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.

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.

Diagnosis of acute myeloblastic leukemia with minimal differentiation – M0 according to FAB classification

Acute myeloblastic leukemia with minimal differentiation (M0 according to FAB classification):

• is about 5% of all ONL;
• blasts of medium size, with a delicate chromatin structure and 1-2 nucleols in the nucleus, no inclusions in the cytoplasm, basophilia of varying severity;

• blasts do not have morphological signs of differentiation;
• blasts contain myeloperoxidase, lipids and ASD-chloroacetate esterase in less than 3% of cells, a small amount of nonspecific esterase, PAS-positive substance in a diffuse form;
• blasts express myeloid antigens CD33, CD13, CD117, early hematopoietic antigens CD34, CD38, HLA-DR, react with MCA to peroxidase. They lack linearly specific T and B antigens;
• during ultrastructural cytochemical examination, peroxidase can be detected in small granules of the endoplasmic reticulum;
• loss of chromosomes 5 and 7, translocation (9; 22), additional chromosomes 13, 8 and 4, complex multiple rearrangements of the karyotype can be detected.

Acute myeloblastic leukemia without maturation (M1 according to FAB classification) – diagnostics

Acute myeloblastic leukemia without maturation (M1 according to FAB classification):

• makes up about 10% of all acute non-lymphoblastic leukemias (ONLL);
• in the bone marrow, the number of blasts exceeds 90% of the cells of the non-erythroid line;
• grit and / or Auer sticks can be detected in blasts;
• blasts contain myeloperoxidase, lipids, ASD-chloroacetate esterase in more than 3% of blasts, a small amount of nonspecific esterase, PAS-positive substance in a diffuse form;
• blasts express at least two myeloid antigens CD33, CD13 and / or react with MCA to peroxidase and with MCA CD34, specific lymphoid antigens are absent;
• in rare cases translocation can be detected (8; 21). In accordance with the WHO classification, these observations are categorized into an independent category of acute non-lymphoblastic leukemia (ONLL) with recurring anomalies.