Acute myeloid leukemia (AML) is an oncological disease in which the spinal cord produces abnormal myeloblastic cells (the type of leukocyte cells), erythrocytes or platelets.
Acute myeloid leukemia occurs in people of all ages, but mostly in adults. The likelihood of developing acute myeloid leukemia increases in the event of exposure to large doses of radiation and the use of certain chemotherapy agents for malignant tumors.
Acute myeloid leukemia is a relatively rare malignant disease. Thus, in the USA, 10,500 new cases of AML are detected annually, and the incidence remains unchanged from 1995 to 2005. The mortality from AML is 1.2% of all cancer deaths in the United States.
The incidence of AML increases with age, the average age of detection is 63 years. On AML accounts for about 90% of all acute leukemia in adults, but in children it is rare.
The incidence of AML associated with previous treatment (that is, AML, caused by previous chemotherapy) is increasing. At present, such forms reach 10-20% of all cases of AML. AML is more common in men, the incidence is related to 1.3 to 1.
There are some geographical differences in the incidence of AML. In adults, the highest incidence in adults is in North America, Europe and Oceania, and in Asia and Latin America, the incidence of AML is lower. Conversely, children's AML in North America and India is less common than in other parts of Asia. These differences can be determined by the genetic characteristics of the population and the characteristics of the environment.
What causes / Causes of acute myeloid leukemia (acute non-lymphoblastic leukemia, acute myelogenous leukemia):
A number of factors contributing to the onset of AML were identified-other disorders of the hematopoiesis system, exposure to harmful substances, ionizing radiation, and genetic influence.
"Pre-leukemic haemorrhage disorders, such as myelodysplastic syndrome or myeloproliferative syndrome, can lead to AML, the likelihood of the disease depends on the shape of the myelodysplastic or myeloproliferative syndrome.
An antineoplastic chemotherapeutic effect, especially with alkylating agents, may increase the likelihood of AML occurring in the future. The highest probability of the disease is 3-5 years after chemotherapy. Other chemotherapeutic drugs, especially epipodophylotoxins and anthracyclines, also bind to post-chemotherapeutic leukemias. leukemias of this type are often explained by specific changes in the chromosomes of leukemia cells.
The impact of benzene and other aromatic organic solvents associated with occupational activity as a possible cause of AML remains controversial. Benzene and many of its derivatives show carcinogenic properties. The data from some observations confirm the possibility of the influence of professional contacts with these substances on the likelihood of developing AML, but other studies confirm that if there is such a danger, it is only an additional factor.
The effect of ionizing radiation increases the likelihood of AML disease. In the survivors of the atomic bombing of Hiroshima and Nagasaki, the incidence of AML is increased, as well as in radiologists receiving high doses of X-rays at a time when radiological protection measures were inadequate.
Probably, there is a hereditarily increased likelihood of AML disease. There are a large number of reports of many family cases of AML, when the incidence rate exceeded the average. The probability of occurrence of AML in the nearest relatives of the patient is three times higher.
A number of congenital states can increase the likelihood of AML. Most often it is Down's syndrome, in which the probability of AML is increased 10 to 18 times.
During acute myeloid leukemia (acute non-lymphoblastic leukemia, acute myelogenous leukemia):
The pathogenesis of leukemia is associated with the activation of cellular oncogenes (protooncogenes) under the influence of various etiological factors, which leads to a violation of the proliferation and differentiation of hematopoietic cells and their malignant transformation. In humans, increased expression of a number of proto-oncogenes in leukemia has been reported; ras (1st chromosome) - with different leukemias; sis (22nd chromosome) - with chronic leukemia; thue (8th chromosome) - with Burkitt's lymphoma.
The importance of hereditary factors in the development of leukemia is often emphasized by the family nature of the disease. When studying karyotypes of leukemic cells, changes in the set of their chromosomes are revealed - chromosome aberrations. In chronic myeloid leukemia, for example, the decrease in the autosome of the 22nd pair of chromosomes of leukemic cells is constantly found. In children with Down's disease, at which the P chromosome is also found, leukemia occurs 10-15 times more often.
Thus, the mutational theory of the pathogenesis of leukemia can be considered the most probable. However, the development of leukemia (though not all) is subject to the rules of tumor progression. The change in monoclonality of leukemia cells by polyclonality is the basis for the appearance of blast cells, their eviction from the bone marrow and the progression of the disease - blast crisis.
(acute non-lymphoblastic leukemia, acute myelogenous leukemia):
The clinical picture of AML is well known and is manifested by the following syndromes: anemic, hemorrhagic and toxic, characterized by paleness of skin, pronounced weakness, dizziness, decreased appetite, increased fatigue, fever without manifestations of catarrhal phenomena.
Lymph nodes in most patients are small in size, painless, not soldered to the skin and to each other. In rare cases, enlarged lymph nodes of 2.5 to 5 cm in size are observed with the formation of conglomerates in the cervical-supraclavicular region. Changes in the osteoarticular system in some cases are manifested by pronounced ossalgia in the lower extremities and in the region of the spinal column, which is accompanied by a disturbance of movements and gait. On the radiographs of the bone system, destructive changes of different localization, periosteal reactions, and osteoporosis are noted. Most children have a small increase in the liver and spleen (protrude from under the edge of the costal arch by 2-3 cm).
Extramedullary tumor lesions are more often manifested by gingivitis and exophthalmos, including bilateral; In rare cases, there are tumor infiltration of soft tissues, hypertrophy of palatine tonsils, nasopharynx and facial nerve damage, as well as leukemids on the skin.
Extramedullary localization of AML combines the term "granulocyte (myeloblast) sarcoma", including classical chlorine and non-pigmented tumors.
According to autopsy data, granulocyte (myeloblast) sarcoma is diagnosed in 3-8% of cases in patients with AML. It can be preceded or combined with signs of AML, characterized by blastic bone marrow infiltration and the presence of blasts in the peripheral blood, as well as observed with relapse of the disease. The most frequent localization of tumor growth is the orbit (the orbital tissue and internal structures of the skull are affected). Blastic cells are more often M2-type, having translocation t (8; 21). A number of authors indicate a worse prognosis in these patients than with a typical AML.
The prognostic factors in AML patients are less studied than in patients with ALL. A large number of one- and multifactor studies were conducted, with the help of which it became possible to determine the favorable and unfavorable signs of the disease for the purpose of rational treatment. The factors that determine the prognosis of AML in children are divided into clinical and laboratory ones. The clinical age, gender, anamnesis, the size of the parenchymal organs, the severity of the hemorrhagic syndrome, the initial CNS lesion, the time of remission, the number of chemotherapy courses can be referred to clinical. Among the laboratory prognostic factors, the sensitivity of blast cells to chemotherapy in vitro, the number of leukocytes in the analysis of peripheral blood, the FAB variant of AML, the level of fibrinogen, the level of lactate dehydrogenase, the presence of Aueur sticks in blasts.
The prognosis for AML depends on the FAB-morphological variant, the genetic research data and the immunophenotype of blast cells. Thus, the most favorable group consists of patients with morphological variants M1, M2 and t (8; 21), t (9; 11), M3 and t (15; 17) or M4 and inv (16). Adverse to the prognosis group includes patients with variants M4 without inv (16), M5, M6 and M7, and also patients, when studying the karyotype of tumor cells, the following chromosomal abnormalities were detected: t (9; 22), t (6; 11 ), t (10; 11), del5q-, del7q-, monosomies -5, -7. In addition, our studies have proved that the prognosis of AML is adversely affected by the expression of erythroitic and B-linear antigens on the surface of the blasts.
Diagnosis of acute myeloid leukemia (acute non-lymphoblastic leukemia, acute myelogenous leukemia):
The diagnosis of AML is established in more than 30% of cases of detection of blasts in the bone marrow. The blasts should have a morphological and cytochemical characterization of one of the FAB variants of AML.
Cytochemical data aimed at diagnosis of variants of the disease is a positive reaction to myeloperoxidase, with Sudan black B and nonspecific esterase inhibited by sodium fluoride. At the same time, the totality of these indicators differs for different AML variants. Thus, the presence of a positive reaction to myeloperoxidase is characteristic of variants M1, M2, M3 and M4, and nonspecific esterase inhibited by sodium fluoride is specific for variants M4 and M5.
An essential addition to the diagnosis of AML are immunophenotypic studies,clarifying standard morphological diagnostics and AML variants.
The most common and widely used to confirm the non-lymphoid nature of leukemia are the antigens CD13 and CD33, somewhat less commonly used CD65. The evaluation of these three markers confirms the myeloid nature of tumor cells in 98% of AML cases in children.
Chromosomal analysis is necessary to predict the outcome of AML treatment. Approximately 75% of children with AML can detect one or another chromosomal aberration, among which there are anomalies that are characteristic only of certain AML variants. Thus, t (8; 21) is associated with the M2-variant, t (15; 17) - with the M3-variant, inv (16) - with the M4-variant with eosinophilia. The anomaly 11q23 occurs in the variants M4 and M5 and t (1; 22) with the M7 variant. With the help of methods of molecular biological diagnostics - polymerase chain reaction (PCR) and FISH (fluorescent in situ hybridization) - it is possible to determine chromosomal aberration not detected in a standard cytogenetic study. This is especially important for choosing a certain type of treatment in case of confirmation of the M3 variant. In addition, thanks to the introduction of molecular diagnostic methods for AML, patients can now not only clinicohematological, but also molecular remission, followed by monitoring of the minimum residual disease and the determination of molecular relapse.
Treatment of acute myeloid leukemia (acute non-lymphoblastic leukemia, acute myelogenous leukemia):
Treatment of patients with AML is based on the principle of maximum destruction of the leukemic cell clone. The main method of treatment of the disease is polychemotherapy. Currently, there are several areas in the treatment of AML, including both the use of new cytotoxic drugs, and increasing the doses of already known chemotherapy drugs. In addition to these already sufficiently studied and traditional methods of influencing the leukemia process, there are experimental approaches using natural biologically active drugs that in one way or another affect the process of hematopoiesis (all growth factors, interleukins). Along with cytostatic agents, drugs that have a powerful modeling effect on the immune system (cyclosporine, antileukocyte immunoglobulin) are also being used. The use of growth factors in AML is currently debated in connection with the evidence that they can contribute to the proliferation of the tumor cell clone. At present, some researchers have demonstrated the possibility of using colony-stimulating factors (granulocyte, etc.) in patients with AML.
In recent years, bone marrow transplantation (TCM) has been widely introduced into the treatment of acute non-lymphoblastic leukemia (ONLL) - both allogeneic (in the presence of an HLA-compatible donor) and autologous transplantation of peripheral stem cells or bone marrow.
Modern programs for AML treatment consist of different stages - induction, consolidation, intensification and maintenance treatment during remission (lasting, as a rule, at least 2 years). At the same time, neuroleukemia is prevented by the endolumbal administration of chemotherapy drugs (cytosine arabinoside). In recent years, preventive distance gamma-therapy has become more widely used in the brain area.
When conducting induction and consolidation courses of chemotherapy, the maximum intensification is necessary, which leads to the fastest achievement of complete remissions. The consequence of such therapy is bone marrow aplasia, during which the probability of infectious and hemorrhagic complications increases sharply, and therefore patients need complex accompanying treatment, including substitution, antibacterial and detoxification therapy.
The main drugs included in the polychemotherapy programs used are combinations of cytosine arabinoside and anthracycline antibiotics. Until the 1980s, DAT schemes and "7 + 3" schemes were applied. Since the mid-80s etoposide began to be introduced into treatment programs, which led to a higher number of complete remissions and an increase in disease-free survival. The most effective treatment programs, including etoposide, are the BFM-83 and BFM-87 programs. Remission induction consists of cytosine arabinoside, daunorubicin and etoposide, and consolidation from vincristine, daunorubicin, cytosine arabinoside, 6-thioguanine, prednisolone, cyclophosphamide followed by maintenance therapy (cytosine arabinoside and 6-thioguanine up to 104 weeks after the onset of remission). According to the BFM-87 study, the five-year event-free survival rate was 47%.
One way to intensify chemotherapy and achieve longer remissions is to increase the doses of cytosine arabinoside (up to 3000 mg / m2 every 12 hours).
Recently, work has appeared on the use of mitoxantrone for the treatment of AML in children, especially in patients with poor prognosis (M5, M7, M6, M4 without eosinophilia and inv (16), M2with leukocytosis more than 50х109 / l) and with relapse of the disease. The most effective therapy was a combination of high doses of cytosar, mitoxantrone, etoposide. This therapy leads to severe myelodepression, without which it is impossible to achieve complete remission with AML, especially in patients with poor prognosis and relapses of the disease. The use of mitoxantrone (12 mg / m2) in patients with unfavorable prognosis did not lead to an increase in the number of complications when more complete remissions were achieved in patients with resistant forms of ONLL.
The data available to date show that, on the one hand, the intensification of chemotherapy has significantly increased the effectiveness of treatment, on the other, the number of adverse reactions and complications has increased, in some cases they are the cause of death of patients.
The direction of treatment associated with the use of differentiating agents, such as isomers of retinoic acid, has reached the greatest result in the therapy of acute promyelocytic leukemia (M3). In chromosomal aberration t (15; 17) corresponding to M3 FAB, the point of rupture of chromosome 17 involves a gene corresponding to the nuclear receptor of alpha-retinoic acid, which makes it possible to restore the affected gene and promotes apoptosis of tumor cells with a reduction in the number of episodes of hemorrhagic complications.
The experience of the last 20 years has shown that the improvement of the technology of accompanying treatment, mainly methods of infection control in patients with induced granulocytopenia, and the emergence of techniques for obtaining thromboconcentrate have made it possible to achieve 80% of complete remissions, despite a significant tightening of the polychemotherapy regimens. That is why the main directions of modern protocols are various options for chemotherapy intensification, which can be carried out with the help of a number of options: introduction of additional cytostatic agents into the already known protocols; use of new cytotoxic drugs as an alternative to those studied, for example, more active second-generation anthracyclines (idarubicin and mitoxantrone); cyclic intensive chemotherapy for 1.5-2 years after remission; modification of standard chemotherapy programs based on the kinetic parameters of blast cells during therapy and the characteristic features of hematopoiesis recovery after cytostatic action; application of growth factors to accelerate the release of post-chemotherapeutic aplasia; early application of autologous and allogeneic bone marrow transplantation. The principle of early intensification is now the main in AML therapy and, according to many studies, has an advantage over the standard one. It allows reducing the number of patients with resistant forms of AML by increasing the power of the cytostatic effect in the first, early stages of therapy.
When analyzing data from different research groups, it becomes obvious that approximately half of the patients who achieve remission have relapsed AML. And 75% of relapses are detected within the first year from the beginning of therapy, another 15% - during the second year and 10% of relapses are registered after 2 years from the beginning of therapy. In this regard, the goal of post-renal therapy is the eradication of the residual leukemic clone. Post-therapy therapy is usually classified as follows: 1) Consolidation therapy - post-treatment therapy, similar in intensity with induction, using repeatedly repeated drugs with non-cross resistance; 2) Intensification therapy: post-therapy therapy, whose goal is to overcome drug resistance (usually drugs previously used induction); 3) maintenance therapy: significantly less intensive post-treatment therapy (in some studies up to 3 years).
At present, it is proved that the results of treatment of patients with AML who received all the stages of polychemotherapy (remission induction and post-treatment therapy) in full are much higher.
In most protocols for AML treatment, the most prevalent is the maintenance-recommended BFM-group therapy, which consists of daily administration of 6-thioguanine in a dose of 40 mg / m2 in combination with subcutaneous administration of cytosine arabinoside (40 mg / m2 x 4) every 4 weeks. It is carried out for up to 18 months from the beginning of treatment. However, as the intensity of post-treatment therapy increases, the duration of maintenance treatment is reduced.
Prophylaxis of neuroleukemia consists of endolumbal administration of cytosine arabinoside, methotrexate or a combination of these drugs with hydrocortisone, with or without cranial irradiation. A number of authors consider cranial irradiation of patients with AML as an essential component of therapy, while others hold the view that cranial irradiation is necessary only for children with primary lesion of the nervous system, as well as for patients with variant M4, with chromosomal disturbances of inv (16). Preference in carrying out cranial irradiation is expressed by researchers from the BFM group who showed a decreasefrequency of not only neuroleukemia, but also bone marrow relapses during its conduct.
The question of the role of allogeneic BMT (allo-TCM) in children with AML in the first clinical-hematologic remission is currently actively debated. Although allo-TCM is an effective therapy for AML, the availability of the donor and the toxicity of the process limit its use. The key issue of the use of allo-TCM in children with AML in the first remission is the detection of the ratio of the antileukemic effect, an increase in the survival rate of patients with a further acceptable quality of life.
Currently, candidates for allo-TCM are high-risk patients with an HLA-identical bone marrow donor. The problem of autologous TCM (auto-TCM) or peripheral stem cells (PUK) is currently being studied. In the Research Institute of Pediatric Oncology and Hematology RCRC. NN Blokhin RAMS developed protocols for the treatment of patients using auto-TCM and PUK in patients with high-risk AML in the first remission and relapses of the disease. Already to date, encouraging results have been obtained.
Due to the fact that AML is represented by a group of heterogeneous diseases, the main optimization plan for treatment is the individualization of therapy, supplemented by the prevention of the risk of relapse, knowledge of the biology of individual sub-variants of AML.
New drugs introduced into the therapeutic protocols of AML in children in the last decade are 2-chlorodeoxyadenosine (2-CDA) and fludarabine. The use of new agents, including interleukin-2 immunotherapy, lymphokine-activated killers (LAK), generated from peripheral blood mononuclear cells, allows us to hope for significant success in the treatment of AML in the future.
In the department of leukemia chemotherapy of the Research Institute of Children's Oncology and Hematology, organized 25 years ago, 200 patients with AML aged from 1.5 months to 16 years were treated. Over the past 10 years, thanks to the application of new approaches to the treatment of children with AML, including new chemotherapeutic agents and TCM, it has been possible to increase the survival rate of patients to 50%, which is two times higher than the results of therapy using the 7 + 3 treatment program (cytosine arabinoside and rubomycin).
Owing to the introduction of new technologies into diagnostics and program therapy of AML, considerable progress was made in the results of treatment of relapses of AML in children.
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