Chronic lymphocytic leukemia: causes, symptoms, diagnosis, stages, treatment

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.

Causes and provoking factors

There is no single and scientifically reliable cause for the development of lymphocytic leukemia today. For this reason, it is almost impossible to prevent the disease. One of the most plausible theories is gene mutation. Since quite a few cases of family illness have been described, and the more relatives in the family were sick, the greater the chance of inheritance. The primary risk is if your mother, father, brother or sister has been diagnosed with this type of cancer. Therefore, doctors recommend regular medical examinations and screenings for people whose first-degree relatives are ill.

It is also worth noting risk factors that can provoke the disease:

1. Age. The older the patient, the greater the chance of developing lymphocytic leukemia;
2. Effect of harmful radiation. Radiation, magnetic fields and other radiation have a detrimental effect on the hematopoietic system.
3. Regular contact with chemicals. Paint products, agricultural chemicals, heavy metals and other chemicals are considered carcinogens.
4. Smoking. It can cause not only lung cancer, but also almost all forms of leukemia.

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.

Questions and answers

How long do people live with acute lymphoblastic leukemia?

The disease has a rapid course, so without medical care, death occurs within a few months. With timely treatment, 80-90% of children and about 40% of adults have a chance to live more than 7 years.

How long does treatment for acute lymphoblastic leukemia last?

• The preparatory stage of treatment lasts 1-2 weeks.
• Induction – up to 8 weeks.
• Consolidation – up to 4 months.
• Reinduction – several months.
• Maintenance therapy – up to one and a half years.

The total duration of treatment is approximately two or two and a half years.
How do you know if you have acute lymphoblastic leukemia?

If you have:

• symptoms of general malaise – lethargy, weakness, fever;
• bleeding from the nose, gums, and other mucous membranes;
• poorly healing wounds on the skin;
• severe sweating at night -

It is necessary to contact an oncologist or hematologist as soon as possible and have tests done. The listed symptoms do not always indicate the onset of acute lymphoblastic leukemia, but this disease develops rapidly and aggressively. For the success of treating roads literally every day.

Attention! You can cure this disease for free and receive medical care at JSC "Medicine" (clinic of Academician Roitberg) under the State Guarantees program of Compulsory Medical Insurance (Compulsory Medical Insurance) and High-Tech Medical Care. To find out more, please call +7(495) 775-73-60, or on the VMP page for compulsory medical insurance

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.

Patient care

After diagnosing chronic lymphocytic leukemia, even in the initial stages, the patient is registered with the general public. This is necessary for the purpose of constant monitoring of its parameters.

Such people need to constantly prevent infectious diseases: get vaccinated. Treat inflammatory and autoimmune processes only under the supervision of doctors, as they can progress quite quickly.

During remission, do a blood test every 4-5 months and come for a preventive examination by a doctor.

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.

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.

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.

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