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ALL PART 2

DIAGNOSIS

A diagnosis of ALL begins with a physical examination of the patient and the microscopic examination of a blood sample. If the results of these two tests seem suspicious, a sample of bone marrow is then also examined under a microscope.

The physical symptoms of ALL can often mimic those of many other diseases. Additionally, ALL cells may or may not initially appear in large quantities in the blood and lymph systems, but significant numbers will always be present in the bone marrow. Therefore, a bone marrow sample must be obtained and examined in order to accurately confirm the diagnosis and to classify the disease by the predominant type and developmental stage.

Obtaining a bone marrow sample is a relatively straightforward procedure which takes about 15 minutes to complete. Samples are commonly taken from the blood-making marrow of the iliac bone located in the rear hip area. A small area of the skin and underlying bone is anesthetized, following which a needle is inserted into the bone, and a tiny amount of marrow is withdrawn.

Once a diagnosis of ALL is confirmed, a sample of cerebrospinal fluid is examined for leukemia in the central nervous system. This procedure is usually completed within a few minutes. Here, a small area at the base of the spine is anesthetized, a syringe-type needle is inserted between two of the lumbar vertebrae into the reservoir of cerebrospinal fluid surrounding the spinal cord. The fluid is then withdrawn through the syringe.

The procedures outlined in this section have become standard practice and are essential for an accurate diagnosis of ALL. The results of tests taken on samples of blood, bone marrow, and cerebrospinal fluid are invaluable tools which are used in evaluating prognostic factors, identifying patients according to risk of relapse, and planning treatment programs. Tests performed on samples throughout treatment, and even after it is completed, are useful monitors of the disease course, providing advance warning for any neccessary adjustments in existing treatment and serving as early indicators of recurrence.

These procedures are not painful and can be performed quickly. Usually the anxiety caused by these tests is worse than the tests themselves. However, they are slightly uncomfortable and can be extremely frightening, especially to young patients. Parents are often upset and apprehensive about having their children undergo these tests. Medical personnel are aware of, and sympathetic to, these reactions and make every attempt to assure that these procedures go as smoothly and pleasantly as possible. Pharmacologic preparations and, often, self-hypnosis effectively minimize the pain and anxiety.

TREATMENT

Thirty years ago, patients with ALL usually lived for only a few months after diagnosis. There has been such dramatic progress in treating this disease, particularly over the last decade, that today at least 95 percent of patients go into remission, 50 to 75 percent live for five years or longer, with a potential cure rate in ALL in excess of 50 percent of children. There has also been a dramatic improvement in survival rates for adult patients.

Immediate treatment is essential and is usually started within a day or two after diagnosis. It is best that patients be treated by board-certified hematologist/oncologists - specialists in the diagnosis and treatment of malignant blood diseases and their related disorders and, depending on the age of the patient, by physicians previously certified in pediatric or adult medicine.

Major medical centeres that are university-based are best equipped to provide the optimal care necessary during the inital phase of treatment. Once treatment is successfully underway, patients may be referred to a community-based physician in the local area for continued care with intermittent review in the major treatment center.

The goal in treating ALL is to cure patients by inducing and prolonging remission, a state in which all leukemic cells appear to be eradicated and bone marrow function and blood cell balance are restored to normal.

ALL is considered to be a systemic disorder because it affects all the organs of the body as diseased cells circulate through the blood and lymph systems. Chemotherapy, i.e., the use of anit-leukemic drugs which also travel throughout the body, is an exceedingly effective method of treating the disease. Radiation is also frequently used. Localized areas, like the brain and the spinal column, may be treated with radiation as adjuncts to chemotherapy, as well as large masses anywhere else, if indeed such masses severely impair normal function. Bone marrow transplantation is a unique therapeutic modality which will be discussed later.

CHEMOTHERAPY

Treatment consists of a combination of drugs, with dosage levels adjusted to meet individual requirements. Patients are generally classified according to risk of relapse and are placed on a therapeutic program which corresponds to the degree of risk. Treatment for average-risk patients, which includes the majority of children, usually consists of three phases: induction, central nervous system prophylaxis, consolidation, and continuation or maintenance therapy.

INDUCTION THERAPY

The purpose of the initial phase of treatment is to obtain a stable remission by destroying as many abnormal cells as possible in the shortest amount of time. Induction usually lasts for a period of four to six weeks, with most patients achieving remission in approximately four weeks. Patients may be hospitalized for a portion of this phase because of the need for red blood cell or platelet transfusions. Some may have a high fever and need treatment with antibiotics to fight infection. If patients feel well enough, however, they can often be treated as outpatients.

Most ALL induction programs include vincristine, prednisone, and L-asparaginase. Others include daunomycin as well. Vincristine is given as an injection once a week, prednisone orally two to three times a day for 28 days, and L-asparaginase every other day subcutaneously for nine to twelve doses. This drug combination is much less toxic than many other forms of chemotherapy. There is little or no nausea. However, the drugs do cause some side effects. For instance, vincristine can result in temporary hair loss and nerve damage, which is felt as a tingling sensation in the arms and legs, muscle weakness, and constipation. It can also depress normal bone marrow function, especially red cell prodcution. Prednisone can cause an increase in appetite, weight gain, puffy appearance, and, in some instances, may affect blood sugar levels. L-asparaginase may cause pancreaitis, diabetes, and abnormal clotting or allergic reactions.

CENTRAL NERVOUS SYSTEM PROPHYLAXIS

CNS prophylaxis, also called CNS preventive treatment or sanctuary therapy, is designed to prevent ALL cells from multiplying within the central nervous system. The blood-brain barrier is a network of capillary walls which makes it difficult for anti-leukemic drugs to reach the brain and spinal cord in effective concentrations, thereby creating a natural haven for ALL cells. CNS prophylaxis consists of combinations of the drugs methotrexate, cytosine arabinoside and hydrocortisone administered in the lower portion of the spine into the spinal canal at designated intervals.

CNS prophylaxis is an essential phase of treatment, for without it, patients run a serious risk of relapse in the central nervous system despite intensive chemotherapy. Yet CNS therapy itself is associated witha number of temporary, as well as long-term, side effects.

Radiation treatment can cause temporary hair loss and lethargy or sleepiness. However, radiation is also linked with long-term learning and other central nervous system disabilities, such as impaired development of mathematical skills and loss of motor function, particularly when accompanied by excessive use of intrathecal (intraspinal) or high dose intravenous methotrexate.

CONSOLIDATION AND MAINTENANCE THERAPY

After induction and CNS prophylaxis are completed, and remission is induced, patients are placed on one or two courses of consolidation followed by maintenance therapy. Consolidation therapy consists of new agents in high doses to serve as a wrap-up regimen. The purpose of maintenance therapy is to destroy any leftover ALL cells before they have a chance to multiply. The maintenance drugs, usually weekly methotrexate and daily 6-mercaptopurine, are given in moderate doses, so they rarely cause any noticeable side effects. Patients are therefore able to function fairly normal, engage in most activities, and go to work or attend school.

The major problem for patients during this period is that the treatment used to cure ALL also lowers the body's resistance. Common infections or illnesses, which would otherwise be minor or self-limiting, become serious threats to the health of patients in remission. Patients should therefore contact their doctors immediately upon being exposed to any contagious disease or at the first sign of infection or illness.

The maintenance period is especially problematic for parents of children with ALL, since it is almost impossible to prevent them from being exposed to any number of childhood diseases. Chicken pox, in particular, can cause serious complications, such as pneumonia, and death. Although children should be encouraged to play with friends and schoolmates rather than be isolated from them, they should be protected as much as possible from exposure to these diseases. If they are exposed to children with infections such as measles or chicken pox, the doctor should be notified immediately so that immunization can be administered.

Samples of blood, bone marrow, and cerebrospinal fluid are examined periodically. Many programs require that patients receive brief courses of more intensive chemotherapy designed to eradicate any residual cells.

Maintenance can last from 18 to 36 months, at which tme all chemotherapy is stopped. Patients are then monitored closely for any recurring disease. ALL cells sometimes find sanctuary in the tests or central nervous system. It is therefore mandated to perform testicular biopsy and spinal tap at the end of maintenance therapy. If ALL cells are found in the tests, therapy usually consists of radiation to both testes combine with systmic reinduction followed by maintenance and CNS prophylactic therapy.

If ALL recurs in the central nervous system or throughout the body, treatment consists of CNS therapy plus treatment with the same or a different combination of drugs designed to induce second, third, and even fourth remissions. However, each remission tends to be shorter than the once preceding it. The long-term survival and cure of ALL patients, therfore, depends upon achieving a durable first remission. The treatment of choice in recurrent ALL is bone marrow transplantation or, if a donor is not available, the use of the patient's own purged marrow.

INTENSIFIED TREATMENTS

Induction therapy for higher-risk patients - which includes a small percentage of children, a substantial portion of adults, and patients who have not responded to average-risk treatment - usually consists of high doses of vincristine, prednisone, and L-asparaginase, combined with cyclophosphamide (also known as cytoxan) and adriamycin (doxorubicin) or daunorubicin (daunomycin and rubidomycin).

Induction and CNS therapy are followed by consolidation or intensification therapy, which consists of a different combination of drugs which can include ARA-C (also known as cytosine arabinoside, cytosar, or cytarabine), thioguanine (6-thioguaine), VM-26 (teniposide), or VP-16 (etoposide) and methotrexate.

These drugs can be given orally, intravenously or intramuscularly. Their side effects and toxicity vary according to dosage. However, patients should be aware that high doses of these drugs can depress the production of all marrow elements. Reactions can also include nausea, vomiting, mouth and throat sores, hair loss, and a temporary change in urine color to red or orange. In addition, adriamycin (or daunorubicin) and vincristine can cause local irritation if leaked onto the skin. Adriamycin may permanently damage heart muscle, possibly producing a failure to the heart to pump blood adequatley. ARA-C may cause liver damage.

After consolidation, patients receive lower doses of standard maintenance chemotherapy for a period up to 36 months. Newer approaches both to supportive care and treatment include the use of cytokines (hormones that stimulate blood cell production) so that the period of toxic effects to the marrow is shortened.

BONE MARROW TRANSPLANTATION

Bone marrow transplantation is an effective adjunct to therapy for patients in high risk disease; those patients who do not respond to chemotherapy, who have relapsed, or who are at a high risk of relapse. Transplants fall into three basic categories; from an identically matched twin (syngeneic) or sibling: from a partially matched related or unrelated donor (allogeneic), and self (autologous) transplants, when the patient acts as his or her own donor.

Bone marrow transplantation is more likely to succeed in patients who are in complete remission (in whom the residual load of leukemic cells is less than 3 to 4 percent) rather than in those who are in partial remission or replapse. For this reason, many physicians recommend that trnasplants be performed during the first remission of high-risk ALL patients and no later than during the second, or at worst, the third, remission of all remaining patients.

Bone marrow transplantation is a highly technical and potentially hazardous procedure in which the bone marrow and hopefully all leukemic cells are completely destroyed by the combination of total body irradiation and intensive chemotherapy. The destroyed marrow is then replaced with that of a compatibly matched or partially mismatched donor, or via purged, autologous marrow.

Until the donated marrow begins to function (usually 3 to 4 weeks), patients are totally dependent upon supportive care to defend against anemia, bleeding and infection. In addition, patients are at risk of developing graft versus host disease, a potentially lethal immune reaction in which the donated bone marrow rejects the tissue of the patient.

If the procedure is successful, the transplanted marrow produces a new population of normal cells. Early evidence suggests that many patients who might have otherwise relapsed have greatly increased their chances fro an ALL-free survival. Overall, the disease-free survival after marrow transplantation is first or second remission is 45 percent in children and 35 percent in adults.

A considerable amount of research is therefore being conducted in an effort to broaden the range and minimize the toxicity of bone marrow transplantation, particularly in the areas of partially matched donor and autologous transplantation.

Autologous bone marrow transplantation is a procedure in which a small amount of bone marrow is removed from patients during remission, purged to remove all, or as many as possible, of the undetectable leukemic cells, and then stored at very low temperatures. Patients are then given total body irridation and/or intensive chemotherapy to destroy their existing marrow and are reinfused with their own perviously purged and thawed marrow.

Initial findings indicate that this approach currently is less promising than allogeneic transplantation, although studies are ongoing in an effort to remove leukemia cells which may contaminate the marrow. Also, an attempt is being made to manipulate low grade graft versus host disease into a graft versus leukemia effect in order to improve on a 20 to 25 percent disease-free survival in autologous transplantation.

CAUSES AND RISK FACTORS AND EMOTIONAL ASPECTS

CAUSES AND RISK FACTORS

The exact cause of ALL and the means of preventing it are not known. However, certain chromosomal abnormalities like Down's Syndrome, Blum's Syndrome, and Fanconi's Syndrome, as well as certain highly treated lymphomas are associated with a very increased risk for the development of ALL High dose radiation therapy (as in exposure to atomic radiation) and certain chemicals (benzene derivatives) are all potent casues of leukemia. Many believe that the disease involves a complex interaction of individual genetic and body chemistry factors with the possible participation of a virus. ALL, however, is not contagious.

EMOTIONAL ASPECTS

ALL is not an easy disease for patients and their families to live with and accept. A confirmed diagnosis can trigger any number of emotional responses, ranging from denial to devastation. Adult patients commonly feel frightened, confused, and angry. Some are embarassed by the disease, and many are concerned about the economic hardship and emotional strain placed on their families.

Children with ALL are usually petrified of hospitals. They often feel they've been abandoned or are being punished for something they've done wrong. They can become angry with the hospital staff for hurting them and with their parents for allowing it. Parents are also often angry and confused. Feelings of guilt and loss are common reactions. There may be idsagreements between parents about the discipline of the sick child or about the extra financial burden created by the disease. Siblings, too, may have problems adjusting to ALL. They are often resentful of the ill child or feel that something they may have thought or done something that made their brother or sister sick.

Naturally, patients and families have questions about chemotherapy and alternative methods of treatment. It is best for patients and parents of children with ALL to speak directly with their doctor regarding any specific medical questions, and they should not hesitate to discuss any problems or reactions they may have. It can also be helpful to talk with other health professionals, patients, and families who understand the complexity of emotioins and special ongoing needs of those living with leukemia. There are a variety of programs designed to help ease the emotional and economic strain created by ALL. Information can be obtained from The Leukemia Society of America Headquarters in New York or from one of their local chapters. They will be glad to provide patients and their families with further assistance regarding available community-sponsored programs.

This information was taken directly from a phamphlet from the Leukemia Society of America.