a donor exists. This should be done early in the chronic phase since the best results are obtained during that time.
For patients ineligible for interferon therapy or allogeneic bone marrow transplantation, chemotherapy and autologous bone marrow transplantation exist as additional treatment options, which can control CML's symptoms, and can induce periods of remission in both the chronic and accelerated phases.
The best results have been obtained when these procedures are performed during the chronic phase of the disease, so it is essential that patients discuss this option with their doctor soon after diagnosis.
The chronic phase of CML can be easily controlled with mild doses of a wide range of drugs. These drugs are usually taken orally and produce relatively minor side effects. There can be additional complications associated with long-range chemotherapeutic treatment.
The drug most frequently used during this phase is hydroxyurea, which can be administered on either a daily or intermittent basis. Patients should be aware that this drug can cause a reduction in the number of normal white bone marrow cells. Another drug called Busulfan (also known as Myleran) is only rarely used since it is associated with formation of fibrous tissue in the marrow and other organs, slight darkening of the skin, temporary hair loss and occasional lung problems. Breasts of men may become enlarged, and the drug may also reduce their sperm count. Menstruation may become less frequent or stop, and conception may become impossible. However, there is also a risk that a baby conceived while a woman is taking a chemotherapeutic drug may be abnormal, so contraception should be practiced. Patients may experience some nausea, vomiting and diarrhea. These reactions are slightly more common to Cyclophosphamide. Patients taking Cyclophosphamide may also notice some blood in their urine caused by the local ulceration of the bladder wall.
Once the disease begins to accelerate, treatment is dependent upon whether the abnormal cell is an early lymphocyte or myeloblast. The treatment usually consists of vincristine and prednisone or a combination of Cyclophosphamide, vincristine, adriamycin, and the steroid dexamethasone if the cell is lymphoid. Vincristine is given by injection, and can cause local burns if it leaks onto the skin, depression of red bone marrow cells, temporary hair loss, constipation, and possible neurological effects such as pain, numbness or tingling in the arms, legs or extremities. Prednisone is taken orally and may result in fluid retention, weight gain, an increased risk of infection, and a possible loss of minerals such as potassium.
Combinations of chemotherapeutic drugs or autologous bone marrow transplantation can also be used for the lymphoid or myeloid blast crisis, but this therapy is more effective if given in the chronic phase of the disease.
Additional and Alternative Treatments
Chemotherapy is the standard, and only, treatment necessary for the majority of patients. Rarely are any supplementary or alternative procedures required, although some patients, including those with a high platelet count, may also be given a drug called interferon. Still in the experimental stages, interferon seems to be effective in treating CML and reducing excessive blood clotting.
Based on encouraging preliminary results at the University of Texas, additional studies of various forms of interferon in treatment of CML are ongoing at certain centers throughout the country.
Occasionally, a patient's condition may warrant radiation therapy to reduce an enlarged spleen and a high white cell count, or the surgical removal of the spleen to relieve abdominal discomfort. Older patients, or those who cannot be seen regularly, are sometimes treated with injections of radioactive phosphorus which lowers the white cell count by localizing to the bone and destroying stem cells.
Additional methods of treatment are leukapheresis and extracorporeal irradiation of the blood. In leukapheresis, a continuous-flow blood processor is used to remove large numbers of leukemic white cells from the blood before returning it to the patient. Extracorporeal irradiation involves the insertion of one shunt (tube) in the artery and one in the vein. As blood flows through these shunts, white cells are radiated and destroyed. Both of these procedures temporary reduce the white cell count and relieve some symptoms. However, they are time-consuming and uncomfortable for the patient and therefore their application is extremely rare.
Bone Marrow Transplantation
Another treatment for CML is bone marrow transplantation. It has recently been found successful in younger patients, and presently offers the best hope of curative treatment for this type of leukemia. The procedure basically consists of using aggressive chemotherapy and radiation treatment to defeat the patient's leukemia, then replacing marrow destroyed by the treatments with the marrow of a compatible donor. In time, the transplanted marrow reproduces a whole new population of healthy blood cells.
So far the best results have been obtained with patients who have an identical twin or a genetically matched brother or sister. Donors are usually chosen from among siblings. Of these, only about one in four proves to be genetically compatible. In addition, it is now possible to use donors from outside the family who are compatible. Even if one is suitable, other factors such as age, general health, and the stage of the disease must be evaluated before a patient's eligibility can be finally determined.
Once eligibility is confirmed, the major consideration for most patients becomes one of timing. Results of transplants attempted during the accelerated stages have been disappointing. The procedure is usually successful when performed during the chronic phase - the length of which is uncertain, and a period which usually finds patients feeling completely well. Understandably, many patients are hesitant to interrupt their normal activities for the recuperative period required by the major transplant procedure. In addition, bone marrow transplantation does involve a certain element of risk. Candidates must weigh this risk against that of misjudging the length of the chronic phase and, perhaps missing the chance for therapy-free survival. For many, this gamble has paid off with not just the return of their health, but also that of their future.
Since most patients lack a genetically compatible donor, considerable attention has been focused on auto or self-transplantation which, in effect, allows patients to become their own donor. So far, this approach has been limited to attempts at reversing CML's progress by removing small amounts of the patient's bone marrow during the initial stage of the disease and storing it at very low temperatures. Once acceleration begins, the patient is treated with aggressive chemotherapy and given back this stored marrow. This approach has been successful in returning some patients to the chronic phase for greater than a year in only 10 to 20 percent of patients.
In an attempt to improve these results, investigators from many institutions are separating autologous marrow with substances called antibodies which bind in different ways to normal or leukemic cells. In addition, treatment of autologous marrow outside the human body with chemotherapy has also appeared to help reduce the number of leukemia cells which contaminate preparations of autologous marrow used for transplant. These approaches are called "marrow purging." Experimental programs involving purging of leukemic cells from the autologous marrow are being developed at many large cancer centers.
CAUSES AND RISK FACTORS
The specific cause of CML and the means of preventing it are not known. Studies indicate that people exposed to excessive amounts of radiation have a slightly greater chance of developing the disease. However, most patients do not have a history of radiation exposure. The importance of CML's specific chromosomal abnormalities or of the roles played by drugs, chemicals and viruses is still uncertain. Researchers have recently discovered that a protein, produced by one of about 20 suspected "cancer" genes, functions aberrantly, causing the abnormal cell growth characteristic of CML.
Researchers do know that the disease has no apparent hereditary pattern. Nor is there evidence of any ethnic, dietary or environmental risk factors. CML is not contagious.
It is not easy for patients and their families to accept CML or five with its side effects. A confirmed diagnosis can trigger any number of emotional responses ranging from denial to devastation. It is not uncommon for patients to feel frightened and helpless against this rare and difficult disease, angry and confused by this sudden threat to their future. Some patients are embarrassed by CML. Many, stricken during their most productive years, worry about the economic hardship on their families. And, naturally, patients have questions about therapy, side effects and optional treatments.
Of course, patients should speak directly with their doctor regarding any specific questions about their illness, and they should not hesitate to discuss any problems or reactions they may have. The patient may find help from talking with other health professionals, patients, and families who understand the complexity of emotions and special ongoing needs of those living with leukemia. The Leukemia Society and representatives from our local chapters win be glad to help ease the emotional and economic strain on CML patients and their families.
HOPE FOR THE FUTURE
Although CML is a serious disorder, many patients five for years with little or no discomfort or disability, thanks in part to chemotherapy. New combinations of antileukemic drugs are yielding higher remission rates m CML. The hope is that in the future these remissions will extend to cures.
In one recent study, patients with CML achieved good responses from treatments with alpha interferon. The overall significance and long-term results of this still experimental treatment are not presently known.
Another promising approach to treating CML lies in the area of bone marrow transplantation. Compatible donor transplants, no longer considered experimental, have extended - and probably cured - the lives of many patients. Medical investigators are working very hard at finding ways to broaden the range of suitable donors and at improving auto-transplant procedures.
Research continues on every major continent with more attention being given to the cause and treatment of CML than ever fore. As the focus on this disease increases, so does the hope for a longer life and the possibility of a cure for even more of its victims.
FURTHER READINGS IN CHRONIC MYELOGENOUS LEUKEMIA
McCredie, Kenneth B. and Margolies, Cynthia P Understanding Leukemia.
New York: Charles Scribner's Sons, 1983.
CaneLlos, George P. "Chronic Leukemias" in Cancer. Principles and Practices of Oncology. (DeVita, Vincent T. et al, eds.) Philadelphia: Lippincott, 1985.
Henderson, Edward S. and Lister, Andrew T. Leukemia. 5th ed. Philadelphia: W.B. Saunders Company, 1990.
Butturini, Anna et al. "Autotransplants in Chronic Myelogenous Leukemia" Lancet. 26 May 1990: 1255-1258.
Champlin, Richard et al. "Chronic Leukemias." Annals of Internal Medicine 1986; 104:671-688.
Clift, R.A. et al. "Treatment of Chronic Granulocytic Leukemia in Chronic Phase by Allogeneic Marrow Transplantation' Lancet 18 September 1982:621-629.
Koeffler, H. Phillip and Golde, David W -Chronic Myelogenous Leukemia - New Concepts." (Two-part series.) New England Journal of Medicine 304 (20):1201-1209 and 304 (21):1269-1274,1981.
Talpaz, Moshe et al. "Interferon-Alpha Produces Sustained Cytogenic Responses in CML". Annals of Internal Medicine. 1991; 114: 532-538.
Thomas, E. Donnall and Clift, Reginald. "Indications for Marrow Transplantation in CML". Blood 73;4(March), 1989:861-864.
PUBLIC EDUCATION MEDICAL ADVISORY COMMITTEE
Kathleen A. Hays, R.N., M.N.
Clinical Nurse Manager
University of Pittsburgh Medical Center
Lawrence D. Ellis, M.D.
Clinical Professor of Medicine
University of Pittsburgh
Samuel Gross, M.D.
Professor and Chief,
University of Florida, Gainesville
Lynna M. Lesko, M.D., Ph.D.
Assistant Director, International Clinical Research-CNS
Hoffman LaRoche, Inc.
Nutley, New Jersey
Adjunct Associate Attending Psychiatrist
Memorial Sloan-Kettering Cancer Center
New York, New York
Dennis F. Moore, M.D.
Clinical Professor of Medicine
Kansas University School of Medicine, Wichita
Peter J. Quesenberry, M.D.
Head, Cancer Center and Professor of Medicine
University of Massachusetts Medical Center, Worcester
Seth A. Rudnick, M.D.
President and CEO
Cyto Therapeutics, Inc., Providence
Vice Chairman, Medical and Scientific Affairs
Ronald P McCaffrey, M.D.
Chief, Section of Medical Oncology
Boston University Medical Center
Special thanks to Dr. Albert Deisseroth, Chairman, Department of Hematolog, Univesity of Texas M.D. Anderson Cancer Center, Houston, who contributed and reviewed much of the material presented in this booklet.
The Leukemia Society of America, Inc. a voluntary health agency founded in 1949, provides financial aid to patients and sponsors research investigators in studies directed against leukemia, lymphomas, and multiple myeloma. The Society has provided over $84 million to research since its founding. A full-scale national program of public and professional education is conducted to create public understanding of medical advances and to bring the medical and scientific communities up to date on current findings. An annual report is available on request.
For further information about leukemia, the Society and its programs, contact its national office (1-800-955-4LSA) or one of the chapter offices (located in the following states and cities).
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|Title Annotation:||includes bibliography|
|Publication:||Pamphlet by: Leukemia Society of America|
|Date:||Jan 1, 1993|
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