Chronic lymphocytic leukemia. Why does it occur and how does it proceed?

For a long time there were two opposing concepts on the nature of Richter's syndrome. According to one of them, Richter syndrome is a combination of two genetically unrelated diseases. In clinical practice, this hypothesis is directly confirmed only in those exceptional cases when the course of a B-cell lymphatic tumor is complicated by the addition of a large cell lymphoma with a different (T-cell) immunological phenotype.

More difficult interpretation of observations, when both diseases have the same, less often T-, and more often B-linear, affiliation.

In cases where membrane cells of lymphocytic and large cell tumors exhibit immunoglobulins identical in the type of H- and L-chains, it seems obvious that both diseases develop from the same original clone. Sometimes the expression of identical L-chains can be combined with different isotypes (classes) of immunoglobulins. Such findings also confirm rather than refute the idea of ​​clonal progression in Richter syndrome, since, unlike lymphocytic lymphoma/chronic lymphocytic leukemia, isotypes characteristic of later stages of the immune response were found on the tumor elements of large cell lymphoma - (M + D) => M = > G => A (phenomenon of H-chain isotype switching).

If on lymphocyte membrane and large tumor elements, immunoglobulins of the same class are detected, but with different types of L-chains, for example Igrvk-IgMA or IgMh-IgMk, suggesting that the diseases originate from different clones of tumor cells.

It has been established that each polypeptide chain immunoglobulin encoded by several genetic elements that are spatially separated in the embryonic configuration. In the precursors of B lymphocytes, these elements, as a result of DNA recombination, must be located nearby to form a single active gene complex capable of encoding the synthesis of heavy (VHD-JH + CH) or light (VLJL + CL) polypeptide chains.

In other words, as a result somatic rearrangement of the DNA molecule Dispersed (V1=>n - variable, D1-5 - diversity, J1-4 - joining, Cu,q,y,a,e - constat) gene segments are combined, and from many options one, unique for a given population, is assembled clonal marker cells. This process, referred to as immunoglobulin gene rearrangement, results in the formation of a DNA fragment that differs from the germline configuration.

Sample of perestroika(rearrangements) of the heavy and K or X light chain genes is unique in each individual B-cell tumor. In this case, the tumor contains multiple copies of identical V(D).1-units, reflecting that the cells belong to the same clone. In Richter syndrome, analysis of immunoglobulin gene rearrangement using Southern blotting is used as an important additional molecular biological method for studying the clonal relationship between two populations of tumor cells that are different in their morphological characteristics.

Blot hybridization method allows not only to identify DNA restriction fragments reflecting V(D)J gene associations in blood/bone marrow lymphocytes and extramedullary tumor tissue cells, but also to compare them. The discovery of identical clonal bands of H- and/or L-chain gene rearrangement suggests that Richter syndrome is most often a monoclonal malignant process. Typically, in such cases, both populations of tumor cells express on their surface only one type of L-chains - either K or X. In cases where in lymphocytes and large tumor elements the immunoglobulin genes are rearranged differently, it is argued that diseases with Richter syndrome have no clonal relationship with each other. In these cases, tumors tend to differ in the type of L chains synthesized.

Seems difficult to interpret situations, in which of the two types of rearrangement of immunoglobulin genes present in the tumor, only one matches the rearrangement pattern in blood/bone marrow B lymphocytes. Serious difficulties in interpretation may arise if the results of gene studies conflict with data obtained from immunological phenotyping of tumor cells. A similar situation was described by K. Miyamura et al.

The publication refers to a 71-year-old patient with blood/bone marrow lymphocytosis, cervical lymphadenopathy, hepato- and splenomegaly and symptoms of general intoxication. Morphologically, specimens of the lymph node revealed a picture of diffuse large cell lymphoma.

In the presented observation of cells lymphocytic and large cell tumors, on the one hand, had an identical immunophenotype (CD5+CD19+CD20+HLA-DR+) and identical IgH gene rearrangements, on the other hand, they differed in the type of expressed L-chains - X and K, respectively. The latter circumstance did not prevent the authors from concluding that both diseases most likely had a common clonal origin, at least in the initial stages of malignancy.

For theoretical justification of this approach Two hypothetical points of view are proposed. According to one of them, the oncogenic event in this patient could have occurred very early in the series of B-cell differentiation: after the rearrangement of the H-chain genes, but before the rearrangement of the immunoglobulin L-chain genes. Another explanation for the common origin of the two diseases is that the original (lymphocytic) tumor clone had membrane IgMk. Following clonal evolution into large cell lymphoma, deletion of k genes and rearrangement of h genes occurred only in the population of tumor lymphocytes. It seems to us that there is another possible explanation for this observation: perhaps the parent cells of the lymphocytic tumor did not delete k-genes and persisted throughout the disease in “minor” quantities that were not captured by the Southern method.
Subsequently, it was probably this clone that most effectively transformed into large cell lymphoma.

For a long time it was unclear how lymphocytes lymphocytic lymphoma/chronic lymphocytic leukemia are functionally active and capable of further differentiation. The solution to this problem was to a certain extent facilitated by the work of L. F. Bertoli et al., which, in addition, demonstrated a different approach to the study of clonal relationships in Richter syndrome. The authors obtained monoclonal antibodies to the idiotypic (antigenic) determinant of X-type Ig(M+D) molecules expressed on lymphocytes of a patient with chronic lymphocytic leukemia.

In two-color immunofluorescence B cells with membrane Ig(M+D)A. were identified using anti-idiotypic antibodies as the predominant cell population in the leukemic clone. At the same time, it was shown that in a certain part of IgG and IgA B cells, as well as in the majority of IgG plasma cells in the bone marrow and blood, an idiotypic determinant was found, similar to that in leukemic B lymphocytes. Consequently, leukemic lymphocytes, or at least some of them, are capable of perceiving antigenic stimuli, isotypic switching and differentiation into plasma cells.

6 years after establishment diagnosis Chronic lymphocytic leukemia, the patient died due to symptoms of respiratory failure caused by tumor infiltration of the lung tissue. An autopsy revealed diffuse large cell lymphoma, the cells of which expressed IgMh on their surface with the same idiotype as the lymphocytes of the original clone. In addition, Southern blotting in leukemic blood cells and lymphoma tissue revealed identical clonal rearrangement bands of immunoglobulin H-chain genes.

Thus, in this observation the general clonal origin of chronic lymphocytic leukemia and diffuse large cell lymphoma was confirmed not only by studying the immunophenotype and gene rearrangements, but also by using anti-idiotypic antibodies to immunoglobulin molecules expressed on tumor cells. As a result of these studies, indirect evidence was simultaneously obtained of the ability of B-lymphocytes of chronic lymphocytic leukemia to differentiate up to plasma cells throughout the disease itself. When the development of leukemic cells is blocked at a later stage of differentiation, transformation into large cell lymphoma is apparently possible.

This possibility is confirmed by the observation E. Cofrancesco et al.. A patient with a 6-year history of chronic lymphocytic leukemia developed large cell lymphoma with generalized damage to the lymph nodes, liver, spleen, intestines, adrenal glands, kidneys, and bones. Both populations of lymphoid cells (small and large) had identical immunoglobulin gene rearrangements and similar immunophenotypic characteristics (CD5+CD19+CD20+HLA-DR+CD10). However, large lymphoma cells differed from lymphocytes (lymphocytic leukemia cells) in a greater degree of immunological differentiation in the direction of plasma cells. This was confirmed by the appearance of cytoplasmic IgM, CD38 expression, loss of membrane IgD, and decreased rosette formation with murine erythrocytes.

For combined B cell tumors The clonal relationship between malignant processes was also studied through structural analysis of immunoglobulin genes. The work of V. Cherepa-khin et al. was the first in which, based on the DNA nucleotide sequence, it was shown that the cells of large cell lymphoma and chronic lymphocytic leukemia in Richter syndrome can originate from the same clone, despite the different immunophenotype: the cells of the large cell tumor in the patient were CD5-negative.

J. Seymour And J. Campbell analyzed known cases of Richter syndrome studied using modern methods. They found that in approximately 2/3 of cases chronic lymphocytic leukemia and developed large cell lymphoma originate from the same clone, in 1/3 - from different ones.

Hematologists know that it is not always the case that mature cell lymphatic tumor large cell lymphoma develops. Moreover, Richter's syndrome is a rare clinical and morphological phenomenon. According to various authors, it occurs only in 3-10% of patients with lymphocytic lymphoma/chronic lymphocytic leukemia. In such a situation, it is understandable to try to find out how the bulk of lymphocytic tumors differs from the small part that is complicated by the development of large cell lymphoma. A rather logical assumption is put forward and substantiated about the possible existence of a subgroup of B-cell lymphatic tumors that are more susceptible to external influences and/or uncontrolled blast transformation.

This can be confirmed by the discovery in lymphocytes when complicated by the development of large cell lymphoma, replacing mutations in the D- and/or Jn-segments of immunoglobulin genes. Most cases of lymphocytic lymphoma/chronic lymphocytic leukemia are usually represented by a population of B lymphocytes that do not have such mutations. The results of studying the rearrangement of proto-oncogenes BCL-1, BCL-2, c-MYC, some suppressor genes, as well as TP53 are sometimes very difficult to interpret. For example, with different rearrangements of immunoglobulin genes in tumor cells in lymphocytic leukemia and large cell lymphoma, identical rearrangements of the BCL-2 proto-oncogene can be detected.

The mechanisms are still unclear development of large cell tumor in cases where it comes from the same cell clone as chronic lymphocytic leukemia. The study of the influence of growth factors (TGF-p, G-CSF), cytogenetic changes, mutations of the TP53 and p16 genes, which are more often observed in Richter syndrome than in CLL, c-MYC, the rearrangement of which was found in some cases of Richter syndrome, did not provide certainty.

Many works are devoted to studying the role of the Epstein-Barr virus in development of Richter syndrome. It was shown that viral DNA was detected only in the development of large cell lymphoma with cells resembling Reed-Sternberg cells and large cell tumors with a T-cell immunophenotype. In all these cases, it was proven that CLL lymphocytes and lymphoma cells originate from different clones.

The role remains unclear immunosuppression, in particular, caused by treatment with fludarabine. Some reports, based on a small number of observations, show a certain increase in the incidence of Richter's syndrome in patients with CLL treated with fludarabine. In large series based on observations of several hundred long-term patients, no increase in Richter's syndrome was noted in those receiving purine analogues. Perhaps the increase in the incidence of large cell lymphoma during treatment with fludarabine, indicated by some authors, is explained by the more aggressive course of CLL in these patients, which required the use of fludarabine.

Development large cell lymphoma in patients with mature cell lymphoproliferative diseases is a poor prognostic sign and, as a rule, is accompanied by the appearance of a number of new clinical symptoms. The most commonly observed are the following:
1) a sharp increase in lymph nodes, especially in the abdominal cavity, significant, sometimes isolated damage to the spleen and/or the appearance of isolated extranodal tumor formations;
2) the appearance of general symptoms: an increase in body temperature to 38 C or more without an apparent infectious cause, loss of body weight, severe sweating;
3) increased LDH levels;
4) hypercalcemia;
5) regression of lymphocytosis of the blood and/or bone marrow, coinciding with, and sometimes preceding in time, the appearance of general symptoms and generalization of the extramedullary tumor process;
6) a sharp deterioration in the patient’s condition.

Life expectancy after detection of large cell tumor usually ranges from 6 to 12 months, despite the use of combination chemotherapy methods adequate for high-grade lymphomas.

At Richter's syndrome Sometimes isolated extranodal localization of foci of large cell lymphoma is observed. Thus, damage to the skin, soft tissues with invasion into the vertebra and its destruction, the substance of the brain, testicles, stomach and/or intestines, and the bronchial tree with endobronchial growth of the tumor are described. The appearance of these signs in patients with a lymphocytic tumor should serve as the basis for a diagnostic biopsy.
Subsequently it is necessary immunomorphological study of tumor tissue with mandatory cytological examination of prints to exclude Richter syndrome.

We observed 13 patients with malignant lymphoproliferative diseases, proceeding with lymphocytosis of the blood and bone marrow, in which large cell lymphoma developed. These patients accounted for 3.2% of the total number of patients with peripheral small cell B lymphomas. Among the patients with Richter syndrome there were 6 women and 7 men aged from 40 to 77 years.

Main clinical manifestation of a malignant process 12 patients had enlargement of lymph nodes of different groups with lymphocytosis of the blood and bone marrow. In one patient, the extramedullary component of the lymphocytic tumor was characterized by isolated lesions of the spleen.

In morphological substrate In all patients, small lymphocytes predominated. The lymphocytic tumor substrate was characterized by typical coexpression of CD5 and CD23 markers by mature B lymphocytes. Tumor elements of large B-cell lymphoma differed immunophenotypically from the substrate of lymphocytic lymphoma by the absence of CD5 expression in all, and CD23 in half of the studied cases.

Through 8-180 months(median 65 months) the course of the mature cell lymphoproliferative process was complicated by the development of large cell lymphoma with damage to the lymph nodes and/or extranodal localization of foci of tumor growth. In different patients, damage to various organs and tissues was observed: skin, soft tissues, bones, mammary gland, omentum, pleura with the development of pleurisy, nasopharynx. Such a “transformation” in 8 patients was accompanied by a deterioration in their condition, and four had general symptoms. The rest of the patients felt unchanged. During the development of large cell (immunoblastic) lymphoma, 5 out of 13 patients experienced spontaneous regression of lymphocytosis in the blood and bone marrow, i.e., the disappearance of the main symptom of a lymphocytic tumor. In 2 patients, on the contrary, the generalization of immunoblastic lymphoma was accompanied by an increase in blood and bone marrow lymphocytosis to the highest values ​​for the entire observation period.

Chronic lymphocytic leukemia/small lymphocyte lymphoma is a disease of lymphoid tissue characterized by clonal proliferation due to constant activation of the B-cell receptor with autonomous and ligand-dependent stimulation of neoplastic committed lymphocytes (mainly CD5+ “antigen-trained” B cells with varying levels of variable region gene mutations immunoglobulin heavy chain), which leads to the steady accumulation of long-living tumor cells in the peripheral blood, bone marrow, lymph nodes, spleen, liver, and subsequently in other organs and tissues (heart, lungs, kidneys, stomach, intestines, etc. .).

The history of the study of chronic lymphocytic leukemia begins in 1856, when R. Virchow first associated enlargement of the lymph nodes and spleen with peripheral blood lymphocytosis, and subsequently, in 1903, W. Turk gave a detailed description of the clinical picture of chronic lymphocytic leukemia.

In the 60s XX century D.A. Galton and W. Dameshek proposed a modern concept of the pathological basis of chronic lymphocytic leukemia, based on the assumption that chronic lymphocytic leukemia is a homogeneous disease arising from long-lived, immunologically incompetent lymphocytes that accumulate in the body over time. Subsequently, on this basis, clinical staging systems for chronic lymphocytic leukemia were developed according to K. Rai and J. Binet. However, a continuous series of studies beginning in the 1990s naturally led to questions related to the heterogeneity of the course of chronic lymphocytic leukemia, and explanations for some of the biological mysteries of this disease were soon proposed.

EPIDEMIOLOGY
Chronic lymphocytic leukemia is the most common type of leukemia affecting representatives of the white race in the western hemisphere, accounting for 25-30% of all leukemias, while in the eastern hemisphere it affects less than 5%, while the median age of chronic lymphocytic leukemia at the time of diagnosis is about 70 years, but in 10-15% of patients the disease occurs before age 50.

According to the statistical cancer prevalence registry of the US National Cancer Institute, for the period from 2006 to 2010, 30% of all cases of chronic lymphocytic leukemia detected in the United States were diagnosed in patients aged 45-64 years.

Men are more likely to get sick than women - the incidence is 5.8 and 3.0 per 100,000 men and women, respectively.

The number of new cases of chronic lymphocytic leukemia in the United States in 2014. R. Siegel et al. was estimated at 15,720 patients, and the number of deaths from chronic lymphocytic leukemia was 4,600 people. The life expectancy of patients varies: despite the fact that in some patients it does not differ from the population, some patients die quite quickly. By the beginning of the 21st century, advances had been made in understanding the biology, natural history, and treatment of chronic lymphocytic leukemia. Survival of patients with chronic lymphocytic leukemia varies significantly depending on the stage of the disease: patients with low-risk chronic lymphocytic leukemia (Rai stage 0) had a median life expectancy of 14.5 years, compared with 2.5 years for patients with high-risk chronic lymphocytic leukemia .

ETIOLOGY AND PATHOGENESIS
The cause of chronic lymphocytic leukemia remains unknown to date.

Chronic lymphocytic leukemia prevails in first-degree relatives (risk factor), occurs

At a younger age and increasing in severity in each subsequent generation, the phenomenon of anticipation is also associated with a higher frequency of autoimmune disorders in relatives of patients with chronic lymphocytic leukemia. In first-degree relatives of patients with chronic lymphocytic leukemia, “monoclonal lymphocytosis of undetermined significance,” or monoclonal B-cell lymphocytosis, occurs in 13-18% of cases. The term “monoclonal B-cell lymphocytosis” was proposed in 2005 and involves the detection of a monoclonal B-cell population in the blood of less than 5x109/l without any other signs of a lymphoproliferative disease. B-cell lymphocytosis is also detected in 3% of adults over 40 years of age and 6% over 60 years of age. The rate of progression of B-cell lymphocytosis to chronic lymphocytic leukemia, which requires treatment, is 1-4% per year.

Environmental factors such as ionizing radiation, chemical agents (benzene and solvents in the rubber industry), and drugs do not play a clear etiological role in chronic lymphocytic leukemia.

The nature of chronic lymphocytic leukemia is most accurately reflected by biological concepts that explain the disruption of biological processes in B cells based on knowledge of the mechanisms of apoptosis, the cell cycle of B lymphocytes, genetic differences in tumor B cells and chromosomal abnormalities, overexpression of CD38, ZAP-70 and other signaling molecules, as well as data on disturbances in the processes of functional activity of B cells and their microenvironment in the lymph nodes and computed tomography.

Chronic lymphocytic leukemia is a disease model of impaired apoptosis (programmed cell death). Slow-growing cells of chronic lymphocytic leukemia accumulate in the body, mainly in the G0 phase of the cell cycle. An imbalance in the ratio of the main pro- and anti-apoptotic proteins of the bcl-2 gene family, such as BAX and BAK (apoptosis inducers), BCL-2 (anti-apoptotic), BAD, BIK and HRK (anti-apoptotic inhibitors), plays an important role in the course and in response to treatment of chronic lymphocytic leukemia. Despite the frequent overexpression of the BCL-2 protein, genetic translocations caused by overexpression of the BCL-2 gene, such as t(14;18), have not been identified in patients with chronic lymphocytic leukemia. Increased overexpression of BCL-2 is associated with deletion of regulatory microRNAs miRNA15a and miRNA16-1, which is detected in 70% of patients with chronic lymphocytic leukemia.

Cytokines produced and released by CLL cells, such as tumor necrosis factor TNF-alpha, IL-8, as well as IL-2, which is produced by T lymphocytes and taken up by CLL cells through special receptors, are involved in autocrine and paracrine regulation. and cause CLL cells to survive and proliferate. Elevated levels of IL-8 are of great importance as a factor associated with poor prognosis and high risk of death in patients with chronic lymphocytic leukemia.

CD38 expression is an important prognostic factor for chronic lymphocytic leukemia and should be considered to identify patients most likely to progress to chronic lymphocytic leukemia. With increased expression of CD38, detected by quantitative flow cytometry, the overall survival of patients was 34% over five years, in contrast to the group without increased expression of CD38 (70%). A low level of CD38 expression as a good prognostic factor was also confirmed in a study of the co-expression of CD38 and CD31 on CD19 chronic lymphocytic leukemia cells.

No specific chromosomal abnormalities have been identified in chronic lymphocytic leukemia. At the same time, the development of new technologies, such as fluorescence in situ hybridization (FISH), has increased the detection of multiple structural chromosomal abnormalities in almost 50% of patients with chronic lymphocytic leukemia. The most common (51%) deletion found is 13q14 (the miRNA15a and miRNA16-1 genes are located there); carriers of this anomaly have a relatively indolent course of the disease, which usually manifests as stable or slowly increasing isolated lymphocytosis. Deletion 11q22 - q23 (in 17-20%) is associated with severe lymph node involvement, aggressive disease and shortened overall survival. Trisomy 12 occurs in 15% of cases and is associated with atypical morphology and disease progression.

Deletion of 17p13 is also associated with rapid progression, short remission, and decreased overall survival due to loss of the suppressor function of the p53 antioncogene. In 8.5% of patients, the p53 mutation without 17p deletion occurs and also leads to a poor prognosis. Despite the fact that many mutations are considered reliable prognostic markers of chronic lymphocytic leukemia, an important area of ​​modern research is the distinction between mutations that actually cause the development of chronic lymphocytic leukemia (driver mutations), and those that are secondary and do not affect the phenotype and biology of chronic lymphocytic leukemia (passenger mutations). mutations).

At the end of the 1990s, the existence of two genetic variants of chronic lymphocytic leukemia was revealed, depending on the origin from one of two types of B cells, differing in the mutational status of the genes for the variable regions of the heavy chains of immunoglobulins (Vjj-genes) in the germinal (germinal) center - the center reproduction in a secondary B-cell follicle in the cortical zone of the lymph node. There is a variant of chronic lymphocytic leukemia, originating from naive B cells that have not undergone the stage of VH gene mutations in the germinal center (the homology of VH genes is ≥98% of the germinal sequence), and a variant of chronic lymphocytic leukemia, arising from memory B cells that have undergone somatic hypermutations of VH genes of immunoglobulins in the germinal center (the homology of VH genes is
Thus, the median survival in patients with a variant of chronic lymphocytic leukemia without VH gene mutations and with CD38 expression was 8 years, while the presence of somatic VH gene mutations without CD38 expression determined the median survival rate of 25 years. However, the majority of patients were in stage A. Other publications also indicate that the presence of mutations in the VH genes of B cells is often associated with the absence of CD38 expression in a group of patients with good clinical outcome and better survival. In the work of E. Nikitin et al. It was found that the 5-year overall survival rate in the group of patients with chronic lymphocytic leukemia without mutations in the VH genes of immunoglobulins was 35%, and in the group with mutations - 80% (p = 0.07). At the same time, the CD38 marker was expressed on more than 50% of cells in 7 of 14 patients with chronic lymphocytic leukemia without mutations in the VH genes of immunoglobulins and in none of 10 patients with chronic lymphocytic leukemia with mutations (p = 0.007). Studies using DNA chip techniques showed that chronic lymphocytic leukemia cells have a characteristic gene expression profile, the product of one of which is the signaling molecule ZAP-70, which strongly correlates with the mutational status of VH genes. It is found in a subgroup of patients with chronic lymphocytic leukemia without B-cell VH gene mutations and is associated with a poor prognosis.

At the same time, it is possible to use a relatively simple detection of ZAP-70+ cells (using polymerase chain reaction, immunofluorescence, flow cytometry) with a high degree of sensitivity and specificity (91 and 100%, respectively) as a substitute for a complex and expensive method for detecting VH gene mutations . A. Wiestner et al. in a group of 107 CLL patients showed the important role of the ZAP-70 gene in determining the mutational status of chronic lymphocytic leukemia: in patients without VH gene mutations, ZAP-70 was expressed 5.54 times more than in patients with VH gene mutations. In this study, ZAP-70 expression correctly predicted mutation status in 93% of patients.

It was also revealed that the mutation of the VH genes of B cells is positively associated with telomere length: it was significantly shorter in patients with chronic lymphocytic leukemia without a mutation of this gene. Moreover, telomere shortening was associated with worse survival (median 59 months) compared with the group of patients with long telomeres (median overall survival was 159 months).

In patients with chronic lymphocytic leukemia with mutant VH genes of B cells, polymorphism of the P2X7 receptor gene (involved in the process of apoptosis of hematopoietic cells and chronic lymphocytic leukemia cells) contributes to significantly better survival of these patients (median - 151 months versus 98 months in patients without P2X7 polymorphism).

In addition, a German group of researchers proposed dividing patients with chronic lymphocytic leukemia according to the level of serum thymidine kinase, which is significantly increased in patients with chronic lymphocytic leukemia with early progression of the disease, and when studying the ability to predict the mutational status of the s-CD23 molecule and serum thymidine kinase, it turned out that they were significantly more often (p = 0.03) are determined in patients without VH gene mutations and determine a poor prognosis. Another predictor of poor prognosis in patients with chronic lymphocytic leukemia is mutational activation of the NOTCH-1 (or NOTCH1) gene. It is detected in 8.3% of patients with chronic lymphocytic leukemia at diagnosis, increases significantly in chemoresistant patients - up to 20.8%, and also with progression of the disease with transformation into Richter syndrome - in 31%. In 5-10% of patients with chronic lymphocytic leukemia, upon diagnosis, mutations of another group of genes that contribute to worsening survival are detected - SF3B1 and BIRC3 - ​​with an increase to 20-25% in the group of fludarabine-resistant patients.

Recently, the hypothesis about the significant role of the microenvironment in the pathogenesis of chronic lymphocytic leukemia, at least in the initial stages, has again been confirmed, when leukemic cells receive survival signals from the local environment with the help of antigens, cytokines and chemokines. It has been shown that chronic lymphocytic leukemia cells without activating signals undergo rapid apoptosis in vitro, while in vivo various ways of interaction of the tumor microenvironment have been identified (bone marrow stromal cells, dendritic follicular cells, monocytic nurse cells, or nurse cells, macrophages and T -cells) with a leukemia cell via signal transduction through the B-cell receptor or activation of the kinase pathway.

The tumor cell recirculates between the peripheral blood and tissues (bone marrow and lymphatic organs) in which proliferative centers or pseudofollicles are located, where the proliferation of the tumor clone occurs, as shown, at a rate of 1-2% per day (of the entire clone). A key role in tumor proliferation in lymphatic tissue is played by the mechanism of signal transmission through VCR. VCR consists of antigen-specific immunoglobulin on the surface membrane (smIg) and heterodimers of immunoglobulins - Ig-a/Ig-β (CD79A, CD79B). Antigen binding to smIg induces phosphorylation of the amino acid residues of ITAMs of immunoglobulins CD79A and CD79B by Lyn tyrosine kinase. This in turn activates SYK, BTK, and PI3Kδ kinases and downstream signaling pathways, including calcium mobilization, gamma-2 phospholipase C activation, protenkinase Cβ, NF-kB, MAP kinases, and nuclear transcription.

The exact mechanism of triggering VCR activation remains controversial. The main mechanism of VCR stimulation is ligand-dependent interaction. In general, SCR in chronic lymphocytic leukemia cells with an unmutated genotype has a low binding affinity to a wide range of autoantigens, while affinity mature SCR in CLL cells with a mutated genotype bind to limited, more specific antigens. It has also been established that VCR in patients with chronic lymphocytic leukemia can induce antigen-independent signaling associated with the HCDR3 heavy chain region and the internal epitope of VCR. This form of autonomous activation of VCR, along with external ligand-mediated stimulation, contributes to the growth and survival of chronic lymphocytic leukemia tumor cells. Data on the structure and function of VCR on leukemic cells of chronic lymphocytic leukemia serve for the development of targeted antitumor therapy.

CLINICAL PICTURE
About 40-60% of patients with chronic lymphocytic leukemia are diagnosed in the absence of symptoms associated with the disease, even with a very high number of circulating lymphocytes (>100x109/l). Often, the presence of lymphadenopathy or an elevated white blood cell count during a routine physical examination is the only reason to suspect a diagnosis of chronic lymphocytic leukemia. The remaining patients may have weakness, fatigue, prolonged (more than a month) night sweats, low-grade fever or fever for several weeks without signs of infection, infectious or autoimmune diseases. Physical examination usually reveals enlarged, firm, painless and mobile lymph nodes, splenomegaly (30-54% of cases) and hepatomegaly (10-20%). Metabolic abnormalities (hyperuricemia) or mechanical abnormalities (airway obstruction) associated with tumor compression may also be present.

Chronic lymphocytic leukemia cells can infiltrate any part of the body, including the skin and meningeal membranes, but such findings are rare. Manifestation of computed tomography involvement, especially severe anemia (hemoglobin less than 110 g/l) or thrombocytopenia (platelet count less than 100x109/l), is noted during diagnosis in 15% of patients with chronic lymphocytic leukemia. A positive direct antiglobulin test (Coombs test) is found in 20% of patients at the time of diagnosis, but is usually not associated with hemolytic anemia.

The course of chronic lymphocytic leukemia is often complicated by autoimmune disorders (hemolytic anemia, thrombocytopenia), infection, and the appearance of second tumors.

The appearance of chronic lymphocytic leukemia in patients with previously diagnosed chronic myeloid leukemia with the Ph "-chromosome was reported by R. Salim et al. The combination of primary myelofibrosis and chronic lymphocytic leukemia is rare; by the end of 2003, 8 cases were described in the literature. In one of them, the appearance of chronic lymphocytic leukemia through 13 years after the diagnosis of primary myelofibrosis was combined with the patient’s stable condition during 16 years of follow-up. Chronic lymphocytic leukemia can occur in patients with essential thrombocythemia.

DIAGNOSTICS
With the development of the ability to diagnose chronic lymphocytic leukemia with increasingly low lymphocyte counts, it is necessary to be confident in the correct diagnosis and distinguish between chronic lymphocytic leukemia and B-cell lymphocytosis. Patients with lymphocytosis less than 5x109/L and lymphadenopathy without cytopenia may have small lymphocyte lymphoma, which should be diagnosed by lymph node biopsy.

A distinctive feature and diagnostic criterion for chronic lymphocytic leukemia, recommended by the National Cancer Institute-sponsored Working Group (NCI-WG), is a threshold value of the number of lymphocytes in the peripheral blood equal to at least 5x109/l, which morphologically must be represented by mature forms. In addition, the blood is characterized by the detection of Gumprecht’s “shadows” (destroyed during the preparation of a smear of lymphocytes).

Lymphocyte clonality should be confirmed by flow cytometry. Chronic lymphocytic leukemia cells express CD19, CD20 and CD23 antigens, as well as CD5 antigen in the absence of other pan-T cell markers; B lymphocytes are monoclonal in the expression of kappa or lambda light chains of immunoglobulins. It should be noted that 7-20% of patients with chronic lymphocytic leukemia lack CD5, the presence of which is associated with autoimmune reactions. When studying two groups of patients in a case-control study with the presence of CD5 cells of chronic lymphocytic leukemia and without CD5 cells of chronic lymphocytic leukemia (less than 5% of cells express CD5), it was found that in the early stages of chronic lymphocytic leukemia, splenomegaly, lymphadenopathy and hemolytic anemia were found in CD5 + patients in a significantly higher proportion than in CD5 patients. The median survival rate in CD5- patients was 97.2 (22-130) months, significantly exceeding that in CD5+ patients - 84.0 (19-120) months, p = 0.0025. CD5-positive patients have a milder course of disease and have a favorable prognosis compared with CD5-expressing patients.

Although bone marrow is involved in all patients, obtaining a bone marrow aspirate and biopsy is generally not necessary to make the diagnosis of chronic lymphocytic leukemia, although these procedures should be performed to identify cytogenetic abnormalities and before initiating myelosuppressive therapy or when cytopenia of unknown origin. If an aspirate is present, lymphoid cells in the smear should account for at least 30% of all nucleated cells. When examining the diagnostic value of computed tomography aspirate, trephine biopsy, and flow cytometry, it was shown that flow cytometry and trephine biopsy allow better determination of B-cell infiltration, and flow cytometry itself allows better monitoring of minimal residual disease.

Computed tomography is not a mandatory method in the diagnosis and staging of chronic lymphocytic leukemia, as well as positron emission tomography, except in cases where it is necessary to select the most metabolically active lymph node for biopsy during transformation into Richter syndrome.

CLASSIFICATION OF CHRONIC LYMPHOLIC LEUKEMIA
In these systems, the detection of isolated cytopenia may not always indicate stage III or IV of the disease, since patients with chronic lymphocytic leukemia may have immune cytopenias (thrombocytopenia or anemia), which do not increase the stage of the disease. According to the J. Binet system, the presence of lymphocytosis alone is not classified at all, and none of the systems includes the detection of splenomegaly only. Another limitation is the small number of patients on the basis of which both staging systems are based.

In this regard, A.I. Vorobyov and M.D. Brilliant proposed a classification of chronic lymphocytic leukemia, in which an attempt was made, based on morphological and clinical signs, including response to therapy, to identify forms of chronic lymphocytic leukemia: benign, classical (progressive), tumor, splenomegalic, bone marrow, prolymphocytic, chronic lymphocytic leukemia, complicated by cytolysis, chronic lymphocytic leukemia occurring with paraproteinemia, hairy cell leukemia, T-cell chronic lymphocytic leukemia. In the revised classification of chronic lymphodeiosis, the last four forms are excluded and the abdominal form of chronic lymphocytic leukemia is added.

However, taking into account new knowledge about the nature of chronic lymphocytic leukemia, this division may not be entirely justified, since it mixes several different diseases into one group or serves as a reflection of the clinical dynamics in patients with chronic lymphocytic leukemia. Since the clinical manifestations of the natural course of chronic lymphocytic leukemia are heterogeneous, we believe that the division of chronic lymphocytic leukemia along the course can be included in the classification, since in clinical practice two variants of chronic lymphocytic leukemia that are fundamentally different in manifestations are most often encountered - slowly (many years and even decades) current chronic lymphocytic leukemia and relatively rapidly developing with steady progression. Stable flow still I.A. Kassirsky described it as a “frozen” form of chronic lymphocytic leukemia. E. Montserrat et al. proposed to distinguish between “smoldering” or “asymptomatic” chronic lymphocytic leukemia. The term myeloblastic leukemia is also used, reflecting both the group of patients examined with monoclonal B-lymphocytosis of undetermined significance, and the preclinical stage of chronic lymphocytic leukemia, often developing into chronic lymphocytic leukemia after a long period of time.

As a result of identifying two types of chronic lymphocytic leukemia based on the mutational status of the VH genes of immunoglobulins, which are strikingly different in survival, there is reason to believe that patients with chronic lymphocytic leukemia with a stable course (congealed chronic lymphocytic leukemia) belong to the group with mutations of the VH genes (and without the ZAP signaling protein -70), and in patients with progressive chronic lymphocytic leukemia there are no VH gene mutations and the ZAP-70 protein is expressed.

Data on the mutational status of chronic lymphocytic leukemia even lead to a discussion of the question of whether chronic lymphocytic leukemia is one or two diseases. It is known that the subtype of chronic lymphocytic leukemia with VH gene mutations is equally common among men and women, while chronic lymphocytic leukemia without VH gene mutations is 3 times more common in men. Although complications such as autoimmune hemolytic anemia and hypogammaglobulinemia occur in patients with late-stage VH gene mutations, it is believed that the two subtypes of B cells in patients with chronic lymphocytic leukemia are fundamentally different and do not transform into each other.

At the same time, even mutations of the VH genes are not always a reliable predictor, since among patients with somatic mutations, a new subtype of CLL cells with mutations in the VH 3-21 immunoglobulin genes has been identified, in which the survival rate of these patients corresponds to that without somatic mutations. At the same time, in patients with the VH 3-21 genotype, a shortening of the hypervariable region CDR3 was detected, which, together with CDR1, CDR2 and CDR4, is responsible for the physical complementary binding of the antigen. In addition, this group has a predominant expression of immunoglobulin λ light chains. One possible explanation for the clinical course of chronic lymphocytic leukemia in patients with few or no VH gene mutations may be the more frequent presence of cytogenetic changes that predict a poor outcome (11q22-23 and 17p deletions, trisomy 12, or p53 dysfunction), while cells patients with a biologically significant number of VH gene mutations more often have a 13q14 deletion, which is associated with a favorable clinical course.

Thus, based on literature data and our observations, in 2004 we (O. Rukavitsyn, V. Pop) proposed to distinguish the following variants of the course of chronic lymphocytic leukemia:
1) slow-acting chronic lymphocytic leukemia (indolent);
2) progressive chronic lymphocytic leukemia;
3) chronic lymphocytic leukemia with transformation into large cell lymphoma (Richter syndrome) or prolymphocytic leukemia.

Slow-acting chronic lymphocytic leukemia is characterized by a stable (chronic) course with long-term persistence of stage 0 (I) according to K. Rai or stage A according to J. Binet, and the absence of infectious complications. When studying the mutational status of the VH genes of immunoglobulins, the majority of these patients reveal mutations of the VH genes and the absence of the ZAP-70 protein. It has been shown that 50-70% of patients with chronic lymphocytic leukemia have signs of somatic hypermutations of the VH genes of leukemic B cells. Cytogenetic analysis often reveals a 13q14 deletion, which is associated with a favorable clinical course.

The progressive course of chronic lymphocytic leukemia is initially characterized by a relatively rapid increase in the stages of the disease according to K. Rai or J. Binet or the diagnosis of the disease already at an advanced stage. This variant is often associated with atypical morphology, high blood lymphocytosis and diffuse bone marrow infiltration. Characterized by increasing lymphadenopathy, spleno- and hepatomegaly, the appearance of general symptoms of tumor intoxication, frequent infectious complications against the background of hypogammaglobulinemia, as well as the development of autoimmune hemolytic anemia, thrombocytopenia. Most of these patients do not have VH gene mutations when examining the mutational status of immunoglobulin VH genes and express the ZAP-70 protein. The frequent presence of cytogenetic changes that predict a poor outcome (deletions 11q22-23 and 17p, trisomy 12 or p53 dysfunction) is also determined. In patients with a progressive course of chronic lymphocytic leukemia, sensitivity to therapy decreases, the effect of treatment is short-lived, and the disease steadily progresses.

The transformation of chronic lymphocytic leukemia is a transition to a much more malignant condition called Richter's syndrome. In patients with chronic lymphocytic leukemia/small lymphocyte lymphoma, Richter syndrome refers to the development of diffuse large B-cell lymphoma, prolymphocytic leukemia, Hodgkin lymphoma, or acute leukemia. Richter syndrome develops in 2-10% of patients with chronic lymphocytic leukemia during the course of their disease, with a transformation rate of 0.5-1% per year. First described in 1928 by M. Richter (generalized reticular cell sarcoma), the term was proposed in 1968. The WHO classification of hematological tumors defined Richter syndrome as the transformation of chronic lymphocytic leukemia into a more aggressive lymphoma. Large cells in Richter syndrome can occur as a result of transformation of the original cells of chronic lymphocytic leukemia, and also indicate the emergence of a new malignant clone.

The transformation of chronic lymphocytic leukemia into large cell lymphoma is accompanied by clinical signs of generalization of the tumor process, but does not always indicate a terminal condition, a later stage of tumor progression and a poor prognosis. A biopsy is required for diagnosis, but due to the fact that Richter syndrome does not develop simultaneously in all lymph nodes, it is necessary to perform positron emission tomography to select a node for biopsy with the most pronounced metabolic activity (SUV, standardized uptake value, standardized accumulation value of at least 5 , or better - more than 7). The transformation of ordinary mature cell chronic lymphocytic leukemia into prolymphocytic leukemia (5-8% of cases) is characterized by the appearance of an aggressive, treatment-resistant course of chronic lymphocytic leukemia with high lymphocytosis, represented by prolymphocytes (in the blood and bone marrow), as well as splenomegaly. De novo B-cell prolymphocytic chronic leukemia is more benign than those associated with aggressive transformation.

PROGNOSTIC FACTORS
Currently, possible risk factors are being actively clarified and much attention is being paid to the study of prognostic factors in patients with chronic lymphocytic leukemia. It is assumed that, based on this knowledge, the selection of patients for starting therapy and choosing (changing) a treatment strategy can be improved.

Unfavorable prognostic factors, regardless of clinical stage, include age greater than 55 years, male gender, black race, poor general physical status, and clinically significant comorbidities. Very important is attached to the mutational status of B cells (or the presence of increased expression of the ZAP-70 protein), which distinguishes between two types of chronic lymphocytic leukemia.

At the same time, the expression of ZAP-70 protein is limited in chronic lymphocytic leukemia cells with unmutated VH genes. In various laboratories, the immunofluorescent method for identifying ZAP-70+ cells in patients with chronic lymphocytic leukemia is not fully standardized, which requires clarification of the value of ZAP-70 for routine clinical practice. When comparing ZAP-70 results and mutation status in one US comparative study, a discrepancy of 23% was found, which is higher than in two previously conducted European studies. The discrepancy may be explained by the fact that the American study had 50% more patients than the two European studies, as well as the younger age of the patients studied in the USA.

The question of whether the severity of bone marrow infiltration and the degree of lymphoid infiltration (blood, lymph nodes and internal organs and tissues) are independent factors remains controversial. The predictive value of bcl-2, fas, and multidrug resistance gene expression remains unclear.

The presence of aberrant expression of the myelomonocytic antigen CD14 was studied by V. Callea et al. as a prognostic factor in patients with chronic lymphocytic leukemia. Moreover, they showed that the median overall survival of patients with a CD14+ cell count of more than 5x109/L was 63 months and 136 months in patients with a CD14+ cell count of less than 5x109/L. In addition to clinical and laboratory data and genetic characteristics (17p deletion/p53 mutation), according to T. Zenz et al., refractoriness to fludarabine and early relapse (within 24 months) or progression after R-FC (or R-FC-like) therapy.

The course of the disease is autoimmune in nature, in other words, the human immune system begins to work in the opposite direction, producing antibodies that do not protect the diseased organ, but damage it. Young men most often suffer from Reiter's syndrome due to untreated chlamydia that has become chronic.

Causes

In addition to infection with chlamydia due to unprotected sexual contact, Reiter's syndrome can develop as a result of enterocolitis caused by salmonella. The immune system malfunctions and begins to react inadequately to the appearance of foreign bodies. The body produces antibodies aimed at damaging its own tissues, thereby helping foreign antigens. Thus, the first to suffer are the articular connective tissues, which are destroyed under pressure from the immune system.

It is currently unknown what causes Reiter's syndrome to occur in some people and not in others. Modern medicine cites the main cause as a tendency to malfunction of the immune system at the genetic level. This partly explains why Reiter's disease is quite often a harbinger of AIDS: pathologies of the immune system provoke a genitourinary or intestinal infection and involve neighboring organs in the disease.

As for Reiter's syndrome as a result of a sexually transmitted infection, it most often affects the male sex at the peak of sexual activity, between the ages of 20 and 40 years. Women suffer from joint disease infrequently; they are mainly carriers of chlamydia pathogens.

But with an intestinal infection, men, women, and children fall into the same risk zone, and in 80% of cases this is the result of a genetic predisposition.

Features of the disease

Reiter's syndrome develops in stages, involving the disease process one organ after another, without affecting all at the same time.

It all starts with the infection described above. Since it happens that the disease does not give visible symptoms, no connection with inflammation is found. But in general, the history of Reiter's disease is clear enough to form a complete picture:

• Damage to the genitourinary system or intestines;
• Inflammation of the organs of vision;
• Inflammation of joint tissues.

The first two symptoms may last for a short time without being noticed. And only when the patient comes with complaints of joint pain, the doctor determines the connection between the ailments of the eyes, genitourinary area and joints that have arisen in a short period of time.

Symptoms

The development of the disease occurs in two stages.

Infectious - as a result of sexual contact, chlamydia enters the genitourinary area, where it begins to spread (urethra, prostate in men, cervix in women). This process takes from a couple of days to a month.

Men experience the following symptoms:

1. Itching and burning sensation occurs on the genital organ.
2. The urethral outlet becomes red and swollen.
3. Discharge appears.
4. Urination becomes painful.

The disease progresses to the chronic stage, and inflammation is transferred to the appendages and prostate gland. The result is prostatitis and epididymitis.

Symptoms of the disease in women are as follows:

• Inflammation develops in the cervix (cervicitis);
• Pain occurs in the lower abdomen;
• Mild purulent discharge appears;
• There is pain when urinating;
• Sexual intercourse causes discomfort.

The chronic stage of chlamydia in women brings with it menstrual irregularities and bleeding from the uterus.

Reiter's syndrome due to intestinal infection initially begins as a common gastrointestinal disorder. As a result of consuming products of poor quality, symptoms such as:

Due to intoxication, the patient suffers from chills, fever, aching joints and headache.

Immunopathological - the infection goes beyond the genitourinary area and begins to devour the mucous membrane and joint tissues of the body.

1. The mucous membrane of the eyelids swells.
2. Discharge like conjunctivitis.
3. Itching appears in the eyeballs, “sand ingress” syndrome.
4. The mucous membrane turns red, the vessels on the sclera dilate.

Sometimes pathological processes occur in the iris, cornea, and optic nerve.

Even “advanced” joint problems can be cured at home! Just remember to apply this once a day.

The main symptom of Reiter's syndrome is a malfunction of the musculoskeletal system.

Signs of joint disease:

1. Pain appears in the joints of the legs (knees, ankles, phalanges of the fingers).
2. Peak pain occurs at night and early morning.
3. The skin in the joint area turns red, reaching a purplish hue on the fingers.
4. Diseased joints begin to swell to a spherical state.

Reiter's disease is characterized by the fact that it affects the joints of the legs in an ascending manner, starting from the phalanges of the fingers and rising to the knee joint. At the same time, the disease affects the joints of the upper extremities very rarely, and then in the complete absence of treatment for the disease.

An important symptom of Reiter's syndrome is the asymmetry of inflammatory signs. On the left foot it could be, say, the toes and metatarsus, and on the right foot it could be the heel and Achilles tendon.

In addition to inflammation of the organs of vision, ulcerative stomatitis in the mouth can be observed, and ulcers appear on the head of the penis.

The feet and palms become covered with areas of keratinized, flaky skin. The nail plates break and turn yellow.

As the disease progresses to a severe stage, the most important internal organs are affected:

• Heart – expressed by myocarditis;
• Lungs – pleurisy or pneumonia develops;
• Nervous system – meningoencephalitis or polyneuropathy occurs.

Diagnosis of the disease

Collecting complete information about the development and course of the disease to make a correct diagnosis is extremely important. And the main determining factor is the presence of urogenital infection. Under no circumstances should you hide its presence out of a sense of false shame. Only a complete clinical picture will enable the doctor to make the correct diagnosis.

After compiling an anamnesis, a series of laboratory tests are carried out on samples of blood, urine, conjunctiva and mucous membranes of the urethra in men and the cervix in women. Sometimes semen is taken for analysis to determine the extent of the infection.

When Reiter's syndrome progresses to the stage of immunopathology and articular tissues are damaged, an analysis of synovial fluid taken by puncture is required. Such a study is extremely important if the course of the disease is aggravated by cardiac pathologies - it allows you to accurately determine the cause of arthritis, finding out whether infection or rheumatism is to blame.

In addition to laboratory tests, X-rays of the joints are performed to determine articular pathologies accompanying the disease.

Stool culture identifies pathogens causing intestinal infections. Gene analysis determines the presence of a predisposition to pathologies of a rheumatic nature.

Treatment

Reiter's disease is complex in its course, and its treatment requires the involvement of specialists from various fields. Regardless of what stage the disease is at, treatment tactics are developed only after consulting the patient with a number of doctors: urologist, rheumatologist, ophthalmologist and other specialists.

This is done in order to exclude the occurrence of complications or relapse after the course of treatment.

Treatment with medications has two fundamental principles: anti-inflammatory and antibacterial.

To suppress the infection, 2-3 different types of antibiotics are used, which are taken over a period of 2 to 3 weeks:

1. Tetracycline or Doxycycline.
2. Ciprofloxacin, Lomefloxacin, Ofloxacin.
3. Erythromycin, Azithromycin, Clarithromycin.

Anti-inflammatory therapy is carried out to eliminate inflammatory processes in joint tissues due to chlamydia damage:

It is necessary to change the drug after two weeks of treating the disease to avoid the body becoming addicted to it.

At the same time, complications are treated. This includes treatment with hormones, antihistamines and other types of therapy.

It is extremely necessary, in parallel with the treatment of Reiter's syndrome, to stop its concomitant diseases - cholecystitis, prostatitis, acute respiratory infections and other diseases that inhibit the effectiveness of treatment, slow down the healing process and can cause complications.

Adjuvant treatments for Reiter's syndrome

After relieving acute inflammation in the joints, physiotherapy is used for the most effective treatment:

• Phonophoresis of joints with medicinal applicators;
• Magnetotherapy.

At the stage of just beginning Reiter's syndrome, a complex of exercise therapy is used in order to maintain joint mobility. If muscle atrophy occurs, massage and mineral baths with radon or hydrogen sulfide are used.

For the treatment and prevention of DISEASES OF THE JOINTS and SPINE, our readers use the method of quick and non-surgical treatment recommended by leading rheumatologists in Russia, who decided to speak out against pharmaceutical lawlessness and presented a medicine that REALLY TREATS! We have become familiar with this technique and decided to bring it to your attention. Read more.

How to forget about joint pain?

• Joint pain limits your movements and full life...
• You are worried about discomfort, crunching and systematic pain...
• You may have tried a bunch of medications, creams and ointments...
• But judging by the fact that you are reading these lines, they did not help you much...

If you want to get the same treatment, ask us how?

CHAPTER 25 RICHTER'S SYNDROME

Richter's syndrome is a peculiar and unique clinical and morphological phenomenon, characterized by a combination of two, usually sequentially developing malignant processes - lymphocytic and large cellular.

“Generalized reticulosarcoma of the lymph nodes associated with lymphatic leukemia” was first clearly described by M.K.Shcher in 1928. Since then, due to a radical change in ideas about hematopoiesis and the widespread introduction of immunological research methods, the lymphoid nature of a large cell tumor, complicating the course of chronic lymphocytic leukemia or lymphosarcoma with the lymphocytic type leukemizacin, has been proven and is currently not the subject of debate. Nevertheless, for 70 years, the main pathogenetic question, which logically follows from the problem of “associated” lymphoproliferative diseases, remains open - about the origin of large cell lymphosarcoma: is it the result of transformation of lymphocytes (prolymphocytes) or is it a second tumor, clonally (genetically) not related with lymphocytic leukemia/chronic lymphocytic leukemia?

It would seem that Richter's syndrome is a rather simple clinical situation when a patient is consistently found to have two different, often B-cell tumors - lymphocytic with blood/bone marrow lymphocytosis and large cell extra medullary. However, behind the apparent simplicity of the phenomenon lies an extremely “problematic” clinical and morphological phenomenon from the point of view of interpreting its essence.

We have to admit that the current level of knowledge does not allow us to formulate a unified concept of the pathogenesis of “associated” lymphoproliferative diseases. The main achievement of recent years is the transition from the cellular to the molecular genetic level of examination of patients with Richter syndrome with the study of rearrangements/mutations of immunoglobulin genes, some oncogenes (p53, etc.) only allowed us to get closer to the final solution to the problem. The most difficult thing to prove is that diseases originate from different clones and there is no genetic (clonal) connection between the oncogenic events that led to the development of first a lymphocytic and then a large cell tumor. In other words, it is much easier to confirm the single-clonal origin of lymphocytic leukemia/chronic lymphocytic leukemia and large cell lymphosarcoma in Richter syndrome than to reject it. Even the detection of various types of immunoglobulin gene rearrangements in the cells of lymphocytic and large cell tumors does not always indicate the origin of these diseases from different clones. Apparently, this is due to the very nature of immunoglobulin genes, which are subject to somatic hypermutations, deletions, and class switching with selection of the most affinity cell clones.

Most likely, the concept of “Richter syndrome” is much broader than it seems at first glance, and includes cases of both clonal progression and the occurrence of second tumors. To a certain extent, this is confirmed by the results of morphological and immunological and in-depth molecular genetic studies, which, despite the complexity of the problem, still shed light on the clonal relationship between two malignant processes - lymphocytic and large cell. However, the question

whether there is one clone or two unrelated ones, one disease or two independent ones, often remains open. Essentially, Richter syndrome has become a special and extremely complex area of ​​immunological and molecular genetic research.

It is known that not every erelocell lymphatic tumor ends with the addition of large cell lymphosarcoma. Bo

Moreover, Richter's syndrome is a rare clinical and morphological phenomenon and, according to various authors, occurs only in 3-10% of patients with chronic lymphocytic leukemia/lymphocytic lymphoma.

Judging by the literature, the development of large cell lymphosarcoma in patients with mature cell lymphoproliferative diseases is a poor prognostic sign and, as a rule, is accompanied by deterioration of the condition, the appearance of general symptoms and generalization of the extramedullary tumor process. Life expectancy after the discovery of large cell sarcoma usually does not exceed six months, despite the use of combination chemotherapy methods that are adequate for high-grade lymphomas.

Analysis of our 8 observations of Richter syndrome indicates that the development of large cell lymphoma during the course of a chronic lymphatic tumor does not always mean a terminal condition, a later stage of tumor progression and a poor prognosis. Only in half of the patients such a “transformation” was accompanied by a deterioration in condition and the addition of general symptoms, while in the rest the state of health remained unchanged. After diagnosis of large cell lymphosarcoma, life expectancy ranged from 3.5 months to 9 years.

In Richter syndrome, isolated extranodal localization of foci of large cell lymphosarcoma is sometimes observed. Thus, an isolated lesion of the vitreous body, skin, soft tissues with destruction of the vertebra, brain substance, testicles, stomach and (or) intestines, kidneys, bronchial tree with epdobronchial tumor growth is described.

It must be borne in mind that the spectrum of malignant lymphoproliferative diseases occurring with lymphocytic infiltration of the bone marrow and leukemic blood picture is not limited to chronic lymphocytic leukemia and its clinical variants. In all mature cell forms of lymphomas (lymphocytic, lymphoppasmocytic, centrofollicular, mantle cell, from marginal zone cells, including MAS”), early involvement of the bone marrow in the tumor process is possible with the development of a picture of chronic lymphocytic leukemia. In a word, the name “lymphocytic leukemia” can hide a wide range of mature cell lymphoproliferative tumors, in which the development of large cell lymphosarcoma is possible, which is fully consistent with the concept of Richter’s syndrome.

The name “large cell lymphoma” also combines a number of lymphosarcoma with a diffuse growth pattern: centroblastic (macrolymphoblastic), immunoblastic, from cells with multilobulated nuclei, as well as large cell and plastic escuto,

Of particular interest are those rare clinical observations in which the development of large cell lymphosarcoma is accompanied by the disappearance of blood and bone marrow lymphocytosis. Some authors describe such cases as a rare variant of Richter's syndrome with regression of chronic lymphatic leukemia. It is difficult to explain this course of a lymphocytic tumor. It is possible that it is in these cases that we can talk

about the transformation (clonal progression) of one variant of malignant non-Hodgkin lymphoma into another, more aggressive one.

However, the assumption of transformation does not find proper morphological confirmation. The fact is that in tissue infiltrates, tumor changes of two clearly different types are most often simultaneously detected - lymphocytic and large cell. It seems that both tumors coexist and develop simultaneously in the same tissues and organs. Our research confirms this. Indeed, in histological preparations, cellular forms transitional between small lymphocytes and large lymphoid elements were not found. However, when studying the fingerprints of individual patients, the cytogram was mixed-cellular: between the smallest cells - lymphocytes and the largest - nm-munoblasts, a fairly noticeable population of medium-sized tumor elements was found, which may have been at various stages of morphological differentiation and which could well be attributed to transitional forms.

During the development of large cell (immunoblastic) lymphosarcoma, we observed spontaneous regression of lymphocytosis in more than half of the patients, i.e. disappearance of the main symptom of a lymphocytic tumor. However, the basis of combined lymphoproliferative diseases is not so much cases with regression of lymphocytosis (there are extremely few of them), but Richter's syndrome, when both diseases - lymphocytic and large cell - coexist in parallel, often affecting the same tissues, including the bone marrow. Consequently, the disappearance of lymphocytosis during the development of a large cell tumor is by no means a pattern. On the contrary, in our observations in 2 patients the generalization of immunoblastic lymphoma was accompanied by

was driven by an increase in blood and bone marrow lymphocytosis to the highest values ​​for the entire observation period.

The immunological study of malignant lymphoma cells at the modern level involves not only assessing linear affiliation, state of activation or dormancy, but also determining the degree of differentiation. The detection of diffuse large cell lymphoma in the blood and bone marrow picture, characteristic of a lymphocytic tumor, only at first glance represents a difficult clinical situation to interpret. In such cases, for correct diagnosis, optimal solution of tactical issues and selection of the most adequate method of chemotherapy, it is very important to have number and results of nmmunolo-

1. Anikin B.S., Likhachev A.A., Pekina L.N. and others Ter. arch.-1979.-No. 9,-P.118-121.

2. Arutyunov VD. Arch. Pat, - 1956, - ​​No. I. - P. 56-59.

3. Demidova A.V. Vorobyov A.I., Datsenko S.F. and others. Probl. hematol.-1967.--T.!2, No. I.-S.10-17.

4. Krtoe A.A. Ter. arch.-1974.-No. 8,-P.49-51.

5. Probatova N., Mamedov R.D., Kruglova G.V. Arch. Pat, - 1988.-T.b, No. 3.-S, 37-43.

6. Faya\itein F.Z., Polyanskaya A. M. Ter. arch.-1984.-No. 10.-S-80-83.

7. AShog S.. ()1.-1987,-WaSh, N 12.-R.901-903.

13. Oipp R., Kii T.T., Tgep N.G. b Rogguz Month A 85-

1995. -Uo1.94, N 1b-R.686-688.

14.Sh%e1 O.O., Ussh§kp O.U., EipN E.E. eg a1. Ateg. b Ca1goepS, -!995, -Vo1.90, N 4.-P.635-637.

15.Eoget V., Con/Lotep R. Mtshua Mei-1984.-Vo1.75, N 45-46.-R.2741-2749.

16.Ezhsat K., Nut YaE Sapseg -1980.-’Uo1.4“.-RL18-134.

Reiter's disease

Reiter's disease (Reiter's syndrome) is a sequentially or simultaneously developing combined lesion of the eyes (conjunctivitis), joints (reactive mono- or oligoarthritis) and genitourinary organs (usually nonspecific urethroprostatitis). Reiter's disease develops when genetically predisposed people have chlamydial infection. As a rule, this disease develops at a young age; men are affected approximately twenty times more often than women. The peak incidence occurs in the age range from twenty to forty years (about 80%). There are isolated cases of morbidity in children

Reiter's disease - causes

Most often, in addition to genetic predisposition, various infections of the digestive and urinary systems play a role in the development of Reiter's disease. Usually the disease begins with urethritis, which occurs after an exacerbation of any chronic urinary tract infection or after sexual intercourse. In the presence of an unfavorable epidemic situation, which is often present in tourist and military camps, the catalyst for the development of Reiter's disease can be acute enterocolitis of yersinia, salmonella or shigella origin. In the mechanism of joint damage, the main importance is given to hereditary predisposition and immune processes.

Reiter's disease can be caused by certain types of chlamydia, which usually affect the mucous membranes of a person, entering the body through the genitourinary organs and subsequently affecting other systems and organs. Due to the fact that chlamydia can remain in the patient’s body for quite a long time, there is a high probability of exacerbations and relapses of this disease, or the development of chronic Reiter’s disease

The manifestations of conjunctivitis, arthritis and urethritis come to the fore in the clinical picture of Reyer's disease. In addition, changes in the mucous membranes and parenchymal organs (central nervous system, aorta, myocardium, kidneys, liver, etc.) may be observed.

The sequence of the main symptoms may be different, but most often Reiter's disease begins with the development of diseases such as cystitis, urethritis or prostatitis. With this disease, urethritis can vary in severity - from erased, prone to a protracted/chronic course, to acute with the presence of strong purulent discharge. Urethritis is manifested by burning, itching, scanty discharge from the vagina and urethra, hyperemia around the exit opening of the urethra and unpleasant sensations when urinating. The discharge is usually mucous in nature.

Soon after urethritis, a person experiences eye damage, which most often manifests itself as conjunctivitis, less often keratitis, retrobulbar neuritis, retinitis, uveitis, iridocyclitis, iritis. Conjunctivitis with Reiter's disease is most often bilateral, mild and resolves after one to two days. Very often it goes unnoticed.

Joint damage in Reiter's disease is the leading symptom and develops after one to one and a half months from the development of an acute genitourinary infection. The most characteristic lesion is asymmetric arthritis, involving the joints of the lower extremities - interphalangeal, metatarsophalangeal, ankle and knee. Joint pain is usually worse in the morning and at night, the skin over it is hyperemic, and there is effusion. After several days, a characteristic sequential (from bottom to top) involvement of the joints is observed. The development of heel spurs, heel bursitis, and inflammation of the Achilles tendon are often observed. Some patients experience pain in the spine, which subsequently leads to the development of sarcoileitis.

30% of patients experience relapses of arthritis; in 20% of patients, arthritis enters the chronic stage with atrophy of adjacent muscles, as well as limitation of joint function; in 50% of patients, articular symptoms completely disappear. Due to damage to the tarsal joints, some patients may develop flat feet. Damage to the joints of the upper extremities is observed extremely rarely. About 50% of patients are susceptible to damage to the skin and mucous membranes. Painful ulcers appear in the area of ​​the glans penis and on the oral mucosa, balanoposthitis or balanitis develops, glossitis and stomatitis may develop. Skin lesions are characterized by the appearance of small red papules and sometimes erythematous spots. Reiter's disease is characterized by keratoderma, which, against the background of skin hyperemia, is expressed by confluent foci of hyperkeratosis with peeling of the palms and soles. Also, often foci of hyperkeratosis are observed on the skin of the torso and forehead.

With Reiter's syndrome (disease), a painless enlargement of the lymph nodes (usually inguinal) may be observed; about 20% of patients have signs of heart damage (myocarditis, myocardial dystrophy), kidney damage (renal amyloidosis, nephritis), nervous system (polyneuritis), lungs (pleurisy, focal pneumonia) and prolonged subfebrile body temperature

Diagnosis of Reiter's disease

In the presence of the triad characteristic of this disease (conjunctivitis + urethritis + arthritis), diagnosing Reiter's disease does not cause practically any difficulties. In case of insufficient severity of individual symptoms, or in atypical cases, an X-ray examination of the joints is indicated. A test of the synovial fluid will reveal signs of inflammation. A biopsy of synovial fluid will reveal a picture of nonspecific subacute or acute inflammation. A general biochemical blood test does not reveal any abnormalities. There is pus in the urine

Treatment of Reiter's disease solely for joint damage, which is the most disturbing and striking manifestation of the disease, does not give the desired results and usually leads to a protracted or chronic course of the disease. Treatment with drugs of the cephalosporin and penicillin group leads to the same result. It is necessary to treat both the patient himself and his sexual partner.

For Reiter's disease, all therapeutic measures can be divided into such main areas as anti-inflammatory therapy of the joint substance and antibacterial therapy for infection.

Antibacterial treatment of urethritis is primarily carried out with tetracycline drugs. In the treatment of arthritis, non-steroidal anti-inflammatory drugs such as voltaren, indomethacin, aspirin, diclofenac, etc. are used. In case of high disease activity and with pronounced systemic manifestations, the use of glucocorticoids is indicated. In cases of chronic or prolonged arthritis, the use of gold salts or quinoline derivatives is indicated.

Primary prevention of Reiter's disease is based on compliance with standard sanitary and hygienic rules, timely treatment of cystitis, urethritis and other genitourinary infections. In case of chlamydial infection, treatment of both sexual partners is mandatory.

Reiter's syndrome: symptoms and treatment

Reiter's syndrome is accompanied by a triad of inflammatory lesions of the joints, eyes and genitourinary organs. In 80% of cases, it is observed in young men, less often in women, and extremely rarely in children. If left untreated, it can cause severe complications, including disability of the patient.

In this article we will introduce you to the symptoms and main methods of treatment and prevention of Reiter's syndrome. Having this information, you will be able to make a timely decision about the need to see a doctor to prevent such complications of this pathological process as chronicity of the disease, impaired spinal mobility and the development of visual impairment (even blindness).

Reiter's syndrome was first described as a complication of an intestinal infection, and later it became known that it can also be provoked by infectious processes in the genitourinary system. The cause of the development of this disease is an autoimmune reaction that occurs in response to the introduction of a bacterial or viral agent.

More often it develops against the background of chlamydia, and sometimes it is not possible to identify its exact cause of development.

In addition to chlamydia, the syndrome can be provoked by ureaplasma, salmonella, shigella and yersinia. And most experts are inclined to the theory that there is a hereditary predisposition to the occurrence of such an autoimmune reaction in response to infection.

Symptoms

Reiter's syndrome develops 1.5-2 months after a genitourinary or intestinal infection. And its course can be:

• acute – up to six months;
• protracted – up to 1 year;
• chronic – more than 1 year.

Symptoms from the genitourinary system

It is the signs of damage to the genitourinary system that often become the first signals of the onset of the development of Reiter's syndrome. They manifest themselves as symptoms of urethritis, cystitis, prostatitis, vaginitis, etc.

Men usually experience the following symptoms:

• discomfort when emptying the bladder: itching, burning, mucous discharge;
• frequent urination;
• hyperemia of the external urethral opening;
• pain or discomfort during sex;
• pain in the lower abdomen.

Women usually experience the following symptoms:

• vaginal discharge;
• burning, pain and stinging when urinating;
• frequent urination;
• pain during sexual intercourse;
• discomfort or pain in the lower abdomen.

Laboratory tests - smears and urine - determine leukocytosis.

Visual symptoms

After a short period of time after the appearance of signs of damage to the genitourinary tract, the patient begins to show signs of inflammation of the eyes. Subsequently, they lead to the development of conjunctivitis, and in severe cases cause iritis, iridocyclitis, retrobulbar neuritis, uveitis or keratitis.

With Reiter's syndrome, the patient is concerned about the following symptoms of eye damage:

• pain and discomfort;
• lacrimation;
• mucous or purulent discharge;
• blurred vision;
• redness of the eyes;
• photophobia.

Sometimes mild manifestations of conjunctivitis are observed only during the first two days and go unnoticed.

Joint symptoms

The main manifestation of Reiter's syndrome is joint damage, which first makes itself felt 1-1.5 months after the appearance of signs of damage to the genitourinary system or their exacerbation. Usually, with this disease, inflammation of 1-2 joints occurs (mono- or oligoarthritis), but sometimes the course of the pathological process involves many joints and the patient develops polyarthritis. More often, the joints of the legs become inflamed and this process spreads according to the bottom-up principle (i.e., arthritis of the ankle joint develops first, and then the knee, etc.).

With Reiter's syndrome, the patient is concerned about the following symptoms of joint damage:

• pain;
• asymmetry of joint damage;
• change in skin color over the joint (from red to bluish);
• hyperthermia and swelling of the skin in the area of ​​inflammation.

In some cases, Reiter's syndrome affects the sacroiliac joint and joints of the spinal column. In this case, the patient experiences stiffness in movements in the morning and pain. And when the joints of the foot are damaged, flat feet can quickly form.

According to statistics, in half of patients the symptoms of arthritis disappear completely, in 30% recurrent arthritis occurs, and in 20% chronic arthritis occurs, leading to limited functionality of the joints and atrophy of adjacent muscles.

Other symptoms

Sometimes with Reiter's syndrome, which is always accompanied by a triad of characteristic symptoms, signs of damage to other organs appear.

Red spots may appear on the skin, which rise above its surface in the form of tubercles. Typically, such changes are observed on the palms and soles. In the future, the formation of compacted zones with signs of peeling and keratinization of the skin is possible.

Sometimes the syndrome causes damage to the mucous membranes. Such signs are observed on the genitals and in the oral cavity.

Against the background of arthritis, inflammatory processes may occur in the area of ​​attachment of tendons and ligaments. Such processes are accompanied by the appearance of pain, redness and swelling. As a rule, such an inflammatory process is localized in the area of ​​the Achilles tendon.

In extremely rare cases, Reiter's syndrome leads to inflammation in the kidneys, lungs or heart.

Diagnostics

A presumptive diagnosis of “Reiter's syndrome” can be made on the basis of information about a previous genitourinary or intestinal infection and the presence in the patient's complaints of data on a triad of symptoms typical for this disease. To confirm the diagnosis, the patient is prescribed a number of laboratory tests:

• clinical blood test - leukocytosis, increased ESR;
• scraping from the urethra or vagina - detection of chlamydia or ureaplasma;
• analysis of joint fluid - detection of chlamydia;
• blood biochemistry – absence of rheumatoid factor and presence of C-reactive protein;
• scraping of the mucous membrane of the eye - identification of chlamydia;
• immunological blood test - high titer of immunoglobulins M and G;
• genetic analysis - determination of the HLA-B27 gene;
• Blood PCR – detection of chlamydia/ureaplasma DNA.

To identify disorders in the joints and adjacent tissues, the following instrumental methods can be prescribed:

Treatment

Therapy for Reiter's syndrome is always complex and takes from 3 to 12 months. Its main goals are aimed at eliminating the infectious agent, stopping the inflammatory process and suppressing the autoimmune reaction.

To treat chlamydia or ureaplasmosis, several antibiotics are prescribed in maximum doses. To prevent re-infection, it is recommended that the sexual partner take the same medications. The patient may be prescribed combinations of the following drugs:

• macrolides: Klacid, Z-factor, Clarithromycin, Roxithromycin;
• fluoroquinolones: Ciprofloxacin, Sparfloxacin, Ofloxacin;
• tetracyclines: Doxycycline.

Antibiotic therapy is carried out for a long time - for 3-8 weeks - and can lead to the development of candidiasis and damage to the digestive tract. To prevent these undesirable consequences, the following drugs are used:

• hepatoprotectors: Legalon, Heptral, Karsil, Hepa-Merz, Essentiale, Gepabene, etc.;
• antifungal agents: Clotrimazole, Pimafucin, Fluconazole, etc.;
• multivitamin complexes: Biovital, Alphavit, Dexavit, Vitrum, etc.

For maximum effectiveness of antibacterial therapy, parallel administration of proteolytic enzymes: trypsin, chymotrypsin or Wobenzyme is recommended.

To treat inflammatory eye lesions, antibacterial and anti-inflammatory drops and ointments based on tetracycline and erythromycin are used. Lotions made from infusions of medicinal herbs (chamomile, calendula, etc.) can reduce inflammatory reactions.

• non-steroidal anti-inflammatory drugs: Nimesulide (or Nimegesic), Arcoxia, Dicloberl, Celecoxib;
• glucocorticosteroids: Prednisolone, Polcortolone, Diprospan, Kenalog.

These drugs eliminate inflammation, pain, swelling and reduce body temperature.

An important part of treating Reiter's syndrome is the use of drugs to suppress the autoimmune reaction aimed at destroying connective tissue. They are used for a long time (4-12 months), and in severe cases they are prescribed to the patient for lifelong use.

The following immunosuppressants are used to treat Reiter's syndrome:

While taking such drugs, the body’s resistance to infectious diseases decreases, and to prevent them, the patient is recommended to take immunomodulators:

To enhance immunity, techniques such as ultraviolet blood irradiation and intravenous quantum therapy can be used.

When the temperature rises and intoxication, the patient is prescribed desensitizing agents (Pheniramine, Loratadine, Ketotifen) and intravenous administration of solutions of rheopolyglucin or rheosorbilact. Such detoxification therapy not only alleviates the patient’s condition, but also increases the effectiveness of other medications.

After the inflammatory process subsides, physiotherapy is prescribed:

• physical therapy;
• amplipulse therapy;
• magnetic therapy;
• electrophoresis with novocaine solution.

Prevention

There are no specific measures to prevent Reiter's syndrome. To prevent its development, measures aimed at the prevention and timely treatment of sexually transmitted diseases are recommended.

Which doctor should I contact?

The severity of Reiter's syndrome is determined by the damage to the joints, so the main therapy is prescribed by a rheumatologist. In case of concomitant pathology of the external genitourinary organs, consultation with a urologist, gynecologist and venereologist is necessary. Eye damage is a reason to consult an ophthalmologist. Treatment by a physiotherapist is also necessary.

A specialist from the Moscow Doctor clinic talks about Reiter’s syndrome:

Channel One, program “Live Healthy!” with Elena Malysheva, in the “About Medicine” section, a conversation about Reiter’s syndrome (from 32:45):

Help the children

Useful information

Contact the specialists

Phone number for appointments with medical specialists in Moscow:

The information is provided for informational purposes only. Do not self-medicate. At the first signs of illness, consult a doctor.

Editorial office address: Moscow, 3rd Frunzenskaya st., 26

Leukemia is a cancer of white blood cells. Chronic lymphocytic leukemia (C.91 according to ICD 10), in contrast to a disease such as acute lymphocytic leukemia (C. 91.0 according to ICD 10), tends to progress slowly and affects mainly mature cells that are able to perform their functions.

Its other name is chronic lymphocytic leukemia. The most common type is B-cell lymphocytic leukemia with damage to B-lymphocytes. The share of T-cells accounts for only 10%.

Chronic leukemia is classified according to the type of cells affected by the cancer.

Symptoms of the disease

The early stage of chronic lymphocytic leukemia is usually not characterized by any noticeable symptoms, and the quality of life does not change. The medical history shows that the blood test is unchanged. When leukemia develops, the following signs appear:

• repeated infections that occur over a short period of time;
• fatigue due to a lack of red blood cells (anemia);
• unusual bleeding or bruising;
• chills or fever;
• sweating, especially at night;
• bone pain;
• rapid weight loss;
• splenomegaly;
• enlargement of lymph glands.

What happens in chronic leukemia

Bone marrow is a spongy substance found inside the bones that contains specialized cells called stem cells. These stem cells develop into any of three types of blood cells: red blood cells, white blood cells, and platelets.

Leukemia causes stem cells to produce an excess amount of underdeveloped white blood cells. In chronic lymphocytic leukemia, these cells are lymphocytes.

This overproduction of lymphocytes at the expense of other blood cells results in few red blood cells and platelets, which can cause symptoms of anemia such as fatigue, and also increases the likelihood of heavy bleeding.

In some people with chronic lymphocytic leukemia, the body's immune system may start producing red blood cells and cause another type of anemia called hemolytic anemia. This may require long-term treatment throughout your life.

White blood cells also do not form properly. These immature lymphocytes are much less effective at fighting bacteria and viruses, leaving you more vulnerable to infection.

Causes of chronic lymphocytic leukemia

In most cases, it is not known what causes leukemia. However, there are some risk factors that can increase your chances of developing chronic leukemia.

Known risk factors for chronic leukemia include:

• hereditary predisposition or family history;
• ethnic factor;
• frequent infections: pneumonia, sinusitis, shingles;
• Leukemia most often affects males.

Heredity

In most cases, chronic lymphocytic leukemia is inherited. When inheriting a mutation gene, the tendency to develop the disease increases. This means that there may be relatives who carry certain genes in your family. This will be the basis for the development of chronic lymphocytic leukemia.

Family influence

Research has shown that the development of leukemia is influenced by family history, meaning people who have a parent or sibling with chronic lymphocytic leukemia are more likely to develop lymphocytic leukemia.

Ethnicity

Chronic lymphocytic leukemia most often affects people of European, American and Australian descent. The disease rarely occurs in people from China, Japan and Southeast Asia, and also affects people with black skin to a lesser extent. It is still not clear why the disease manifests itself in people of certain nationalities.

Other medical conditions

Research has shown that having certain conditions significantly increases your risk of developing this disease. These are mainly infections, autoimmune hemolytic anemia, chronic arthrosis, prostatitis.

It has been proven that in addition to the fact that chronic lymphocytic leukemia develops due to these diseases, the listed diseases themselves can arise against the background of leukemia due to decreased immunity. This is typical when there is an early stage of the disease.

Chronic lymphocytic leukemia occurs if a person has a disease such as HIV or AIDS, or if a person takes medications after an organ transplant. All this can also increase the risk of developing the disease and reduce life expectancy.

Radiation exposure

Exposure to radiation is known to increase the likelihood of other types of leukemia, but this does not apply specifically to the occurrence of chronic lymphocytic leukemia.

Age and gender

For unknown reasons, men are about twice as likely to develop the disease as women. The risk of developing leukemia increases with age.

Main symptoms

Basically, lymphocytosis is determined in the blood up to only 40-50%, although the total number of white blood cells is within normal limits. Lymph nodes are not enlarged, but their growth is noticeable during various bacterial and viral infections. With the elimination of the pathological focus, they are reduced to normal sizes.

The growth or enlargement of lymph nodes occurs gradually and begins in the neck area, and subsequently affects the mediastinum, axillae, some areas of the abdominal cavity and inguinal folds. In this case, patients complain of a weak state and night sweats. It should be noted that blood tests do not reveal either anemia or thrombocytopenia.

Over time, there is a significant increase in lymphocytes - their percentage reaches 80-90%. But the production of other blood cells may not be affected.

There is no stability in the development of changes if you do a blood test. The study identifies both B-lymphocytes and T-lymphocytes, and they are mature, without pathological forms.

A detailed study reveals nonspecific, modified cells. But the main symptom of chronic lymphocytic leukemia is the presence in the blood of deformed lymphocyte nuclei, the so-called Gumprecht's shadows. The more there are, the more pronounced the process.

As the disease progresses, a blood test shows the presence of prolymphocytes and lymphoblasts. The advanced stage of the disease is characterized by the fact that there are quite a large number of them.

Diagnostics

A routine blood test can help diagnose chronic or acute lymphocytic leukemia. However, you should definitely visit your doctor if you suspect you have signs or symptoms of leukemia. In this case, the doctor carefully collects anamnesis to determine the influence of mutated genes.

The therapist will also perform a physical examination to check for swollen glands, significant enlargement of the spleen, and any signs of abnormal bleeding.

If your doctor suspects leukemia, they will refer you to a hematologist, who specializes in diseases of the blood, blood cells, and blood-forming organs. You should also undergo some other tests, such as an x-ray to rule out other possible causes of your symptoms, an ultrasound scan or a CT scan to check your organs.

Chronic lymphocytic leukemia is diagnosed after a thorough count of lymphocytes and immunophenotyping. This test looks at the lymphocytes in more detail to differentiate chronic lymphocytic leukemia from other diseases that may also cause high lymphocyte counts.

Bone marrow biopsy

In most cases, a bone marrow test is required. To do this, a biopsy is performed from a site on the back of the pelvic bone under local anesthesia. The bone marrow sample will be examined for cancer cells. Their presence indicates a disease. This study helps in the diagnosis of diseases: acute lymphocytic leukemia and chronic lymphocytic leukemia (according to ICD 10). The following studies are used:

• cytogenetic analysis;
• flow cytometry (used for immunophenotyping).

Treatment of leukemia depends on the form and stage of the lesion.

Treatment of chronic lymphocytic leukemia

The early stage of the disease, chronic lymphocytic leukemia, does not require treatment. Some people can live for years or decades with chronic lymphocytic leukemia without developing symptoms. A medical history in an oncology or hematology center is most often obtained for patients who have a terminal stage.

This is because most treatment programs involve chemotherapy or cytotoxic therapy, which has side effects. In such cases, a “watchful waiting” policy is recommended, which involves regular visits to the doctor and blood tests to closely monitor the general condition. If treatment is required, chemotherapy is usually recommended.

Radiation therapy may also be needed to improve the quality of lymph node function. Treatment of any kind cannot cure chronic lymphocytic leukemia completely, but it can slow its progression and lead to remission (periods when there are no signs or symptoms).

JANUARY - MARCH 2008

CLINICAL

ONCOhematology

RARE AND COMPLEX HEMATOLOGICAL SYNDROMES

Richter's syndrome with primary skin lesions in a patient with chronic lymphocytic leukemia

M. A. Volkova, M. Yu. Kichigina, D. Sh. Osmanov, A. M. Kovrigina,

N. A. Probatova, A. I. Pavlovskaya, M. A. Frenkel,

N.N. Tupitsyn, E.N. Sholokhova, A. I. Karseladze, E. A. Nikitin,

A.V. Pivnik, V. A. Tumakov, R. A. Makhmudov

ABSTRACT_________________________

A description is given of a patient who was diagnosed with chronic lymphocytic leukemia at the age of 48 years. Periodically he received various courses of chemotherapy, including alkylating drugs, purine analogues (fludarabine), anthracyclines (mitoxantrone), monoclonal antibodies (mabthera), corticosteroid hormones (dexamethasone). In the 4th year of the disease, the patient developed tumor formations on the scalp, trunk and limbs, nasal mucosa and oropharynx. Histological and immunohistochemical studies diagnosed the development of diffuse large B-cell lymphoma - Richter syndrome.

Keywords

chronic lymphocytic leukemia, skin, Richter's syndrome

Richter syndrome with primary cutaneous presentation in a patient with chronic lymphocytic leukemia

M.A.Volkova, M.Yu. Kitchigina, E.A.Osmanov, A.M. Kovrigina, N.A. Probatova, A.A. Pavlovskaya, M.A. Frenkel, N.N. Tupitsyn, E.N. Sholokhova, A.I. Karseladse, E.A. Nikitin, A.V. Pivnik,

V.A. Tumakov, R.A. Mahmudov

It is a case report of the patient with chronic lymphocytic leukemia (CLL) who received treatment with alkylating agents, purine analogs, anthracyclines, rituximab, glucocorticoids, and after 4 years of the disease developed Richter syndrome with primary presentation in the skin.

chronic lymphocytic leukemia, skin, Richter syndrome

N.N.Blokhin Cancer Research Center, Moscow; Research Hematology Center, Moscow; N.I.Pirogov National Medico-Surgical Center, Moscow;

Regional Hospital, Ivanovo

Contacts: [email protected]

INTRODUCTION

Specific skin lesions in chronic lymphocytic leukemia (CLL) are rare. L. Cerroni et al,1 who, judging by the available publications, have the largest number of observations, report on 42 patients with CLL studied for specific skin lesions in a dermatological clinic over 25 years (from 1969 to 1994). K. Agnew et al2, among 750 patients with CLL who they observed over a 30-year period, noted various skin formations in 40 patients, however, only three of them had skin lesions of the nature of lymphoid infiltrates with an immunohistochemical pattern specific to CLL.

The specific skin lesions described by different authors vary in appearance - these are papules, spots, nodules or rather large tumor formations. They can be local or generalized, located on the head and neck, trunk and limbs. Some authors indicate that the most characteristic places are

Some specific sites for skin lesions include the nipples, scrotum, and auricles.3 Old dermatology textbooks identified these areas as the most common areas where skin lesions developed early in CLL.4

Sometimes specific skin lesions appear on the site of scars left after suffering from herpes simplex or, more often, herpes zoster.1 Ulcerations are not typical for skin lesions in CLL.

In some cases, specific skin lesions appear at the very beginning of the development of CLL and are the first reason for the patient to see a doctor. Morphological and immunohistochemical studies in these cases, as a rule, reveal monomorphic infiltrative formations consisting of small CD5- and CD19-positive lymphocytes expressing light chain restriction immunoglobulins on the surface. In all studied cases, using polymerase chain reaction, it was possible to confirm the identity of the lymphocytes forming skin infiltrates and lymphocytes.

GU RONC im. N.N. Blokhin RAMS; Hematological Research Center of the Russian Academy of Medical Sciences; National

Medical and Surgical Center named after. N.I. Pirogova; OGUZ Ivanovo Regional Clinical Hospital

Richter syndrome

Combination of the bone marrow of a given patient to one clone.3-5 As a rule, a small number of T-lymphocytes are also found in the infiltrates. T-cell infiltration in these cases is polyclonal and can be regarded as reactive, reflecting the local immune reaction in response to the occurrence of a tumor.1

Sometimes, however, in the described cases, a specific skin lesion in CLL had the morphological features of large cell lymphoma. The skin could be the only localization of lymphoma or be combined with large cell lymphoma affecting other organs and tissues - lymph nodes, spleen, liver.

The development of diffuse large cell lymphoma in a patient with CLL, first described by M. Richter6 in 1928 and subsequently named after him - Richter syndrome,7 is the outcome of CLL, according to various sources, in 2-6% of patients.8-10 The development of Richter syndrome is usually characterized by the appearance of general symptoms - fever and loss of body weight, heavy sweats, weakness and rapid enlargement of one or, more often, a group of lymph nodes, spleen, liver. The appearance of skin infiltrates as a manifestation of Richter's syndrome is extremely rare and, as far as we know, reports on this are limited to a few publications.1,2,8,11-14 Thus, L. Robertson and et al,8 who published the largest number of observations of Richter's syndrome in patients CLL, skin lesions were noted in only 2 out of 39 patients. L. Cerroni et al1 diagnosed Richter's syndrome in 2 of 42 patients with CLL who visited a dermatology clinic for skin lesions.

We present our own observation of the development of Richter syndrome with skin lesions in a patient with CLL. It is the only one in our practice among hundreds of patients observed for CLL.

CLINICAL CASE

Patient P., 52 years old, applied to the Russian Cancer Research Center named after. N.N. Blokhin in November 2005 regarding the appearance of bumpy formations on the scalp, torso and limbs and a rapid increase in their size and number.

From the anamnesis it is known that in July 2001, when visiting a doctor at his place of residence for an acute respiratory disease, the patient was diagnosed with CLL. The number of leukocytes at that time was 19x109/l, of which 67% were lymphocytes. In the myelogram, lymphocytes accounted for 68.2%. Since the hemoglobin level, red blood cell count, and platelet count were normal, no treatment was prescribed to the patient. In February 2002, the number of leukocytes in the blood reached 49 x 109/l, of which 86% were lymphocytes. The hemoglobin content, the number of red blood cells and platelets remained normal, the size of the lymph nodes was only slightly increased. I did not receive treatment.

In May 2002, the number of leukocytes in the blood increased to 62 x 109/l, of which 92% were lymphocytes. The patient was consulted at the Hematology Research Center of the Russian Academy of Medical Sciences. Treatment with a COP regimen followed by maintenance therapy with cyclophosphamide or chlorobutine was recommended. The patient received 6 courses of SOP, after which he received cyclophosphamide 300 mg 1-2 times a week. The condition remained satisfactory until February 2003, but there was a gradual increase in the size of the lymph nodes in the cervical-supraclavicular, axillary and inguinal areas, and the spleen began to be palpated. Immunophenotyping of blood cells and bone marrow punctate (ROSC RAMS, 02.20.03) confirmed the diagnosis of CLL (in the blood CD19+CD5+ lymphocytes were 61.9%, CD19+Cd23+------ 47%, CD38+---- 15.1%, in bone marrow

In the sample, CD19+ CD19+CD5+ lymphocytes accounted for 79.8%, CD19+ CD23+ - 45.3%, CD38+ - 15.3%).

In February 2003, the patient was again consulted at the Hematology Research Center of the Russian Academy of Medical Sciences, where he was recommended treatment according to the R-MFCD regimen: rituximab (mabthera), mitoxantrone, fludarabine, cyclophosphamide, dexamethasone. During the year, I received a total of 6 cycles of therapy with these drugs: 3 with MabThera and 3 without

Rice. 1. Picture of scalp damage before treatment

Rice. 2. The same area of ​​scalp after treatment

Mabtera. After this, from December 2004 to May 2005, he received only treatment with cyclophosphamide. In May 2005, due to a newly noted increase in the number of leukocytes and lymphocytes in the blood, treatment with fludarabine in combination with Mabthera was started. In total, he received 3 courses of such therapy, the last one in September 2005.

In June 2005, the patient first noted the appearance of formations of various shapes, sizes and colors on the oral mucosa and on the skin throughout the body. Some of them were in the form of spots without clear boundaries, but more often they were dense, lumpy, reddish-bluish tumor-like formations of varying sizes. They somewhat decreased in size during the course of therapy, but a few days after the end of treatment they acquired the same or even greater size. In September, a tumor-like formation appeared in the nasal cavity, making nasal breathing difficult.

The patient went to the Russian Cancer Research Center and on November 17, 2005 was hospitalized in the chemotherapy department for hemoblastosis.

Upon admission, the general condition was satisfactory and active. The voice is changed due to the almost complete absence of nasal breathing. On the skin of the head, torso and limbs there are multiple convex, round reddish-bluish tumor formations ranging in size from a pea to a large walnut (Fig. 1), some have fuzzy edges and a diameter of up to 7 - 8 cm. On the mucous membrane of the mouth and in the corners of the eyes there are small formations of the same type. On the anterolateral surface of the right leg, a dense formation measuring 12 x 7 cm is palpated under the skin. The skin over it is not changed, the skin temperature is not increased.

There is an increase in peripheral lymph nodes - occipital, submandibular, cervical, mental, their sizes are from 2 x 1.5 to 2x3 cm. Inguinal lymph nodes are significantly enlarged and form conglomerates - on the right 8 x 10 cm, on the left 4 x 5 cm, of dense consistency. The liver is not palpable; the edge of the spleen is palpable in a position on the right side.

X-ray and computed tomography of the chest revealed multiple enlarged lymph nodes in the root zones of both lungs. An ultrasound examination confirmed an increase in peripheral

M.A. Volkova et al.

lymph nodes and spleen, which measures 16.3 X 9.2 cm, enlarged lymph nodes were found in the abdominal cavity along the mesenteric vessels with a diameter of up to 2 X 3 cm.

Ultrasound examination of soft tissues

On the right leg, a formation of reduced echogenicity was found, extending almost from the knee to the ankle joints. There are signs of soft tissue swelling around the ankle joint. Dopplerography reveals intense blood flow in the detected formation.

Blood test dated November 18, 2005: hemoglobin - 127 g/l, er. - 4.64 X 1012/l, l. - 8.12 X 109/l, tr. - 111 X 109/l, pal. - 6%, seg. - 42%, eoz. - 3%, lymph. - 39%, mon. - 10%.

During the biochemical blood test, a slight increase in glucose content was constantly noted - 6.6-6.7 mmol/l (norm up to 6.1), total bilirubin - 23-25 ​​µmol/l (norm up to 20), a decrease in the level of total protein - 61 -62 g/l (normal 66-87) and a constantly elevated level of lactate dehydrogenase (LDH) - from 625 to 734 units/l (normal up to 450).

Myelogram dated 11/18/05. The bone marrow is moderately cellular, granulocytic and erythroid lineages are narrowed (the sum of granulocytes is 53.6%, the sum of erythroid cells is 12.6%), lymphocytes, mainly mature forms, make up

31.4%. The immunophenotype is characteristic of B-CLL: CD19+CD23+-

45.6%, CD19+CD5+ - 49%. Noteworthy was the high content of lymphocytes expressing the CD38 antigen - 62.9%.

Cytogenetic study (FISH method) revealed 11q deletion in 52% of cells, and deletion in 23% of cells

When determining the mutational status of the genes of the variable region of the heavy chains of immunoglobulins, a clonal rearrangement of the VH genes of the third family was revealed. The variable region is encoded by the genes VH3-64, D3-3, JH6. When comparing the patient's existing and germinal sequence of the VH3-64 gene, the degree of homology was 96.9%. This indicates the presence of somatic mutations of the VH genes (in the absence of such mutations, the degree of homology of the studied and germline genes is 99-100%).

A trepanobiopsy of the ilium revealed hypercellular bone marrow due to interstitial proliferation of lymphoid cells such as small lymphocytes and numerous prolymphocytes.

Immunocytological examination of a skin biopsy revealed a pronounced polymorphic cellular lymphoid infiltrate. Small lymphoid cells are represented by T lymphocytes, among which CD8-positive cells are predominantly found. The tumor infiltrate is represented by B cells with the immunophenotype CD19+CD20+CD21- CD5+CD10-CD23-. Compared to bone marrow cells, tumor infiltrate cells in the skin are large in size and lack CD23 and CD21 antigens. Expression of the CD38 marker is maintained on most cells. The B-cell immunophenotype of tumor cells, weak expression of the CD20 antigen, typical of CLL, expression of the CD5 antigen in combination with the loss of the CD23 antigen made it possible to regard changes in the dermis as a manifestation of the development of large B-cell lymphoma in a patient with CLL.

A histological examination of a skin biopsy in all parts of the dermis and hypodermis revealed a massive infiltrate of lymphoid cells such as small lymphocytes and prolymphocytes, and an increased number of discretely located paraimmunoblasts. Immunohistochemical examination revealed expression of CD45, CD20, IgM, Bcl2 antigens by lymphoid cells in the infiltrate, focal expression of CD23, and weak expression of CD21. Ki 67 is expressed by 20-25% of cells. The indicated morphological and immunohistochemical data also made it possible to interpret the detected changes as the initial manifestations of the development of Richter syndrome - large cell lymphoma.

The patient was treated with DHAP (cisplatin 200 mg, high doses of cytarabine - 8000 mg, dexamethasone 80 mg), EMVP (methotrexate 2000 mg, etoposide, vincristine, prednisolone), MINE (mesna, iphosphomide, mitoxantrone, etoposide), high doses of methotrexate in mono mode. The use of each of these regimens gave only a short-term effect (no more than 2-3 days) of reducing the size of tumor formations (Fig. 2).

When re-examining the myelogram on 03/09/06, a small number of lymphoid elements were detected

(6%) large monstrous cells of irregular shape. The shape of the nuclei of these cells is folded, the chromatin structure is delicate. The nuclei contain one large nucleolus. The color of the cytoplasm of these cells is moderately or clearly basophilic, and some cells have vacuolization. The grain size is not determined. These cells were considered to be large cell lymphoma cells.

Despite ongoing treatment, the patient’s condition gradually worsened, with rising temperatures, heavy sweats, and increasing weakness. The patient was discharged from the clinic in March 2006 and soon died in the hospital at his place of residence due to bleeding from one of the tumor formations. An autopsy was not performed at the request of the relatives.

DISCUSSION

The case presented concerns a patient who was diagnosed with CLL at the age of 48 years, for which he received multiple courses of therapy, including alkylating drugs, purine analogues, anthracyclines and monoclonal antibodies. After 4 years, the patient developed Richter's syndrome with skin lesions. The treatment turned out to be ineffective.

As is known, the average age of patients with CLL, according to various authors, is 65-69 years. Despite the general rarity of Richter syndrome, some authors note its more frequent development in young patients.

Thus, in a study that included 1011 patients with CLL, the overall incidence of Richter syndrome was 2.2%, while in patients under 55 years of age it was 5 times more common than in patients of older age groups: 5.9 and 1.2% respectively (p< 0,00001).15

In our patient, a large number of prolymphocytes were found in the bone marrow trephine upon admission to the chemotherapy department for hemoblastosis of the Russian Cancer Research Center (4 years from the onset of the disease), which is usually not found in patients with a favorable course of CLL and is a poor prognostic sign. Since the patient did not undergo a bone marrow trephine biopsy before admission to the Russian Cancer Research Center, it is unknown whether prolymphocytes were in the trephine at the beginning of the disease or appeared at a later stage as a sign of a change in the nature of the disease.

The role of an increase in the number of prolymphocytes in the prognosis of CLL is shown in the work of Y. Ma et al.16 Periodically examining bone marrow punctures of patients with CLL, the authors noted that in a number of patients, over time, among a large number of typical lymphocytes, individual large cells with nucleoli were found, larger than the usual size lymphocyte by 2 times, and sometimes the size of the prolymphocytes found in CLL. The analysis showed that in cases where there were more than 7% of such cells, the life expectancy of patients was significantly shorter than that of the others. Having analyzed the significance of various signs for the prognosis of CLL using a large number of observations, the authors noted that the life expectancy of 78 patients in whom the number of large cells exceeded 7% was the same as the life expectancy of 29 patients with Richter syndrome in the study group.

Our patient had chromosomal aberrations associated with a poor prognosis: deletion of 11q and deletion of 17p, causing partial loss of the Tr53 gene, which ensures the stability of the cellular genome.

Of the chromosomal aberrations characteristic of CLL, the most significant for the development of Richter syndrome are, in all likelihood, trisomy of chromosome 12 (+12) and deletion of the long arm of chromosome 11 (11q-). E. Matutes et al,17 examined 544 patients with CLL and found trisomy 12 in 53% of patients with large cells in the bone marrow and only in 9.7% (p< 0,001) без таких клеток. У нашего больного

Clinical oncohematology

Richter syndrome

there was no trisomy 12, but there was an 11q- deletion in 52% of the cells examined. The significance of 11q23 deletion in CLL is well known. Patients with this chromosomal aberration are often considered to have a “tumor form of CLL”, since they are characterized by significant enlargement of lymph nodes, especially in the abdominal cavity and mediastinal, and, according to our observations, also in the submandibular and cervical supraclavicular areas. Y. Zhu et al,18 examined 161 patients with various lymphoproliferative diseases and diagnosed Richter syndrome in three patients with CLL, and all of them had a deletion of 11q23.

Some authors note that deletion of 11q23 occurs almost exclusively in patients with CLL in whom the IgVH genes do not show signs of somatic hypermutations, 19 but in our patient, a study of the mutational status of these genes revealed the presence of such mutations.

It should be emphasized that our patient had two unfavorable chromosomal abnormalities - deletion 11q and deletion 17p. As is known, simultaneously various karyotype abnormalities in Richter syndrome occur much more often than in CLL.16,20 The importance of combined karyotype abnormalities for the development of Richter syndrome is confirmed by the work of E. Matutes et al,17 who found that in a group of patients with trisomy 12 and at the same time other chromosomal aberrations, large cells with atypical morphology were found in 70% of patients, while in patients with trisomy 12 as the only chromosomal aberration - only in 40%.

As already mentioned, before the development of Richter syndrome from May 2002 to June 2005, our patient repeatedly received treatment with a combination of various drugs: 6 cycles of COP, followed by maintenance therapy with cyclophosphamide for 6-7 months, then 3 cycles including Mabthera, mitoxantrone, fludarabine, cyclophosphamide, dexamethasone, and 3 cycles of the same therapy without MabThera, then maintenance therapy with cyclophosphamide for 2-3 months, followed by 3 courses of treatment with a combination of MabThera and fludarabine. Skin changes first appeared in the patient during the first course of treatment with MabThera and Fludarabine.

Some observations indicate an increase in the incidence of Richter's syndrome with increasing intensity, number of courses and number of different chemotherapy regimens. Thus, at the MD Anderson Cancer Center from 1972 to 1992, 1374 patients with CLL were observed. Richter syndrome developed in 39 of them, which amounted to 2.8%.8 In the next 10 years, from 1992 to 2002, 2147 patients with CLL were observed in the same center, Richter syndrome developed in 105 of them, which amounted to 4.9 %. The incidence of Richter syndrome was significantly higher in patients who received more than two different chemotherapy regimens for CLL.15 Of course, when assessing the role of previous treatment in the development of Richter syndrome, one cannot fail to take into account that 2-3 or more different therapy regimens are received by patients with progressive and poorly treatable CLL, in which the development of Richter syndrome is generally more common.

In recent years, some researchers have noted a more frequent development of Richter's syndrome in patients receiving purine analogues for the treatment of CLL. Thus, the publication by S. Tabuteau et al20 reported that Richter syndrome was observed in 6% (37 out of 620) of patients receiving fludarabine, which was significantly higher than the incidence of this syndrome in the group of patients treated with combinations of drugs that did not contain fludarabine. An even higher incidence of Richter's syndrome in patients treated with fludarabine was noted by P Thornton et al:21 for 10 years, from 1990 to 2000, treatment with fludarabine or fludarabine in combination.

101 patients received treatment with other drugs (most often with cyclophosphamide and mitoxantrone). Richter syndrome developed in 12 (12%) of them. This is one of the highest rates of development of Richter's syndrome in CLL known to us from publications. None of the 12 patients had skin lesions. It should be noted that only one of these patients received fludarabine as the first treatment, the rest - as the second or third line of therapy after treatment with chlorambucil, prednisolone, and anthracyclines. In 6 out of 12 patients, Richter's syndrome developed within four months after the end of treatment with fludarabine. The same rapid development of Richter's syndrome was observed after treatment of patients with CLL and follicular lymphoma with a combination of fludarabine, cyclophosphamide and MabThera

Y. Cohen et al.22

Nevertheless, the role of purine analogues and monoclonal antibodies in the development of Richter's syndrome cannot be considered proven based on the above studies, since there are also opposing data. Thus, L. Robertson et al8 reported the development of Richter syndrome in 22 (3.4%) of 649 patients with CLL treated with purine analogues, and in 17 (2.3%) of 725 patients treated only with alkylating drugs, which does not account for statistically significant difference. There was no difference in the interval from the start of treatment to the development of Richter's syndrome in different treatment programs. Leporrier et al23, as a result of a large randomized study, also noted no difference in the incidence of Richter syndrome in patients with CLL treated and not treated with purine analogues. T. Robak et al,24 having analyzed the frequency of second tumors and Richter's syndrome in 1487 patients with CLL, of which 251 patients received only cladribine, 913 - alkylating drugs and 323 - both, did not note a significant difference in the frequency of both second tumors and Richter syndrome in these groups: Richter syndrome developed in 1% of patients treated with cladribine, in 0.9% of those treated with alkylating agents, and in 0.6% of patients treated with both treatment regimens. The same results were obtained by B. Cheson et al,25 who analyzed the frequency of second tumors and Richter syndrome in 2014 patients with CLL.

The pathogenesis of Richter syndrome is not entirely clear to date. Epstein-Barr virus (EBV) is given some importance in its development. It is a lymphotropic virus that infects more than 90% of the world's population.26 EBV has been shown to induce the proliferation of B lymphocytes in vitro, blocking the apoptosis pathways of these cells by increasing the expression of the BCL-2 protein.27 Cells infected with EBV are less dependent on the action of immune factors and therefore can survive longer.28 Patients with Richter syndrome infected with EBV have a particularly rapid progression and resistance to therapy.29 Increased proliferation of EBV-infected cells contributes to the occurrence of genomic aberrations in them.

It is known that diffuse large cell lymphoma in Richter syndrome develops from the same clone as CLL in 2/3 of patients.19 In other cases of Richter syndrome, different clonal affiliations of CLL and diffuse large cell lymphoma are found. Recent studies30 have confirmed a previously established fact:31 the true transformation of CLL into diffuse large cell lymphoma, i.e., the development of lymphoma from lymphocytes of the same clone that constitutes the substrate of CLL, was found in patients in whom IgVH genes did not undergo somatic mutations. In the same cases when the development of large cell lymphoma occurs in patients with mutated IgVH

www.medprint.ru

M.A. Volkova et al.

genes, as was the case in our patient, lymphoma develops from a different cell clone than CLL. In these cases, the appearance of large cell lymphoma should be regarded as the development of a second tumor in a patient with a defective immune system. There is no doubt that intensive treatment, especially those containing purine analogs, which cause long-term suppression of the T-cell immune system, can contribute to the development of second tumors, especially in patients with chromosomal aberrations, reflecting the instability of the cellular genome.

When skin lesions develop as the first manifestation of CLL, they usually respond well to drugs used to treat CLL and low-grade lymphomas. E. Robak et al11 described a patient whose reason for visiting a doctor was the appearance of dense infiltrates on the skin. Examination of the patient showed that he had CLL, and morphological and immunological studies established the specific nature of the skin infiltrates and the belonging of lymphocytes from the infiltrates and lymphocytes of the patient’s bone marrow to the same clone. Treatment with cladribine led to normalization of the blood picture and the disappearance of skin infiltrates. The successful use of local ultraviolet irradiation for the treatment of specific skin lesions in CLL has been described.32

Rarely described cutaneous T-cell tumors (mycosis fungoides, Sézary syndrome) that develop in patients with CLL usually have a similar course and treatment as in patients without CLL.33-35

At the same time, the treatment of Richter syndrome remains a difficult problem, regardless of the location of the developed large cell lymphoma. As a rule, remission is rarely obtained, and the life expectancy of patients from the time of development of Richter syndrome is estimated at five to eight months. L. Robertson et al,8 using intensive treatment regimens (CHOP-BLEO, MACOP-B, AHAP, PFA) to treat 39 patients with Richter syndrome, obtained an effect in 16 (42%) patients, and complete remissions were achieved in 10 patients . However, the median life expectancy from the time of development of Richter syndrome was only 5 months. Only three patients lived for more than 1 year, and in all of them Richter's syndrome was diagnosed as the first manifestation of the disease, and they had not previously received any treatment. In the observations of T.Han et al36, one of three patients with Richter syndrome lived for more than three years. His Richter syndrome was also the first reason for seeing a doctor, and he had not previously received any treatment for CLL. In the observations of L. Robertson et al8, the longest life expectancy for Richter syndrome was achieved in patients for whom fludarabine was used: 17 months on average, while in patients treated without fludarabine - 5 months. With this in mind, MD Anderson Cancer Center developed a treatment regimen containing fludarabine, cytosine arabinoside, cyclophosphamide, cisplatin, and granulocyte-macrophage colony.

estimulating factor (GM-CSF). However, this treatment regimen turned out to be not only toxic, but also ineffective: complete remission was achieved in only one of 16 patients.37 Slightly better results were obtained using a regimen developed at MD Anderson Cancer Center, which the authors called hyper-CVAD: high doses of cyclophosphamide , vincristine, liposomal form of daunorubicin, dexamethasone, Mabthera and GM-CSF. Remissions were achieved in 43% of patients, including complete remissions in 27% (8 out of 30). The average duration of remissions was 8.5 months, 9 patients lived for 12 months, but 18% of patients died from treatment-related complications.38,39

Experience with hematopoietic stem cell (HSC) transplantation for Richter syndrome is still limited. J. Rodriguez et al40 published data on eight patients with Richter syndrome who underwent allogeneic HSC transplantation, including two patients from an unrelated donor. The average duration of CLL before the development of Richter syndrome was 48 months. All patients with CLL, and then due to the development of Richter's syndrome, received 2-5 different treatment courses, including those containing fludarabine. During the first 30 days after transplantation, 5 of 8 patients died from infectious complications. At the time of publication, 3 patients, including 2 who received unrelated donor transplantation, were in complete remission for 14, 47, and 67 months. In a very interesting observation by I. Español et al41, a patient with CLL underwent allogeneic HSC transplantation. Four months later, he developed a relapse of CLL and was simultaneously diagnosed with diffuse large cell lymphoma. After complete cessation of immunosuppressive therapy and several infusions of donor lymphocytes, complete remission of both CLL and lymphoma was achieved, which lasted 18 months at the time of publication.

CONCLUSION

Thus, Richter's syndrome remains a disease, the pathogenesis of which is not fully understood, and therapy has not been developed.

LITERATURE

1. Cerroni L, Zenahlik P, Hofler G et al. Specific cutaneous infiltrates of B-cell chronic lymphocytic leukemia: a clinicopathologic and prognostic study of 42 patients. Am J Surg Pathol. 1996; 20:1000-10.

2. Agnew KL, Ruchlemer R, Catovsky D et al. Clinical and laboratory investigations cutaneous findings in chronic lymphocytic leukemia. Br J Dermatol. 2004; 150:1129-35.

3. Cerroni L, Hofler G, Back B et al. Specific cutaneous infiltrates of B-cell chronic lymphocytic leukemia (B-CLL) at sites typical for Borrelia burgdorferi infection. J Clin Pathol. 2002; 29:142-7.

4. Artz L, Tappeiner J Atlas der Haut und Ge-schlechtkrankheiten. Wien, Urban und Schwarzenberg; 1953.

5. Robak E, Robak T, Biernat W et al. Successful treatment of leukemia cutis with cladribine in a patient with B-cell chronic lymphocytic leukemia. Br J Dermatol. 2002; 147:775-80.

6. Richter MN. Generalized reticular-cell sarcoma of lymph nodes associated with lymphatic leukemia. Am J Pathol. 1928; 4:285-92.

7. Lorhalary P, Boiron M, Ripault J et al. Chronic lymphoid leukemia secondarily associated with a malignant reticulopathy: Richter’s syndrome. Nouv Rev Fr Hematol. 1964; 78:621-44.

8. Robertson LE, Pugh W, O'Bien S et al. Richter's syndrome: a report on 39 patients. J Clin Oncol. 1993; 11:1985-9.

9. Morrison VA, Rai KR, Peterson BL et al. Transformation to Richter’s syndrome or prolymphocytic

Clinical oncohematology

Richter syndrome

leukemia (PLL): an Intergroup study (CALGB9011). Blood 1999; 94:539a.

10. Mauro FR, Foa R, Giannarelli D et al. Clinical characteristics and outcome of young chronic lymphocytic leukemia patients: a single institution study of 204 cases. Blood 1999; 94:448-54.

11. Robak E, Gora-Tybor J, Kordek R et al. Richter syndrome first manifesting as cutaneous B-cell lymphoma clonally distinct from primary B-cell chronic lymphocytic leukemia. Br J Dermatol. 2005; 153:833-7.

12. Ratnavel R, Dunn-Walters DK, Boursier L et al. B-cell lymphoma associated with chronic lymphatic leukemia: two cases with contrasting aggressive and indolent behaviuor. Br J Dermatol. 1999; 140:708-14.

13. Zarco C, Lahuerta-Palacios JJ, Borrego L et al. Centroblbastic transformation of chronic lymphocytic leukemia with primary skin involvement - cutaneous presentation of Richter syndrome. Clin Exp Dermatol. 1993; 18:263-7.

14. Fraitag S, Bademer C, Rousselot P et al. Cutaneous transformation of chronic lymphoid leukemia into immunoblastic lymphoma. Cutaneous manifestation of Richter's syndrome. Ann Dermatol Venerol. 1995; 122:530-3.

15. Tsimberidou A-M, Keating MJ. Richter Syndrome. Biology, incidence, and therapeutic strategies. Cancer 2005; 103:216-28.

16. Ma Y, Mansour A, Bakele BN et al. The clinical significance of ladge cells in bone marrow in patients with chronic lymphocytic leukemia. Cancer 2004; 100:2167-75.

17. Matutes E, Oscier D, Garcia-Marco J et al. Trisomy 12 defines a group of CLL with atypical morphology: correlation between cytogenetic, clinical and laboratory features in 544 patients. Br J Haematol. 1996; 92:382-8.

18. Zhu Y, Monni O, Franssila K et al. Deletions at 11q23 in differents lymphoma subtypes. Haematologica 2000; 85:908-12.

19. Krober A, Seiler T, Benner A et al. VH mutation status, CD38 expression level, genomic aberrations, and survival in chronic lymphocytic leukemia. Blood 2002; 100:1410-6.

20. Tabuteau S, Fernandez J, Garidi R et al. Richter’s syndrome in B-CLL: report of 37 cases. Blood 1999; 94:306b.

21. Thornton PD, Bellas C, Santon A et al. Richter’s transformation of chronic lymphocytic leukemia. The possible role of fludarabine and the Ep-stein-Barr virus in its pathogenesis. Leukemia Res. 2005; 29:389-95.

22. Cohen Y, Da'as N, Libster D et al. Large-cell transformation of chronic lymphocytic leukemia and follicular lymphoma during or soon after treatment with fludarabine-rituximab-containing regimens: natural history or therapy-related complication. Eur J Haematol. 2002; 68:80-3.

23. Leporrier M, Chervet S, Cazin B et al. Randomized comparison of fludarabine, CAP, and CHOP in 938 previously untreated stage B and C chronic lymphocytic leukemia patients. Blood 2001; 98:2319-25.

24. Robak T, Blonski JZ, Gora-Tybor J et al. Second malignancies and Richter syndrome in patients with chronic lymphocytic leukemia treated with cladribine. Eur J Cancer 2004; 40:383-9.

25. Cheson BD, Vena DA, Barrett J et al. Second malignancies as a consequence of nucleoside analog therapy for chronic lymphoid leukemia. J Clin Oncol. 1999; 17:2454-60.

26. Gratama JW, Ernberg Y. Molecular epidemiology of Epstein-Barr virus infection. Adv Cancer Res. 1995; 67:197-255.

27. Fagard R, Mouas H, Dusanter-Fourt Y et al. Resistance to fludarabine-induced apoptosis in Ep-stein-Barr virus infected B cells. Oncogene 2002; 21;4473-80.

28. Thompson MP, Kurzrock R. Epstein-Barr virus and cancer. Clin Cancer Res. 2004; 10:803-21.

29. Ansell SM, Li CY, Lloyd RV et al. Epstein-Barr virus infection in Richter transformation. Am J Hematol. 1999; 60:99-104.

30. Timar B, Fulop Z, Csermus B et al. Relationship between the mutational status of VH genes and pathogenesis of diffuse large B-cell lymphoma in Richter;s syndrome. Leukemia 2004; 18:326-30.

31. Cherepakhin V, Bair SM, Meisenholder GW, Kipps TJ. Common clonal origin of chronic lymphocytic leukemia and high-grade lymphoma of Richter syndrome. Blood 1993; 82:3140-7.

32. Porter WM, Sidwell RU, Catovsky D et al. Cutaneous presentation of chronic lymphatic leukemia and response to ultraviolet B phototherapy. Br J Dermatol. 2001; 144:1086-99.

33. Hull PR, Saxena A. Mycosis fungoides and chronic lumphocytic leukemia - composite T-cell and B-cell lymphomas presenting in the skin. Br J Dermatol. 2000; 143:439-44.

34. Grange F, Avril M-F, Esteve E et al. Coexistent cutaneous T-cell lymphoma and B-cell malignancy. J Am Acad Dermatol. 1994; 31:724-31.

35. Daenen S, van Voorst Vader PC, Blomm N et al. Clonal chronic lymphocytic leukemia-like B-lymphocytes in the blood of patients with cutaneous T-cell disorders. Br J Haematol. 1993; 85:307-12.

36. Han T, Barcos M, Gomez GA et al. Clinical, immunological and cytogenetics studies in chronic lymphocytic leukemia with large cell lymphoma transformation (Richter’s syndrome). Proc Am Soc Clin Oncol. 1988; 7:185.

37. Dabaja BS, O'Brien SM, Kantarjian HM et al. Fractionated cyclophosphamide, vincristine, liposomal daunorubicin, and dexametasone regimen in Richter’s syndrome. Leuk Lymphoma 2001; 42:329-37.

38. Tsimberidou AM, O'Brien SM, Cortes JE et al. Phase II study of fludarabine, cutarabine, cyclophosphamide, cisplatin and GM-CSF in patients with Richter’s syndrome or refractory lumphoproliferative disorders. Leuk Lymphoma 2002; 43:767-72.

39. Tsimberidou AM, Kantarjian HM, Cortes J et al. Fractionated cyclophosphamide, vincristine, liposomal daunorubicin, and dexametasone plus rituximab and granulocyte-macrophage-colony stimulating factor (GM-CSF) alternating with methotrexate and cytarabine plus rituximab and GM-CSF in patients with Richter syndrome or flu-darabine-refractory chronic lymphocytic leukemia . Cancer 2003; 97:1711-20.

40. Radriguez J, Keating MJ, O'Brien S et al. Allogenic haematopoietic transplantation for Richter’s syndrome. Br J Haematol. 2000; 110:897-9.

41. Espanol Y, Bichler T, Ferra C et al. Richter’s syndrome after allogenic stem cell transplantation for chronic lymphocytic leukemia successfully treated by withdrawal of immunosuppression, and donor lumphocyte infusion. Bone Marrow Transplant 2003; 31:215-8.