STOP LEUKEMIA

In recent years, patients with tumor and progressive forms of CLL are treated with fludarabine both as monotherapy and in combination with other drugs: cyclophosphamide (FC), rituximab (FCR), mitoxantrone (FCM). In the overwhelming majority of patients treated according to these protocols as the first line of therapy, they managed to achieve complete or partial remission of CLL. Since treatment according to these protocols has been carried out over the past few years, the median overall survival in this cohort has not yet been reached.

An important role in the treatment of splenic CLL was assigned to splenectomy and radiation treatment, the median survival rate was 61 months. The treatment of the abdominal form was carried out similarly to the treatment of the tumor form. The bone marrow and prolymphocytic forms of CLL were very rare. The disease in these cases was malignant, was accompanied by profound anemia and thrombocytopenia, and a fatal outcome quickly occurred.

Life expectancy was primarily affected by the stage of the disease in which hemoblastosis was diagnosed (table 5). Patients whose CLL was diagnosed in stage A according to the Binet classification had a significantly longer life expectancy than patients with B and C stages at the time of detection of the disease. Patients who had a high expression of the CD38 marker at the time of diagnosis of the disease had a significantly lower survival rate.

Infectious complications were observed in 85% of patients with CLL. The most common diseases were the bronchopulmonary system (pneumonia, bronchitis, pleurisy, etc.) – 38.8% and pathology of upper respiratory tract – 28.6%; Herpes zoster was observed less frequently – 16.3%; abscesses, phlegmon, sepsis – 5.3%; erysipelas – 5.3%; mycoses – 5.7%. In 13 people, the disease was complicated by autoimmune hemolytic anemia (5.5% of the total number of CLL patients).

Note: Pulmonary tuberculosis and chronic bronchitis were attributed to comorbidities in cases where they were previously diagnosed with CLL. The accession of these diseases on the background of CLL was attributed to its complications.

The terminal stage of CLL was more often manifested by cachexia, transformation into lymphosarcoma, “prolymphocytic crisis” was observed only in two patients, “blast crisis” CLL was not registered. In the vast majority of cases, the bronchopulmonary complications of hemoblastosis were the direct cause of death – 59.9%. In 23.8% of cases, death was due to concomitant cardiovascular pathology (ischemic heart disease, myocardial infarction, hypertensive disease).

The classification of J. Binet (1981) is taken as a basis when dividing patients with CLL into three groups, since it allows staging of hemoblastosis taking into account the stages of tumor progression.

Group I (48 people) – CLL patients in stage A according to J. Binet classification. In 39 patients with CLL, blood samples showed moderate leukocytosis and absolute lymphocytosis, the lymph nodes of all groups were of normal size. In 9 patients, except for leukocytosis and lymphocytosis, an increase in peripheral lymph nodes (1-2 groups) up to 2 cm in diameter, soft-elastic consistency; but for many years they have not experienced progression of the disease. No patient in group I had splenomegaly, anemia and thrombocytopenia. Thus, group I consisted of patients with a benign form of the disease. Course cytostatic therapy was not prescribed to these patients. They were monitored dynamically, sometimes given primary restraint therapy with chlorambucil. The average age of patients of group I is 58.7 ± 2.0 years,longevity is the same as in the population.

Group II – 112 people. This group includes patients with stage B according to the classification of J. Binet. The majority of patients belonged to the progressive and splenic (partially tumor) forms according to A.I. Vorobyov et al. (1985 – 2005). These patients were characterized by high leukocytosis, increasing lymphadenopathy (an increase in more than three groups of lymph nodes), splenosis and hepatomegaly. In blood tests, Hb values> 100 g / l and platelets> 100 × 10 9 / l. Lymph nodes were of a soft-elastic consistency, painless, not welded between themselves and the surrounding tissues. With the progression of CLL, infectious complications developed. In 80 patients of group II, according to ERTGS and CT, an increase in mediastinal lymph nodes was diagnosed. The average age of patients in group II was 58.5 ± 3.2 years. The median survival is 97 months.

Group III included 68 patients. This group consisted of patients in stage C according to the classification of J. Binet. The majority of patients belonged to the A.I. Vorobyov et al. (1985 – 2000). This group included 6 patients with the spleen form of CLL, all patients with abdominal, bone marrow and pro-lymphocytic forms of hemoblastosis, as well as patients who at the time of the survey were diagnosed with Richter syndrome. In all patients, anemia was diagnosed in blood tests (HB <100 g / l), in 33 patients thrombocytopenia (Tr <100 × 10 9 / l) Patients of group III are characterized by increasing lymphadenopathy (the lymph nodes reached considerable size, had a dense elastic consistency, were soldered to conglomerates), hepato-and splenomegaly, the appearance of pronounced symptoms of tumor intoxication, frequent infectious complications, the development of auto-immune complications, often there was a transformation into large – cellular lymphoma. In a number of patients of the third group, high leukocytosis with atypical lymphocyte morphology was noted. In all patients of group III, CT and ERTG of the mediastinum were shown to show an enlarged lymph nodes. The average age of patients in group III was 61.2 ± 5.5 years. Median survival – 43 months.

The clinical characteristics of the bronchopulmonary system in patients with CLL, outside the administration of AML, depended on the stage of the disease. In patients of group I, peripheral lymph nodes were not enlarged and, according to x-ray studies, no increase in lymph nodes in the chest cavity was detected. In all patients of this group, the lower edge of the liver was palpated along the edge of the rib arc; the spleen was not detected by palpation. In patients of group I, the chest was the correct form, both of its halves equally participated in the act of breathing. A clear pulmonary sound was determined perkutorno over the entire lung surface, vesicular respiration was heard during auscultation, and there were no spurious respiratory sounds. In 4 patients with the presence of concomitant Nedo sufficiency blood circulation in the lower parts of the lungs during auscultation listened to wet fine bubbling rales, percussion determined the dullness of the pulmonary sound.

In 80 patients of group II (71%), according to x-ray methods, an increase in broncho-pulmonary and mediastinal lymph nodes was diagnosed. However, none of the patients showed clinical symptoms of compression of the bronchi and lung tissue due to an increase in the lymph nodes in the chest cavity. In 61 patients, an increase in the spleen and / or liver was diagnosed, but there were no clinical signs of compression syndrome. When viewed in 82 patients of group II, the chest was the correct form. In 72 patients, during a percussion, a clear pulmonary sound was detected over the entire lung surface, vesicular respiration was heard during auscultation, and there were no adverse respiratory sounds.In 10 patients with the presence of concomitant circulatory failure in the lower lung during auscultation listened to wet finely wheezing, percussion determined the dullness of the pulmonary sound.

All patients in group III were diagnosed with swollen lymph nodes, including in the chest cavity. Of these, 14, according to peripheral lymph node biopsy, were diagnosed with Richter syndrome (transformation into large cell lymphoma).

However, the clinical manifestations of compression syndrome in the chest cavity (shortness of breath, asphyxiation, cough, pain syndrome) were diagnosed only in 5 people with Richter syndrome. In 6 patients, the spleen occupied a large part of the abdominal cavity (splenic form of CLL); radiologically, these patients were diagnosed with a high standing of the diaphragm dome. In the terminal stage of the disease, such a spleen caused compression syndrome in the abdominal cavity, chest compression was observed, which was clinically manifested by shortness of breath. In 12 patients in the terminal stage of the disease, with a significant increase in the liver and spleen, which had a dense consistency, insufficiency of blood circulation developed. Clinically, this was manifested by the accumulation of fluid in the pleural cavities (transudate), shortness of breath, cough, ascites, edema in the lower extremities.In the presence of fluid in the pleural cavities, a significant weakening of breathing and voice tremor was determined over the zone of lesion of the pleura, dull pulmonary sound. In 6 patients in the lower parts of the lungs, moist rales were heard.

In 21 patients of group III (9.2%), in the terminal stage of the disease, a specific lymphoproliferative pleurisy was diagnosed as a manifestation of leukemic pleural infiltration. In the presence of initial manifestations of lymphoproliferative pleurisy, clinical symptoms were absent. As it progressed, clinical symptoms appeared: dyspnea (19 patients), weight loss (21 patients), anorexia (21 patients), fever (10 patients). Only 9 patients with lymphoproliferative pleurisy experienced chest pain; they characterized the pain as dull and aching. During auscultation of the lungs in such patients, a significant weakening of respiration was determined over the area of ​​pleural lesion, percussion – a dulling of pulmonary sound, and a weakening or strengthening of voice jitter was determined.When a large amount of exudate accumulated in the pleural cavity, a lag of the affected lung was noted during breathing.

Infectious complications occur from 75 to 80% in patients with CLL . As CLL progresses, the incidence of bacterial and viral infections increases . Specific lymphoid infiltration of the lung tissue and hyperplasia of the lymphoid follicles of the bronchial tree contribute to bronchopulmonary complications in CLL. All this leads to the development of atelectasis, impaired ventilation and gas exchange function of the lungs and the drainage function of the bronchi . At the same time, the lifetime diagnosis of leukemic infiltration with the use of rontgenological methods causes considerable difficulties. . The source of infiltration is lymphoid follicles located around the bronchi and large veins. In the phase of malignant transformation of CLL, the tumor can grow from the lymph nodes into the fatty tissue of the mediastinum, the lesion of the interalveolar septa of the lung, the wall of the bronchi and pleura .

Of course, one of the main methods for recording the prevalence of the tumor process in CLL is renn-tomography and tomography . As an example, we present one of the observations . Patient V., 62 years old. On the radiograph of the organs of the thoracic cavity in a direct projection (Fig. A), bilateral, moderately pronounced root lymphadenopathy is determined without infiltrative changes in the lung tissue. When the sighting ERTG determined specific lymphoid infiltration of the lung tissue, muftoobrazno covering the upper lobe bronchus and circularly narrows their Enlightenment Russian you . On the radiograph, these changes are not differentiated.

If we summarize the available information in the literature and our own experience, then it can be noted that radiologically much more often we have to diagnose complications of leukemia in the form of various kinds of pneumonia than the actual leukemic infiltrates. Specific leukemic infiltrates with traditional radiography are rarely diagnosed, because they do not reach significant sizes. With significant leukemic infiltration of the peribronchial tissues, it is possible to note a pronounced increase in the pulmonary pattern and its deformation, corresponding to the delicate mesh -looped structure .

As the process progresses against this background, small focal shadows appear, the anatomical substrate of which can be both specific and non-specific processes in the lungs. Focal shadows in some cases can be a display of peribronchial and perivascular couplings in their cross section. With a friend On the other hand, specific leukemic infiltrates that go to the alveoli and perform them form small foci, which can be radiologically similar in the form of foci. Concomitant pneumonia, among which quite often small-focal forms occur, is also sometimes an anatomical substrate of small focal-like shadows. X-ray manifestations of specific leukemic infiltration and the accompanying or self-induced pneumonia may be similar. This similarity is so pronounced that it is difficult to decide which elements of the shadow pattern are associated with inflammatory changes, which are caused by specific infiltration, even with the use of modern technology – CT and ERTG.

The introduction of X-ray computed tomography into practice, especially of high resolution, significantly improves the diagnosis of pulmonary manifestations of CLL. In 102 patients with CLL, chest CT was performed (during the polar phases of respiration, planimetric and densitometric measurements), pathology was detected in 85 patients (83%), radiographs and linear tomograms changes were detected only in 46 patients (45%). At CT scan the following changes were revealed: root and mediastinal lymphadenopathy – in 68 (66.7%); compression of the bronchi and lung tissue by the lymph nodes with Richter syndrome – in 15 (14.7%); pneumonia – in 45 (44.1%); lymphoid infiltration of the lungs – in 5 (4.7%); lymphoid infiltration of the pleura – in 14 (13.7%); pleurisy – in 28 (27.5%); pulmonary tuberculosis – 10 (9.8%); emphysema – in 78 (76.5%); pneumosclerosis – in 37 (36.3%); post-pneumonic pneumofibrosis – in 14 (13.7%).

The enlarged lymph nodes of the mediastinum, according to different authors, I diagnose in 25-64% of patients with CLL . For the most part, peripheral lymph nodes are larger than the intrathoracic, but reverse relationships can also be observed. The severity of mediastinal lymphadenopathy depends on the stage of development of the tumor process. Lymphoadenopathy in patients with CLL is mainly peripheral. On this occasion, it is mainly patients who go to the doctor. Only a few of them at this time radiographically determine the enlargement of the lymph nodes of the median. Later, in the advanced stage of the disease, mediastinal lymphadenopathy is detected in more than half of the patients, sometimes reaching considerable sizes. However, for the classical course of the disease, even with a significant increase in lymph nodes, compression syndrome is not characteristic .

The rapid growth of lymph nodes, their acquisition of stony density, compression and infiltration of neighboring organs and tissues, causing swelling and pain, are characteristic of sarcomas, malignant transformation of CLL – the so-called. Richter syndrome. At this stage of the disease, compression of the enlarged lymph nodes of the bronchi and lung tissue is possible, accompanied by impaired ventilation of the lungs and the drainage function of the bronchi. In the stage of malignant transformation, the germination of the lymph node tissue into the lung tissue and the lumen of the bronchi is possible, which is not typical for the classic course of CLL. For verification of Richter syndrome, a histological examination of sarcomotransformed lymph nodes is necessary. Operational biopsy is not difficult if the transformation occurs in the peripheral lymph nodes,and it is very difficult to defeat mediastinal or abdominal nodes. Without replacing the histological examination, CT can help in the diagnosis of sarcoma transformation. lymph nodes of the chest cavity. Development of a compression syndrome in the chest cavity, associated with enlarged lymph nodes and / or germination of the lymph node tissue into the surrounding tissues, favors the development of Richter syndrome . In patients with Richter syndrome due to impaired lung ventilation and drainage of the bronchi, infection of the bronchopulmonary system is a fairly common and very serious complication. But in addition to inflammatory infiltrates, in the stage of malignant transformation of CLL, specific leukemic infiltration may appear in the lungs, the differential diagnosis of which with inflammatory infiltrates is very difficult .

There are great prospects in the use of CT for the objectification of X-ray images and parameters characterizing the selective status of the ventilation function of light . Radiographic findings on the state of pulmonary pattern and emphysema are very subjective . A.V. Lenshin (2004) developed a method for quantitative assessment of X-ray data on CT using the Hitachi W-800 computerized tomograph using the Level Detect program. The most optimal AV Lenshin considers sections at the level of the trachea bifurcation, made with a deep breath (the level of the pulmonary artery stem) [159]. Experienced by examining 100 healthy patients, 57 – with COPD and 54 – with bronchial asthma, the author found that in the density range –950 …- 1000 units. HU is detected (“contrasted”) with emphysematous transformed lung tissue.Counting the selected pixels in fixed (dominant) areas of a particular axial tomographic slice allows to obtain quantitative (in% per unit area) diagnostic tests of pulmonary emphysema [159]. This technique was used by us in patients with CLL (Fig. 9). In the studied groups of CLL patients, the following results of the quantitative determination of pulmonary emphysema were obtained: in group I, the percentage of emphysematous tissue per unit. the average area was 27.24 ± 0.24; in group II – 34.27 ± 0.31%; in group III – 42.29 ± 0.21%.the average area was 27.24 ± 0.24; in group II – 34.27 ± 0.31%; in group III – 42.29 ± 0.21%.the average area was 27.24 ± 0.24; in group II – 34.27 ± 0.31%; in group III – 42.29 ± 0.21%.

The quantitative determination of pulmonary emphysema in CLL patients is an important method of X-ray functional study, since many functional disorders of the bronchopulmonary system are associated with emphysematous transformation of the lung tissue in these patients, and CT scan is one of the most reliable methods for in vivo diagnosis of emphysema.

Summarizing what has been said, the following conclusion can be made:

1. A comprehensive X-ray examination of the organs of the thoracic cavity using ERTG and CT significantly improves the diagnosis of bronchopulmonary pathology in patients with CLL.

2. X-ray differential diagnosis between inflammatory and specific leukemic infiltrates in the lungs in CLL patients is significantly complicated. However, in the overwhelming majority of cases , X-ray studies reveal inflammatory infiltrates. Lymphoid infiltration in the lungs in CLL rarely reaches a size that can be detected radiographically.

3. CT scan is the best method of registering compression syndrome in the chest cavity in CLL patients in the stage of malignant transformation.

4. When using the method of quantitative evaluation of radiological data at CT in patients with CLL as the tumor progression revealed an increase in the percentage of emphysematous tissue.

An important reason contributing to the severe and protracted course of bronchopulmonary infections in CLL is pronounced secondary immunodeficiency. Therefore, the study of the functional state of the bronchopulmonary system of these patients began with a study of immunological parameters. All patients diagnosed with CLL significant inhibition of cellular and immune gumoralno- of ETA .

When conducting a spirographic study, violations of ventilatory function of the lungs (VFL) in obstructive and mixed types were detected only in patients who had long abused smoking, who had a diagnosis of COPD long before the first signs of CLL (50 people) appeared. In the remaining patients, even with a significant increase in the broncho-pulmonary lymph nodes, there were no violations of VFL during spirography.

To evaluate the bronchial permeability and its daily monitoring, peak flow metering was used, which was used to measure peak expiratory flow rate (PSV) for 1 to 2 weeks. This chapter provides data only for those patients who did not have a history of COPD and did not abuse smoking. In CLL patients of all groups, the PSV indices averaged 95% of the required values ​​in the morning and 100% in the evening. Daily fluctuations of PSV did not exceed the repeatability of the test and amounted to 5% of the initial value.

Indicators of bronchial resistance in patients with I (2.7 ± 0.1 cm.water.st / l / s on inspiration, 3.0 ± 0.14 cm.water.st / l / s on exhalation) and II (2, 8 ± 0.1 cm.water / l / s on inhalation, 3.0 ± 0.11 cm.water / l / s on exhalation) groups did not have significant differences compared with similar indicators in the control (2.8 ± 0.1 and 3.0 ± 0.06 see water supply / l / s, respectively). In patients with group III, there was an increase in bronchial resistance compared with the control (3.4 ± 0.11 cm. Water / l / s on inspiration; 3.5 ± 0.11 cm. Water / l / s / s on the exhale; P <0.001).

Diagnostic fiberoptic bronchoscopy (FBS) was performed on 60 CLL patients who did not abuse smoking and outside the administration of AML (20 patients of group I, 20 patients of group II, and 20 patients of group III). All patients of group I had a bronchoscopic picture of a normal tracheobronchial tree. But 10 patients had vascular injection.

In 10 patients of the II group, when conducting PBS, bilateral diffuse endobronchitis was diagnosed, the intensity of inflammation (IW) of the I degree. Not marked hyperreactivity of the bronchi. These patients had no clinical manifestations of bronchitis. A bronchoscopic picture of a normal tracheobronchial tree was diagnosed in 10 patients of group II. In 15 patients of this group, plethora and vasodilation were noted.

In 14 patients of the third group, fibrobronchoscopy was diagnosed with bilateral diffuse endobronchitis, IV – 1 and II degrees (12 and 2 people, respectively). No bronchial hyperreactivity was detected. Only four patients noted a slight cough in the morning. Other patients had no clinical symptoms of bronchitis. A bronchoscopic picture of a normal tracheobronchial tree was observed in 6 patients of group III. Expansion and plethora of blood vessels were diagnosed in 16 patients , which in CLL is a manifestation of hemoblastosis, and not bronchopulmonary pathology.

Thus, during fibrobronchoscopic examination, 60% of patients with a progressive course of CLL (40% of the total number of patients with CLL) were diagnosed with a latent course of chronic non-obstructive bronchitis.

Endobronchial biopsy was performed on 10 patients of group I, 10 patients of group II, and 5 patients of group III. Topeka biopsy specimens – 1.5 cm distal to the spur of the right upper lobe bronchus. Patients of group I were diagnosed with moderate proliferation or dystrophy of the bronchial epithelium. In patients with benign CLL, no lymphoid infiltration of the bronchi was detected. In patients with groups II and III, the histological examination of biopsy specimens determined the signs of chronic inflammation, edema, atrophy of the bronchial mucosa, and focal squamous metaplasia of the epithelium was often noted. Under the basement membrane revealed diffuse lymphocytic infiltration of varying severity. Most lymphoid infiltration was expressed in patients of group III.

In patients of group I, there was a slight dilatation of capillaries, a plethora of arterioles, capillaries and venules. In patients with CLL in stage A, no leucostasis was found in the vessels of the microcirculatory bed of the bronchi. In patients with group II, dilatation and plethora of arterioles, capillaries, and venules were observed with varying degrees of severity. In 6 patients of group II, accumulations of lymphocytes with the formation of leuco- stasis were observed in the vessels of the microcirculatory bed. In patients with group III, dilatation of arterioles, capillaries and venules was also diagnosed with varying degrees of severity. All group III patients were diagnosed with leukostasis in the vessels of the microcirculatory bed.

In order to study microhemocirculation in the proximal parts of the bronchial tree, endobronchial laser Doppler flowmetry (LDF) was performed in 25 patients with CLL. The results were compared with the data of 20 people from the control group, who were conducted PBS and LDF. According to the research data in patients with CLL, in the process of tumor progression, various types and degree of severity of microcirculatory circulation were registered.

The LDF method is based on probing tissue by laser radiation and subsequent processing of radiation reflected from a tissue in accordance with the Doppler effect. The amount of probed tissue in the LDF method is determined by the geometry and optical parameters of the light probe. The amplitude of the reflected signal is formed as a result of the reflection of radiation from erythrocytes, moving at different speeds and differently quantitatively distributed in arterioles, capillaries, venules and arterial venous anastomosis. Thus, PM determines the change in blood flow per unit time in the volume of tissue being probed and is represented by the following expression: PM = K × Ner × Vav; where: PM – microhemocirculation parameter , K – proportionality coefficient, (K = 1), Ner – red blood cell count, Vav – average erythrocyte rate – tov in the probed volume . A decrease in the PM values ​​may be due to a change in the number of blood cells and their speed in the microvessels of the area being examined. In CLL, microhemocirculation in the lungs and bronchi is undoubtedly promoted by accumulations of lymphocytes in small caliber vessels and anemic syndrome. In order to minimize the effect of anemia on the PM, in patients with group III (stage C, according to the J. Binet classification), the anemic syndrome was stopped before the study. The hemoglobin level during LDF was not lower than 100 × 10 9 / l, the content of red blood cells was at least 3 × 10 9 / l. Thus, they tried to establish a decrease in the speed of red blood cells in the microvessels, which in CLL may be primarily due to the presence of vascular accumulations of lymphocytes.