Etiology of acute leukemia

In most cases, the etiology of the disease is impossible to establish. In connection with the frequent detection of various chromosomal changes in tumor blast cells, various carcinogens are assumed to be the causes of acute leukemia.

Ionizing radiation as a cause of acute leukemia. Persons who survived the atomic bombing of Hiroshima and Nagasaki had a 30–50-fold increase in the frequency of secondary acute leukemia (almost always AML), with the largest number of diseases occurring 4–8 years after exposure to ionizing radiation.

An increased risk of developing acute myeloblastic leukemia (AML) is promoted by radiation therapy and, especially, combined chemoradiotherapy. Leykozogenny effect of small doses of ionizing radiation (diagnostic x-ray or radionuclide studies) and electromagnetic fields has not been proven.

Cigarette smoke contains many different carcinogens and therefore is a risk factor for the development of acute leukemia (OL). In smoking patients over 60, specific chromosomal abnormalities that are typical for exposure to chemical mutagens are often detected. It is estimated that at least 20% of AML cases are associated with smoking.

Chemical compounds with strictly proven leukemic properties are benzene and cytotoxic drugs. Benzene contributes to the development of secondary acute leukemia with prolonged production contact.

Secondary leukemias are acute myeloblastic leukemias (AML) that occur at different times (more often 5-6 years) after the completion of chemotherapy and / or radiation therapy for tumor or non-tumor diseases. Among cytostatic drugs, alkylating agents and podophyllotoxins have the greatest leukemic potential. The likelihood of developing secondary AML is increased in patients with breast and ovarian cancer who received alkylating agents.

Among the alkylating agents, cyclophosphamide has the lowest leukemic potential. The use of podophyllotoxins (etoposide and teniposide) and alkylating agents in children with acute lymphoblastic leukemia increases the incidence of secondary acute myeloblastic leukemia (AML).

Treatment of podophyllotoxins in adults and children is accompanied by an increased frequency of secondary acute monoblastic leukemia with a chromosomal abnormality llq23. The use of etoposide, doxorubicin increases the risk of developing acute promyelocytic leukemia (APL) with t (15; 17).

Genetic diseases as a cause of acute leukemia. Some genetic defects (Down syndrome, Fanconi anemia, Blum syndrome, ataxia-telangiectasia) are accompanied by an increased risk of developing OL. In Down syndrome, there is a 20-fold increase in the frequency of OL (in children under 3 years of age – megakaryoblastic leukemia, older than 3 years – pre-B-ALL). In patients with Fanconi anemia, AML is significantly more likely to develop, with ataxia-telangiectasia, ALL and non-Hodgkin lymphomas.

Viruses as a cause of acute leukemia. Human T-lymphotropic retrovirus (HTLV-1) has been found to be relevant in the occurrence of adult T-cell leukemia / lymphoma. The role of oncogenic retroviruses in the development of human NL has not been proven. Epstein-Barr virus (EBV) is important in oncogenesis in B-ALL, endemic Burkitt lymphomas and lymphomas associated with the human immunodeficiency virus.

The immunological susceptibility to the development of acute leukemia has not been proven, however, analysis of various cytogenetic variants of acute myeloid leukemia (AML) revealed an association between certain HLA loci and karyotype disorders.

Acute leukemia – a history of study, causes

Oncohematological diseases (hemoblastosis) are malignant tumors originating from blood cells. The main groups of hemoblastosis include acute leukemia, myelodysplastic syndromes, chronic myeloproliferative diseases and lymphoproliferative diseases.

Acute leukemia (OL) is a life-threatening cancer, the tumor cells of which originate from blood cells. The first description of leukemia (leukemia, or “leukemia”) belongs to R. Virchow (1845). Soon NLs were described by German and Russian doctors E. Freidreich (1857), K. Slavyansky (1867) and V. Kussner (1876). The terms “acute” and “chronic” used to identify and classify leukemias are of historical origin: prior to the introduction of effective methods of treatment, the patients with NL died within a few weeks; the life expectancy of patients with chronic leukemia ranged from several months to several years.

Acute leukemias are a separate nosological form and never transform into chronic leukemias.

The incidence of acute leukemia averages 4–5 cases per 100,000 population per year and is about the same in different regions. The share of NL accounts for only 3% in the structure of cancer incidence, however, significantly reduces the overall survival in persons younger than 35 years.

There are two types of diseases that differ in their course, the nature of chemotherapy and the results of treatment: 1) acute lymphoblastic leukemia (ALL), accounting for 80-90% in the structure of leukemia in children; 2) acute myeloid leukemia (AML), which in 80% of cases develop in adults.

The average age of patients with ALL is 10 years, AML is 60-65 years old, but both forms of acute leukemia can occur at any age.

The incidence of acute myeloblastic leukemia is 2.5-3 cases per 100,000 population per year, acute lymphoblastic leukemia – 1.5-2 cases per 100,000 population per year.

The incidence of acute myeloid leukemia is slightly higher in men (1.5: 1.0). The disease is relatively rare before the age of 40 (1 case per 100,000 population), after which it begins to increase, reaching 15 per 100,000 in people 75 years and older. In ALL, the peak incidence occurs in the age group up to 10 years (this is the most common malignant tumor in children).

In general, about 80% of patients with OL are adults. In connection with the peculiarities of the course of the disease at different ages, there are two main groups: acute leukemia in children (up to 15 years) and acute leukemia in adults (older than 15 years). There is also a third group – OL elderly (over 60 years), the effectiveness of which is significantly lower because of the poor tolerance of intensive chemotherapy.

Treatment of acute lymphoblastic leukemia

Induction of remission of acute lymphoblastic leukemia. Before starting treatment for the disease, anemia is corrected by blood transfusion, the risk of bleeding is minimized in case of platelet transfusions. Conduct rehabilitation of chronic foci of infection.

Additional hydration and administration of allopurinol (or urotoxicity, when the number of leukocytes is high and the risk is increased) is prescribed in order to protect the kidney tissue from the toxins that occur during tumor lysis syndrome. Remission implies the absence of blasts and the restoration of normal bone marrow functions. A 4-week course of combined chemotherapy is carried out; current induction is achieved in 95% of cases.

Intensification of acute lymphoblastic leukemia. Chemotherapy intensification courses are prescribed to achieve consolidation of remission. They improve the effectiveness of treatment, but at the expense of increased toxicity.

Cytotoxic drugs do not penetrate the central nervous system. Since the leukemic cells in this place can survive an effective systemic treatment, they use an additional treatment using the administration of drugs under the meninges to prevent recurrences in the CNS. Previously, treatment included the irradiation of the head area or the administration of high-dose methotrexate, but this therapy leads to adverse neuropsychic effects, so both methods are now excluded from the first-line treatment.

Continuing maintenance therapy for acute lymphoblastic leukemia. Low-intensity chemotherapy is continued for a relatively long period of time — up to 3 years after diagnosis. Cotrimoxazole is prescribed to prevent pneumonia caused by Pneumocystis jiroveci (carinii). Treatment of recurrent acute lymphoblastic leukemia. High-dose chemotherapy, often with total body irradiation and bone marrow transplantation, is used as an alternative to conventional chemotherapy after relapse.

Classification of hematopoietic and lymphoid tissue tumors. WHO

Less than 7 years separates this edition from the first consensus classification of lymphomas, published in the journal Blood in 1994. The implementation of this project in one of the most difficult areas of onco-hematology can be an example of the coordinated work of pathologists from various countries and scientific schools aimed at achieving a common goal – systematization and generalization of extensive molecular biological, genetic, immunological and morphological knowledge of lymphomas in the form of a list of actually existing ones (consonance to the accustomed abbreviation REAL — from English. Revised Eur opean American Lymphoma classification) of nosological units.

To be fair, it should be noted that by far not all the publication of the REAL classification in 1994 was accepted without objection. The work was criticized by the editors of the journal Blood. Serious complaints related to the clinical significance of the classification, its reproducibility, and even the very principle of diagnosis, taking into account the T or B linearity of the tumor cells, has been questioned.

A special clinical committee of leading hematologists of the world was established, which confirmed the clinical significance of the classification.

The final classification takes into account the comments made, and it differs significantly from the first publication. Added new nosological forms, many of the previously proposed are excluded.

“Nowhere in pathology is the chaos of names obscured by clear concepts to the same extent as in the subject of lymphoid tumors.” I want to believe that these words of RA Willis are in the past, and the modern names of variants of lymphomas, giving an increasingly complete picture of the nature of tumor cells based on their degree of maturity and linear affiliation, will, on the contrary, clarify the essence of these diseases and contribute to their more effective treatment. .

Acute myeloid leukemia

Acute myeloid leukemias with multilinear dysplasia in residual normal sprouts of hemopoiesis are distinguished on the basis of certain morphological features, the presence of which sometimes makes it difficult to diagnose a specific variant of acute leukemia. In accordance with recent views in the classification indicates that the presence of multilinear dysplasia is a poor prognostic sign. A number of authors, including us, have shown that the presence of dysplasia does not in itself have a negative prognostic value, and a poor prognosis is determined by the frequent presence of unfavorable chromosomal aberrations in patients of this group. Most likely, this rubric will disappear from the classification in the future.

Rationally, in our opinion, the selection in a separate section of acute myeloid leukemia and myelodysplastic syndromes, the development of which can be associated with previous therapy, mainly with the use of alkylating drugs, topoisomerase II inhibitors and radiation therapy. These leukemias also have fairly well-defined biological features — often a period of myelodysplasia preceding the development of leukemia, often with characteristic or multiple chromosomal aberrations, often worse than de novo response to therapy and prognosis. In this group, in each case, when making a diagnosis, the notation is used in accordance with the FAB classification.

If acute myeloid leukemias do not belong to any of the listed groups, they are characterized in accordance with the FAB classification. It should be noted that in practice the classification of FAB is always used, and this must be recognized as rational, as it allows you to accurately determine which variant of acute myeloid leukemia is involved, and thus avoid erroneous conclusions in assessing the results obtained by different authors.

Myelodysplastic syndrome

Significant changes have been made in the classification of myelodysplastic syndromes compared with the FAB classification. Cases with the number of power cells of more than 20%, previously designated as RAIB-T (refractory anemia with an excess of blast at the stage of transformation into acute leukemia), are now considered as acute leukemia, which should be considered completely fair, given the further development of the disease in cases of with so many blast cells and, as a rule, the rapid emergence of all signs of acute leukemia.

It is fair to recognize the release of refractory cytopenia with dysplasia of two or more sprouts of hemopoiesis {refractory cytopenia with multilinear dysplasia). Hematologists are well aware that there are various variants of cytopenia with dysplasia or cases of multilinear dysplasia, but without anemia. Previously, they all had to be designated as refractory anemia.

The allocation of unclassifiable myelodysplastic syndrome is correct, since it is often in the group of myelodysplastic syndromes that there are often cases when, in the presence of obvious features of myelodysplasia, the disease for a very long time is difficult to attribute to a specific variant. A completely new is the allocation of myelo-dysplastic syndrome with an isolated deletion of the long arm of chromosome 5 – 5q- syndrome. In recent years, this syndrome has been considered as a special variant of myelodysplastic syndrome, characterized by significant anemia and at the same time a favorable long course. It is a more favorable prognosis than with other variants of myelodysplastic syndromes, and the absence of the need for intensive therapy serve as the basis for highlighting this option in a separate rubric.

In the rubric of acute myeloid leukemia, the WHO classification has made significant changes compared to the FAB classification, but it should be immediately emphasized that the FAB classification has also been preserved.

According to the WHO classification, all acute myeloid leukemias are divided into 5 categories based on the biological properties of the tumor: 1) with recurring chromosomal abnormalities; 2) with multilinear dysplasia; 3) acute leukemia and myelodysplastic syndromes, the development of which is associated with previous therapy; 4) acute leukemia, which cannot be characterized on the basis of any biological features; 5) acute leukemia of unclear linear affiliation (undifferentiated, bilinear and biphenotypic).

Acute leukemias with recurring chromosomal abnormalities are acute myeloblastic leukemia with t (8; 21), acute myeloid leukemia with eosinophilia in the bone marrow and aberrations of chromosome 16, acute promyelocytic leukemia with t (15; 17) and acute myeloid leukemia with aberrara leukemia with aberara leukemia with aberara leukemia with ab (15; 17) chromosomes 11-11q23.

All leukemias of this group are distinguished by certain biological features: often the characteristic morphology of tumor cells, which allows a diagnosis to be made on the basis of a morphological study and, in most cases, a predictable reaction to modern therapy. Isolation of this group of leukemias is important because they have certain approaches to therapy.
Translocation (15; 17) is pathognomonic for acute promyelocytic leukemia, in which the use of ATRA is necessary from the first days of treatment. This drug has fundamentally changed the prognosis of the disease. With modern therapy, the prognosis for leukemias with t (8; 21) and aberrations of chromosome 16 with eosinophilia in the bone marrow is generally favorable, but for leukemia with aberrations of chromosome 16, only with consolidation of remission with high doses of cytosar. The prognosis is much worse in the presence of changes in the llq23 region, therefore the detection of this aberration necessarily implies intensive therapy.

Thus, the biological characteristics of the leukemias of this group, as well as a specific reaction to therapy, justify the isolation of the leukemias of this group into a separate heading in the classification. At the same time, when establishing a diagnosis for a specific patient, each of the leukemias of this rubric is still characterized in accordance with the FAB classification.

Myeloproliferative Diseases

Among myeloproliferative diseases, “unclassifiable” is also indicated. This category includes diseases that have all the features of myeloproliferative, but without a sufficient number of signs that can be attributed to any specific nosological unit. The merit of the authors of the classification is in strict caution against making a diagnosis of myeloproliferative unclassifiable disease in those cases when all modern diagnostic methods that make it possible to accurately identify the diagnosis were not used. It is indicated that most often after some time, in cases initially diagnosed as unclassifiable, certain features of true polycythemia, or chronic idiopathic myelofibrosis, or essential thrombocythemia, appear.

In chronic myeloproliferative / myelodysplastic diseases, there are features of delayed maturation and dysplasia in any of the hematopoietic lines and / or ineffectiveness of hematopoiesis in this line. It seems to us absolutely correct to assign chronic myelomonocytic leukemia to this group, which was previously considered as one of the variants of myelodysplastic syndromes and which certainly has features of both myeloproliferative and myelodysplastic diseases. There is no doubt that the classification of juvenile myelomonocytic leukemia to this category is correct.

This group also contains a rare disease – atypical chronic myeloid leukemia, for which the term “subacute myeloid leukemia” was used long ago. The disease is characterized by hyperleukocytosis, the presence of young forms of granulocytes in the blood (promyelocytes, myelocytes, metamyelocytes), the absence of basophilia and the presence of signs of dysplasia in the cells of the granulocytic germ and sometimes also in the cells of the erythroid and / or megakaryocytic germ hemopoiesis. Chromosomal aberrations are common, but there are no specific ones among them, in particular, Ph (BCR-ABL) is not detected. The level of alkaline phosphatase in neutrophils can be any. Most likely, pathogenetic mechanisms of the development of this disease will be established in the future and it will be identified more specifically.

In this category also has unclassifiable myelodysplastic / myeloproliferative disease, which the authors designated as a disease having both laboratory features of one embodiment myelodysplastic syndrome and myeloproliferative process, such as thrombocytosis, or simultaneously features myeloproliferative and myelodysplastic processes which can not be attributed to any specific category . Chromosomal aberrations can occur, but are not specific to a particular disease.

It should be recognized that almost every hematologist meets with diseases that can not be attributed to any particular category. The merit of the authors of the classification is that they have designated this provision, although the term “unclassifiable” disease, even assigned to a specific group, cannot fully satisfy. It reflects the current state of science and the obscurity of the biological mechanisms underlying some clinical and morphological syndromes.

Morphology and cytochemistry of acute leukemia – cytochemical reactions

Blasts in acute myeloblastic leukemia are usually large cells with a round or irregularly shaped nucleus. A pathognomonic morphological marker of acute myeloblastic leukemia is the detection of granules or linear azurophilic granularity (Auer sticks) in the cytoplasm of blast cells.

Most forms of acute myeloblastic leukemia, unlike acute lymphoblastic leukemia, can be morphologically identified. Myeloblasts are divided into types depending on the number and quality of granules (in type I blasts there are no granules; type II blasts contain up to 15 delicate granules; in type III blasts, there are a lot of azurophilic granules).

Lymphoblasts are usually small, the core of a more regular form, the cytoplasm is scanty and agranular.

The essence of cytochemical research is to identify in the cell enzymes and cytoplasmic inclusions characteristic of a particular cell type. During the cytochemical reaction, an enzyme or other substance in the cell interacts with the working solution reagents.

The main cytochemical reactions used for the diagnosis and differential diagnosis of acute leukemia:

1) the most important detection of myeloperoxidase (the enzyme azurophilic granules of cells of granulocyte and monocyte series); this reaction may be positive in the absence of visible granules;

2) the second most significant is Sudan black B; if one of the two reactions is positive in more than 3% of blasts, this indicates that they belong to the myeloid line;

3) nonspecific esterase is typical for monocytes and monoblasts, but can be detected in acute lymphoblastic leukemia and MH; these reactions are sensitive to sodium fluoride inhibition, which is used for differential diagnosis;

4) positive PAS-reaction indicates the presence of glycogen in the cells and is most typical for acute erythromyelosis; glycogen is also detected in acute lymphoblastic leukemia and other types of acute myeloblastic leukemia

5) naphthol AS-D chloroacetate esterase is found in the maturing myeloid cells;

6) acid phosphatase is detected at T-ALL;

7) a-naphtholbutyrateterase indicates monocytic differentiation of cells.

Other methods are used to verify the variant of acute leukemia. So, for the diagnosis of M4 and M5 variants of acute myeloblastic leukemia, a cytobacterial lysozyme test is used.

Chronic neutrophilic leukemia

Chronic neutrophilic leukemia differs in the blood picture from chronic myeloid leukemia by its lower leukocytosis and the absence of immature forms of myelopoiesis in the blood or by the presence of very small numbers of them. These signs are not enough for the differential diagnosis of these diseases, so the diagnosis of neutrophilic leukemia is made only on the basis of cytogenetic data. Previously, Ph (BCR-ABL) -negative cases and BCR-ABL-positive chronic myeloid leukemia with p230 protein production were ranked as chronic neutrophilic leukemia. In this classification, the diagnosis of chronic neutrophilic leukemia is left only for the BCR-ABL-non-affective variant; a disease with t (9; 22) and p230 protein production is considered as a variant of chronic myeloid leukemia. This seems to us to be absolutely fair and corresponding to the role of t (9; 22) in the pathogenesis of the disease.

In determining chronic eosinophilic leukemia and the hypereosinophilic syndrome, difficulties in differential diagnosis are emphasized. Currently, the hypereosinophilic syndrome includes a heterogeneous group of diseases characterized by persistent high eosinophilia of unknown origin. Appeared work, which showed that, at least in some cases, high eosinophilia occurs as a result of interstitial deletion of the long arm of chromosome 4 and the consequent formation of a chimeric gene with tyrosine kinase function. It is possible that such cases will be referred to as eosinophilic leukemia and the name “hypereosinophilic syndrome” will disappear, but now this term is used in all publications.

It should be recognized that this introduces a certain confusion, since reactive eosinophilia is sometimes described in practice under this term. At the same time, hypereosinophilic syndrome is a clearly defined symptom complex with a severe course and almost always an extremely poor prognosis. Cytogenetic analysis in cases of hypereosinophilia of unclear genesis is very important, since with eosinophilic syndrome with interstitial deletion of chromosome 4, Gleevec is effectively used.

Classification of hematopoietic and lymphoid tissue tumors. WHO

Work began in 1995. Initially, it was carried out by 10 national committees, which included more than 50 leading pathologists in the world. The classification is based on the same principles that were used as the basis for the REAL classification of lymphomas (Revised European-American Classification of Lymphoid Neoplasms): morphological (histological and cytological) studies, immunophenotyping, cytogenetic research and analysis of clinical data are necessary to establish the diagnosis. Thus, when creating the classification, the authors were based on the biological features of the tumor determined by modern methods.

As soon as the classification was formulated by pathologists, a committee was created to verify its clinical value, which included more than 40 leading oncologists and hematologists in the world. After their work in 1997 at a special meeting of clinicians and pathologists, all the disputed clinical issues were discussed and agreed upon. Only after an agreement was reached at this meeting, was the WHO classification finalized and published.

Thus, as a result of the involvement of many specialists in most countries, the WHO classification has become the first classification of hematological tumors that is currently accepted and used throughout the world. Nevertheless, there are controversial issues in the classification. In all likelihood, it will still be refined and changed.

In the WHO classification, all hematological neoplasms are divided into groups according to the blood line to which the cells constitute the morphological substrate of this tumor: tumors from myeloid cells, lymphoid cells, histiocytic / dendritic cells (histiocytosis) and mast cells (mastocytosis).
Tumors from lymphoid cells in accordance with this classification are discussed in detail in the manual, but here is the view of one of the well-known immunologists, prof. N. N. Tupitsyn on the value of this classification. At the same time, the section on tumors of myeloid cells, in our opinion, should be considered.

Tumors from myeloid cells are divided into 4 large groups:

1) chronic myeloproliferative diseases;
2) diseases that have features of both myeloproliferative diseases and myelodysplasias;
3) myelodysplastic syndromes;
4) acute myeloid leukemia.