ACUTE MIELOBLASTIC LEUKEMIA
myelocytic leukemia
chronic myeloid leukemia
what is leukemia
aml compliance
all leukemia
cml (Chronic myelogenous leukemia)
aml Leucemia mielógena aguda
leukemia symptoms
Acute Myelogenous Leukemia, One Type of Blood Cancer
III.1 DEFINITION
 |
| myeloblastic |
Acute myeloblastic leukemia (LMA) is a disease characterized by neoplastic transformation and differentiation disorders of progenitor cells of the myeloid series. If left untreated, the disease will show rapid death within a few weeks, until the month after diagnosis. Before the 1960s the LMA treatment was primarily palliative, but since about 40 years ago the treatment of the disease developed rapidly and today many LMA patients can be disemhuhkan of the disease. The progress of LMA treatment was achieved with better chemotherapy regimens, high-dose chemotherapy with bone marrow transplant support and better supportive therapy such as new generation antibiotics and transfusion of blood components to overcome the side effects of treatment. In addition since about 2 decades another year has also developed leukemia diagnostic techniques by means of immunophenotyping and cytogenetic analysis resulting in a more accurate diagnosis. 1
III.2 INCIDENCE
In developed countries like the United States, LMA accounts for 32% of all leukemia cases. This disease is more common in adults (85%) than in children (15%). The incidence of LMA generally does not differ from childhood to adulthood. After the age of 30 years, the incidence of LMA increases exponentially with age. The incidence of LMA in people aged 30 years is 0.8%, in people aged 50 years 2.7%, while in people aged in the base 65 years is 13.7%. There is generally no ethnic variation in the incidence of LMA, although there has been an incidence of M3-type MID that is 2.9 to 5.8 times greater in Hispanic race living in the United States than in Caucasians. 1
III.3 ETIOLOGY
In most cases, the etiology of the LMA is unknown. Nevertheless there are several factors that are known to cause or at least be a predisposing factor of LMA in a particular population. Benzene, a chemical compound widely used in the leather tannery industry in the developing world, is known to be a leukomogenic agent for LMA. In addition, ionic radiation is also known to cause LMA. This is known from studies of the high incidence of leukemia cases, including LMA, in people who survived the atomic bomb attacks on Hiroshima and Nagasaki in 1945. Leukomogenik effects of radiation ion exposure began to appear since 1.5 years after the bombing and reached its peak 6 or 7 years after the bombing. Another factor known to predispose to LMA is the trisomy of chromosome 21 found in hereditary syndrome of Down syndrome. Down syndrome patients with trisomy chromosome 21 have a 10 to 18 times higher risk for leukemia, particularly M7 type LMA. In addition, patients with several genetic syndromes such as Bloom syndrome and Fanconi anemia are also known to have a much higher risk than normal populations to suffer from LMA. 1
Another factor that can lead to LMA is treatment with cytotoxic chemotherapy in solid tumor patients. LMA due to therapy is a serious long-term complication of lymphoma treatment, multiple myeloma, breast cancer, ovarian cancer and testicular cancer. The most common type of chemotherapy that triggers the onset of LMA is the alkylating agent group and the topoisomerase II inhibitor. LMA due to therapy has a poorer prognosis than the LMA de novo so that in the World Health Organization (WHO) leukemia classification is grouped separately. 1
Table 1. Etiological factors in acute leukemia
• Unknown (usually)
• Hereditary
Down's syndrome
Bloom's syndrome
Fanconi's anaemia
Ataxia telangiectasia
Kleinfelter's syndrome
Osteogenesis imperfecta
Wiskott-Aldrich syndrome
Leukaemia in siblings
• Chemicals
Chronic benzene exposure
Alkylating agents (chlorambucil, melphalan)
• Radiation
• Predisposing haematological diseases (myeloproliferative
disorders, myelodysplasia, and aplastic anaemia)
• Viruses (HTLV-I causing adult T cell leukemia / lymphoma)
(Taken from: T Everington, R J Liesner, A H Goldstone Acute Leucemia Ed .: Provan D. Clinical Haematology Second edition BMJ books 2003. Q: 30)III.4 PATHOGENESIS
The main pathogenesis of LMA is the presence of maturity blockade which causes the differentiation process of myeloid series cells to stop in the young cells (blast) with the result of blast accumulation in the bone marrow. The accumulation of blast in the bone marrow will cause a normal hematopoesis disorder and in turn will result in bone marrow failure syndrome characterized by the presence of cytopenia (anemia, lecopenia and thrombocytopenia). The presence of anemia will cause the patient to tire easily and in more severe cases shortness of breath, the presence of thrombocytopenia will cause signs of bleeding, while leukopenia will cause the patient vulnerable to infection, including opportunistic infections of normal bacterial flora present in the human body. In addition, the blast cells also have the ability to migrate out the bone marrow and infiltrate into other organs such as skin, bone, soft tissue and central nervous system and damage the organs with all the consequences. 1
III. 5 SIGNS AND SYMPTOMS
Unlike the general assumption so far, in patients with LMA always found Ieukositosis. Leukocytosis occurs in about 50% of cases of LMA, while 15% of patients have normal leukocyte counts and about 35% of patients have neutropenia. However, blast cells in significant amounts in the peripheral blood will find 85% of cases of LMA. It is therefore very important to examine the details of the types of leukocyte cells in peripheral blood as a preliminary examination, to avoid misdiagnosis in people suspected of having LMA.The main signs and symptoms of LMA are the presence of fatigue, bleeding and infection caused by the bone marrow failure syndrome mentioned above. Bleeding usually occurs in the form of purpura or petechia often found in the lower extremities or in the form of epistaxis, bleeding gums and retina. More severe bleeding is rare except in cases accompanied by DIC. The DIC case is most common, in the case of M3 type LMA. Infection is common in the throat, lungs, skin and peri rectal areas, so these organs should be thoroughly examined in LMA patients with fever.
In patients with very high leukocyte counts (more than 100,000 / mm3), leukostasis often occurs, which is the occurrence of clots that block the flow of veins and arteries. The symptoms of leukostasis vary greatly, depending on the location of the blockage. Symptoms that are often encountered are impaired consciousness, shortness of breath, chest pain and priapismus. Very high leukocyte numbers also often cause metabolic disorders of hyperuricemia and hypoglycemia. Hyperurisemia results from rapidly proliferating leukocyte cells in large numbers. Hypoglycemia occurs because of the consumption of in vitro sugar from the blood sample to be examined, so that asymptomatic hypoglycemia may be present because hypoglycemia only occurs in vitro but not in vivo in the patient's body.
Infiltration of blast cells will cause signs / symptoms that vary depending on the infiltrating organs. Infiltration of blast cells in the skin will cause leukemia kutis ie a lump that is not pigmented and without pain, while infiltration of blast cells in soft tissue will menycbabkan nodules under the skin (kloroma). Infiltration of cells in the bone will cause spontaneous bone pain or with mild stimulation. Swelling of the gums is often encountered as a manifestation of infiltration of blast cells into the gums. Although infrequent, LMA can also be found in infiltration of blast cells into the mening area and for diagnosis of cytologic examination of spinal cerebrospinal fluid obtained through lumbar puncture procedures.
III.6 DIAGNOSIS
Diagnosis of LMA is established on the basis of physical examination, cell morphology, and cytochemical painting. As already mentioned, since about two decades years ago developed 2 (two) latest examination techniques: immunophenotyping and cytogenetic analysis. Based on the examination of cell morphology and cytochemical painting, the combined hematologists of America, France, and Britain in 1976 established an LMA classification consisting of 8 subtypes (MO to M7, Table 2). This classification is known as FAB (French American British) classification. The FAB classification is still a basic diagnosis of LMA. Essential cytochemical paintings for LMA patients are Sudan Black B (SBB) and mieloperoksidase (MPO). Both cytochemicals will give positive results in LMA patients type M1, M2, M3, M4 and M6.
Immunophenotypic examination is a modern painting technique developed based on antigen and antibody reactions. It is known that the membrane surface of blood cells expresses different antigens depending on the type and degree of differentiation of the blood cells. For example, lymphocyte cells express different antigens with granulocyte cells and platelet cells. Similarly B lymphocytes have different antigenic expressions with T lymphocytes. In addition, blast cells express different antigens with more mature leucocyte cells such as promielocytes and myelocytes. If the antigen contained in the cell surface can be identified with specific antibodies, it will be able to identify the cell type and maturity level more accurately. Identification of cells with immunophenotyping techniques is usually labeled as CD (cluster of differentiation). Currently there are more than 200 CDs that mark the various types and levels of maturity of blood cells. In addition to functioning as a diagnostic tool, immunophenotyping techniques also have prognostic and therapeutic values. For example, LMA patients who express CD7 have a poor prognosis and patients who express CD2 have a better prognosis. There is also currently being developed antibody therapy that specifically targets CD33 therapy, gemtuzumab osagamicin, which is indicated for elderly LMA patients who express CD33.
Cytologic Findings in Bone Marrow Specification and Peripheral-Blood Smears from a Patient with Subtype M2 AML and
the t (8; 21) (q22; q22) Translocation.In Panel A, a bone marrow specimen contains medium-sized blasts, cytoplasm with no granulation, and nucleoli that are sometimes
clearly visible (May-Grünwald-Giemsa, ¬1600). Panel B shows a bone marrow specimen with myeloperoxidase-stained blasts
(¬1600). Panel C shows a leukemic blast with an Auer body (arrow) (May-Grünwald-Giemsa, ¬1600). Panel D shows a blast stained
with May-Grünwald-Giemsa in a peripheral-blood smear (¬1000). Panel E shows the results of fluorescence in situ hybridization
of the cell shown in Panel D with probes specific for the breakpoint regions of chromosome 8 (q22) (isolated green spots) and chromosome
21 (q22) (isolated magenta spot) (¬1000). The arrow indicates the chromosomal fusion (clustered green and magenta
spots).
Cytogenetic analysis of hematologic malignancies has begun since the early 1960s and has grown more rapidly since the early 1980s. There are 2 basic cytogenic abnormalities in LMA: disorders that cause loss or increase of chromosomal material and abnormalities cause balanced changes without causing loss or increased chromosomal material. The first disorder may be the loss of some chromosome material (deletion / del) or the loss of a whole chromosome material (monosomy). The addition of chromosome material may also be partial (duplication / d) or increase of one or more chromosome materials intact (trisomy, tetrasomy). The second disorder is a balanced chromosome change in the form of a reciprocal change between two or more chromosomes (translocation / t) or changes in various parts within a single chromosome (inversion / inv).
Based on the patient's cytologic profile abnormalities, WHO proposed a change in the classification of LMA, which has been adopted in many countries (Table 1). Table 3 shows the correspondence of LMA diagnosis based on FAB classification and cytogenetic analysis.
WHO Classification for LMA
I. LMA with recurrent cytogenetic translocation
LMA with t (8; 21) (q22; q22), AML1 (CBFa) / ETO
APL with 15; 17) (q22; q11 -12) and its variants. PMLRARα LMA with abnormal bone marrow eosinophils with inv (16) (p13q22) or t (16; 16) (p13; q1), CBFβ / MHY11
LMA dem, an abnormality of 11q23 (MLL)
II. LMA with multilineage dysplasia
with myelodysplasia syndrome
without myelodysplasia syndromeIII. LMA and myelodysplastic syndromes associated with therapy
due to alkylation drugs
due to epipodofilotoxin (some are lymphoid abnormalities)
other types
IV. Unspecified LMA
LMA minimal differentiation
LMA without maturation
LMA with maturation
LMA with monositic differentiation
Acute monocytic leukemia
Acute erythroid leukemia
Acute megakariocytic leukemia
Acute basophilic leukemia
Acute panmielosis with mielofibrosis
Table 2. WHO Classification for LMA
(Taken from: Kurniada A. Leukemia Acute Mieloblastic In: Sudoyo A., Setiyohadi B., Alwi I., (Ed.) Internal Medicine Handbook Volume II Edition IV Publisher Hall FKUI Jakarta 2006. Pages: 717)
Table 3. Comparability of LMA Subgroup Diagnosis based on FAB classification and cytogenetic abnormalities.
(Taken from: Kurniada A. Leukemia Acute Mieloblastic In: Sudoyo A., Setiyohadi B., Alwi I., (Ed.) Internal Medicine Handbook Volume II Edition IV Publisher Hall FKUI Jakarta 2006. Pages: 718)
(Taken from: http://www.medicastore.com Acute Mieloid Leukemia 2004 and T Everington, RJ Liesner, AH Goldstone Acute Leucemia Ed: Provan D. Clinical Haematology Second edition BMJ books 2003. Q: 31)
Hypertrophy of the gums as a manifestation of acute myeloid leukemia M5.
(Taken from: T Everington, R J Liesner, A H Goldstone Acute Leucemia Ed .: Provan D. Clinical Haematology Second edition BMJ books 2003. Q: 31)
III.7 THERAPY
The goal of treatment in LMA patients is to eradicate leukemic clonal cells and to restore normal hematopoesis in the bone marrow. Long-term survival is only obtained in patients who achieve complete remission. The doses of chemotherapy need not be lowered due to cytopenia, since this reduced dose will still cause severe side effects of bone marrow suppression without the sufficient effect to eradicate leukemic cells or to restore bone marrow function.
To achieve eradication of leukemik cells maximum, required a good treatment strategy. Generally chemotherapy regimens for LMA patients consist of several phases: phase induction of consolidation phase dart. Induction phase chemotherapy is an intensive chemotherapy regimen that aims to completely eradicate leukemic cells in order to achieve complete remission. A complete remission term is used when the number of blood cell cells in the peripheral bloodstream returns to normal as well as the recovery of cell populations in the bone marrow including the achievement of the number of blast cells <5%. It needs to be emphasized here, although complete remission does not mean that leukemic clonal cells are completely eradicated, since leukemic cells will be clinically detectable if the number is more than 109 log sets. So in the case of complete remission, there remains a significant amount of leukemic cells in the patient's body of therapy not detectable. Left untreated, these cells have the potential to cause recurrence in the foreseeable future. Therefore, even if the patient has achieved complete remission, it is necessary to follow up with the next treatment program that is consolidated chemotherapy. Consolidated chemotherapy usually consists of several cycles of chemotherapy and uses drugs of the same type and dose or greater than the dose used in the induction phase.
As mentioned above, the primary goal of LMA treatment is to eradicate leukemic cells in the bone marrow. This action will also eradicate the remnants of normal haematopoisis cells present in the bone marrow, so that LMA patients will experience a period of post-induced aplasia therapy. At that time the patient is very susceptible to infection and bleeding. In severe cases these two complications can be fatal. Therefore supportive therapy in the form of antibiotics and transfusion of blood components (especially red blood cells and platelets) is essential to support the success of LMA therapy.
1III.8 PROGNOSIS4
50-85% of people with LMA respond well to treatment.
20-40% of patients no longer show signs of leukemia within 5 years after treatment; this number increases to 40-50% in patients undergoing bone marrow transplantation.
The worst prognosis found in:
- patients over the age of 50 years
- patients undergoing chemotherapy and radiation therapy for other diseases.
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