Symptoms, causes, diagnosis and treatment of chronic lymphocytic leukemia

Chronic lymphocytic leukemia is a clonal malignant lesion of the hematopoietic system. In this pathology, it is the bone marrow damage that is primary, and the substrate is the lymphocytes developing in it, and not metastases brought from other organs, which gave secondary growth here.

Diseases similar to leukemia can also occur if the tumor cell focus is located outside the bone marrow, for example, in the lymph node (lymphoma). In advanced cases, lymphoma also affects the bone marrow – in such a situation it can be extremely difficult to distinguish lymphoma from chronic leukemia.

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Clinic Features

In the early stages of the development of the disease, specific manifestations are absent. Patients complain of a constant feeling of weakness, a steady decrease in body weight, night sweats. Hematological pathology can be suspected only by a general blood test – already in the early stages of CLL, absolute leukocytosis is detected.

As chronic lymphocytic leukemia progresses and leukemia cells accumulate in the bone marrow, the following manifestations join:

  • Generalized enlargement of different groups of lymph nodes. An increase in the size of peripheral lymph nodes is determined by palpation, an increase in the intrathoracic or intra-abdominal lymph nodes is detected by x-ray or ultrasound.
  • At later stages of the development of the disease, hepatosplenomegaly can develop. These changes, most likely, will be manifested by the patient’s complaints of heaviness in the right and / or left hypochondrium, as well as by early satiation with food intake.
  • As the tumor clone of the cells grows, and they displace normal hematopoietic structures of the bone marrow, anemia and thrombocytopenia are possible. This can be manifested by complaints of general weakness, dizziness, bleeding with minor damage, during examination, identification of petechiae and ecchymosis is possible.
  • Inhibition of hematopoiesis causes changes primarily in the humoral immunity. Immunosuppression in such cases is manifested primarily by frequent infectious diseases.

Symptoms of chronic lymphocytic leukemia are also found in many other diseases, it is impossible to establish a diagnosis only by the clinical picture.

To select the optimal treatment methods, as well as to determine the prognosis of the course of the disease and survival, for leukemia, as for all other malignant neoplasms, stages are distinguished. Rai classification includes five stages in the development of such a lymphoproliferative disease as chronic lymphocytic leukemia:

  1. Stage 0. Only lymphocytosis detected in the peripheral blood and bone marrow puncture is detected in a laboratory. On average, patients with this stage live more than twelve years. The degree of risk is considered low.
  2. Stage 1. An increase in lymph nodes determined by palpation or instrumentation is attached to lymphocytosis. Life expectancy is up to nine years, the degree of risk is intermediate.
  3. Stage 2. In addition to lymphocytosis, examination of the patient reveals hepatomegaly or splenomegaly. On average, these patients live up to six years.
  4. Stage 3. hemoglobin less than 110 g / l, lymphocytosis and a clear increase in the size of the lymph nodes in the presence or absence of hepatosplenomegaly. The risk is high, life expectancy of up to three years.
  5. Stage 4. Thrombocytopenia is added to the previous manifestations – less than 100 * 109 cells per liter. The risk level in this case is considered high, and the average life expectancy of patients with this stage is less than a year and a half.

There is another option for separation into stages, somewhat simplified. According to Binet, there are only three stages:

  • A. A hemoglobin level of more than 100 g / l is characteristic, thrombocytopenia is more than 100 * 109 cells per liter, lymph nodes are enlarged in no more than two anatomical areas. The risk level in this case is low, patients live on average about 10 years.
  • B. Laboratory indicators are the same as in the case of A stage, however, an increase in lymph nodes is detected in more than three anatomical areas. The risk is intermediate, life expectancy at stage B averages about five years.
  • C. At this stage, anemia and thrombocytopenia are more pronounced – the hemoglobin level does not exceed 100 g / l, platelets are less than 100 * 109 cells per 1 liter. The number of anatomical zones with enlarged lymph nodes and the presence / absence of hepatospenomegaly at this stage do not affect the prognosis. The risk is high, the average life expectancy in these patients is up to two years.

For the diagnosis, the situation in the peripheral blood is important, because in most cases the suspicion of leukemia arises from a blood test. At different stages of the development of pathology, the picture can significantly change (including lymphocytic leukemia with a normal content of lymphocytes is possible), however, such changes are considered characteristic for this disease:

  • Leukocytosis. The severity of this manifestation depends on the stage of the disease – at the initial stages of development, leukocytosis can be relatively small – 10 * 109 cells per 1 liter, however, as the disease develops, these numbers can increase to 200 * 109 cells or more.
  • The number of lymphocytes determined by the study of peripheral blood is more than 5 * 109 cells per 1 liter.

The pathological cells in structure have features characteristic of adult lymphocytes. One of the characteristic signs of chronic lymphocytic leukemia is the presence in the peripheral blood of the so-called Botkin-Gumprecht-Klein eye shadow. These shadows are nothing more than lymphocyte nuclei destroyed during the preparation of the drug.

Chronic lymphocytic leukemia is also characterized by anemia. The lack of hemoglobin and erythrocytes in this pathology can be caused by both the displacement of erythropoiesis cells from the bone marrow by the cells of the tumor clone and the autoimmune mechanisms of erythrocyte damage (autoimmune hemolytic anemia).

The level of platelets in the early stages of the disease is most often within normal limits, however, with the progression of lymphocytic leukemia with megakaryocytes (platelet precursors), the same thing happens with red blood cell precursors – they are replaced by a tumor clone from the bone marrow.

A study of the material obtained during bone marrow puncture is mandatory for the diagnosis of chronic lymphocytic leukemia. A sign of the presence of a disease is considered to be the content of more than 30% of lymphocytes in the material obtained by biopsy, however, in advanced cases, lymphocytes can fill almost the entire volume.

With trepanobiopsy, it is possible to establish the nature of the changes – focal or diffuse. With diffuse tumor cell infiltration, the prognosis is extremely poor.

There are no specific changes that could be detected by a biochemical blood test for chronic lymphocytic leukemia. An increase in the level of bilirubin (a consequence of hemolysis), as well as an increase in the activity of lactate dehydrogenase, which also indicates cytolysis and is not a specific sign, can be determined.

When examining the level of immunoglobulins contained in the blood plasma, a decrease in the concentration of all normal immunoglobulins is determined.

Immunophenotyping. The study of differentiation antigens in some cases helps not only in choosing the most appropriate treatment regimen, but also makes it possible to distinguish leukemia from lymphoma in the stage of leukemia.

Cytogenetic study – in the vast majority of patients, one or another chromosome aberration is detected during the study. These can be deletions of the shoulder of the chromosome, trisomy, translocation – depending on the type of aberration and the affected chromosome, the prognosis for the patient can differ significantly.

Also, information obtained during cytogenetic research can affect the choice of treatment methods.

Ultrasound examination, X-ray examination, computed and magnetic resonance imaging can establish the presence of enlarged chest or abdominal lymph nodes.

Therapies

Chronic lymphocytic leukemia at the current level of development of medical technology cannot be completely cured. In the best case, it is possible to restrain the progression of the disease for a long time.

Actually, far from all cases, treatment begins immediately after diagnosis, since it has been proven that earlier treatment at the early stages of the disease does not contribute to better patient survival.

For many people, a diagnosis of lymphocytic leukemia or blood cancer sounds like a 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.

This is a cancerous disease in which white blood cells, bone marrow, peripheral blood are affected, and lymphoid organs are involved in the process.

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Scientists are inclined to believe that the cause of the disease lies at the genetic level. The so-called family predisposition is very pronounced. It is believed that the risk of developing the disease in immediate relatives, namely in children, is 8 times higher. In this case, a specific gene causing the disease was not found.

The disease is most common in America, Canada, in Western Europe. And almost uncommon, lymphocytic leukemia is in Asia and Japan. Even among representatives of Asian countries that 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 suggested 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) ─ cancer, which is morphologically represented by immature lymphocytes (lymphoblasts). There are no specific symptoms for which an unambiguous diagnosis can be made.

Chemotherapy is the most effective treatment for cancer

Causes of the disease

This disease is somewhat knocked out of the general series of leukemia for a number of causes.

  1. The appearance of this pathology has absolutely no effect on external negative factors – carcinogens, ionizing radiation, lifestyle and nutrition.
  2. The risk of the disease may increase slightly upon contact with insecticides and the Orange agent. Most often, this pathology occurs in people belonging to the Caucasian race. This type of disease is diagnosed in every third person with cancer of the blood in the United States and Europe. In other races, CLL is extremely rarely diagnosed. The reasons for this racial selectivity are not yet known.
  3. In addition, chronic lymphocytic leukemia usually affects people who have already crossed the age threshold of 70 years. Patients, whose first signs of the disease began to manifest somewhat earlier than 40 years, make up no more than 10% of patients with this diagnosis, although doctors have registered a gradual rejuvenation of this pathology.
  4. Most often, CLL affects men. Women face this disease 2 times less often.
  5. One of the most important factors in the development of this disease is the principle of heredity. If we consider the dependence of the occurrence of CLL on this side, it should be noted that the hereditary moment occurs 8 times more often than just the disease that arose in a person who does not have relatives with this disease.

CLL lasts a very long time completely without symptoms and manifests itself in the later stages. At an early stage of development, the disease is detected, most often by accident, when taking blood for a general analysis, although here the lymphocyte count is practically the same. Patients usually complain of rapid fatigue, incomprehensible weight loss, sweating, and “jumping” temperature.

As the disease progresses in patients with chronic lymphocytic leukemia, the following symptoms begin to appear:

  • The pathological condition of the lymph nodes. Lymph nodes are greatly enlarged and can reach 5 cm. On palpation, they are clearly tightened, but completely painless. An increase in deep lymph nodes can be seen by ultrasound.
  • Anemia The patient’s skin becomes very pale, weakness and dizziness appear. Stamina and performance are greatly reduced.
  • Thrombocytopenia. A critical decrease in platelets occurs, which entails a significant decrease in blood coagulation. The skin can have rashes of a hemorrhagic type – ecimoses or petechiae.
  • Granulocytopenia. Outwardly, this pathology does not manifest itself, but the patient may develop various infectious diseases.
  • Decreased immunity. The patient becomes susceptible to any diseases of an infectious and bacterial nature. The body practically loses any ability to fight on its own and the illnesses proceed in a severe form with complications. A person is constantly harassed – cystitis, urethritis, colds and viral diseases.
  • Autoimmune disorders. It is these processes that lead to the occurrence of acute anemia and thrombocytopenia. These conditions are characterized by a sharp increase in temperature and bilirubin in the blood, which leads to severe bleeding.
  • Enlarged spleen and liver. These symptoms appear already in the later stages of the disease. The patient begins to feel a feeling of heaviness and severe discomfort.

In the case of the worst outcome in chronic lymphocytic leukemia, patients most often die from complications of seemingly simple diseases.

To date, a system for distinguishing the disease by stages has been developed. The stages of chronic lymphocytic leukemia are usually divided into three main groups.

  • Stage A (initial) – characterizes the onset of the disease, in which the patient quite often does not have an increase in lymph nodes, one or two groups of lymph nodes are much less enlarged. At this stage, signs of anemia or thrombocytopenia are completely absent.
  • Stage B (detailed) – in the absence of anemia and thrombocytopenia in a patient, lesions of at least three groups of lymph nodes can be detected and their pathology progresses rapidly. Constantly recurring diseases of an infectious nature are manifested. At this stage, active treatment is already required.
  • Stage C (terminal) – already has anemia or thrombocytopenia. The chronic form becomes malignant.

Always next to the letter designation of the stage of the disease, Roman numbers can be seen. These signs indicate the presence of a specific symptom.

0 – the initial stage with a survival period of about 10 years.

I – lymphadenopathy, survival is reduced to about 7 years.

II – an increase in the spleen or liver, an average risk group with a life expectancy of about 7 years.

III – anemia in varying degrees, complements all previously existing symptoms. The life span after transition to this stage is reduced to 1, 5 years.

IV – thrombocytopenia. The patient falls into the highest risk group with a survival period not exceeding more than 1,5 years.

The results of a study of chronic fludarabine resistant lymphocytic leukemia are shown in table 18. The treatment outcome in patients immune to fludarabine is unfavorable with a median OS of approximately 8 months. The use of alemtuzumab alone gives a total response rate of 30-35%. The combination of alemtuzumab with high doses of steroids leads to an improvement in the overall frequency of response, but survival without progression and OM remains unsatisfactory.

Table 18. Treatment of recurrent / refractory patients with high-risk CLL

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PR – complete remission; OO is the general answer; PFS – progression-free survival; OB – overall survival; A is alemtuzumab; A HDMP – alemtuzumab high doses of methylprednisolone; AF / FA – alemtuzumab fludarabine; O – ofatumumab; CFAR – cyclophosphamide fludarabine alemtuzumab rituximab; BF – bendamustine fludarabine; ND – no data.

Regimes including fludarabine and alemtuzumab are active in patients who are resistant to any of the components separately, but the responses are short-lived and the risk of infectious complications is high. Since the duration of remission during the initial treatment of a high-risk disease after the use of regimen including alemtuzumab is short, consolidation therapy such as allo-HSCT is recommended for suitable patients.

Treatment options for patients in whom alemtuzumab-based therapy was ineffective, or relapse developed after it, are very limited. Active drugs include ofatumumab, lenalidomide, and high doses of corticosteroids with or without rituximab. Corticosteroids given in standard doses can provide short-term control of the disease and improve symptoms associated with CLL.

The choice of therapy depends on the suitability of the patient, previous treatment and the availability of the drug. In a registration study by Wierda et al., When using ofatumumab, the overall response rate was achieved in 58% of patients resistant to both fludarabine and alemtuzumab (dual resistance) and in 47% of patients with progressive chronic lymphoid leukemia resistant to fludarabine, in which alemtuzumab was considered inappropriate. The median progression-free survival in both groups was approximately 6 months.

The effectiveness of ofatumumab was not affected by massive lymphadenopathy, previous use of rituximab or resistance to FCR. The overall response rate was lower (14%) among patients with 17p deletion in the group with massive lymphadenopathy and at the same time resistant to fludarabine form of the disease, but in the group of patients with double resistance with 17p it was 41%.

E.V. Zukhovitskaya, A.T. Fiasco

Posted by Konstantin Mokanov

The reasons for the development of this pathology differ from the causes of other oncological processes. This is the only type of leukemia that does not occur due to exposure to carcinogens or ionizing radiation. Today, researchers agree that chronic lymphocytic leukemia is of a genetic nature. As lymphocytic leukemia develops, pathological lymphocytes first replace healthy lymphocytes, and then other cells that make up the blood.

Factors that can trigger a pathology include:

  1. Intestinal infections;
  2. Constant stress;
  3. History of surgery;
  4. The development of infectious diseases;
  5. Long-term treatment with strong antibiotics.

All these factors are not proven, but are often detected in a patient with a diagnosis.

Each stage of chronic lymphocytic leukemia has its own characteristics:

  1. At the zero stage, an increase in lymphocytes is noted only in the bone marrow, there is no anemia, platelets are within normal limits, and lymph nodes are not enlarged.
  2. In the first degree, lymphocytes increase in the blood, lymph nodes, liver, spleen. There is no anemia yet, platelets are normal or near it, an increase in lymph nodes occurs.
  3. The second stage is characterized by the absence of anemia. The spleen enlarges, the liver remains normal.
  4. With stage 3, anemia occurs, the platelet level is normal, the condition of the spleen and liver is identical to the second degree of the disease.
  5. At the fourth stage, severe anemia is present, the number of platelets in the blood decreases.

According to the level of hemoglobin, platelets, the number of affected areas, the pathology is also divided into stages A, B, C.

B-cell chronic lymphocytic leukemia – the most dangerous and most common type of leukemia

It is believed that B-cell chronic lymphocytic leukemia mainly affects Europeans at a fairly advanced age. Men suffer from this disease much more often than women – they have this form of leukemia occurs 1.5-2 times more often.

It is interesting that among representatives of Asian nationalities living in Southeast Asia, this disease practically does not occur. The reasons for this feature and what makes the people from these countries so different are still not established. In Europe and America among the white population, the incidence rate per year is 3 cases per 100 population.

Epidemiology

A blood test is the main method for diagnosing chronic lymphocytic leukemia

List of Abbreviations

LML – lymphoma from small lymphocytes

MVL – monoclonal B-cell lymphocytosis

IFT – immunophenotyping by flow cytometry

CT – computed tomography

PET positron emission tomography

MRI – magnetic resonance imaging

DECL – B-large cell lymphoma

HL – Hodgkin’s lymphoma

SR – Richter syndrome

MPI – International Forecast Index

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Burger JA, et al. Safety and activity of ibrutinib plus rituximab for patients with high-risk chronic lymphocytic leukaemia: a single-arm, phase 2 study. Lancet Oncol. 2014; 15 (10): 1090-9

Dreger P, et al., Managing high-risk CLL during transition to a new treatment era: stem cell transplantation or novel agents? Blood 2014; 124 (26): 3841-9

Dreger P, et al. Indications for allogeneic stem cell transplantation in chronic lymphocytic leukemia: the EBMT transplant consensus. Leukemia. 2007; 21 (1): 12-7

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Wierda WG, et al. Ofatumumab is active in patients with fludarabine-refractory CLL irrespective of prior rituximab: results from the phase 2 international study. Blood 2011; 118 (19): 5126-9

Mauro FR, et al. Diagnostic and prognostic role of PET / CT in patients with chronic lymphocytic leukemia and progressive disease. Leukemia. 2015; 29 (6): 1360-5

Conte MJ, et al. Use of positron emission tomography-computed tomography in the management of patients with chronic lymphocytic leukemia / small lymphocytic lymphoma. Leuk Lymphoma. 2014; 55 (9): 2079-84

Omoti CE, Omoti AE. Richter syndrome: a review of clinical, ocular, neurological and other manifestations. Br J Haematol. 2008; 142 (5): 709-16

Falchi L, et al. Correlation between FDG / PET, histology, characteristics, and survival in 332 patients with chronic lymphoid leukemia. Blood 2014; 123 (18): 2783-90

Vitale C, Ferrajoli A. Richter Syndrome in Chronic Lymphocytic Leukemia. Curr Hematol Malig Rep. 2016; 11 (1): 43-51

Terms and definitions

Chronic lymphocytic leukemia is a B-cell tumor of small lymphoid cells. Chronic lymphocytic leukemia and lymphoma from small lymphocytes are biologically the same tumor. The difference between them is that with chronic lymphocytic leukemia in the blood there is significant lymphocytosis (gt; 5000 monoclonal B-lymphocytes), while with lymphoma from small lymphocytes (LML), there is no clinically manifest lymphocytosis, despite damage to the lymph nodes, spleen, and bone marrow.

The International Prognostic Index (MPI) for chronic lymphocytic leukemia is based on five parameters:

the presence of del (17p) and / or TP53 mutations,

mutational status of genes of the variable region of immunoglobulins,

Assessment of the response to treatment should be carried out in accordance with the criteria proposed by the International Working Group on CLL (IWCLL) in 2008 (Appendix B, Table 3). In patients who have not achieved PR or CR and do not meet the criteria for progression, stabilization of the process is established, which is equivalent to a lack of response to treatment.

The use of ibrutinib will entail a revision of the effectiveness criteria, since it often leads to a complete response from the lymph nodes and spleen, but with persisting leukocytosis in the blood due to redistribution of CLL cells. Persistent lymphocytosis with ibrutinib therapy is not a sign of refractoriness.

Appendix B. Patient Information

Chronic lymphocytic leukemia is an oncological disease that affects blood cells and bone marrow. In chronic lymphocytic leukemia, the bone marrow produces pathologically altered lymphocytes that are unable to perform their functions. They accumulate in the blood and various organs and displace normal blood cells. The word “chronic” in the name indicates that this disease is benign.

Ten years ago, it was believed that elderly people were mostly affected by chronic lymphocytic leukemia. However, as the diagnosis improved, it turned out that this disease can also occur in young people (40 – 50 years old), and at this age it proceeds less favorably.

The doctor may suspect CLL, based on your complaints and finding the corresponding symptoms during the examination. In this case, it will be necessary to undergo a series of examinations, including a blood test and bone marrow. The most important test is a blood test, without which a diagnosis is not made. An analysis of the blood reveals an increase in the number of lymphocytes.

Unfortunately, today chronic lymphocytic leukemia is not curable. However, in some patients, the need for treatment never arises – chronic lymphocytic leukemia can remain in a stable state for many years and even decades. Many studies have been conducted comparing expectant follow-up and early initiation of therapy (immediately after diagnosis).

It turned out that treatment in the early stages does not give any benefit, but causes toxic effects. Therefore, the tactics of managing chronic lymphocytic leukemia is built taking into account the course of this disease – treatment is used as necessary, since it, in itself, is unsafe, and the tactics of expectant observation remains and is the standard for many patients.

If there are clear signs of the progression of the disease – a steady increase in lymphocytosis, an increase in lymph nodes, spleen, anemia and thrombocytopenia, the doctor will offer a specific course of treatment.

When choosing a treatment, the doctor takes into account:

disease state (clinical picture and prognostic factors)

patient condition (age, concomitant diseases)

what treatment was done before and when did relapse occur?

As a result, in most patients, the disease can be effectively controlled with the available modern medicines. Chemotherapy is the basis of treatment. In chronic lymphocytic leukemia, chlorambucil, fludarabine, cyclophosphamide, as well as monoclonal antibodies, rituximab, are most often used.

Appendix A2. Clinical Guidelines Development Methodology

This disease is usually detected by accident during a general blood test. Studying the patient’s leukocyte blood group, the doctor draws attention to the pathological deviations of the indicators. In order to accurately confirm or refute the suspicions that have arisen, doctors prescribe a number of additional examinations to the patient.

  • Bone marrow puncture When conducting this analysis, it is determined whether there is a replacement for lymphoproliferative tissue of the red brain. At the initial stage with this pathology, less than 50% of leukocytes will be contained in the bone marrow, and then this indicator may exceed 90%.
  • Cytogenetic examination will detect and determine the characteristics of malignant tumors.
  • Biopsy of an enlarged lymph node and its histological studies.
  • Immunophenotyping – provides markers characteristic of this disease.
  • Biochemical blood test. This study allows you to determine the presence of deviations in the patient’s immune system.

Chronic lymphocytic leukemia is very easily diagnosed with laboratory tests. Diagnostics includes decoding of blood test parameters, namely:

  • general clinical analysis – determines the increase in the level of lymphocytes, white blood cells;
  • myelograms – shows that red bone marrow cells have replaced lymphoproliferative tissue;
  • biochemical blood test – helps to identify malfunctions in the immune system, liver, spleen and other organs;
  • immunophenotyping – reveals specific proteins – cell tumor markers.

To make an accurate diagnosis, the doctor can prescribe a biopsy of the enlarged lymph node, after which the taken material is sent for cytogenetic and histological examination. Additionally, computed or magnetic resonance imaging and ultrasound are performed. After the completion of the diagnostic measures, the doctor prescribes therapy, depending on the degree of malignancy of lymphocytic leukemia, its spread throughout the body, symptoms and associated pathologies.

The diagnosis of chronic lymphocytic leukemia requires a complete blood count and immunophenotypic study using multicolor flow cytometry, which is preferable to perform by blood. The diagnosis is made when more than 5000 monoclonal B-lymphocytes are detected in 1 μl of peripheral blood.

If the absolute number of monoconal B-lymphocytes in the blood does not exceed 5000 in 1 μl, but there is lymphadenopathy, and / or splenomegaly, and / or cytopenia caused by bone marrow damage, then lymphoma from small lymphocytes (LML) is diagnosed. The immunophenotype of tumor B-lymphocytes in LML is similar to CLL. The diagnosis of LML should be confirmed by a biopsy of the lymph node, bone marrow, or affected organ.

It is recommended to perform a detailed clinical blood test with the determination of hemoglobin, red blood cells, platelets, leukocytes, counting the leukocyte formula and the number of reticulocytes

Level of evidence of recommendations I (level of evidence evidence A)

It is recommended to perform a CT scan of the chest, abdominal and pelvic organs (with contrast), a chest x-ray in two projections (if CT cannot be performed), ultrasound of the peripheral lymphatic, intraperitoneal and retroperitoneal nodes and abdominal organs, PET, ECG and Echo KG. 37

Target audience of these clinical recommendations:

Evidence Collection Methodology

Search for publications in specialized periodicals with impact factor gt; 0.3;

Search in electronic databases.

The evidence base for the recommendations are publications included in the Cochrane library, PUBMED and MEDLINE databases. The search depth was 30 years.

Methods used to analyze evidence:

Reviews of published meta-analyzes;

Systematic reviews with tables of evidence.

Methods used for the quality and strength of evidence:

Assessment of the significance of evidence in accordance with the rating scheme of evidence (Table 4,5).

These clinical guidelines in square brackets show the levels of evidence of recommendations according to the scales developed by the American Society of Clinical Oncology (ASCO) and the European Society of Medical Oncology (ESMO).

Table A1. Levels of Evidence

At least one large randomized controlled trial of high quality (with a low probability of errors) or a meta-analysis of homogeneous randomized trials of high quality

Small randomized trials or large randomized trials with a high probability of errors. Meta-analysis of similar studies or meta-analysis of heterogeneous studies

Prospective cohort studies

Retrospective cohort or case-control studies

Studies without a control group, individual cases, expert opinion

Table A2. Degrees of evidence

Reliable evidence of high clinical efficacy, highly recommended

Reliable or convincing evidence of moderate clinical efficacy, recommended

Inaccurate data on effectiveness that does not outweigh the risk or treatment deficiencies (adverse events, cost, etc.) can be used as one of the options

The good practice of recommendations is based on the qualifications and clinical experience of the team of authors.

Recommendation Validation Methodology

Recommendations validation methods:

External peer review;

Internal peer review.

These recommendations in the preliminary version were reviewed by independent experts, who were asked to comment on how well the evidence was interpreted and recommendations developed. An expert assessment of the presentation of recommendations and their accessibility for understanding was also conducted.

The recommendations were discussed and approved by leading experts of the relevant federal centers of the Russian Federation and practitioners. The draft clinical recommendations were considered at meetings of the working group in 2015-2016, at the Forum of experts on the diagnosis and treatment of malignant lymphoproliferative diseases “Lymphorum”, the annual Russian conference with international participation “Malignant lymphomas”, as well as the III Congress of Russian hematologists.

Chronic lymphocytic leukemia refers to malignant diseases. But this type of disease differs from other oncological diseases at a slow pace of development. A person can live long and feel good, not even suspecting the presence of the disease.

This is an oncological disease of lymphoid tissue, which results in the accumulation of pathological tumor lymphocytes in the liver, bone marrow, spleen, lymph nodes and their release into peripheral blood.

In other words, this is a condition of the body in which it produces an excess of white blood cells. The disease mainly develops after 60 years. Moreover, it is more common in the male part of the population.

Currently, the causes of chronic lymphocytic leukemia are not fully known. The most recognized theory of the onset of the disease is the viral genetic hypothesis.

According to her, there are several types of virus that, under favorable conditions, cause a breakdown of immunity in the human body. They penetrate into immature cells of the lymph nodes and bone marrow, causing their frequent division.

Also often this pathology is found in people with a damaged chromosome structure, i.e., carriers of hereditary information.

  • x-ray irradiation;
  • exposure to chemicals;
  • long-term use of certain drugs;
  • infectious diseases;
  • stress and nervous breakdowns.

In the early years, chronic lymphocytic leukemia may not appear. The symptomatology of the disease develops gradually for a rather long time. Every fourth patient found out about his illness by accident during a blood test taken for another reason. Early signs of the disease:

  • painful and enlarged lymph nodes;
  • fatigue and weakness;
  • poor appetite;
  • fever;
  • increased sweating;
  • weight loss;
  • frequent infections;
  • bone aches;
  • a feeling of heaviness under the left rib due to pressure of an enlarged spleen.

In the later stages of the disease, a violation of the process of blood formation occurs. Diagnosis of the disease includes several types of studies: a blood test, a biopsy of a diseased lymph node, a cell study of peripheral blood and bone marrow.

Compared with other oncological diseases, the treatment of this pathology at an early stage is not carried out.

Basically, treatment is prescribed after the signs of disease progression are manifested: a rapid increase in the number of lymphocytes in the blood, a significant increase in the spleen and lymph nodes, the progression of anemia, etc.

Traditional medicine uses several approaches in the treatment of chronic lymphocytic leukemia: chemotherapy, radiation therapy, or removal of part of the spleen with a significant increase in it.

Traditional medicine for all leukemia recommends remedies from medicinal plants rich in ascorbic acid and iron. 1. Vitamin tea – brew 25 g of rowan berries and wild rose in a cup of boiling water. Prepare a drink once a day. 2. The tool from the red brush – pour 500 ml of vodka 50 g of dry root. The remedy should be infused for a month.

Take the medicine 40 drops three times a day half an hour before eating. 3. A decoction of blackcurrant and rose hips – pour 50 g of berries 400 ml of boiling water. Take a drink of 100 ml every 4 hours. 4. Tincture of the marsh cinquefoil – place 60 g of grass in a half-liter jar and fill completely with vodka.

Therapy of relapse within 2 years after combination therapy with fludarabine or chemoimmunotherapy

  • The initiation of CLL therapy is recommended in the presence of the following indications according to IwCLL 2008 -69 criteria. One or more symptoms of intoxication:

weakness (ECOG? 2, disability);

low-grade fever without signs of infection;

night sweats lasting more than a month without signs of infection.

Increasing anemia and / or thrombocytopenia due to bone marrow infiltration.

Autoimmune anemia and / or thrombocytopenia resistant to prednisone.

Massive and growing lymphadenopathy.

Duplication of lymphocytes (Vul) less than 6 months.

Level of evidence of recommendations I (level of evidence evidence A)

To date, several studies have been published on the use of antibodies to CD20 as maintenance therapy for CLL. Efficacy data suggests that when partial remission is achieved, a residual population of CLL cells in the blood or bone marrow is detected, rituximab maintenance therapy may increase the time to relapse.

The choice of therapy for relapses depends on the following factors:

first line therapy;

time of onset of relapse;

clinical picture in relapse.

Patients with early relapse are guided by the recommendations presented in the section “High-risk CLL treatment”.

In patients with late relapse, the choice depends on first-line therapy. Repeated fludarabine-containing courses are possible provided that during the course of this therapy no significant toxicity was observed in the first line – severe protracted cytopenia, leading to months-long interruptions in treatment, and the development of severe infectious complications.

As a second-line therapy, you can return to the same scheme. If previously the treatment was carried out according to the FC program, FCR can be used as the second line. In patients with cytopenia, the R-HDMP regimen (rituximab in combination with high doses of steroids) may be effective. In phase II studies, compelling evidence has been obtained on the effectiveness of the BR regimen (bendamustine rituximab). In patients previously treated with chlorambucil, bendamustine, BR, and FCR-Lite regimens may be effective.

The results of three studies indicate the high effectiveness of ibrutinib in the treatment of CLL relapses. The effectiveness of ibrutinib monotherapy in patients with relapses is 71–90%. The efficacy of the combination of bendamustine, rituximab, and ibrutinib (iBR) significantly exceeds the effectiveness of the BR regimen in patients without 17p deletion.

The median BPV in patients receiving the BR regimen was 13,3 months, while the median was not achieved in the iBR group (2-year-old BPV was 75%). An indirect comparison of the results of two different trayls, conducted by an international team of researchers, indicates the comparable efficacy of ibrutinib monotherapy and iBR regimen in patients with CLL relapses.

These data need confirmation in a randomized trial, but additionally emphasize the high effectiveness of the drug. Ibrutinib is comparatively effective in the high-risk group of patients with markers of poor prognosis (refractoriness to purine analogues, unfavorable chromosome aberrations).

An important conclusion of these studies is that the sooner ibrutinib therapy is started, the more effective it is. Recent findings from the HELIOS study show that BPV2 (non-progressive survival after retreatment) with iBR is better than with BR. At the same time, ibrutinib has less toxicity than possible combinations of other drugs recommended for the treatment of CLL.

The choice of therapy for the third and subsequent lines is not regulated by these recommendations.

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The use of radiation therapy as the only and primary treatment for CLL is not recommended.

To date, there are no phase III studies involving patients who have recurred after the FC or FCR regimen. A phase II non-randomized trial in 284 patients with CLL relapse showed a higher rate of complete response, longer progression-free survival, and overall survival in patients receiving FCR than in a retrospective group of patients receiving FC.

78 out of 284 patients received initial treatment using regimens that included fludarabine and an alkylating agent. 13% and 9% of patients were resistant to fludarabine and chlorambucil, respectively. The overall frequency was 73% with 42% PR, nodular partial remission (NCR), progression-free survival was 19 months.

Among the cases sensitive to fludarabine, the incidence of PDR was 46% compared with 8% for cases resistant to fludarabine. In non-randomized phase II trials with the BR regime, a response rate of 60% and 45% was shown, respectively, for patients with relapse or resistant to fludarabine, with an event-free survival duration of 14,7 months. Of the 14 patients with a 17p deletion, only two responded.

Patients with a relapse of at least 2 years after treatment with FC, FCR or similar regimens without TP53 abnormality remain fully suitable for treatment with regimens including fludarabine, and patients should be given FCR therapy if clinically indicated .

Further studies are needed to evaluate the role of bendamustine in combination with anti-CD20 antibodies.

Chronic lymphocytic leukemia refers to diseases that cannot be completely cured. But if the diagnosis is made at an early stage and the doctor selects the right therapy, then a sick person can live for a long time, and his quality of life will deteriorate extremely slowly.

At the initial stage of the disease, patients do not need special medication. Such people for a very long time can feel completely normal and lead a normal life. The most important thing here is regular monitoring by a hematologist and taking specialized drugs only begins when a significant increase in the number of leukocytes makes itself felt – at least double the established norm.

In the case of rapid progression of chronic lymphocytic leukemia, the patient is prescribed complex treatment, the basis of which is chemotherapy. The best results are obtained from a combination of drugs such as rituximab, cyclophosphamide, and fludarbin.

Chemotherapy is often supplemented with the use of hormonal drugs in fairly large doses.

If the patient has a strong enlargement of the lymph nodes or spleen, as well as with the occurrence of organ infiltration, doctors almost always resort to the use of radiation therapy.

In the absence of positive results from conservative methods of treatment, the patient can undergo a bone marrow transplant or remove the spleen.

CLL treatment is further complicated by the fact that those who are ill are all elderly people. For them, many procedures are quite difficult and doctors are constantly looking for alternative ways to slow the progression of the disease.

1.3 Epidemiology

Chronic lymphocytic leukemia (CLL) is the most common type of leukemia in adults. In European countries, its frequency is 4: 100 000 per year and is directly related to age. In persons older than 80 years, it is gt; 30: 100 per year. The median age at the time of diagnosis in European countries is 000 years. In Asian countries, CLL is much less common.

Folk ways

Unfortunately, there are no recipes that have a scientifically proven result for the treatment of chronic lymphocytic leukemia with folk remedies. But the means that can support the body of an elderly person at this stage of life are quite diverse.

All patients with cancer need constant strengthening of immunity. For this purpose, it is very important to use decoctions and tinctures containing ascorbic acid and vitamin B. These plants include rosehip, hawthorn, sea buckthorn, mountain ash, etc. It is very desirable to make all kinds of “vitamin” teas from these plants.

Mountain ash and rosehip tea

The daily diet of patients with CLL

The immunity of older people is reduced by itself, but if there is also chronic leukocytosis, then the problem is naturally exacerbated. Given the fact that the disease develops very slowly and at first does not have any external manifestations, such patients are not prescribed medication. Health in this situation will need to be supported by natural methods.

Patients must observe a rational regime of alternating activity and rest.

Importance will also be given to nutrition in lymphocytic leukemia. In the diet of such people, there must necessarily be foods with the highest possible content of vitamins B and C. Therefore, there should be various berries on the table – grapes, strawberries, blackberries, gooseberries, cherries, cranberries, etc. Of the fruits, it is most preferable – pear, apricot, orange.

What to expect sick

As noted earlier, chronic lymphocytic leukemia tends to very slow progression in a benign variant of the disease. In the event that the disease is detected on time and the doctor prescribes effective therapy, then the patient has a significant improvement and such a patient lives for a long time – sometimes several decades.

The prognosis of CLL survival is quite optimistic, only 15% of all reported cases of chronic lymphocytic leukemia are rapidly developing, resulting in a fatal outcome after about a year. In all other cases, the patient will live 7-10 years.

1.6 Staging, diagnosis

Binet staging is most applicable (Table 1).

Table 1. Stage CLL by Binet

Median survival, months

% of patients in debut

or platelet count lt; 100 x 109 / l

axillary lymph nodes (from one or two sides);

inguinal lymph nodes (from one or two sides);

International Forecast Index

Each of these indicators was assigned a score reflecting the ratio of the risks of progression or death (table 2). MPI for CLL allows to discriminate patients into four groups: low (0–1 points), intermediate (2–3 points), high (4–6 points) and very high (7–10 points). There is evidence that the index allows stratification of patients in CLL relapse.

Table 2 international prognostic index

Possible scale values

The formulation of the diagnosis of CLL consists of five components:

Binet classification stage (indicated at the moment). The diagnosis is recommended to note the presence of massive lymphadenopathy (dimensions gt; 5 cm, conglomerate formation).

Indication of CLL risk group according to the international prognostic index. If only TP53 status is known, high risk is indicated.

Information about prior therapy.

Phase: without indications for therapy, remission, early relapse, late relapse (first, second, n-th), progression.

The diagnosis indicates what is essential to describe the current situation and make a decision about therapy.

Examples of formulating a diagnosis of CLL:

CLL, stage A, MPI 0, without indications for therapy;

CLL, stage B, MPI 4, massive abdominal lymphadenopathy, high risk;

CLL, stage B, MPI 5, condition after six courses of FC, remission;

CLL, stage A, condition after chlorambucil therapy, progression;

CLL, stage C, MPI 3, autoimmune hemolytic anemia of the II degree of severity;

CLL, stage C, condition after five courses of FCR, six courses of R-CHOP, monotherapy with alemtuzumab, third relapse. Aspergillosis of the lungs.

Prevention that helps prolong life and reduce risks

CLL prophylaxis methods currently do not exist, since the etiological factor (s) leading to the development of the disease is unknown. Clinical observation by a hematologist or oncologist is carried out throughout the patient’s life – both during treatment and outside of CLL treatment.

The prognosis of chronic lymphocytic leukemia and the life expectancy of a person depends on the stage of the disease and the nature of its course. Complete remission after treatment occurs only in thirty percent of cases, but it usually does not last long. Under complete remission is meant the absence of any symptoms, normal blood counts and sizes of the spleen, as well as lymph nodes for two months.

Partial remission means that during the same period, part of the manifestations disappears, and part remains. Basically, doctors manage to translate a progressive disease into a stable form, in which the patient’s condition does not improve or worsen. There are no specific preventive measures that can prevent the development of chronic lymphocytic leukemia. A person needs to lead a healthy lifestyle, this helps strengthen the immune system.

The development of chronic lymphocytic leukemia is not associated with any negative external factors. All available studies did not find provoking factors that would unambiguously entail the emergence or sharp progression of the disease. The only known cause of CLL in medicine is a hereditary factor.

Despite the fact that chronic B-cell lymphocytic leukemia is an oncological disease, you can live with it for many years, while maintaining normal body functions and enjoying life completely. But for this it is necessary to take certain measures:

  1. You need to take care of your health and seek medical help when the slightest suspicious symptoms appear. This will help to identify the disease in the early stages and prevent its spontaneous and uncontrolled development.
  2. Since the disease greatly affects the functioning of the patient’s immune system, he needs to protect himself as much as possible from colds and infections of any kind. In the presence of infection or contact with patients, sources of infection, the doctor may prescribe the use of antibiotics.
  3. To protect his health, a person needs to avoid potential sources of infection, crowded places, especially during periods of mass epidemics.
  4. The habitat is also important – the room should be cleaned regularly, the patient needs to monitor the cleanliness of his body, clothes and bedding, as all this can be sources of infection. .
  5. Patients with this disease should not be in the sun, trying to protect themselves from its harmful effects.
  6. Also, to maintain immunity, you need a proper balanced diet with an abundance of plant foods and vitamins, rejection of bad habits and moderate physical activity, mainly in the form of walking, swimming, light gymnastics.

A patient with such a diagnosis should understand that his illness is not a sentence, that you can live with him for many years, while maintaining good spirits of mind and body, clarity of mind and a high level of performance.

Appendix A2. Clinical Guidelines Development Methodology

The first symptoms of chronic lymphocytic leukemia, as a rule, occur long after the onset of pathology. The onset of signs of lymphocytic leukemia in children is noted earlier, however, babies rarely encounter this form of the disease. At the initial stage of the development of the disease, you can identify it only by passing a blood test, which will show the level of leukocytes at the border of normal and increase. The very first signs are not specific, they can occur in other pathological conditions. These include:

  1. General weakness;
  2. Fast fatiguability;
  3. Malaise;
  4. Insomnia;
  5. Dizziness;
  6. Weight loss;
  7. Intensified sweating.

The development of lymphocytic leukemia is accompanied by its characteristic symptoms:

  • Autoimmune processes (hemolytic anemia and thrombocytopenia) – enlarged lymph nodes, acute anemia, hyperthermia, obstructive jaundice, increased risk of bleeding.
  • Reducing the body’s overall resistance – frequent infectious diseases in a severe long-term form with complications.
  • Thrombocytopenia, granulocytopenia, anemia – pallor of the skin, dizziness, decreased stamina, weakness, fatigue. Blood coagulates poorly, any wound bleeds heavily and heals for a long time. A hemorrhagic rash sometimes appears on the skin.
  • Hepatomegaly and splenomegaly. The patient has painful sensations, a feeling of heaviness in the hypochondrium on the right and left due to an increase in the liver and spleen. Such an increase and displacement of the faces of the liver can be determined by palpation examination. Sometimes jaundice occurs with its inherent signs.
  • Enlarged and densified lymph nodes. To the touch, the lymph nodes may resemble a dough, but on palpation they are not painful.

For a long time, the patient’s condition is normal, but progressing, pathology adds new complications.

Epidemiology

Statistics show that annually 3 cases are recorded per 100000 people, and also that:

  1. the disease affects most of the elderly;
  2. the female sex is sick 2 times less often;
  3. the disease can be inherited;

Classification

In modern medical practice, 9 forms of chronic lymphocytic leukemia are distinguished:

  • Benign. The disease proceeds extremely slowly, complications, if they develop, then by old age. With a benign form, the patient can live up to 50 years.
  • Progressive. The number of white blood cells in the blood and the size of the lymph nodes, spleen is growing rapidly. This leads to the early development of complications and a short lifespan (up to 10 years).
  • Tumor. It is characterized by an increase in the size of the lymph nodes.
  • Bone marrow. It is characterized by extensive lesions of the bone marrow.
  • Splenomegaly. It is characterized by a rapid increase in the size of the spleen.
  • Complicated by cytolytic syn-mom. With this form, tumor cells die under the influence of the immune system, which causes intoxication of the body.
  • Prolymphocytic. A feature of this form is its rapid development, an increase in the spleen and peripheral lymph nodes. Immunological analysis shows either B-cell chronic lymphocytic leukemia, or the T-cell nature of lymphocytic leukemia, most often the first.
  • Complicated by paraproteinemia. In this case, tumor cells secrete a protein that should not be present in the body.
  • Hairy cell. It is named so because tumor cells have processes that look similar to villi.
  • T-shape. The disease develops rapidly, affecting the skin to a greater extent.

Not only the forecast, but also the risk group depends on the form. So, the T-form more often than not affects young Japanese.

Causes

It is not known for certain why chronic lymphocytic leukemia occurs. There are several theories, the most popular of which is viral genetic.

This theory says that a virus that invades the human body undermines the body’s defenses thanks to certain factors. Due to the weakened immune system, the virus penetrates into unripe bone marrow cells and lymph nodes, thereby causing their uncontrolled division without maturation stage. Today, 15 types of viruses are known that are capable of such a process.

Factors causing the destructive effect of the virus include:

  1. exposure to ionizing radiation;
  2. exposure to strong x-rays;
  3. exposure to vapor varnishes and other chemicals;
  4. long-term intake of gold salts and strong antibiotics;
  5. concomitant viral diseases;
  6. the presence of intestinal infections;
  7. constant stress;
  8. transferred operations;

A determining role is played by a genetic predisposition to the disease. In the vast majority of patients, cases of chronic lymphocytic leukemia were found in the family history.

Clinical signs are determined by the stage of the disease, the presence of complications, etc. Therefore, clinical manifestations may be absent at an early stage of the disease. As the disease develops, B-symptoms appear – weakness, fatigue, sweating, weight loss. There is an increase in lymph nodes (initially more often peripheral), an increase in the spleen. With the development of anemia and thrombocytopenia, symptoms associated with them appear. Often there is an increase in inflammatory and infectious diseases.

2.1. Complaints and medical history

Complaints may be absent, and then the signs of the disease are detected by a random examination.

An asymptomatic increase in lymph nodes of any location can be determined.

Complaints of weakness, sweating, and weight loss may be present.

Any complaints related to organ and tissue involvement may be present.

An anamnesis is required (including family history).

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Editor-in-chief of the Detonic online magazine, cardiologist Yakovenko-Plahotnaya Tatyana. Author of more than 950 scientific articles, including in foreign medical journals. He has been working as a cardiologist in a clinical hospital for over 12 years. He owns modern methods of diagnosis and treatment of cardiovascular diseases and implements them in his professional activities. For example, it uses methods of resuscitation of the heart, decoding of ECG, functional tests, cyclic ergometry and knows echocardiography very well.

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