Treatment of chronic lymphocytic leukemia in Israel

Chronic lymphocytic leukemia is a malignant lymphoproliferative disease in which the tumor cells are pathological B lymphocytes that can accumulate in the bone marrow, peripheral blood and lymph nodes. Normally, B lymphocytes during their life transform into an immunoglobulin-secreting cell, which provides acquired immunity. Tumor B-lymphocytes are deprived of this function, and, thus, the patient’s immunity suffers and the risk of infectious diseases increases. In addition, as the disease progresses, the production of red blood cells, neutrophils and platelets is impaired, and autoimmune processes may develop. Finally, chronic lymphocytic leukemia can transform into B-cell prolymphocytic leukemia, into well-differentiated non-Hodgkin lymphoma, in particular into diffuse large B-cell lymphoma.

• Reasons for the development of lymphocytic leukemia
• Symptoms
• Diagnosis of chronic lymphocytic leukemia
• Stages of the disease
• Treatment
• Evaluation of treatment effectiveness
• Forecast

Reasons for the development of lymphocytic leukemia

Chronic leukemia is the most common type of leukemia, accounting for up to 30% of the total incidence structure. The incidence rate is 4 cases per 100 thousand population; in persons over 80 years of age, the frequency is more than 30 cases per 100 thousand population.

Risk factors for the development of chronic lymphocytic leukemia are:

• Elderly age. Up to 70% of all identified cases occur in people over 60 years of age,
• Male gender. Men get sick twice as often as women,
• Exposure to ionizing radiation,
• Contact with benzene and gasoline.

Who is at risk?

In acute lymphocytic leukemia, the risk group includes:

• people who have undergone chemotherapy or radiation therapy as part of treatment for another form of cancer);
• people who have been exposed to radioactive radiation;
• people suffering from Down syndrome and other genetic disorders;
• people whose sisters or brothers have been diagnosed with acute lymphocytic leukemia.

In case of chronic lymphocytic leukemia, the risk group includes:

• people whose relatives suffered from leukemia;
• people over 60 years of age;
• representatives of the Caucasian race.

Symptoms

Chronic lymphocytic leukemia is characterized by a long asymptomatic course; The main reason for visiting a doctor is changes in a general blood test taken as part of a preventive examination or for another disease. The patient may not present active complaints at the time of the initial examination, but often even in this situation an enlargement of the lymph nodes and a change in their consistency to a doughy consistency are already detected. The lymph nodes themselves are not compacted and remain mobile relative to the surrounding tissues. In case of infection, the lymph nodes become significantly enlarged; As chronic lymphocytic leukemia progresses, lymph nodes—primarily those of the abdominal cavity—are capable of forming conglomerates.

The first complaints that arise are usually not specific: increased fatigue, weakness, severe sweating. As the disease progresses, autoimmune manifestations may occur, firstly very hemolytic anemia (in 10-25% of cases) and thrombocytopenia (in 2-3% of cases). Hemolytic anemia develops due to the destruction of red blood cells by the body itself; Most often, like chronic lymphocytic leukemia itself, it develops gradually, but it can also manifest as an acute crisis - with an increase in temperature, the appearance of jaundice, and darkening of the urine. Thrombocytopenia can be a much more dangerous condition due to the development of bleeding, including life-threatening bleeding (for example, cerebral hemorrhage).

In addition, since B lymphocytes belong to the cells that provide immunity, the addition of infectious complications, including opportunistic ones, that is, caused by microorganisms that are constantly present in the human body and do not manifest themselves with an adequate immune response, is typical. Most often, opportunistic infections affect the lungs.

Chronic lymphocytic leukemia in Israel: prices for treatment

Chronic and acute lymphocytic leukemia in Israel is treated and treated with high quality! The high level of medical care provided at the Ichilov Complex clinic is accompanied by adequate prices for the treatment of chronic lymphocytic leukemia in Israel. When choosing treatment for acute and chronic lymphocytic leukemia in Israel, you choose high quality at a reasonable cost, which is half that offered by clinics in Europe and the USA. Payment for medical services is made upon receipt of them, in other words, there is no prepayment at the Ikhilov Complex clinic. You can also learn more about the cost of treatment of chronic and acute lymphocytic leukemia in Israel from our manager.

Chronic lymphocytic leukemia: benefits of treatment in Israel

Doctors at the Ikhilov Complex medical center use innovative methods of treating lymphocytic leukemia, each of which provides a positive result. Treatment procedures are carried out under the careful supervision of specialists, and the rehabilitation period is accompanied by professional assistance from the clinic’s leading psychologist.

Both the treatment process and the rehabilitation period take place in conditions of increased comfort. The best confirmation of this is the numerous reviews from former patients of the clinic, in which people thank all the medical staff for their attention and care, and also note the coziness and comfort that reigns in the spacious wards of the modern clinic.

Every foreign patient who decides to fly to Israel for treatment is freed from the need to resolve organizational issues. The staff of the Israeli clinic Ichilov Complex is fully involved in booking plane tickets, providing transfers, as well as renting housing in Israel. In addition to such unique services provided by the Ichilov Complex clinic, the patient is provided with a personal translator who accompanies the patient throughout the entire treatment in Israel.

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(10 votes, average: 5 out of 5)

Diagnosis of chronic lymphocytic leukemia

The diagnosis of chronic lymphocytic leukemia can be suspected when assessing the results of a routine clinical blood test - an increase in the absolute number of lymphocytes and leukocytes attracts attention. The main diagnostic criterion is the absolute number of lymphocytes, exceeding 5 × 10 9 \l and progressively increasing as lymphocytic leukemia develops, reaching numbers of 100-500 × 10 9 \ l. It is important to pay attention not only to the absolute number - if at the beginning of the disease lymphocytes make up up to 60-70% of the total number of leukocytes, then with its further development they can make up 95-99%. Other blood parameters, such as hemoglobin and platelets, may be normal, but as the disease progresses, they may decrease. The absolute criterion for establishing a diagnosis of chronic lymphocytic leukemia is the detection of more than 5000 clonal B lymphocytes in 1 μl of peripheral blood.

A biochemical blood test may reveal a decrease in total protein and the amount of immunoglobulins, but this is typical for later stages of the disease. A mandatory step in the diagnostic search is a bone marrow biopsy. Histological examination of the obtained punctate in the early stages of the disease, as well as in a general blood test, reveals a small content of lymphocytes (40–50%), but with high leukocytosis, lymphocytes can make up 95–98% of the bone marrow elements.

Since changes in the bone marrow are nonspecific, the final diagnosis of chronic lymphocytic leukemia is established on the basis of immunohistochemical studies. The characteristic immunophenotype of chronic lymphocytic leukemia includes the expression of antigens CD19, CD5, CD20, CD23; there is also weak expression on the cell surface of immunoglobulins IgM (often simultaneously with IgD) and antigens CD20 and CD22. The main cytogenetic marker that directly influences the choice of therapy is the 17p deletion. It is advisable to perform an analysis aimed at identifying this deletion before starting treatment, since its identification leads to a change in patient management tactics. In addition to a bone marrow biopsy, in the case of significant enlargement of individual lymph nodes, puncture of them is indicated in order to exclude lymphoma.

Instrumental diagnostic methods include chest x-ray and ultrasound of the most commonly affected groups of lymph nodes and abdominal organs - primarily the liver and spleen, since these organs are most often affected by chronic lymphocytic leukemia.

Chronic lymphocytic leukemia and its treatment

Chronic lymphocytic leukemia (CLL) is a tumor disease that occurs due to mutations in the B-lymphocyte genome. The main function of B lymphocytes is to provide humoral immunity. The final stage of B-lymphocyte development in the body is an immunoglobulin-secreting plasma cell. Due to changes in the cellular genome, B lymphocytes in CLL do not develop into plasma cells. This leads to a sharp decrease in the patient’s body’s production of immunoglobulins, which include all antibodies.

CLL is the most common type of leukemia in Europe and North America, where it accounts for about 30% of all leukemias. Its annual incidence is 3–3.5 cases per 100,000 people, increasing for people over 65 years of age to 20, and for people over 70 to 50 cases per 100,000 people.

CLL was isolated as an independent disease in 1856 by the famous German pathologist R. Virchow.

Men develop CLL 2 times more often than women. CLL is mainly a disease of older people, the average age of patients is 65-69 years. More than 70% become ill over the age of 60 years, less than 10% - before 40 years.

There is no increase in the incidence of CLL among individuals exposed to ionizing radiation or frequently in contact with benol and motor gasoline, i.e., factors that play a leading role in the occurrence of myeloid leukemia.

Diagnosis of CLL in the vast majority of cases does not cause difficulties. This disease should be suspected if the number of leukocytes and lymphocytes in the blood increases. If the absolute lymphocyte count reaches 5x109/L, the diagnosis of CLL becomes very likely. It must be borne in mind that the absolute number of lymphocytes 5x109/l is 55% of the total number of leukocytes 9x109/l, and such a blood picture often does not attract the doctor’s attention. Sometimes, over the course of 2-3 years, with a normal number of leukocytes, a gradually increasing lymphocytosis is observed - 55-60-70% of lymphocytes in the blood count. A patient with such a blood picture must have a blood test repeated at least once every six months, since after a long period of calm the disease may begin to progress rapidly. Currently, there are wide possibilities in the treatment of CLL, so every patient with suspected this disease should be consulted by a hematologist, regardless of the presence of other pathology.

In most cases, when CLL is diagnosed, the number of leukocytes is 20–50x109/l, but sometimes, when you first visit a doctor, there is a high leukocytosis, reaching 100–500x109/l and indicating a long undiagnosed period of the disease. When calculating the leukocyte formula, the content of lymphocytes is usually 60–70%; with high leukocytosis, it reaches 95–99%. The hemoglobin level and platelet count are usually normal, but with high leukocytosis and lymphocytosis exceeding 85–90%, there may be some decrease in hemoglobin values ​​and the number of red blood cells and platelets. A biochemical blood test initially reveals no changes; over time, hypoproteinemia and hypogammaglobulinemia are revealed in most cases.

In the bone marrow punctate in the early stages of the disease, a small content of lymphocytes (40–50%) is detected; with high leukocytosis, lymphocytes can make up 95–98% of the bone marrow elements.

Morphological examination alone is not enough to make a diagnosis of CLL, since a similar picture of blood and bone marrow can be observed in some types of lymphomas. According to modern criteria, the diagnosis of CLL can be considered established only after an immunological study. Lymphocytes in CLL have an absolutely characteristic immunophenotype. They express CD19, CD5, CD23 antigens on their surface; there is also a weak expression on the cell surface of immunoglobulins (IgM is expressed, often simultaneously with IgD) and CD20 and CD22 antigens.

CLL most often begins gradually and in most cases develops very slowly in the early stages, and in some patients there may be no signs of progression for years. When visiting a hematologist for the first time, patients most often do not have any complaints, and the reason for the visit is changes in a blood test done for another reason. In most cases, even with mild changes in the blood, upon examination it is possible to detect a slight enlargement of the lymph nodes. They have a “doughy” consistency, soft, mobile, not fused to each other or to the surrounding tissues. Without concomitant infection, the lymph nodes are completely painless. Sometimes the reaction of the lymph nodes to an infection is the first sign of their damage: the patient complains that during acute respiratory diseases he has enlarged lymph nodes in the neck. Often at this moment the patient’s hearing decreases and a feeling of “fullness” appears in the ears, caused by the proliferation of lymphatic tissue at the mouths of the Eustachian tubes and its swelling at the time of infection. Some patients have a significant enlargement of the pharyngeal tonsils; sometimes, when a respiratory infection is associated, there is slight difficulty in swallowing solid food.

With a significant increase in peripheral lymph nodes, as a rule, the lymph nodes of the abdominal cavity are enlarged, which is detected by ultrasound. Lymph nodes can merge with each other, forming conglomerates. Mediastinal lymph nodes rarely enlarge and usually slightly. The size of lymph nodes in different patients can vary within a very wide range - from 1.5–2 to 10–15 cm in diameter. In one patient, these sizes vary in different areas, but a sharp increase in the lymph nodes of any one area is uncharacteristic. In such cases, a puncture or biopsy of this node is required to exclude the transformation of CLL into aggressive lymphoma.

Splenomegaly in most patients appears later than enlarged lymph nodes. An enlarged spleen without enlarged lymph nodes is completely uncharacteristic of CLL and most often in such cases we are talking about other diseases. Hepatomegaly is uncommon and usually appears later than splenomegaly.

At the onset of the disease there are usually no complaints. Over time, complaints appear of increased fatigue, weakness, and mainly sudden sweating, especially in the hot season.

The rate of development of the disease, the rate of increase in the number of leukocytes, the size of the lymph nodes and spleen vary widely. In a number of patients, the disease progresses steadily, and, despite treatment, even with modern therapy, life expectancy is only 4–5 years. At the same time, in approximately 15–20% of patients, the clinical and hematological signs of the disease remain stable and minimally expressed for many years. Over the course of 10–15 years, and in some cases 20–30 years, there is an increase in the number of leukocytes up to 10–20x109/l, an increase in lymphocytes in the blood - up to 60-70%, in the bone marrow up to - 45-55%; hemoglobin content, number of red blood cells and platelets are normal. With this “frozen” or “smoldering” form of CLL, life expectancy may not depend at all on the presence of this disease. In some patients, however, after several years and with this option, signs of progression also appear.

In most patients, the process develops slowly and is quite successfully controlled with therapy for a number of years. With modern therapy, the life expectancy of most patients is 7–10 years or more.

There are two modern classifications of CLL, dividing it into stages depending on clinical manifestations. One of them was proposed in 1975 by American scientists K. Rai and his colleagues; it is used mainly in the USA ( Table 1

).
Another classification was published in 1981 by French scientists JL Binet and co-authors; it became widespread in Europe and in our country ( Table 2
). Both classifications are based on a single principle: taking into account the mass of the tumor and its spread, which is reflected in: the number of leukocytes, lymphocytosis, the size of the lymph nodes, liver and spleen, the presence or absence of suppressed healthy hematopoietic sprouts. This last factor has an even greater impact on the life expectancy of patients than the volume of the tumor mass.

Due to hypogammaglobulinemia, which gradually deepens as the disease progresses and by 7–8 years of the disease is observed in 70% of patients, with CLL there is an increased tendency to develop opportunistic infections, most often pulmonary.

Infectious complications in CLL can occur at any stage of the disease, including the initial stage, but they develop much more often in patients with pronounced clinical and hematological manifestations of the disease. This fact shows that treatment of a patient should not be delayed, even in old age and in the presence of other diseases, if there are signs of CLL progression.

The terminal stage of CLL is most often characterized by refractoriness to therapy and an increase in infectious episodes without any changes in the previous blood picture. Infections cause death in most patients. Treatment of infections in patients with CLL should begin immediately when they occur and, before obtaining bacteriological analysis data, should be carried out with broad-spectrum antibiotics, preferably in a hospital.

In addition to infectious ones, CLL is characterized by autoimmune complications - autoimmune hemolytic anemia (AIHA) and autoimmune thrombocytopenia. AIHA develops during the course of the disease in 10–25% of patients with CLL. Autoimmune hemolysis of erythrocytes can have the character of an acute and rapidly developing hemolytic crisis, accompanied by an increase in temperature, the appearance of icteric discoloration of the skin and dark color of urine, and an increase in the content of indirect bilirubin in the serum. The rapid development and progression of anemia causes a sharp deterioration in the patient's condition and can be life-threatening, especially in the presence of concomitant heart or lung diseases. More often, autoimmune hemolysis develops gradually. Immune thrombocytopenia is less common than AIHA, in only 2-3% of cases, but can be more dangerous than AIHA due to the frequent occurrence of life-threatening bleeding or hemorrhages in the brain, which causes death in patients.

Autoimmune complications always require treatment. Most often, corticosteroid hormones are used for this in high doses - 1-2 mg/kg of body weight per prednisolone.

There are currently broad opportunities in the treatment of CLL. Until the beginning of the twentieth century. The treatment for all leukemia was the same: arsenic, urethane, symptomatic treatment. Since 1902, X-ray therapy has become the main treatment for chronic leukemia, which has remained the leading treatment method for CLL for 50 years. It gave a good local effect, but did not change the rate of development of the disease: the average life expectancy with symptomatic treatment was 40 months, with radiotherapy - 42 months.

The modern era in the treatment of CLL began in the mid-twentieth century, when evidence was obtained of a decrease in lymphoid proliferation under the influence of steroid hormones. The wide range of action quickly made steroid hormones a universally used treatment for this disease. However, the short duration of the achieved effect, which inevitably occurs with long-term use, decreased effectiveness, the presence of serious side effects and frequent complications have narrowed the scope of hormonal therapy in CLL, leaving autoimmune complications in first place among the indications for its use.

The most important event in the development of CLL therapy was the advent of alkylating drugs. The first of these, chlorambucil, is currently in use. Therapy with chlorambucil or its combination with prednisolone in cases of slow increase in leukocytosis allows for a certain time to control the manifestations of the disease. The life expectancy of patients with CLL with this therapy is 55–60 months. Cyclophosphamide is often used instead of chlorambucil. Therapy with chlorambucil or cyclophosphamide and their combination with prednisone in the vast majority of patients allows one to obtain only partial remissions. The desire to improve existing results led to the creation in the 70–80s of the twentieth century. combination treatment regimens including cyclophosphamide, prednisolone, vincristine and any of the anthracyclines (Rubomycin, Adriblastine or Idarubicin). The most widely used schemes are COP, CHOP and CAP. These regimens allow most patients to achieve a reduction in the size of the lymph nodes and spleen and reduce the number of leukocytes, and as a result of several courses, 30–50% of patients can even obtain complete remissions, which, however, always turn out to be short-lived. International randomized studies have shown that life expectancy using these treatment regimens does not exceed that obtained when treating CLL with chlorambucil and prednisolone.

In the 80s of the twentieth century. A major event in the treatment of CLL occurred - purine analogues were synthesized and introduced into clinical practice, the appearance of which was called a “peaceful revolution” in the treatment of CLL. The most effective of them for CLL is fludarabine.

When treated with fludarabine, remissions, often complete, can be obtained in the majority of patients, including those refractory to all other drugs. However, over time it became clear that even complete remissions after treatment with fludarabine, although they are usually quite long-lasting, are still temporary. This became the reason for the development of combination therapy regimens containing fludarabine and some other drug - cyclophosphamide, mitoxantrone, doxorubicin.

The combination of fludarabine with cyclophosphamide was the most effective and caused the least serious side effects. Numerous studies conducted in different countries have shown that this combination of drugs allows for remissions in 70–80% of previously treated and 90–95% of previously untreated CLL patients, with many remissions, especially complete ones, lasting 20–28 months . This combination proved effective even in a number of patients refractory to previous combination therapy and, no less important, when reused in case of relapse.

Oral fludarabine was introduced in the late 1990s. Its effectiveness at the appropriate dose is similar to that of the intravenous drug. The advent of fludarabine for oral administration allows it to be combined with the oral form of cyclophosphamide. This combination is very convenient for patients, especially the elderly, as it eliminates the need for them to visit the clinic for intravenous injections of drugs.

A new and important stage in the treatment of CLL was the emergence and introduction into clinical practice of monoclonal antibodies. The drug rituximab (MabThera), a monoclonal antibody to the CD20 antigen, was the first to be used in the treatment of CLL. The CD20 antigen is a phosphoprotein, part of the molecule of which is located on the cell surface, the other in the cytoplasm. It is involved in the delivery of calcium to the cell nucleus. Antibodies to the CD20 antigen are chimeric antibodies that have a murine variable region and a constant human IgG region. The combination of antibodies with the CD20 antigen induces apoptosis signals in the cell.

In CLL, there is a low density of CD20 antigen molecules on lymphocytes, so antibodies to this antigen in CLL alone were effective only in large doses. By the time of the introduction of rituximab (MabThera), fludarabine had proven to be the most effective drug in the treatment of CLL, so studies of the effectiveness of the combination of rituximab and fludarabine were undertaken. They showed that this combination is highly effective in both previously treated and untreated patients: the remission rate in previously treated patients is 60–70%, in untreated patients it is 90–95%, and in half of the patients complete remissions are achieved. After such treatment, the majority of previously untreated patients remain in remission for 2 years or longer. The combination of fludarabine, cyclophosphamide and rituximab allows to obtain an effect in 95–100% of previously untreated patients and in those previously treated with chlorambucil (Leukeran) or a combination of prednisolone, vincristine, cyclophosphamide (COP), and in 70–75% of patients complete remissions are achieved.

Rituximab therapy was also effective in a number of patients with autoimmune anemia and thrombocytopenia. In these cases, it is used either alone or in combination with prednisolone or SOP.

Even better results can be achieved using antibodies to the CD52 antigen (Alemtuzumab, Campath-1H).

The CD52 antigen is a glycoprotein that is expressed on the membrane of most mature normal and tumor T and B lymphocytes, eosinophils, monocytes and macrophages, but is not found on the membrane of stem cells, erythrocytes and platelets. Its function in the cell is still unclear. While the CD20 antigen is expressed on pathological lymphocytes in CLL at a density of approximately 8,000 molecules per cell, the density of CD52 antigen molecules is very high, approximately 500,000 molecules per cell.

Campath-1H is a humanized antibody in which only the small region that directly binds to the antigen is rat IgG2a, the rest of the antibody molecule is human IgG1.

The use of Campath-1H is often effective even in patients who have received several courses of fludarabine treatment and become resistant to it. In a large multicenter international study, Campath-1H, 152 patients refractory to fludarabine were treated; 42% achieved remissions, including 5% complete remissions. This result demonstrates the high effectiveness of Campath-1H, since resistance to fludarabine is an extremely poor prognostic sign.

The effectiveness of the drug in a number of patients with a deletion of the short arm of chromosome 17 (17p-) or a mutation of the TP53 gene localized in this region turned out to be extremely encouraging. This gene is called the “guardian of the genome”; in case of any DNA damage in a cell, the TP53 gene is activated, as a result of which the apoptosis signal is turned on and such a cell dies. Before the advent of Campath-1H, patients with CLL with a 17p deletion were considered refractory to therapy, since in most cases the response to treatment was either no or very short-lived. When using Campath-1H in patients with 17p deletion, remissions, including complete ones, can be obtained in 30–40% of cases. In our observation, a patient with a 17p deletion, in whom fludarabine therapy was ineffective, was able to obtain not only complete clinical and hematological, but also molecular remission - no pathological lymphocytes were detected either in the blood or in the bone marrow puncture during immunological examination.

Further studies have shown that the use of the drug in previously untreated patients produces an effect in 80% of cases; in 2/3 of patients, complete bone marrow remission can be achieved.

Even better results were obtained when Campath-1H was combined with fludarabine (FluCam) in 36 patients with CLL who had previously received fludarabine with rituximab or rituximab in combination with a combination of drugs including alkylating agents. The effect was achieved in 83% of these severe and poorly responding patients, with 30% achieving complete remissions. The median life expectancy in this group was 35.6 months and was not achieved during observation in patients with complete remission. In two patients with autoimmune anemia that existed before treatment, by the end of therapy the hemoglobin level was completely normalized without blood transfusions and all signs of hemolysis disappeared.

In several studies, Campath-1H has been used as consolidation therapy in patients effectively treated with fludarabine. In the largest study, which included 56 patients, after fludarabine, complete remissions were observed in 4%, partial in 52% of patients, after additional treatment with Campath-1H, the number of complete remissions increased to 42%, the number of partial remissions was 50%, thus the overall effect increased from 56% after treatment with fludarabine to 92% after adjunctive treatment with Campath-1H.

Treatment with Campath-1H should be carried out only in a hospital under the supervision of hematologists, since due to a sharp decrease in the number of not only B-lymphocytes, but also T-lymphocytes as a result of treatment, without preventive measures the patient often develops complications. The most serious complication of treatment with Campath-1H is the frequent occurrence of infections. The most dangerous is the development of septicemia, Pneumocystis pneumonia, systemic aspergillosis or candidiasis, the appearance of widespread herpes zoster, and reactivation of cytomegalovirus infection. Considering this danger, during treatment and for at least 2 months after its completion, the patient should receive Biseptol prophylactically (for the prevention of Pneumocystis pneumonia), antifungal and antiviral agents. If reactivation of cytomegalovirus is detected, treatment is carried out with ganciclovir; if a fungal infection occurs, treatment is carried out with highly effective antifungal drugs.

Despite the possible complications, the use of Campath-1H is becoming more common. The positive results achieved with its use have placed it among the most effective drugs in the treatment of CLL.

An analysis of the possibilities of CLL therapy over the course of a century shows that over the past two decades, CLL has transformed from an incurable disease into a disease that, in most cases, with timely onset, can be successfully treated, prolonging the life and somatic well-being of patients, and which has now become fundamentally curable.

Literature

1. Guide to Hematology / ed. A. I. Vorobyova. M.: Newdiamed, 2005.
2. Clinical oncohematology / ed. M. A. Volkova. M.: Medicine, 2001.
3. Chronic lymphoid leukemias edited by BD Cheson, Marcell Dekker AG New York, 2001.
4. Volkova M. A., Byalik T. E. Rituximab in the treatment of autoimmune complications in chronic lymphocytic leukemia // Hematology and Transfusiology. 2006. No. 3. pp. 11–17.
5. Volkova M. A. Monoclonal antibodies to the CD52 antigen: optimization of therapy for chronic lymphocytic leukemia // Hematology and Transfusiology. 2006. No. 2. P. 27–33.

M. A. Volkova

,
Doctor of Medical Sciences, Professor Oncological Research Center named after. N. N. Blokhin RAMS, Moscow

Stages of the disease

Currently, staging is carried out according to the classification proposed by Binet:

• A - hemoglobin content more than 100 g\l, platelets - more than 100 × 10 9\l, less than three lymphatic areas are affected (these include: cervical lymph nodes, axillary lymph nodes, inguinal lymph nodes, liver, spleen),
• B - hemoglobin content more than 100 g\l, platelets - more than 100 × 10 9\l, more than three lymphatic areas are affected,
• C - hemoglobin content less than 100 g\ or platelets - less than 100 × 10 9\l.

In addition to the Binet classification, the Rai classification is used, mainly used in the USA. According to it, there are four stages of the disease:

• 0 - clinical manifestations include only an increase in lymphocytes of more than 15 × 10 9 in the peripheral blood and more than 40% in the bone marrow,
• I - the number of lymphocytes is increased, enlarged lymph nodes are diagnosed,
• II - the number of lymphocytes is increased, an enlargement of the liver and/or spleen is diagnosed, regardless of the enlargement of the lymph nodes,
• III - there is an increase in the number of lymphocytes and a decrease in hemoglobin level of less than 110 g/l, regardless of the enlargement of the spleen, liver and lymph nodes,
• IV - there is an increase in the number of lymphocytes and a decrease in the number of platelets less than 100 × 10 9, regardless of the level of hemoglobin, enlargement of organs and lymph nodes.

Stage 0 is characterized by a favorable prognosis, stage I and II - intermediate, stage III and IV - unfavorable.

Treatment

Currently, chronic lymphocytic leukemia is highly treatable thanks to a wide range of chemotherapy drugs. It is important to note that current guidelines do not recommend starting aggressive treatment immediately after diagnosis - in cases where clinical manifestations are minimal, active follow-up is possible until indications for specific treatment arise, which include:

• The emergence or increase of intoxication, which is manifested by a loss of body weight by more than 10% over six months, a deterioration in general condition; the appearance of fever, low-grade fever, night sweats.
• Increasing symptoms of anemia and/or thrombocytopenia;
• Autoimmune anemia and/or thrombocytopenia - if the condition is not corrected with prednisone;
• Significant size of the spleen - the lower edge is at a distance of >6 cm or more below the costal arch;
• The size of the affected lymph nodes is more than 10 cm or its progressive increase;
• Increase in the number of lymphocytes by more than 50% in 2 months, or doubled in 6 months.

The main treatment method for chronic lymphocytic leukemia at the moment is chemotherapy. One of the first chemotherapeutic agents that showed its effectiveness in the treatment of chronic lymphocytic leukemia, chlorambucil, is still used today, albeit to a limited extent. Over time, cyclophosphamide has been used instead of chlorambucil, in combination with other drugs, and appropriate regimens (eg, CHOP, COP, CAP) are currently used in young patients with good physical status.

First introduced into clinical practice in the 80s of the last century, fludarabine showed effectiveness in achieving stable remission, exceeding the effectiveness of chlorambucil, especially in combination with cyclophosphamide. It is important to note that this regimen is effective even in the event of a relapse of the disease. The last word in the treatment of chronic leukemia is currently the use of immunotherapeutic agents - drugs from the group of monoclonal bodies. Rituximab has become firmly established in routine clinical practice. This drug interacts with the CD20 antigen, which is limitedly expressed in chronic lymphocytic leukemia, so effective treatment requires a combination of rituximab with one of the accepted chemotherapy regimens, most often with fludarabine or COP. Rituximab alone can be used as maintenance therapy in case of partial response to treatment.

The use of the drug alemtuzumab, which interacts with the CD52 antigen, looks promising. It is also used both alone and in combination with fludarabine.

Separately, I would like to mention chronic lymphocytic leukemia with 17p deletion. This subtype of lymphocytic leukemia is often resistant to standard chemotherapy regimens.

Some success in the treatment of this subtype of lymphocytic leukemia has been achieved through the use of the above-mentioned alemtuzumab. In addition, ibrutinib is a promising drug in this situation. Currently, this drug is used in monotherapy; its combination with various chemotherapy regimens is being studied; A regimen including ibrutinib, another monoclonal body, rituximab, and bendamustine, showed a certain advantage.

Radiation therapy, which a century ago was practically the only treatment option for such patients, has not lost its relevance to this day: it is recommended that it be carried out as part of an integrated approach to the area of ​​the affected lymph nodes if their continued growth is observed against the background of stabilization of other manifestations of the disease. In this case, the required total dose is 20-30 Gy. Also, the radiation method can be used for relapses of the disease.

In the treatment of chronic lymphocytic leukemia, a surgical method has also found its place, which consists in removing the affected spleen. Indications for this intervention are:

• Enlarged spleen in combination with severe anemia and/or thrombocytopenia, especially if chemoresistance is observed,
• Massive enlargement of the spleen in the absence of response to chemotherapy,
• Severe autoimmune anemia and/or thrombocytopenia with resistance to drug treatment.

If resistance to previously used chemotherapy agents develops or if there is rapid progression after treatment, bone marrow transplantation may be performed. Bone marrow transplantation is indicated in first remission for high-risk patients, young patients in the absence of treatment effect, and patients with 17p deletion/TP53 mutation in the presence of disease progression. It is important to note that after transplantation, the use of rituximab and lenalidomide as maintenance therapy is recommended to prevent relapse.

Finally, patients require maintenance therapy, which includes:

• Transfusion of red blood cells for anemia;
• Platelet transfusion for bleeding caused by thrombocytopenia;
• Antimicrobial agents in case of bacterial, fungal or viral infection, as well as for its prevention;
• Use of prednisolone at a dose of 1-2 mg/kg in the development of autoimmune processes.

In the event of a relapse of the disease, treatment tactics depend on a number of factors, such as: previously administered therapy, the timing of the relapse, and the clinical picture. In case of early (that is, occurring within 24 months or earlier) relapse, the main drug is ibrutinib. It is used both independently and as part of the above-mentioned treatment regimen (ibrutinib + rituximab + bendamustine).

Alemtuzumab may be an alternative drug of choice. While demonstrating comparable efficacy to ibrutinib, it, however, exhibits significantly greater toxicity.

Finally, in some patients, bone marrow transplantation can be performed for early relapse of chronic lymphocytic leukemia.

In case of late relapse (occurring more than 24 months after completion of treatment), the main selection criterion is the early therapy performed.

• If previous fludarabine-based therapy was not accompanied by significant toxicity, then you can return to this regimen and also supplement it with rituximab.
• If cytopenia is detected, it is possible to use rituximab in combination with high doses of glucocorticosteroids.
• In case of previous treatment with chlorambucil, the use of regimens with fludarabine or a combination of bendamustine and rituximab is indicated.
• Monotherapy with ibrutinib or its combination with one of the polychemotherapy regimens can also be effective in relapsed chronic lymphocytic leukemia.

What is CLL and how is it treated?

Oncohematologist Elena Stadnik about chronic lymphoblastic leukemia

Oddly enough, cancer can be chronic. Sometimes they do not even require treatment (but only observation). In other cases, treatment can last a lifetime...

Who makes the diagnosis?

CLL, or chronic lymphocytic leukemia, is characterized by the progressive accumulation of phenotypically mature malignant B lymphocytes. This is a very insidious malignant blood disease. The fact is that it can “lurk” in the body for many years without making itself felt. As a rule, they find it by accident. Maybe an attentive therapist will notice a high level of white blood cells and refer you to a hematologist, or maybe someone will pay attention to enlarged lymph nodes, fatigue, night sweats and temperature.

In order to confirm the diagnosis, you need to do a test. This is a blood test called immunophenotyping. This method allows you to identify and count groups of leukocytes using monoclonal antibodies that are formed against cell surface antigens. Immunophenotyping makes it possible to determine their type and functional state by the presence of a particular set of cellular markers. Simply put, disease cells are found as if according to their passport data. To make a diagnosis of CLL, you don’t need to do scary tests like a bone marrow biopsy: the disease cells in the bone marrow are the same as those in the peripheral blood. In large cities, the result of such a test can be obtained in two hours.

Who is sick?

It used to be that CLL was a disease of grandparents. Young patients, although rare, were encountered. However, no one diagnosed them with CLL. Typically, their condition was diagnosed as non-Hodgkin's lymphoma and, as a result, was treated incorrectly. Now, thanks to high-quality diagnostics, the diagnosis has become younger. There are also patients under 30, but this is still rare.

Indications for treatment?

For many, CLL sounds like an immediate death sentence. However, this diagnosis is not at all a signal to action. Patients with dormant leukemia are not treated. They are being watched. When CLL patients learn of their diagnosis, they find it difficult to believe that the disease will not need to be treated for a while. They rush to turn to foreign doctors for help, wasting time, money and effort, but the answer they receive is the same: wait. Of course, it is unbearably difficult to wait and think every day whether something terrible will happen. But CLL is not the sword of Damocles. Don't think that trouble will come tomorrow. They live with the disease, they treat it...

Here are the indications for starting treatment:

- Anemia, decreased platelet count.

- Bleeding, infections.

- Enlarged lymph nodes.

— The doubling time of leukocytes is less than two months.

- Complications, especially autoimmune ones.

- Special symptoms: fever, weakness, night sweats, weight loss.

How to treat?

Despite the fact that targeted drugs are officially registered as the first line of therapy for CLL, chemotherapy according to the standard protocol is enough for many to reduce the tumor mass. There is a group of patients who are known from the very beginning that they will not respond to chemotherapy. These are patients with a deletion of chromosome 17 or 11, as well as with a non-mutated type of CLL. Such patients are immediately treated with targeted drugs. Young patients, despite the risk, are offered a bone marrow transplant. Successful BMT means a complete cure for chronic lymphocytic leukemia.

Targeted therapy for the treatment of CLL

For a long time, chemotherapy was the only possible treatment for chronic lymphocytic leukemia. Yes, it helped, but the patient suffered a number of side effects and complications. Hair loss, nausea, dizziness, vomiting, bone marrow progenitor cell death, cardiotoxicity and secondary tumors. Healthy cells died along with the diseased ones. Sometimes complications from chemotherapy led to the death of the patient. The advent of targeted therapy has changed a lot...

What it is?

Targeted therapy is a type of molecular medicine that can block the growth of cancer cells by interfering with the mechanism of action of pathogenic molecules that cause tumor growth. Chemotherapy prevents the proliferation of all rapidly dividing cells in the body, while targeted chemotherapy prevents only bad ones. Numbers speak volumes about the effectiveness of targeted therapy. If previously 20% of patients went into remission, now it is 80%.

The question arises: if everything is so good with targeted therapy, why not treat everyone with it? The answer is simple: it's still expensive. However, targeted drugs are already registered as the first line of therapy for CLL. And an economic analysis has shown that treatment with targeted drugs is safer and easier, because the costs for them are lower than for complicated chemotherapy, where you treat not only the disease, but also complications. If it were possible to get targeted drugs out of your pocket and distribute them to everyone in need, chemotherapy in the case of chronic lymphocytic leukemia would sink into oblivion.

Eight years have passed since the first patients began taking targeted drugs as part of clinical trials. Russian patients have less experience: five years. The use of targeted therapy has shown amazing results. Patients tolerate treatment well. Those who were considered hopeless found hope. Now they are waiting not for palliative treatment, but for a full life. The life of a man, looking at whom you would never say that he was sick at all.

Coronavirus and chronic lymphocytic leukemia

Why is it dangerous?

Coronaviruses are a huge group of viruses. Of these, only 7 are dangerous to humans, including coronavirus, or SARS-CoV-2. It causes a potentially severe acute respiratory infection that can be mild or severe. It is dangerous because, as a complication, it most often leads to viral pneumonia, from which acute respiratory distress syndrome develops, and then acute respiratory failure. The problem with acute respiratory failure is that it cannot be cured at home. Oxygen therapy and respiratory support are required. This is why COVID-19 is dangerous not only for people, but also for the healthcare system as a whole. When the number of cases per day is in the thousands, there is a risk that not everyone will receive help due to overcrowding in hospitals. Despite the fact that the overall mortality rate from the new type of coronavirus is 2.3%, the number of its victims in the world is one million people.

Who is at risk?

During a pandemic, it is especially important to take care of people for whom the virus is potentially most dangerous. The risk group primarily includes people over 65 years of age, people with cardiovascular diseases, diabetes mellitus and lung diseases, and only then cancer patients. Those with cancer in remission who are not undergoing chemotherapy or radiation therapy are considered healthy people in terms of their risk of contracting COVID-19.

Who then should pay special attention to preventing infection with COVID-19? Patients receiving chemotherapy or who have just completed it. People who have had a bone marrow transplant in the first year after it. Also for those who are on radiotherapy, hormonal and immunosuppressive treatment. It is very important to take care of people with chronic leukemia and non-Hodgkin's lymphoma. This is due to the fact that such diseases are incurable and are present in the body even during a period of stable remission. All of the above conditions suggest secondary immunodeficiency, which is why COVID-19 is so dangerous.

What to do?

In order to protect yourself, you will have to learn to live differently. At least for a while. Who knows better what it means to “live differently” than a cancer patient? The most important thing is, of course, self-isolation. It is necessary to find other means of communication with family and friends, in addition to personal meetings. Surprisingly, a family dinner can also take place via video call. It is also worth reducing the number of hospital visits. Choose small clinics for this rather than large medical institutions where there are many people. Before performing any medical procedures, you need to evaluate the harm and benefits. Your doctor will help you with this. The rest is telemedicine.

There are cases in which a visit to the hospital is unavoidable. For example, a course of chemotherapy. This carries a particular risk of contracting COVID-19, so if treatment can be delayed, it is best to delay it. If the course is already underway, of course, it needs to be continued. If possible, it is better to switch to targeted therapy. It is tablet-based and does not require hospital monitoring.

Forewarned is forearmed. By following all the rules for preventing COVID-19 infection, you can be confident in your own safety. The main thing is to remember that one day the pandemic will end. In the meantime, drink tea and stay home.

Quality of life in chronic lymphocytic leukemia. Case from practice

The story begins in 2014. Nina, as is usually the case, routinely underwent a biochemical blood test, which showed elevated leukocytes. No one knew where they came from, because Nina was a completely healthy young girl. She was only 28 years old. When the result of immunophenotyping indicated chronic lymphocytic leukemia, Belarusian doctors (and at that moment Nina was vacationing in a sanatorium in Belarus) refused to believe in the diagnosis: young people do not get sick with CLL. Then Nina had to urgently return to Moscow. The diagnosis was confirmed at the National Medical Research Center for Hematology. It was really hard to believe what was happening. Nina felt great. The disease seemed to have subsided, although the level of leukocytes indicated otherwise. A year ago, Nina was absolutely healthy. However, the disease progressed.

Nina’s CLL is one of the most dangerous: with a deletion of chromosome 17. Lymphocytes multiplied, lymph nodes enlarged, and the tumor mass grew. Although Nina felt well, it was necessary to urgently begin treatment. When it comes to older patients, they are treated with chemotherapy or targeted drugs. This helps delay relapse. In her case, there should have been no relapse. As a young patient, she was offered a risky, but the only sure way out - a bone marrow transplant. In order to carry out a transplant, the tumor mass must first be reduced. Doctors tried to achieve this effect with chemotherapy, but, as often happens in patients with deletion of chromosome 17, there was no reduction.

It is worth saying that if this story had unfolded a couple of years earlier, Nina would have had nothing to help, but she was lucky. She was treated already in the era of targeted drugs. The treatment was successful. Leukocytes returned to normal, and the tumor mass decreased.

Now Nina was ready for transplantation. The donor was a woman from Poland. However, it was too early to breathe a sigh of relief. It is not enough to transplant bone marrow; it also needs to take root. Unfortunately, this did not happen for Nina. And yet the young woman was not going to give up. She was looking for a foundation that would help her with a second transplant. And then a miracle happened. When the analysis was repeated, it turned out that the bone marrow had engrafted by 99%.

Now Nina has the fourth negative blood group, the same as her donor, and not the first positive, as before. This is good. When the donor's blood type is different from the patient's blood group, it is easy to determine whose bone marrow is currently working: the donor's or the family's. If Nina's bone marrow donation stopped working, her blood type would again become type 1 positive instead of type 4 negative.

Now Nina is in remission, she lives a normal life, raising her daughter. Two decades ago no one would have believed such a story. Alas, every step along this path is a struggle. The struggle for expensive treatment, for finding a donor, for transplantation, for life. Patients in the last century could not count on targeted therapy. She simply wasn't there. And young patients were left without a diagnosis at all. Who would give them CLL? Everything is different now. You always have to fight and wait. Miracles don't happen any other way.

Quality of life in chronic lymphocytic leukemia. Patient history

The young man worked in production, where he took a blood test every year. During the next clinical examination, the leukocytes in the blood were slightly elevated, but no one paid attention to this, including Shamil himself. Winter, flu epidemic, St. Petersburg. What's surprising? A year later he was going to go to a boarding house. As expected, before leaving I donated blood - and again the lymphocytes were high. This time, the therapist sent the man to a hematologist, who diagnosed him with chronic lymphocytic leukemia. At that time, Shamil Kamilyevich was forty years old.

Although the diagnosis was made, there were no indications for starting treatment. Shamil Kamilyevich was sent home. For three years he returned to his normal life, until he fell ill with pneumonia in 2015. He noticed that in general he began to get sick more often. In addition, the lymph nodes in his neck had enlarged, so much so that it was uncomfortable to turn his head. It turned out that leukocytes and lymphocytes exceeded a hundred. It was necessary to start treatment urgently.

Shamil responded poorly to the standard course of chemotherapy. He had a non-mutated type of CLL, which is very difficult to treat. They prescribed a targeted drug, added another one, and after a couple of weeks the lymph nodes shrank. Shamil, as expected, spent the first month of treatment in the hospital, under the supervision of doctors. He tolerated the medications well. He just said that he wasn’t used to drinking so much water, although he still drank.

Finally, the man was discharged from the hospital, but soon he had to return there. Before the New Year, neutrophils dropped. Again treatment in the hospital, and finally home. After this, Shamil took prescribed medications on an outpatient basis for 2 years. Now he has complete clinical and hematological remission with radiation of minimal residual disease. Simply put, a good deep remission. Although he is still under the supervision of doctors, he feels like an ordinary and healthy person.

The text is based on the broadcasts “Conversation with oncohematologist Elena Aleksandrovna Stadnik.”

Broadcast recordings:

https://bit.ly/3jdFZn5

We thank Abbvie for the opportunity to broadcast.

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Evaluation of treatment effectiveness

Diagnostic studies aimed at assessing the effect of the treatment are carried out no earlier than 2 months after the end of the last course of chemotherapy. The result can be assessed as follows:

• Complete remission: reduction to normal sizes of the liver, spleen, lymph nodes (their increase in size of no more than 1.5 cm is acceptable), reduction in the number of lymphocytes to less than 4 × 10 9 \l in the peripheral blood and less than 30% in the bone marrow, increase in the number platelets more than 100×10 9 \l, hemoglobin - more than 110 g/l, neutrophils - more than 1.54 × 10 9 \l.
• Partial remission: reduction in the size of the lymph nodes, liver and spleen by 50% or more, reduction in the number of lymphocytes in the peripheral blood by 50%, increase in the number of platelets more than 100×10 9 \l, hemoglobin - more than 110 g/l, neutrophils - more than 1, 54×10 9 \l or an increase in any of these parameters by more than 50% from the initial level.
• Signs of disease progression are, on the contrary, an increase in the size of the lymph nodes, liver and spleen by 50% or more, as well as a decrease in the number of platelets by 50% or more from the initial level and a decrease in the number of platelets by 20 g/l or more.

To establish complete remission, it is necessary to meet all of the listed criteria; partial - at least 2 criteria relating to the condition of internal organs, and at least one criterion relating to the cellular composition of the blood.

It should be taken into account that ibrutinib therapy can lead to a complete response in the lymph nodes and spleen, but with preservation of leukocytosis in the peripheral blood. This condition is referred to as partial response with lymphocytosis.

Chronic lymphocytic leukemia. Treatment in Israel. Effective treatments

Treatment of chronic lymphocytic leukemia in Israel is carried out by highly professional oncologists, hematologists, and chemotherapists. Doctors approach prescribing a treatment program thoroughly, taking into account all the characteristics of the patient’s body. The Ichilov Complex clinic practices several types of treatment for lymphocytic leukemia and all of them bring high healing results.

Treatment of chronic and acute lymphocytic leukemia in Israel involves the use of effective drugs, innovative techniques and the latest equipment. Doctors working at the Ikhilov Complex clinic help patients return to a normal, healthy life every day.

Targeted therapy. This method involves introducing drugs into the patient's body that act on the molecules found in cancer cells, resulting in blocking their growth and spread. This type of therapy is highly effective in the treatment of lymphocytic leukemia and is safe for the patient.

Chemotherapy. Tumor cells are destroyed using chemicals injected into the patient's body. Therapy involves several courses, the exact number of which is determined by the attending physician. Unlike other countries, chemotherapy in Israel does not have severe side effects on the patient's body. Israeli doctors use only licensed drugs of the latest generation.

Radiation therapy. Using the latest linear accelerators, areas of the body with the greatest accumulation of cancer cells are irradiated. Radiation therapy is also given before or after surgery to remove the spleen to kill cancer cells and prevent them from entering the bloodstream.

Monoclonal therapy. The drugs that are administered to the patient contain monoclonal antibodies, which are the basis of the immune system. These antibodies detect and kill only cancer cells. The use of monoclonal therapy in combination with chemotherapy doubles the effect of treatment.

Interferon treatment is immune therapy. Interferon is a protective protein with antitumor activity that increases the body's defenses. Interferon therapy is highly effective against certain types of blood cancer.

Bone marrow transplantation is an innovative method of treating lymphocytic leukemia in Israel based on the introduction of immature stem cells from a donor into the body. These cells produce normal blood cells. Before carrying out this procedure, a necessary condition is the implementation of a course of intensive chemotherapy.

Operation. Lymphocytic leukemia in Israel is also treated with surgical methods: in case of damage to the spleen and lymph nodes, these organs must be removed.

The favorable outcome of treatment at the Ikhilov Complex is due to the many years of experience of doctors, the most modern equipment and an individual approach to each patient.

• Chemotherapy
• Targeted chemotherapy
• Radiation therapy
• Bone marrow transplantation
• Latest Trojan Horse Technology

Forecast

Significant advances in the treatment of chronic lymphocytic leukemia have made it possible to make this disease potentially curable or to support a person’s life for a sufficiently long time without progression of the underlying disease while maintaining its quality.

On the contrary, without treatment, the disease slowly but steadily progresses, which can cause the death of the patient several years after the onset of the disease, so timely consultation with a doctor and initiation of adequate therapy are very important.

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Bibliography:

1. Clinical recommendations for examination and treatment of patients with chronic lymphocytic leukemia. Recommendations of the National Society of Hematology. 2014.
2. Volkova M.A. Chronic lymphocytic leukemia and its treatment. Attending doctor. 2007, No. 4.
3. Michael Hallek. Chronic lymphocytic leukemia. Oncohematology. 2010, volume 3, no. 1. pp. 181-182.
4. Fedorov A.B. B-cell chronic lymphocytic leukemia. Clinical oncohematology. Basic research and clinical practice. 2008. P.275-277.
5. Fiyya A.T., Frenkel B.I. Chronic lymphocytic leukemia: diagnosis and treatment. Journal of Grodno State Medical University. 2011. No. 4. P. 93-97.
6. Nikitin E.A. Ibrutinib in the treatment of chronic lymphocytic leukemia. Clinical oncohematology. 2021. 10(3), p. 282-286.
7. Kravchenko D.V., Svirnovsky A.I. Chronic lymphocytic leukemia: clinical picture, diagnosis, treatment. Practical guide for doctors. Gomel, 2021.

Symptoms of lymphocytic leukemia

As a rule, acute lymphoblastic leukemia develops very quickly: within a few weeks. Its main symptoms are:

• headache;
• malaise and weakness;
• pain in the abdomen, in the bones;
• frequent nosebleeds, bleeding gums;
• pallor;
• enlarged lymph nodes in the neck, groin and axillary areas;
• fever.

Chronic lymphocytic leukemia often does not manifest itself at all in the initial stages. It can develop over years: during the development process, the following symptoms gradually appear:

• increased sweating (especially at night);
• heaviness in the stomach;
• pallor;
• malaise and weakness;
• frequent infections;
• dyspnea;
• weight loss for no reason;
• hemorrhages in the mucous membranes and skin.