Acute Myelogenous Leukemia

 

Acute myeloid leukemia (AML) are acute malignant diseases of proliferation and differentiation stop medullary precursors grainy lines, monocytic, erythroid, or platelet. Thus, we see that the term acute non-lymphoblastic leukemia, used by the Anglo-Saxons, would be more appropriate to name this disease that the term acute myelogenous leukemia usually used in France. The acute myeloid leukemia can occur at any age but are more common as the age advances. If the causes are still unclear, some related or not host factors have been identified.Thus, the existence of a constitutional disease (mongolism Fanconi disease), or neoplastic disease treated or untreated (breast or ovarian carcinoma, lymphoid hematological) are contributing factors. Among the non-host-related factors are recognized exposure to benzene or ionizing radiation can rank acute myelogenous leukemia as an occupational disease, previous treatment with chemotherapy and (or) radiotherapy for malignant disease.Responsibility for certain drugs, such as alkylating agents and nitrosoureas recently inhibitors of topoisomerase 2, is better described. Finally, acute myeloid leukemia is the final evolution of certain blood diseases such as chronic myeloid leukemia and myelodysplasia above. In practice, the knowledge of a factor that could induce leukemia distinguishes leukemia called “de novo” leukemia “secondary”. This distinction is important because it usually corresponds to specific morphological and cytogenetic characteristics of leukemia, and a different sensitivity to therapeutics leading to a bad prognosis rule for so-called secondary acute leukemia.

Clinical diagnosis:

Typically, the onset of clinical signs in acute leukemia is fast, in a few weeks. The onset of symptoms over several months is more frequently observed in the evolution to acute leukemia myelodysplasia. Clinical signs are dominated by asthenia, signs of bone marrow failure and tumor signs.

A- marrow failure signs:

Signs related anemia are pallor, dyspnea, angina; with thrombocytopenia purpura, ecchymosis, epistaxis and gingival bleeding. Purpura often begins in the lower limbs. When extensive, that is to say, when it appears the damage quickly in many jurisdictions, it is of a serious nature. Clinical signs associated with neutropenia are essentially at the beginning of the disease, ENT and lung infections associated with fever.

B- tumor signs:

Tumor signs are less often found in acute myeloid leukemia than in acute lymphoblastic leukemia in children.However, there may lymphadenopathy, splenomegaly or hepatomegaly. Some forms as monoblastic acute leukemia are more likely tumor. Especially gingival sites (hypertrophic gingivitis) and the skin (dermal infiltration nodular purple) are highly suggestive of acute monoblastic leukemia. Neurological locations and (or) meningitis are very rare at initial diagnosis of acute myeloid leukemia. Clinical signs are practicing, in order fairly quickly, blood count and City lab will be alerted by the finding of one or more cytopenias and (or) the presence of blast cells. The number of white blood cells and the percentage of circulating blasts are extremely variable. Acute myelogenous leukemia may include leukopenia, number of normal white blood cells or sometimes major leukocytosis.

C- diagnostic confirmation:

The diagnosis of acute myelogenous leukemia should always be focused on the joint study of a blood smear and a bone marrow aspiration smear usually after sternal puncture. If the diagnosis is based on morphological analysis, several techniques can complete it in clarifying the affected line (cytochemistry, survey markers) on the molecular characteristics of blasts (cytogenetics, molecular analysis) and sensitivity chemotherapy (immunological and molecular study of drug resistance factors). Thus, try to provide as many as possible before these studies to realize the aspiration of spinal marrow aspiration for so as not to increase the punctures.

Laboratory diagnosis:

• Morphological analysis is done after staining with May-Grünwald-Giemsa smears of blood and marrow. The morphological diagnostic criteria were established by a group of French-American-British cytologists (FAB classification). By definition, the diagnosis of acute leukemia is brought before spinal infiltration of more than 30% blast cells. The classification takes account of membership in a particular line of blast cells and their maturation state.

• Cytochemical analysis are essentially the reaction of myeloperoxidases highlighting an enzyme contained in the grains of blasts from azurophilic granular line. This reaction may be useful to classify as acute myelogenous leukemia leukemia blasts which are undifferentiated in order to distinguish lymphoblasts. A reaction of esterase positive and not inhibited by sodium fluoride, is in favor of the original monocytic proliferation.

• Analysis of the markers demonstrate specific antigens lineage or cell differentiation at the membrane or the cytoplasm of blast cells. This study is done either by flow cytometry or after immunostaining slide. The markers usually found on myeloid blasts are CD13 and CD33. Positivity found with anti-CD34 antibodies indicates the presence of very primitive blasts.

Cytogenetic diagnosis:

• Chromosomal abnormalities are found in over 50% of cases of acute myelogenous leukemia de novo and in the majority of so-called secondary acute leukemia. The detection of chromosomal abnormalities can be usually by direct identification of chromosomes during mitosis, after culturing cells and blocking cell division. A more recent technique, FISH (fluorescent in situ hybridization) allows, in the absence of mitosis in interphase nucleus, detect chromosomal abnormalities. Anomalies can be number of anomalies: monosomy, trisomy, or hypoploïdie hyperploidy, structural anomalies especially with loss of an entire chromosome or arms (deletion) or exchanges between chromosomes (translocation). In some cases of leukemia, only abnormality is noted. In other cases, anomalies are numerous (complex karyotype).

• Molecular studies help to identify, at the molecular level, the result for example of a chromosomal translocation.Translocation can lead indeed a fusion transcript detected by the analysis of RNA or DNA. Molecular analysis can sometimes highlight the alteration of a gene or fusion transcript while the sensitivity of the cytogenetic examination did not detect chromosomal abnormalities.

Different types of acute myeloid leukemia:

The results of the various laboratory tests that we have enumerated in the acute myeloid leukemia helped to highlight the fact that the initial oncogenic event, the mostly unknown, does not involve random morphological abnormalities, chromosomal or molecular but there is a correlation between the different clinical, morphological and molecular acute myeloid leukemia as well as the de novo nature or secondary leukemia.

• Thus, we can say that there is no acute myeloid leukemia but several types that correspond to clinical-therapeutic entities and soon becoming better defined. For example, acute myelogenous leukemia M2 is morphologically characterized by the existence of a proliferation of myeloblast positive myeloperoxidase persistently abnormal maturation grainy morphologically and attest to the potential maturation of leukemic clone. A special form inside acute myeloid leukemia M2 is seen most often in children and young adults, most often accompanied chloroma (extrahématopoïétique myeloid tumor), is associated with translocation (8; 21) can be detected by cytogenetic analysis or by detection of the fusion transcript for the gene fusion (8; 21) are known. This leukemia is very sensitive to chemotherapy and remission is easily obtained.

• Acute leukemia or acute promyelocytic leukemia M3 is also very special. It combines a morphologically abnormal promyelocytes of proliferation with the presence of numerous very characteristic Auer rods distributed in bundles in the cytoplasm. This leukemia occurs most often in a form leucopenic and the existence of leukocytosis is a sign of poor prognosis. Another very special severity criterion of acute myelogenous leukemia M3 is almost constant existence of disseminated intravascular coagulation at diagnosis, which exacerbates the beginning of chemotherapy and reflects the very dark prognosis with immediate bleeding to death very fast, if haematological resuscitation and treatment measures are not undertaken in extreme emergency. This leukemia only rarely observed in children.Accompanied almost constantly a translocation (15; 17) pathognomonic. This translocation enables the fusion of two genes, one of which is the receptor for retinoic acid (vitamin A). Or acute promyelocytic leukemia is sensitive so very special to treatment with vitamin A that provides maturation of leukemic cells and a complete remission.

• The monoblastic leukemia (M4 and M5) are often hyperleucocytaires and tumor with gingival and cutaneous lesions. The reaction of esterase can sometimes aid in the diagnosis and the positivity of CD14 and CD36 monocyte markers. A variety of acute leukemia M4 with precursors morphologically abnormal eosinophils (acute myelogenous leukemia 4 EO) is associated with an abnormality of chromosome 16 (16 inversion or deletion). Eosinophils M4 are characterized by a very favorable prognosis after chemotherapy. Acute myeloid leukemia M4, 4 acute myeloid leukemia and acute myeloid leukemia eo M5 are the forms that are most injury or meningeal relapse. They can therefore benefit from prevention of relapse in the central nervous system.

• Acute leukemias are called secondary morphologically characterized by a filing difficulty within the FAB classification. This may be due either to the fact that these leukemias are associated with myelofibrosis making aspiration technically difficult, or because it is a very large population heterogeneity blast with abnormal precursors of several lines. In these cases there is often complex karyotype abnormalities and quite specifically abnormalities of chromosome 5 or chromosome 7. acute myeloid leukemia occurring in a patient who has been treated with inhibitors of topoisomerase 2 are associated significantly to other chromosomal abnormality on chromosome 11q23 where the MLL gene is located, it may be interested in several types with different translocation partner genes on different chromosomes. These secondary leukemia generally have poor sensitivity to chemotherapy and thus poor prognosis.

• The acute myeloid leukemia in children are more common than acute lymphoblastic leukemia. Nevertheless, there are some features: the frequency of leukemia in children with DS, the frequency of acute leukemia monoblastic very poor prognosis in young infants with abnormalities on chromosome 11q23, the frequency of chloromas in acute myeloid leukemia M2 translocation (8; 21).

Evolution:

A number of complications are present at diagnosis of acute myeloblastic leukemia and the beginning of the treatment phase. These complications are the result of bone marrow failure and tumor proliferation (metabolic complications). These complications should be treated immediately before the start of specific treatment for acute myelogenous leukemia.

• Complications of bone marrow failure: anemia can result, especially if it was quick installation, and especially if the topic is old, signs of coronary artery disease and the rule is to transfuse so to maintain hemoglobin above 10 g / dL in the elderly. The most serious complication of thrombocytopenia is the occurrence of intracerebral or subarachnoid hemorrhage. It is even more common if there is disseminated intravascular coagulation. Severity of the signs are the existence of headache, the existence of an extensive purpura and the existence of large closet bruising. These signs must begin urgently platelet transfusions associated in case of disseminated intravascular coagulation with heparin therapy and the contribution of fresh frozen plasma. The complications of neutropenia are infectious complications.Fever is rarely specific in the acute myeloid leukemia and until the contrary is to be regarded as a sign of infection.Similarly, hypothermia is a sign of seriousness. The existence of a fever and (or) a clinical infection: infection ENT, lung, skin, anal sepsis syndrome, must begin urgently bactericidal antibiotics without waiting for the results of bacteriological samples.

• a number of complications related to the tumor:

– Pulmonary leukostasis syndrome and (or) brain related to the accumulation in the capillaries of leukemic blasts can be especially observed in acute myeloid leukemia and hyperleucocytaires monoblastic. This leukostasis syndrome can manifest as respiratory failure with severe hypoxia (aggravated by the consumption of oxygen by the blasts in the collection of blood gases) and flaky images on chest radiography. In the brain, leukostasis syndrome causes impaired alertness. The only therapeutic strategy, apart from the oxygen, is to treat the emergency leukemia;

– Certain metabolic complications are related to the proliferation and spontaneous rapid catabolism of leukemic cells and are aggravated at the start of chemotherapy. These complications are hyperuricemia hyperuraturie and resulting in a risk of nephropathy due to precipitation of urate intratubular crystals. It must be fought at diagnosis with a lot of water with alkaline solute to maintain an alkaline diuresis, and uricolytiques. Similarly, there is frequently a hyperphosphatemia resulting also a risk of hyperphosphatemic nephropathy with massive deposits of calcium phosphate crystals in kidney tubules. This complication is opposed by an abundant diuresis. Finally, hyperkalemia should be systematically sought especially at the beginning of treatment. All these complications will worsen during the early treatment require that it be undertaken only when adequate diuresis was obtained.

• The natural course of acute myeloid leukemia is consistently negative in the absence of treatment. In some cases, however, no specific treatment can be undertaken, especially in very elderly patients in whom we saw as leukemias “secondary standard” criteria with a poor prognosis and poor response to treatment are more frequent. In the elderly, it may not be able to offer effective chemotherapy whose toxic effects and the suppression stage it entails are not supported. In this case, only a palliative treatment of bone marrow failure and tumor growth is performed. • The development, once begun chemotherapy treatment depends on the chemosensitivity of the disease. The first important prognostic criterion is to obtain a complete remission at the end of the induction period of the chemotherapy. If complete remission is not achieved, the evolution is dark. With conventional chemotherapies a complete remission was obtained in approximately 70% of cases. The percentage of remission is particularly important that the patient is young, he is a de novo acute myelogenous leukemia, and there is no chromosomal abnormalities poor prognosis. Hyperleucocytaire the nature of the disease is a poor prognostic factor for achieving complete remission. Once complete remission is achieved, maintaining it requires consolidation chemotherapy treatments. The major criterion for the duration of remission and cure is the result of cytogenetic analysis. Certain leukemias, those with translocation (15; 17) translocation (8; 21) or an abnormality of chromosome 16 are called “good prognosis”. Conversely, leukemia with complex karyotype abnormalities or abnormalities of chromosome 5 and 7 have a very poor prognosis. Other forms, which also represent the majority of cases, in which there is no abnormality detected karyotype or other abnormalities, have an intermediate prognosis. The cure rate of acute myeloid leukemia varies from 15% among older adults 50 or even 60% in the form of favorable cytogenetics in children or in acute promyelocytic leukemia thanks to the contribution of acid retinoic.

• The indication for allogeneic bone marrow transplantation from an HLA (human leukocyte antigen) identical sibling or from an unrelated donor should concern primarily the younger patients (age less and 35) because the complications allogeneic marrow transplantation are particularly poorly supported as age increases. Given the risks associated with the procedure, allogeneic marrow transplantation is discussed in the forms of good prognosis, where it is not clear that it can make a profit higher than chemotherapy.

Highlights to understand:

• The diagnosis of acute myelogenous leukemia is a morphological diagnosis made by a trained cytologist on analysis of stained smears of blood and bone marrow.

• Additional biological explorations: immunohistochemistry, cytogenetics, molecular biology are very important because they help to better define the affected spinal lineage.

• The results of these studies provide with biological age and character novo or secondary disease also set very different prognoses.

• Control of complications related to bone marrow failure and catabolism of leukemic cells is required before starting chemotherapy. The evolution depends on the sensitivity of acute myelogenous leukemia with chemotherapy.

Strong Points to remember:

• The prognosis of acute myeloid leukemia is still dark with current treatment methods that are either highly toxic chemotherapy or bone marrow transplantation.

• The effectiveness of treatment should increase. In the future, we will discover, as in acute promyelocytic leukemia, more specific and more effective treatments for various forms adapted to leukemia described above.

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