Chronic lymphocytic leukemia is characterized by. Chronic b cell lymphocytic leukemia. Stages of lymphocytic leukemia depending on the form of the disease

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Chronic lymphocytic leukemia (CLL) is the most common type of leukemia in older people in Europe and North America.

The annual incidence of CLL in these countries is 3-3.5 per 100,000 population, with men being affected more often than women.

In Asian and African countries, B-CLL is a rare disease; in Asian countries, T-cell chronic lymphocytic leukemia predominates; an increase in its frequency among Jews was noted.

The average age at onset of the disease is 55 years, about 70% of patients become ill at the age of 50-70 years. The role of the hereditary factor is confirmed by the increased incidence of CLL in blood relatives, both horizontally and vertically.

It was not possible to establish the role of any mutagenic factors in the development of CLL - chemical agents, ionizing radiation, viruses, alkylating drugs. According to the WHO classification (2001), B-cell chronic lymphocytic leukemia belongs to tumors of the peripheral organs of the immune system and, in general, accounts for about 20% of all non-Hodgkin's lymphomas (NHL). CLL in 95% of cases in Europe and the USA has a B-cell phenotype and in 5% of cases a T-cell phenotype.

The immunophenotypic characteristics of B-cell chronic lymphocytic leukemia allow us to consider it as a tumor, the morphological substrate of which is primary activated B-lymphocytes that have undergone primary activation in the paracortical zone of the lymph node. In B-cell CLL, tumor lymphocytes have the phenotype CD3-, CD10-, CD5+, CD19+, CD20+, CD23.

CD5+ expression is an obligatory marker of B-cell CLL, and CD23+ expression allows distinguishing chronic lymphocytic leukemia from leukemia lymphoma of the mantle zone(LZM). Lymphocytes in CLL, as in other forms of NHL, are characterized by weak expression of light chains of surface immunoglobulins. Cytogenetic analysis can detect chromosomal aberrations in many cases of CLL.

The most common markers are trisomy Xp12 (16%), as well as deletions of Xp11q and Xp17p (localization of the p53 tumor suppressor gene). The presence of the last two changes refers to NFP due to the lack of clinical effect from the procedure. polychemotherapy (PCT). In 55% of cases of chronic lymphocytic leukemia, deletion of 13q is detected, which does not affect the prognosis.

The assumption that CLL is a disease of accumulation of long-living immunoincompetent small lymphocytes has been confirmed and explained. It was found that the majority of patients with CLL have overexpression of the BCL-2 gene, which plays a major role in preventing apoptosis, and the level of expression increases as the disease progresses. Another important risk factor is mutation of the genes responsible for the synthesis of heavy chains of immunoglobulins.

Clinical picture

X-ray examination can reveal enlargement of the mediastinal lymph nodes, with ultrasound examination (ultrasound)- enlargement of abdominal and retroperitoneal lymph nodes. An enlarged spleen in most patients appears later than an enlarged lymph node, and the liver enlarges even later. There is no correlation between the degree of lymphoid infiltration of the bone marrow, the level of leukocytes and the size of the lymph nodes, spleen and liver.

Hematological changes are characterized by gradually increasing leukocytosis, sometimes up to 1000.0x10 9 /l and an increase in the number of lymphocytes in the leukogram to 85-99%, usually with the presence of single prolymphocytes. Characteristic of chronic lymphocytic leukemia is the presence in the blood smear of Botkin-Gumprecht cells - lymphocyte nuclei half destroyed during the preparation of the smear.

When examining bone marrow punctate, lymphocytosis is revealed with a decrease in the number of granulocytes and erythrokaryocytes; already in the early stages of the disease, the myelogram reveals an increase in the level of lymphocytes of more than 40% with a gradual (without treatment) increase. Bone marrow biopsy shows nodular, diffuse, or mixed infiltration.

The number of red blood cells, platelets and HB level in the early stages of the disease are usually within normal limits. These indicators in the late stages of CLL are usually reduced either due to a decrease in the foothold of normal hematopoiesis in the bone marrow due to the displacement of healthy germs by pathological lymphocytes, or due to the addition of autoimmune complications such as autoimmune hemolytic anemia (AIGA) or partial red cell aplasia (PRCA). Some patients may develop hemoderma of the erythroderma type due to infiltration of the skin by lymphocytes.

Classification

Stage A: in the presence of blood lymphocytosis of more than 15.0x10 9 /l and more than 40% of lymphocytes in the bone marrow, which allows establishing a diagnosis, the content of HB is more than 100.0 g/l, platelets are more than 100.0x10%, there is an enlargement of lymph nodes in 1-2 areas;

Stage B, the content of HB and platelets is the same as in stage A, but there is an enlargement of lymph nodes in 3 or more areas;

Stage C HB content is below 100 g/l and platelets - less than 100.0x10 9 /l in any number of areas with enlarged lymph nodes and regardless of organ enlargement.

Diagnosis of chronic lymphocytic leukemia

In CLL, in addition to leukemic lymphoid proliferation, quantitative and qualitative changes in both pathological and normal lymphocytes play an important role. Tumor B lymphocytes produce reduced amounts of normal immunoglobulins. A decrease in the number of normal B lymphocytes causes hypogammaglobulinemia, which leads to severe infections.

This problem plays a special role in CLL, since infectious complications remain the main cause of death in patients with CLL even in the absence of signs of progression of the process. The most common infections are respiratory tract infections, bacterial infections of the urinary tract, skin and soft tissues, herpes zoster (often takes a generalized form with the development of confluent skin lesions and spread to internal organs). Treatment of infectious complications in patients with chronic lymphocytic leukemia is carried out according to the general rules for the treatment of infections in patients with decreased immunity.

Another important consequence of immune disorders in CLL are autoimmune complications. AIHA develops most often (in 10-25% of patients), more often with the detection of antibodies of the IgG class, less often - of the IgM class. Very rarely, immune thrombocytopenia develops, which can cause life-threatening hemostatic disorders.

An extremely rare complication is PRCA with a complete absence of erythrokaryocytes in the bone marrow and reticulocytes in the peripheral blood. Cyclosporine A at a daily dose of 150-200 mg or pulse therapy (high doses of corticosteroids + cyclophosphamide) have a good effect in the treatment of PRCA in a number of patients.

Autoimmune processes more often occur in patients with a detailed clinical and hematological picture of CLL. The leading method in their therapy is the use of high doses glucocorticosteroids (GCS), development prevention disseminated intravascular coagulation syndrome (DIC syndrome) for AIHA and, if necessary, transfusion of platelet concentrate for thrombocytopenia.

In CLL therapy, the most important issue is determining the time to start therapy. In stage A according to J.Binnet, i.e. with minimal manifestations of the disease, the “watch and wait” tactic is maintained.

Treatment

The presence of the following signs is necessary for immediate initiation of cytostatic therapy:

The presence of general symptoms of intoxication: fatigue, sweating, weight loss,
- anemia or thrombocytopenia due to leukemic infiltration of bone marrow,
- autoimmune anemia or thrombocytopenia,
- massive lymphadenopathy or splenomegaly with compression syndrome,
- the number of peripheral blood lymphocytes is above 150.0x10%,
- doubling of the absolute number of lymphocytes in the blood in less than 12 months,
- lymphocytic infiltration of BM - more than 80%,
- presence of complex chromosomal aberrations,
- stage C according to J.Binnet.

Since the 60s of the 20th century, the method of primary restraining therapy began to be used for CLL, the task of which was to restrain the growth of the pathological cell clone and prevent the progression of the disease. It was prescribed for moderate clinical and hematological manifestations of the disease: leukocytosis up to 30.0-50.0x10%, minor lymphadenopathy and/or splenomegaly and a tendency for disease progression.

Typically, chlorbutin (Leukeran) was prescribed at a dose of 10-20 mg per week or cyclophosphamide at a dose of 150-200 mg/day, with subsequent dose adjustments depending on the level of leukocytes. However, such therapy (monotherapy or in combination with GCS - chlorbutin 10-20 mg per day + prednisolone 30-70 mg per day in courses of 7-14 days at intervals of 2-1 weeks) allowed only partial remissions, mainly reducing the number of leukocytes without much reduction in the size of the lymph nodes and spleen.

Therefore, since the 70s. In the 20th century, combined treatment regimens were developed. For a long time, the “gold standard” in treatment was PCT according to the COP, CHOP and SAP protocols. They are currently used as second-line therapy or therapy in patients with aggressive forms of CLL. However, randomized studies have shown that long-term disease-free and overall survival when using the above-mentioned PCT protocols did not change significantly in comparison with those when treating with chlorbutine and prednisolone.

The situation in the treatment of CLL changed in the late 80s. XX century in connection with the synthesis and introduction into clinical practice of analogues of purine nucleosides - fludarabine, cladribine and pentostatin. These drugs act on both dividing and quiescent lymphoid cells, which is why they are effective in treating slow-moving lymphomas, which include chronic lymphocytic leukemia.

The drugs inhibit a number of the most important cellular enzymes necessary for the synthesis of RNA and DNA: DNA primase, DNA polymerase, DNA ligase, ribonucleotide reductase. This leads to cessation of synthesis and disruption of the construction of the DNA chain, as well as disruption of RNA synthesis. Currently, the use of purine nucleoside analogues is recommended as first-line therapy in patients with CLL: therapy according to the FC, FCM, FMD protocols.

Bendamustine is used to treat both CLL and relapsed indolent non-Hodgin lymphomas that do not respond to conventional therapy or progress within 6 months after therapy with rituximab. It is currently used to treat NHL, Hodgkin's lymphoma, chronic lymphocytic leukemia, and multiple myeloma.

The chemical structure of bendamustine results in dual effects similar to both alkylating agents and purine nucleoside analogues. The drug activates the p53-dependent stress pathway, leading to apoptosis and inhibition of mitosis control mechanisms. Bendamustine is prescribed at a dose of 120 mg/m2 on days 1-2 every three weeks for a total of 6 cycles of therapy.

To quickly reduce the number of leukocytes, leukocytapheresis can be used.

In recent years, monoclonal antibodies against B- and T-cell antigens (rituximab, alemtuzumab) have been used in clinical practice. Due to the fact that the effect of rituximab is limited by the degree of CD20 expression on CLL cells, therapy according to the FCR protocol is recommended for refractory or relapsing CLL, especially in cases of newly diagnosed chronic lymphocytic leukemia.

Especially in refractory cases (often associated with p53 deletion), alemtuzumab (Campath), an anti-CD52 antibody, is highly effective. It is administered 3 times per week, starting with a minimum dose of 3 mg/day and gradually increasing the dose with each administration until a dose of 30 mg is administered at a frequency of subcutaneous administration 3 times per week.

The use of the FluCam protocol (fludarabine 25 mg/m2 intravenously on days 1-3 + Campath 30 mg 3 times a week for 6 weeks) appears to be more effective, but is fraught with manifestations of severe immunosuppression. Lumiliximab, which is a monoclonal anti-CD23 antigen, can be used to treat patients with relapsed CLL.

It is used in combination with rituximab, cyclophosphamide and fludarabine (L-FCR protocol). Treatment with this protocol effectively reduces the number of tumor cells in the peripheral blood, regardless of the level of CD23 and CD38 expression. The use of small molecule inhibitors of anti-apoptotic proteins of the BCL-2 family, one of which is abatoclax, is effective in the treatment of CLL.

For patients with a large splenic mass and hypersplenism, splenectomy may be recommended. For young patients with an aggressive course of the disease, auto- hematopoietic stem cell transplantation (HSCT); in the presence of an HLA-compatible donor - allo-HSCT or allo- bone marrow transplantation (BMT).

Chronic lymphocytic leukemia(CLL, small lymphocyte lymphoma or lymphocytic lymphoma) is a clonal lymphoproliferative neoplastic disease characterized by proliferation and an increase in the number of mature lymphocytes in the peripheral blood against the background of lymphocytic infiltration of the bone marrow, lymph nodes, spleen and other organs.

The annual incidence of chronic lymphocytic leukemia in Europe and North America is 3–3.5 per 100,000 population, and among people over 65 years of age - up to 20 per 100,000. Men are affected more often than women (2:1).

Diagnostics. An assumption about the presence of chronic lymphocytic leukemia can be made on the basis of changes in the blood picture - the presence of leukocytosis with relative and absolute lymphocytosis. It is believed that lymphocytic leukemia should be suspected already when the absolute number of lymphocytes in the blood is more than 5.0x10 9 /l.

According to modern criteria established by the International Workshop in 1989. To make a diagnosis of chronic lymphocytic leukemia, three signs must be present:

1) the absolute number of blood lymphocytes exceeding 10.0 10 9 /l;

2) detection of more than 30% of lymphocytes in bone marrow puncture;

3) immunological confirmation of the presence of a B-cell clone of leukemic lymphocytes.

In the B-cell variant of the disease, expression of B-cell antigens CD 19, CD 20, CD 24 and activation antigens CD 5 and CD 23 is detected on the surface of leukemic lymphocytes. The immunological characteristics of B-cell CLL allow us to consider it as a tumor, the morphological substrate of which is primary activated B-lymphocytes. Primary activation (first encounter with antigen) of B-lymphocytes occurs in the paracortical zone of the lymph node, therefore, according to the latest classifications of lymphoid tumors (WHO), B-cell CLL is classified as a tumor of the peripheral organs of the immune system.

B lymphocytes in CLL, unlike normal B lymphocytes, are also characterized by weak expression of surface immunoglobulins. Typically, IgM is detected on the surface of B lymphocytes in CLL, often simultaneously with IgD. In this case, the immunoglobulin molecules of both classes have the same light chains, idiotypes and variable parts, i.e. belong to the same cell clone. Like normal B lymphocytes, in B-CLL the lymphocytes form rosettes with mouse red blood cells. Expression of CD 5 antigen, weak expression of surface immunoglobulins, and rosette formation with mouse erythrocytes are considered the most important immunological characteristics of B lymphocytes in B-CLL. The number of T-lymphocytes in patients with B-CLL can be normal, increased or decreased, but the ratio of T-helper and T-suppressor cells is often disturbed and the number of T-killer cells decreases.

Numerous epidemiological studies have so far failed to assess the role of any mutagenic factors (radiation, chemical agents or alkylating drugs, etc.), as well as the role of the Epstein-Barr virus, in the occurrence of chronic lymphocytic leukemia. At the same time, it has been established that non-random chromosomal aberrations, which usually arise under the influence of mutagens, are observed in the majority of patients with CLL. According to the VIII International Workshop on CLL (1999), the FISH method can detect them in almost 90% of patients. The most common structural chromosomal aberration is deletion of the long arm of chromosome 13 (13q-). It is detected in 55% of patients with CLL. 18% of patients have a deletion of the long arm of chromosome 11 (llq-), 7% have a deletion of the short arm of chromosome 17 (17p-), and 6% have a deletion of 6q-. In 4% of cases, translocations involving chromosome 14 (14q32) are detected. 8-10% have elongation of the long arm of chromosome 14 (14q+).

Deletion of llq- affects the location of the ATM gene (ataxia-telangiectasia gene), which is involved in the control of the cell division cycle. Loss or reduction of ATM gene production can lead to tumor development. The median survival of patients with CLL with the presence of llq- is 2-3 times shorter than that of patients without this anomaly. Deletion 17p - covers exons 5-9 of the short arm of chromosome 17, where the gene is located p53 – tumor suppressor. Only 13q- does not affect the prognosis; the remaining chromosomal aberrations have an adverse effect on the course of the disease (see Appendix No. 2).

Clinical picture. Chronic lymphocytic leukemia begins gradually and in most cases progresses slowly in the early stages. As the disease progresses, leukocytosis gradually increases, while at the same time the number of lymphocytes in the leukocyte formula gradually increases to 75-85-99%. Mature forms predominate, but, as a rule, 5-10% of prolymphocytes and often 1-2% of lymphoblasts are found. The number of red blood cells, hemoglobin content and the number of platelets in the early stages of the disease are often normal, but with high leukocytosis and significant lymphocytosis they are usually reduced either due to the displacement of healthy sprouts by pathological lymphocytes, or due to the addition of autoimmune complications. CLL is characterized by the presence of Gumprecht-Botkin shadows in the blood smear - half-destroyed during the preparation of the smear, blurred nuclei of lymphocytes. When examining bone marrow aspirate from a patient with CLL, an increase in the number of lymphocytes up to 40-50-60% is detected already in the early stages of the disease. Hematological changes may be the only manifestation of the disease at the time of diagnosis, but in most cases, even with mild changes in the blood, it is possible to detect a slight enlargement of the lymph nodes. Over time, the vast majority of patients experience a slow generalized enlargement of the lymph nodes, which have a doughy consistency and are completely painless without infection. An X-ray examination at this time, as a rule, reveals an increase in the lymph nodes of the mediastinum, and an ultrasound examination reveals an increase in nodes in the abdominal cavity and retroperitoneal space. The size of the nodes in different patients and even in one patient in different areas can vary widely - from 1.5-2 to 10-15 cm in diameter. Histological examination reveals blurring of the structure of the lymph node and diffuse infiltration of lymphocytes and prolymphocytes.

An enlarged spleen in most patients appears later than an enlarged lymph node, and only in some of them reaches enormous sizes. Even later, the liver usually enlarges. However, in some patients, the enlargement of the spleen and (or) liver is expressed throughout the entire disease.

The rate of disease development, the rate of increase in the number of leukocytes, the size of the lymph nodes and spleen in CLL varies widely.

In chronic lymphocytic leukemia, in the development of the disease and its clinical manifestations, in addition to leukemic lymphoid proliferation, quantitative and qualitative changes in both pathological and normal lymphocytes play an important role. It is known that leukemic B-lymphocytes in CLL are little sensitive to antigenic stimuli and produce a reduced amount of normal immunoglobulins. At the same time, the number of normal B lymphocytes is sharply reduced, which leads to hypogammaglobulinemia characteristic of CLL, which worsens as the disease progresses. Reduced immunoglobulin levels, often a reflection of the inability of leukemic B lymphocytes to produce antibodies, usually correlate with the frequency of bacterial infections. In addition, even in patients with a normal number of T-lymphocytes and natural killer cells (NK-cells), their function is sharply reduced, which also contributes to the tendency to repeated infections and their severe course characteristic of chronic lymphocytic leukemia. The most common infections are respiratory tract infections (bronchitis, pneumonia, pleurisy), which account for more than half of the infectious diseases in CLL. Pneumonia in CLL tends to spread to both lungs. It should be emphasized that in the initial stages of the development of pneumonia in a patient with CLL, physical data are often scant, therefore, if fever occurs, it is necessary to immediately conduct an X-ray examination. Bacterial or fungal infections of the urinary tract, skin and soft tissues with the development of abscesses and phlegmon, herpes zoster are also quite common. Often there is a combination of several infectious foci - pneumonia, infections of soft tissues, skin, ending with a picture of sepsis.

Another important consequence of immune disorders in CLL is the occurrence of autoimmune complications. Autoimmune hemolytic anemia develops most often, ranking second (after infections) among complications characteristic of CLL. A positive antiglobulin test (Coombs test) is detected in 20-35% of patients, but autoimmune hemolytic anemia develops during the course of the disease in 10-25%. Autoimmune thrombocytopenia occurs much less frequently, occurring in approximately 2-3% of patients. However, it is more dangerous than autoimmune anemia, since a sharp decrease in the number of platelets often leads to life-threatening bleeding. Less common is partial red cell aplasia, characterized by severe anemia with a decrease in hematocrit to 25-20% in the absence of reticulocytes in the blood and the almost complete absence of erythrokaryocytes in the bone marrow. Antibodies against neutrophils appear even less frequently.

Exist two modern classifications of CLL, reflecting the stages of the disease. One of them was proposed in 1975. K. Raiet al. (Table 5).

Table 5. Classification of CLL according toK. Raiet al.

Another was proposed in 1981 . J. Binetet al.(Table 6).

Table 6.Classification of CLL according toJ. Binetet al.

Currently, these 2 classifications are used to evaluate and compare the results of therapy.

Treatment. The most important issue in the treatment of CLL is the question of the time of initiation of treatment, since the rate of development of the disease, the rate of increase in the number of leukocytes, the size of lymph nodes and the spleen in CLL fluctuate widely. The patient does not need treatment only as long as stage 0–I no K.Rai or A according to J.Binet remains stably. The following indications for immediate initiation of cytostatic therapy are currently considered generally accepted and are given in all guidelines:

1) the presence of “general” symptoms – fatigue, sweating, loss of body weight;

2) anemia or thrombocytopenia caused by infiltration of the bone marrow by leukemic cells;

3) autoimmune anemia or thrombocytopenia;

4) massive lymphadenopathy or splenomegaly, creating compression problems;

5) a large number of lymphocytes in the blood (above 150.0 10 9 /l);

6) doubling of the absolute number of lymphocytes in the blood in less than 12 months;

7) increased susceptibility to bacterial infections;

8) massive lymphocytic infiltration of the bone marrow (more than 80% of lymphocytes in the myelogram);

9) the presence of complex chromosomal aberrations;

10) advanced stage of the disease (stage C according to J. Binet, III–IV according to K. Rai).

Most hematologists begin treatment of a patient already with signs of stage B according to J. Binet or I–II according to K. Rai, without waiting for symptoms of decompensation to appear.

The modern era in the treatment of CLL began in the mid-20th century. In 1949 O.Pearson et al. first reported a decrease in lymphoid proliferation in CLL under the influence of steroid hormones. The second most important event in the development of CLL therapy was the advent of alkylating drugs. The first of them, a derivative of nitrogen mustard - chlorambucil (chlorobutin, leukeran) was synthesized in 1953. J. Everett et al, which was successfully used. Following chlorambucil, a number of alkylating drugs were synthesized and tested in the treatment of CLL: cyclophosphamide, degranol, dipin, fotrin, paphencil, etc., of which only cyclophosphamide remains important to this day.

In the treatment of primary patients with CLL, the most preferred drug in monotherapy is fludarabine However, in older patients with an unfavorable clinical status and concomitant chronic inflammatory diseases or recurrent infection, therapy should be started with chlorambucil. Fludarabine is currently the most active agent for the treatment of CLL. It is administered intravenously daily for 5 days every 28 days at the rate of 25 mg/m2. Patients who do not respond to 2-3 cycles of fludarabine treatment should generally be switched to alternative therapy programs. In patients with partial remission, treatment with fludarabine can be continued (1-2 cycles) until a more significant therapeutic effect is obtained, if there is no threat of myelotoxicity or infectious complications. As a rule, the therapeutic effect is observed after 3-6 cycles of fludarabine therapy. Complete remissions are achieved in approximately 30% of untreated CLL patients, with overall positive responses exceeding 70%.

The desire to improve existing results led to the creation in the 70-80s of combined treatment regimens based on alkylating drugs (most often cyclophosphamide). The most widely used regimens are COP, CHOP and CAP, which have become the gold standard in the treatment of lymphomas and have been tested in large groups of patients with chronic lymphocytic leukemia.

cyclophosphamide - 400 mg/m2 per day intravenously or intramuscularly from days 1 to 5

vincristine - 1.4 mg/m2 (but not more than 2 mg) intravenously on day 1

CHOP:

cyclophosphamide - 750 mg/m2 intravenously on day 1

vincristine - 1.4 mg/m2 intravenously on day 1

prednisolone - 60 mg/m2 orally from 1st to 5th day

cyclophosphamide - 500 mg/m2 intravenously on day 1

adriamycin - 50 mg/m2 intravenously on day 1

prednisolone - 60 mg/m2 orally from 1st to 5th day

The intervals between cycles are 21-28 days, depending on blood counts. The dosages of individual drugs in these regimens sometimes vary. Different authors carry out from 6 to 12 cycles, trying to obtain the maximum effect.

Criteria for the effectiveness of CLL therapy presented in table 7.

Table 7.Criteria for assessing response to CLL therapy

Bone marrow transplantation has limitations in CLL (age and concomitant diseases).

Splenectomy indicated for patients with CLL with autoimmune anemia, thrombocytopenia with low effectiveness of corticosteroid therapy, or for patients with severe splenomegaly with clinical signs of compression of internal organs and ineffective chemotherapy.

Patients with low risk of aggressive the course of the disease for many years does not require cytostatic treatment and, as a rule, they die from causes not related to CLL; Spontaneous remissions have been described in patients with CLL. In patients With intermediate risk During the course of the disease, a stable clinical picture may also be observed over a long period of time, while another part of patients with CLL dies from CLL several months after verification of the diagnosis, despite therapy. Death in patients with lymphoma occurs more often from infectious and hemorrhagic complications that develop with the progression of the disease, as well as complications of cytostatic therapy.

For many people, the diagnosis of lymphocytic leukemia or blood cancer sounds like a death sentence. But few people know that over the past 15 years a powerful drug arsenal has appeared in medicine, thanks to which it is possible to achieve long-term remission or the so-called “relative cure”, and even the abolition of pharmacological drugs.

What is lymphocytic leukemia and what are the causes of its occurrence?

This is a cancer that affects leukocytes, bone marrow, peripheral blood, and lymphoid organs are involved in the process.

Scientists are inclined to believe that the cause of the disease is at the genetic level. The so-called family predisposition is very pronounced. It is believed that the risk of developing the disease in close relatives, namely children, is 8 times higher. However, no specific gene causing the disease was found.

The disease is most common in America, Canada, and Western Europe. And lymphocytic leukemia is almost rare in Asian countries and Japan. Even among Asians who were born and raised in America, this disease is extremely rare. Such long-term observations led to the conclusion that environmental factors do not affect the development of the disease.

Lymphocytic leukemia can also develop as a secondary disease after radiation therapy (in 10% of cases).

It is believed that some congenital pathologies can lead to the development of the disease: Down syndrome, Wiskott-Aldrich syndrome.

Forms of the disease

Acute lymphocytic leukemia (ALL) is a cancer that is morphologically represented by immature lymphocytes (lymphoblasts). There are no specific symptoms that can be used to make a definite diagnosis.

Chronic lymphocytic leukemia (CLL) is a tumor consisting of mature lymphocytes and is a long-term, indolent disease.

Symptoms

Symptoms characteristic of LL:

• enlargement of peripheral lymph nodes, liver, spleen;
• increased sweating, skin rashes, slight increase in temperature:
• loss of appetite, weight loss, chronic loss of strength;
• muscle weakness, bone pain;
• immunodeficiency ─ the immunological reactivity of the body is disrupted, infections occur;
• immune hemolysis ─ damage to red blood cells;
• immune thrombocytopenia ─ leads to hemorrhages, bleeding, the presence of;
• secondary tumors.

Stages of lymphocytic leukemia depending on the form of the disease

Stages of ALL:

1. Primary attack ─ the period when the first symptoms appear, see a doctor, and make an accurate diagnosis.
2. Remission (weakening or disappearance of symptoms) ─ occurs after treatment. If this period lasts more than five years, then the patient is diagnosed with complete recovery. However, a clinical blood test must be performed every six months.
3. Relapse ─ resumption of the disease against the background of apparent recovery.
4. Resistance ─ immunity and resistance to chemotherapy, when several courses of treatment have failed.
5. Early mortality ─ the patient dies during chemotherapy treatment.

The stages of CLL depend on blood counts and the degree of involvement of lymphoid organs (lymph nodes of the head and neck, armpits, groin, spleen, liver) in the pathological process:

1. Stage A ─ pathology covers less than three areas, severe lymphocytosis, low risk, survival more than 10 years.
2. Stage B ─ three or more areas are affected, lymphocytosis, average or intermediate risk, survival 5-9 years.
3. Stage C ─ all lymph nodes are affected, lymphocytosis, thrombocytopenia, high risk, survival 1.5-3 years.

What is included in the diagnosis?

Standard examinations for diagnosis:

1. Clinical research methods ─ detailed blood test (leukocyte formula).
2. Immunophenotyping of leukocytes is a diagnostic that characterizes cells (determines their type and functional state). This allows us to understand the nature of the disease and predict its further development.
3. Bone marrow trepanobiopsy is a puncture with extraction of a complete fragment of bone marrow. For the method to be as informative as possible, the tissue taken must retain its structure.
4. Cytogenetic research is mandatory in oncohematology. The method involves analyzing the chromosomes of bone marrow cells under a microscope.
5. Molecular biological research ─ gene diagnostics, DNA and RNA analysis. Helps diagnose the disease in the early stages, plan and justify further treatment.
6. Immunochemical study of blood and urine ─ determines the parameters of leukocytes.

Modern treatment of lymphocytic leukemia

The approach to treating ALL and CLL is different.

Therapy for acute lymphocytic leukemia takes place in two stages:

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1. The first stage is aimed at achieving stable remission by destroying pathological leukocytes in the bone marrow and blood.
2. The second stage (post-remission therapy) is the destruction of inactive leukocytes, which in the future can lead to relapse.

Standard treatments for ALL:

Chemotherapy

Systematic (drugs enter the general bloodstream), intrathecal (chemical drugs are injected into the spinal canal where the cerebrospinal fluid is located), regional (drugs act on a specific organ).

Radiation therapy

It can be external (irradiation with a special apparatus) and internal (placing hermetically sealed radioactive substances in the tumor itself or near it). If there is a risk of tumor spreading to the central nervous system, external beam radiation therapy is used.

TCM or THC

Bone marrow or hematopoietic stem cell (blood cell precursor) transplantation.

Biological therapy

Aimed at restoring and stimulating the patient's immunity.

Restoration and normalization of bone marrow function occurs no earlier than two years after chemotherapy treatment.

CLL is treated with chemotherapy and TKI therapy, tyrosine kinase inhibitors. Scientists have isolated proteins (tyrosine kinases) that promote the growth and production of white blood cells from stem cells. TKI drugs block this function.

Prognosis and life expectancy

Cancer diseases rank second in the world in terms of mortality. The share of lymphocytic leukemia in these statistics does not exceed 2.8%.

Important!

The acute form mainly develops in children and adolescents. The prognosis for a favorable outcome in the conditions of innovative treatment technologies is very high and amounts to more than 90%. At the age of 2-6 years, almost 100% recovery occurs. But one condition must be met - timely seeking specialized medical help!

The chronic form is a disease of adults. There is a clear pattern in the development of the disease associated with the age of the patients. The older the person, the greater the likelihood of occurrence. For example, at 50 years old there are 4 cases per 100,000 people, and at 80 years old this is already 30 cases per the same number of people. The peak of the disease occurs at 60 years of age. Lymphocytic leukemia It is more common in men, accounting for 2/3 of all cases. The reason for this sexual differentiation is not clear. The chronic form is incurable, but the prognosis for ten-year survival is 70% (over these years the disease never relapses).

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Definition and epidemiology

Classification

1. Acute form: accompanied by the accumulation of younger blasts in the blood and bone marrow ( the most immature) cells that are the precursors of lymphocytes ( one of the types of white blood cells that enter the blood through the lymphatic vessels) and are found in the bone marrow and also in the thymus gland. This form is most often observed in children aged 2 to 5 years. It is much less often diagnosed in adolescents, and even less often in adults. As lymphoblastic leukemia develops, both the lymph nodes and the spleen become enlarged. As for the level of leukocytes in peripheral blood, in this case it can be either normal, increased or decreased.

2. Chronic form: characterized by the accumulation of tumor lymphocytes both in the bone marrow and in the peripheral blood, as well as in the lymph nodes. In this case, lymphocytes are more mature, but at the same time functionally inferior. Chronic lymphocytic leukemia most often develops very slowly, as a result of which certain disturbances in the hematopoietic process can be detected only in the later stages of the development of this pathology. In all cases, the disease affects older people ( over 50 years old).

Course of the disease

Signs of acute lymphocytic leukemia

• paleness of the skin;
• increased body temperature;
• pain in bones and joints;
• bleeding;
• irritability;
• anemia ( anemia).

Symptoms of chronic lymphocytic leukemia

• swollen lymph nodes;
• weight loss;
• asthenia ( weakness and general malaise);
• susceptibility to infectious diseases;
• excessive sweating;
• loss of appetite ;
• heaviness in the abdomen, mainly in the left hypochondrium;
• hepatomegaly ( liver enlargement);
• splenomegaly ( enlarged spleen);
• anemia;
• neutropenia ( decrease in neutrophil count below 500);
• thrombocytopenia ( decrease in platelet level below 200 thousand in 1 cubic millimeter);
• frequent allergic reactions.

Stages of chronic lymphocytic leukemia

• Stage A – no more than 2 groups of lymph nodes are affected. Anemia and thrombocytopenia were not detected in this case;
• Stage B – 3 or more groups of lymph nodes are affected, but anemia and thrombocytopenia continue to be absent;
• Stage C – both anemia and thrombocytopenia are present regardless of how many groups of lymph nodes were affected.

• I– indicates lymphadenopathy ( swollen lymph nodes);
• II– indicates an enlarged spleen;
• III– indicates anemia;
• IV– indicates thrombocytopenia.

Diagnostic methods

1. Clinical blood test: helps identify lymphocytosis in peripheral blood;
2. Bone marrow puncture: allows us to establish the characteristic picture of the lesion for this pathology;
3. Cytogenetic analysis: provides data on the characteristics of malignant cells, which in some cases have prognostic value;
4. Biopsy of the affected lymph node: During this study, it is possible to obtain a complete picture of the structure of cells;
5. Immunophenotyping: allows you to identify specific immunological markers that are characteristic of tumor cells in the chronic form of this pathology;
6. Determination of the amount of β 2-microglobulin: makes it possible to predict the further course of the pathology;
7. Determination of the amount of immunoglobulins: necessary to establish how great the risk of developing infectious complications is;
8. Fish research: helps to assess the patient’s prognosis based on the presence of certain chromosomal rearrangements.

Traditional therapies

With a very rapid development of the disease, cytostatics and glucocorticoid hormones cannot be avoided. If it is possible to detect compression of neighboring organs by the lymph nodes, then radiotherapy is performed. Radiation therapy can prevent infiltration of the meninges. In case of thrombocytopenia and anemia, transfusion of the corresponding blood components is carried out. If infectious complications are detected, antibiotic therapy is indicated.

Immunomodulatory agents are necessary to strengthen the immune system. Often, specialists turn to radiotherapy for help. Bone marrow transplantation is the only treatment method that can completely cure the chronic form of this pathology. Since this surgical intervention is very toxic, it is performed in extremely rare cases, mainly for the treatment of children. Complete healing is possible only after allogeneic transplantation, i.e. bone marrow transplant from another person. Autologous transplantation, i.e. Self-transplantation helps achieve remission, but relapse after such treatment cannot be avoided. Allogeneic transplantation is most often performed to treat relapses of lymphocytic leukemia.

Lifestyle and nutrition

Herbal treatment

• Recipe No. 1: 1 tbsp. l. Add dried crushed red brush root to 300 ml of water and boil for 5 minutes in a sealed container. Then we leave the broth to infuse for another 60 minutes, filter it and take 100 ml orally 3 times a day half an hour before meals. Before using, add 1 tsp to each serving. natural
• Recipe No. 4: mix 2 cups of natural honey with 1 cup of crushed dill seeds and 2 tbsp. l. ground valerian root. Mix all components thoroughly, place them in a thermos and pour 2 liters of boiling water. After 24 hours, filter the infusion and take 1 tbsp. l. three times a day 30 minutes before meals for a month.
• Recipe No. 5: Place 60 grams in a 500 ml bottle. marsh cinquefoil grass and fill the raw material with good quality vodka. Leave the tincture in a dark place for 8 days, after which we filter it and take 1 tbsp. l. 3 times a day before meals. The tincture should be taken diluted ( for 1 tbsp. l. 50 – 100 ml water). During a course of therapy you should drink at least 3 liters of this tincture.
• Recipe No. 6: 1 – 2 tbsp. l. crushed dry herb lungwort, pour 500 ml of boiling water and leave to infuse for 2 hours. Then we filter the infusion and use it for oral administration, half a glass in the morning, at lunch and in the evening 20 - 30 minutes before meals. This remedy is endowed with both astringent and wound-healing, anti-inflammatory, as well as antiseptic effects.

Forecast

Chronic lymphocytic leukemia is detected by a blood test, the indicators of which indicate the presence of this disease. The disease is also called small lymphocyte lymphoma or lymphocytic lymphoma, abbreviated as CLL. The disease belongs to clonal lymphoproliferative neoplastic diseases, that is, it is a malignant tumor in which intensive division of mature atypical cells occurs. What is found in the blood that indicates the presence of a dangerous cancer?

Development of the disease

Chronic lymphocytic leukemia in European countries and North America is diagnosed in 3-4 people out of 100 thousand, and in elderly patients this figure increases to 20 people. Moreover, this pathology is detected 2 times more often in men. The disease is accompanied by the uncontrolled division of altered cells - lymphocytes, which affect various tissues of the body, this can affect the bone marrow, nodes of the lymphatic system, spleen, liver and other organs.

On average, in 96% of cases, chronic lymphocytic leukemia is of B-lymphocytic nature, that is, lymphoid stem cells settle in the bone marrow, where they mature into B-lymphocytes. The remaining 3-4% move to the thymus region - the thymus gland, where they mature into T-lymphocytes, therefore the disease is characterized as an illness of T-lymphocyte origin.

Normally, B lymphocytes go through a series of developmental stages until they become plasma cells, which are responsible for the humoral immune mechanisms. But this applies to typical lymphocytes, while cells with atypical development do not reach the final stage and accumulate in the hematopoietic system, provoking various kinds of disturbances in the functioning of the immune system.

This malignant disease progresses extremely slowly and there are even cases of asymptomatic progression of the disease over several years.

The chronic lymphocytic type of leukemia is difficult to diagnose due to the fact that it does not have severe symptoms that force a person to promptly seek medical advice.

Most often, this cancer is detected by chance, when a blood test is prescribed to diagnose another disease or during regular preventive tests. Suspicion of this chronic disease arises if a blood test reveals more than 5000 lymphocyte cells per 1 micron.

Clinical (detailed) blood test

Any diagnostic examination necessarily includes donating blood for a CBC - a general (detailed) blood test. This test detects blood cell levels and in this case pays special attention to the white blood cell count. The first signs of CLL are most often detected during a professional examination, which necessarily includes a CBC analysis. This is the most common option for diagnosing this type of tumor.

Less often, this happens when a patient seeks help from a specialist, complaining of feeling unwell. The first suspicion in this situation falls on ARVI. And the doctor prescribes blood donation for clinical analysis. In most cases, an acute form of lymphocytic leukemia is detected in this way. A blood test for lymphocytic leukemia indicates the presence of lymphocytosis - an increased number of atypical cells in the peripheral blood.

This is considered a clear sign of the disease.

If we consider the norm, the level of lymphocytes ranges from 17 to 37%. This is the broadest group of white blood cells, and in children their level can reach half of all white blood cells. They are the main weapon of immunity against various kinds of diseases, as they are responsible for the antibodies produced.

An increased rate signals a probable threat that the immune system cannot cope with. However, this is not a reason to immediately diagnose lymphocytic leukemia, since such a sign is present in the clinical picture of a number of diseases. A number of further diagnostic studies will be required. In addition to this symptom, there are a number of other signs that indicate the possible presence of a malignant blood formation:

• If a later stage of the disease has developed, the analysis will reveal disturbances not only in the leukocyte formula, but also in the proportions of other blood components. Failures lead to the development of anemia - a decrease in hemoglobin and thrombocytopenia - a low level of platelets.
• Among the signs of CLL, one can note the presence in the blood of immature leukocytes circulating outside the hematopoietic system; these can be lymphoblasts and prolymphocytes. In a normal state, they are found in small quantities in the hematopoietic organs, but do not penetrate into the peripheral blood.
• To confirm lymphocytic leukemia, a blood test reveals half-destroyed lymphocyte nuclei in the biomaterial, which in medical practice are called Gumprecht's shadows. They are a characteristic sign of this malignant disease.

In addition to a general blood test, the patient is prescribed a biochemical test, which reveals a number of abnormalities.

Biochemistry to detect a malignant tumor

Blood biochemistry also reveals a number of changes, deviations in the activity of the immune and other systems, but this occurs in the later stages of the disease. At the initial stages, this type of diagnosis may not show any significant changes in the composition of the blood. The blood picture for chronic lymphocytic leukemia in this case is as follows:

• If the disease progresses, the analysis shows the presence of hypoproteinemia (decreased protein levels in the plasma part of the blood) and hypogammaglobulinemia (decreased concentration of immunoglobulins in the serum part of the blood). The latter factor leads to the fact that the body of a patient with lymphocytic leukemia cannot resist various infectious agents.
• When chronic lymphocytic leukemia affects liver cells, changes in liver tests are observed in blood biochemistry: the level of ALT (alanine aminotransferase - an enzyme from the group of transferases) and AST (aspartate aminotransferase - an element from the same group of enzymes) indicate how much the disease has damaged the cells of the liver parenchyma - hepatocytes. Indicators such as GGT (gamma-grutanyltransferase - a membrane enzyme of liver cells) and alkaline phosphatase enzyme (ALP) show whether there is bile stagnation. Total bilirubin changes depending on how well the liver performs its synthetic functions.

Test results depend on the degree of the disease. But identifying any abnormalities is not an accurate sign of a malignant process. The specialist must obtain data on existing changes, evaluate the relationship of various parameters relative to each other and the available regulatory data.

In addition, a blood test will not be enough, and a number of specific studies will be required to establish an accurate diagnosis.

What therapy is used for this disease?

In modern therapy there is no radical method that can eliminate this malignant formation. If chronic lymphocytic leukemia was detected at the initial stage of development, and the analysis shows stable leukocytosis - no higher than 20-30-10⁹/l, then therapy is not prescribed. The patient is under observation and undergoes a control blood test every 3-6 months.

Treatment will be required if the patient develops obvious symptoms of the disease (fever, weight loss, etc.), an increase in leukocytosis from 50 10⁹/l. In this case, treatment may include the following:

1. Chemotherapy. This is a response to existing symptoms and consists of taking alkylating drugs, for example Chlorambucil for monotherapy or combining it with glucocorticoids. Similar therapy has existed for a long time, but today experts consider the drug Fludarabine to be the most effective, as it provides longer remission periods.
2. Glucocorticoid therapy. It is recommended for immunohemolytic anemia and thrombocytopenia. A course of Prednisolone is prescribed, but certain precautions must be observed, as there is a risk of infectious lesions.
3. Use of monoclonal antibodies. The first drug in this group is Rituximab. It gives a response rate of about 75% if chronic lymphocytic leukemia has not previously been treated with this method. In this case, complete remission occurs in every fifth patient who has undergone treatment. There are other drugs with similar effects that are prescribed exclusively individually.
4. Radiation therapy. A similar method is necessary if the disease has entered the last, fourth period and is not amenable to other methods of treatment. In this case, the body exhibits anemia, thrombocytopenia, lymph nodes or the spleen enlarge, and lymphocytic infiltration of the nerve trunks occurs. The level of lymphocytes increases significantly. Therapy consists of local irradiation of the organ that has undergone infiltration.
5. Splenectomy. For the treatment of CLL, this method is ineffective and is used in extreme cases when glucocorticoid therapy does not have an effect or when the spleen is significantly enlarged.

Despite the unpredictability of tumors, early diagnosis and surveillance are important. But there is no prevention against this type of illness.

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