Chronic Myelogenous Leukemia

 Definition

Chronic Myelocytic leukemia (mieloid, mielogenous, granulocytic, CML) is a disease in which a cell in the bone marrow turn into malignant and produce a large number of granulocytes (a type of white blood cells) are abnormal . When this happens, infectious anemia, or bleeding easily occurs. CML seldom attack individuals under the age of 20 years, but the incidence increases with age.

CML clinical picture similar to the AML, but milder symptoms, namely: In the early stages, CML may not cause symptoms. But some patients may experience fatigue and weakness, loss of appetite, weight loss, fever or sweating at night, full feeling in his stomach (because of an enlarged spleen). Most of the granulocytes leukemic produced in the bone marrow, but some are made in the spleen and liver. In CML, the cells consist of cells that are very young to a mature cell, while the LMA is only found in young cells.

Leukemic Granulocytes tend to shift the normal cells in the bone marrow and often led to the formation of large amounts of fibrous tissue that normal bone marrow depend on During the course of the disease, more and more young granulocytes that enter the bloodstream and bone marrow (acceleration phase). In these phases, anemia and thrombocytopenia (decreased platelet count) and the proportion of young white blood cells (blast cells) increased dramatically. Sometimes granulocytes leukemik experience more change and evolve into blast crisis disease. In blast crisis, the malignant stem cells only produce young granulocytes only, a sign that the disease is getting worse.

Etiology

According to Smeltzer and Bare (2001), although the cause of leukemia is unknown, presdiposistion of genetic and environmental factors seem to play a role. Environmental factors in the form of high-dose radiation exposure pergion accompanied by manifestations of leukemia that arose many years later. Chemicals (eg benzene, arsenic, pesticides, chloramphenicol, fenilbutazone, and antineoplastil agent) is associated with an increased frequency especially alkyl agents.

The cause of most types of leukemia is unknown.

Viruses cause some of leukemia in animals. Virus HTLV-I (human T-cell lymphotropic virus type I), which resemble the virus that causes AIDS, is thought to cause a rare type of leukemia in humans, namely  adult T-cell leukemia .Exposure against radiation (radiation) and certain chemicals ( such as benzene) and the use of anticancer drugs, increases the risk of leukemia. People who have certain genetic abnormalities (eg Down syndrome and Fanconi's syndrome), are also more susceptible to leukemia..

Epidemiology

In Kenya, China, and India, the CML of patients aged 20-40 years. This disease can be about all age groups, both men and women, but rarely found in children aged less than 10 years.

Pathophysiology

In normal circumstances, white blood cells serve as our defense to infection. These cells normally develop in accordance with instructions, can be controlled according to the needs of our bodies. Leukemia increase production of white blood cells in bone marrow that is more than normal. They look different from normal blood cells and does not function as usual. Tues leukemia block production of normal white blood cells, impairing the ability of the body against infection. Tues leukemia also damages other blood cell production in bone marrow, including red blood cells where the cell's function is to supply oxygen to the tissues .

According to Smeltzer and Bare (2001) analysis cytogenic generate a lot of knowledge about the chromosomal aberrations found in patients with leukemia,. Changes may include changes in chromosome numbers, which add or remove an entire chromosome, or changes in the structure, which includes this translocation, two or more chromosomes alter the genetic material, with the development of genes that change is considered cause onset of abnormal cell proliferation.

Chromosomal disorders occur in Ph chromosome (Philadelphia), namely the loss of some long arm of chromosome 22 andtranslocate Darim with the long arm of chromosome 9. So there is a merger between the genes that exist in the long arm of chromosome 9 that ABL with BCR gene located on the long arm of chromosome 22 as look in the picture. Because of this translocation, there was an excessive proliferation of pluripotent stem cells in the system hematopoiesis. In addition to excessive proliferation, white blood cells produced more of survival than normal cells because the gene is anti-apoptotic BCR_ABL. The impact of these two mechanisms, the formation of abnormal clones that finally urged hemopoesis other systems. Eventually these cells control bone marrow and replace the place of cells that produce blood cells are normal. This cancer can also infiltrate into other organs, including liver, spleen, lymph nodes, kidneys and brain.

Signs and symptoms of clinical

CML is divided into 3 phases, namely chronic phase, accelerated phase and blast crisis. Generally, when enforced, the patient still in chronic phase, diagnosis is often discovered accidentally at the time of preoperative preparation, which found great leukocytosis without symptoms of infection.
In the chronic phase, patients often complain of an enlarged spleen or feeling full quickly because of the insistence spleen against the hull. Sometimes there is pain like perur squeezed in the upper right. Other complaints are not specific, among others, feeling tired, weak body, which is not very high fever, night sweats. Weight loss occurred after a prolonged illness. All the complaints above is an illustration of hipermetabolism caused proliferation of leukemia cells.
After 2-3 years, some patients will get worse progressively . Characteristic acceleration phase is a difficult leukocytosis mielosupresif controlled by medication, mieloblast in peripheral 15-30%, promielocyte> 30% and platelets <100.000/mm3. The main complaint of severe anemia, resulting petekie, ekimosis, if accompanied by fever, usually no infection. Fever, enlarged lymph nodes and the formation of lumps of skin that are filled with granulocytes leukemik (kloroma) is a bad omen.

Investigations

According Mbah Dukun stated that investigation of leukemia are:
• A complete blood count showed normocytic, anemia normocytic
• Smear of peripheral blood: normochrom normositer, often found in the polichromate eritroblas asidosis or polikromatofil. Looks all levels of differentiation and maturation of granulocyte series, the percentage of cells increased metamielosit mielocyte and so does the percentage of eosinophils or basophils.
• Hemoglobin: normal or slightly decreased, to less than 10 g/100 ml
• reticulocyte count: the number is usually low
• Platelet count: probably very low (<50.000/mm)
• SDP: more than 50.000/cm with increasing SDP are immature (probably deviated to the left).

• PT / PTT: elongated

• LDH: may increase
• Uric acid serum / urine: may increase
• Copper serum: increased
• Zinc serum: increased
• Bone marrow biopsy: abnormal human resources is usually more than 50% or more of the SDP in the bone marrow. Often 60% - 90% of the blast, with precursor eritroid, mature cells, and megakariositis decline.
• Photos chest and lymph node biopsy: to indicate the degree of involvement.


Chronic Mielogenus  Leukemia Treatment

Most treatments do not cure the disease, but only slow the progression of the disease. Treatment is considered successful if the number of white blood cells can be reduced to less than 50.000/microliter blood. Even the best treatment that can not destroy all cells of leukemic. The only chance of healing is with bone marrow transplantation. Transplantation most effective if done at an early stage and less effective if done on the acceleration phase or blast crisis. . Indication of bone marrow transplantation: 1. Age not more than 60 years, 2. There is a suitable donor, 3. Includes low-risk groups according to the calculation of Sokal.
Drug alpha interferon can normalize bone marrow and cause remission. Hydroxyurea by mouth (swallowed) is the most widely used chemotherapy for this disease. Busulfan is also effective, but because it has serious side effects, then its use should not be too long. Radiation therapy to the spleen sometimes help reduce the number of leukemic cells . Sometimes the spleen must be surgically removed (splenectomy) to: reduce discomfort in the stomach, increasing the number of platelets, reducing the possibility of transfusion.

Hidroxyurea (Hydrea)
• It is elected for induction remission therapy hematologic on LGK.
• More effective than busulfan, melfalan (Alkeran), and Klorambusil.
• Effects mielosupresif still take several days to 1 week after treatment was stopped. Unlike busulfan can cause aplastic anemia and pulmonary fibrosis.
• 30mg/kgBB/day dose given as a single dose or divided into 2-3 doses. If leukocyte> 300.000/mm3, the dose may be raised until maksimal2, 5 grams / day.
• Its use was discontinued when leukocyte <8.000/mm3 or platelets <100.000/mm3
• Drug interactions can occur when used in conjunction with 5-FU, causes neurotoxicity.
• During use hydrea should be monitored Hb, leucocytes, platelets, kidney function, liver function.
Busulfan (myleran)
• Includes an alkyl group which is very strong.
• 4-8mg/dayper oral dose, can be increased up to 12mg/hari.
Should be discontinued if the leukocyte between 10-20.000/mm3, and only started again after leucocytes> 50.000/mm3.
• It should not be given to pregnant women.
• Drug interactions: acetaminophen, cyclophosphamide, and itrakonasol will increase the effect of busulfan, whereas phenytoin would reduce its effect.
• When leucocytes are very high, busulfan administration should be accompanied by either allopurinol and hydration.
• Can cause lung fibrosis and prolonged bone marrow suppression.

Imatinib mesylate (Gleevec = Glyvec)
• Classified as menoklonal antibody designed to inhibit the tyrosine kinase activity of BCR-ABL fusion gene.
• aborted in either the gastric mucosa by oral administration.
• For the clonic phase, 400mg/hari dose after a meal. The dose may be increased to 600mg/hari if not achieve hematologic response after 3 months of delivery, or never achieve a good response but there was deterioration in hemotologik, the hemoglobin is low and / or leucocytes increases with / without a change in platelet counts.
• The dose should be reduced if there neutropeniaweight (<500/mm3) or thrombocytopenia weight (<50.000/mm3) or elevated SGOT / SGPT and bilirubin.
• For accelerate phase or blast crisis phase, can be given directly 800mg/day (400mg bid).
• hypersensitivity reactions can occur, although very rarely.
• It should not be given to pregnant women.
• Drug interactions: ketoconazole, simvastatin and venitoin will enhance the effect of imatinib mesilat.
• In addition to hematologic remission, these drugs can produce remission Cytogenetics characterized by the loss / reduction in Ph chromosome and biological remission was also characterized by reduced expression of BCR-ABL gene or the protein it produces.
• In contrast to imatinib mesilat, interferon can not produce biological remission can achieve remission despite Cytogenetics
• 5 million IU/m2/day subcutaneous dose to achieve remission Cytogenetics, usually after 12 months of therapy. Based on data from studies in Indonesia, which can be tolerated dose is 3 million IU/m2/day. It is now available pegylated interferon preparations, so that the injection once a week, do not need every day.
• Required premedication with analgesic and antipyretic before giving interferon to prevent / reduce the side effects of interferon in the form of flue-like syndrome.
• Drug interactions: theophylline, cimetidine, vinblastine and zidovudin interveron toxin can enhance the effect.
• Exercise caution when given at an advanced age, impaired liver function and kidney weight, patients with epilepsy.
Bone marrow transplant
• It is the definitive therapy for LGK. The data show that bone marrow transplantation (CST) to extend the period of remission up to> 9 years, especially in allogeneic CST.
• Not done on LGK with negative Ph chromosome or BCR-ABL negative.