Experience with the use of rituximab in the treatment of rheumatoid arthritis

Rituximab is a revolutionary chemotherapy for some malignant lymphomas, and also produced using genetic engineering.

• Chemical properties and composition
• pharmachologic effect
• Pharmacodynamics and pharmacokinetics
• Indications for use
• Contraindications
• Side effects
• special instructions
• Overdose
• Interaction
• Fertility, pregnancy and lactation
• Best before date
• Analogs

Chemical properties and composition

Rituximab refers to biological drugs, and specifically to monoclonal antibodies or MAbs for short.

This is an immunoglobulin, that is, a large protein synthesized by immune cells.

Functionally, it is an antibody that in the human body must contact a certain type of antigen - a foreign protein, a bacterial product or a certain kind of cellular substrate. Rituximab needs to bind to a receptor on the surface of the unhealthy blood cell.

This is a monoclonal antibody because it is not produced by all blood cells, but by a specific group or clone.

The protein consists of three different length chains of amino acids synthesized by mouse and human cells, so the antibody is called chimeric, that is, mixed from animal and human proteins, to reduce the toxicity of the drug.

pharmachologic effect

In the human body, rituximab looks for a special antigen, CD20, which exists on the surface of most malignant cells that make up B lymphomas and on ordinary B lymphocytes. There should not be such an antigen on other blood cells and it does not float in the blood plasma.

Having contacted the antigen, rituximab breaks off the vital chain of cellular biochemical reactions, and as a result, the cell turns on the program of suicide or apoptosis. In addition, the drug enhances the damaging effects of other cytostatics, so it is included in chemotherapy regimens for lymphomas and lymphocytic leukemia.

Since MAB also kills normal B lymphocytes that have CD20, they also die. As we can see, the selectivity of the drug does not lie in the ability to find and destroy a tumor cell, but in the killing of cells possessing the antigen. In one in a hundred patients with lymphoma, the body produces antibodies that neutralize the chimeric proteins, which makes the use of the drug useless.

Pharmacodynamics and pharmacokinetics

Almost all of the administered rituximab reaches the site of application of force in the blood, which is designated as 100% bioavailability. The concentration of the drug in the blood increases with each administration, by the fourth dropper the amount of active substance is twice as large as the initial one, and by the eighth dropper the maximum is reached. This process is not affected by the patient’s age, gender, or nationality.

It will take more than three weeks to remove half the dose of the drug from the body, but traces are found six months after completion of treatment. The elimination of rituximab is entrusted to macrophages, which also ingest bacteria, viruses and everything foreign to humans, but this is only an assumption. The kidneys and liver do not appear to be involved in the process of removing the drug; in any case, in patients with insufficient liver function, there is no need to change the dosage.

Sjögren's disease

BS is a chronic, slowly progressive autoimmune disease associated with the production of autoantibodies to the components of the cell nucleus, characterized by B-cell hyperreactivity, manifested mainly by damage to the exocrine glands (salivary, lacrimal), as well as damage to other organs and systems.
The prevalence of BS varies from 0.1% to 3.3% in the general population and from 2.8% to 4.8% among people over 50 years of age. Women get sick 10–25 times more often than men. The disease debuts at the age of 20–50 years [1]. Most researchers consider BS as a consequence of immunopathological reactions to viral antigens. Isolation of viral particles from the affected tissue of the salivary glands, the presence of antiviral antibodies in the blood in patients with sclerosis, and identification of the phenomenon of molecular mimicry between viruses and autoantigens suggest the possible participation of viruses in the development of this disease. The etiological role of viruses with sialotropic (cytomegalovirus, Epstein-Barr virus, herpes virus type 6) and lymphotropic (HIV, human T-lymphotropic virus type 1) effects is discussed. However, there is no direct evidence of the viral etiology of the disease [1–5].

BS is characterized by an autoimmune genesis of the development of the disease. The main autoimmune phenomena include focal lymphoplasmacytic infiltration of epithelial glands and polyclonal B-cell activation with the formation of organ-specific and/or nonspecific autoantibodies, polyclonal and monoclonal immunoglobulins, mainly IgM [1–5]. Although T lymphocytes were initially considered key cells in the development of the autoimmune process, there is now evidence that B cells play an equally important role. The presence and sometimes predominance of CD4+ T cells in salivary gland infiltrates highlights their potential contribution to the pathogenesis of BS. Increased levels of these cells are associated with a higher degree of inflammation in secreting epithelial structures. In BS, B lymphocytes are adaptive immune cells and are responsible for the secretion of antibodies and antigen presentation [2–5].

One of the key factors in this process is B-cell activating factor (BAFF), a cytokine that promotes the proliferation and maturation of B cells and is primarily induced by interferons (Fig. 1). It has been suggested that some viruses (for example, Epstein-Barr virus) activate toll-like receptors (TLR), leading to overproduction of interferon. It has been noted that in patients with BS, the level of BAFF in the blood and salivary glands is significantly increased, which correlates with high immunological activity of the disease and with a higher risk of developing B-cell lymphoma [2–5]. Considering the above, BAFF may be a potential target for BS therapy. The first results of studies on anti-BAFF therapy (belimumab) showed a significant decrease in disease activity after 1 year from the start of therapy, assessed by The EULAR Sjögren's syndrome disease activity index (ESSDAI) [3].

There is no typical clinical picture of BS, since many patients have varying degrees of involvement of organs and systems in the pathological process. Clinical symptoms can be divided into 3 groups: symptoms associated with damage to secreting epithelial structures (“sicca” syndrome), general symptoms and systemic manifestations of the disease [1–5].

“Dry” syndrome is a combination of dry skin, eyes (xerophthalmia), mouth (xerostomia), pharynx and/or larynx, which are classic symptoms of sclerosis. Women also experience vaginal dryness [2]. Xerostomia often contributes to the development of oral candidiasis (33%) and periodontal damage [2]. Xerophthalmia due to chronic irritation can lead to destruction of the corneal epithelium and infection of the eyeball. In addition, “dry” syndrome may include hoarseness and nonproductive cough [1–5]. The most common general symptom is fatigue, which occurs in 70–80% of patients with BS [2]. Depression and anxiety disorders are also common among them.

Systemic (extraglandular) manifestations are observed in approximately 70% of patients with BS. Extranodal MALT lymphoma is the most common of these manifestations. It can transform into a highly aggressive large cell lymphoma, which can become the direct cause of death of the patient [1–5]. Risk factors for the development of lymphomas include clinical symptoms such as unilateral enlargement of the salivary glands, lymphadenopathy, splenomegaly, skin vasculitis, cryoglobulinemia and the development of glomerulonephritis [1–5].

Joint damage in BS is predominantly manifested by symmetrical, intermittent, non-erosive arthropathy [2]. Arthritis is less common. The pathological process mainly involves the proximal interphalangeal (35%), metacarpophalangeal (35%) and wrist joints (30%) [1–5]. Raynaud's syndrome is often detected at the onset of BS; it proceeds relatively benignly in most patients. Lung damage in the form of interstitial pneumonitis, alveolar pulmonary fibrosis, lymphoid infiltration of the lungs with the formation of infiltration foci are the most characteristic changes in BS (20%). Compared with SLE, exudative pleurisy and pericarditis develop less often. Bacterial, viral and fungal pneumonia often complicate the course of interstitial lung disease [1–5]. Kidney damage in patients with BS includes a wide range of manifestations, of which the most common is interstitial nephritis [2]. Consistent screening of renal function is important as renal failure (GFR<60 ml/min) occurs in approximately 24% of cases [2]. In patients with BS, both the central and peripheral nervous systems are involved in the pathological process. In many patients, neurological symptoms precede the onset of other clinical symptoms of the disease. HD may be associated with hepatitis C (12%), autoimmune thyroid diseases (10%), autoimmune chronic active hepatitis (2%) and primary biliary cirrhosis (5%).

The diagnosis of BS is based on the SICCA classification criteria (Sjogren's International Collaborative Clinical Alliance, 2012): 1. The presence of anti-SSA/Ro- and/or SSB/La-antinuclear antibodies, or positive rheumatoid factor (RF) and antinuclear factor (ANF). 2. In the biopsy of the minor salivary glands, the presence of focal lymphocytic infiltration (≥1 focus in 4 mm2). 3. The presence of dry keratoconjunctivitis - ≥3 points on the ocular epithelium staining scale with fluorescein and lissamine green (antiglaucoma eye drops that inhibit the production of intraocular fluid, corneal surgery and blepharoplasty should be excluded).

The disease can be classified as Sjögren's syndrome if two of three criteria are met, excluding head and neck radiation, hepatitis C virus infection, HIV infection, sarcoidosis, amyloidosis, IgG4-related disease, RA, SLE, SSc, and other autoimmune diseases [4] .

Treatment is carried out depending on the presence of glandular and extraglandular manifestations and the immunoinflammatory activity of the disease. To treat glandular manifestations, local therapy for “dry” syndrome is used (moisturizing substitutes, immunomodulatory drugs), stimulants of endogenous secretion of the salivary and lacrimal glands [6]. To treat systemic extraglandular manifestations of BS, glucocorticosteroids (GCS), alkylating cytostatics (chlorambucil), cyclophosphamide, methotrexate, mycophenolate mofetil, and biological drugs are used. Nonsteroidal anti-inflammatory drugs (NSAIDs) are used in the presence of arthralgia or arthritis. Methotrexate is also used in the treatment of arthritis in BS [7]. The use of GCS is indicated for severe skin manifestations, involvement of the lungs, kidneys, and nervous system in the pathological process. If the effect of glucocorticoid therapy is insufficient or there is intolerance to glucocorticoids due to the development of side effects, mycophenolate mofetil, cyclosporine A, and azathioprine are prescribed [8–10]. The presence of resistant forms of BS with systemic manifestations of the disease with the ineffectiveness of standard GCS and basic anti-inflammatory therapy is an indication for the initiation of genetic engineering biological therapy (GEBT). Moreover, in this disease, the main promising target is the B cell, since it plays an important role in the pathogenesis of BS [11–13].

Rituximab is a drug that is a chimeric monoclonal antibody to the CD20+ B-lymphocyte marker, developed for the treatment of non-Hodgkin lymphomas, and is currently actively used in the treatment of many autoimmune diseases. CD20+ is expressed on the membrane of B cells, from pre-B cells to mature B cells. This marker is absent on plasma cells and stem cells, which determines the absence of a pronounced decrease in the level of immunoglobulins and the low frequency of opportunistic infections with its use. This molecule reversibly interacts with CD20 receptors on the surface of the B lymphocyte, inhibiting its activity and suppressing the ability to produce antibodies [14–17].

Indications for use

Only cell colonies containing CD20 receptors on their surface are sensitive to rituximab, and today such lymphoproliferative processes are specifically detected by tests. As a rule, non-Hodgkin's large B-cell lymphomas and low-aggressive follicular lymphomas respond well to therapy. The drug is used both at the very beginning and for maintenance treatment, and when the disease progresses on other regimens, and when relapses occur.

The second indication is chronic lymphocytic leukemia, used in the first line, in case of ineffectiveness of previous chemotherapy or relapse, usually in combination with other cytostatics.

Clinical observation

We present a clinical observation of a patient with BS.
The main goal of the demonstration is to demonstrate the effectiveness of using genetically engineered anti-B cell therapy in a patient with high acute-phase and immunological activity of the disease and extensive comorbid pathology. Patient Ch., 68 years old, is under observation in our clinic. She first turned to a rheumatologist in 2008 with complaints of spastic pain in the left half of the abdomen, relieved by taking gabapentin and duspatalin, pain and discomfort in the epigastrium, severe dry mouth, frequent urination, a feeling of difficulty swallowing, dry conjunctiva, periodic feeling “ tightness" in the chest, headache in the occipital-parietal region, noise in the head, pasty legs, shortness of breath during exercise, irritability, tearfulness, restless sleep.

The diagnosis of BS was established in 2010. Since September 2010, the patient received corticosteroids, and since December 2010, azathioprine (does not remember drug doses). In April 2011, she was hospitalized in the faculty therapy clinic to evaluate the effectiveness of treatment and its correction due to complications that had arisen from taking GCS.

Main diagnosis: Sjögren's disease. Chronic course with damage to the eyes (xerophthalmia), skin and mucous membranes (xerostomia).

Complications: osteoporosis of mixed origin (senile, glucocorticosteroid, secondary to a chronic autoimmune disease). Iatrogenic Itsenko-Cushing syndrome.

Background: stage 2 hypertension, stage II, risk 4. Coronary heart disease. Angina pectoris II FC. Atherosclerosis of the aorta and coronary arteries. Atherosclerotic cardiosclerosis with rhythm disturbances such as frequent ventricular extrasystole. Aortic valve stenosis 2nd degree. CHF II FC.

Concomitant: polyosteoarthrosis with predominant damage to the knee, hip and small joints of the hands. Chronic parenchymal pancreatitis with mild exocrine insufficiency. Fatty hepatosis of the 2nd degree with moderate impairment of liver function. Obesity of the 3rd degree, nutritional-constitutional, stabilization phase. Impaired glucose tolerance. Autoimmune thyroiditis. Euthyroidism. Discirculatory encephalopathy of the 2nd degree, of mixed origin, mainly in the vertebrobasilar region, in the form of diffuse neurological symptoms. Restless legs syndrome. Asthenoneurotic syndrome. Varicose veins. Varicose veins of the saphenous veins of the right lower limb. Chronic venous insufficiency of the 1st degree. Consolidated fracture of the lateral malleolus of the right leg with the presence of fixing metal structures. Chronic subatrophic rhinopharyngitis. The only right kidney. Nephrectomy in 2007 for a tumor of the left kidney. Chronic kidney disease C3b. Bladder formation (polyp).

The diagnosis was made based on the diagnostic criteria of the disease (SICCA 2012), as well as a number of laboratory and instrumental studies performed, including ultrasound of the salivary glands (diffuse, heterogeneous changes in the structure of the salivary glands, characteristic of BS) [18].

The treatment included a therapeutic and protective regimen, table No. 9, metypred 4 mg/day and azathioprine 100 mg/day, gastroprotectors, enzymes, antihypertensive and hypoglycemic drugs, antiplatelet agents, venotonics. Infusion metabolic neuro-, hepato- and cardiotropic therapy was also carried out. During therapy, positive dynamics were noted: hemodynamic parameters stabilized, compensation of carbohydrate metabolism was achieved, tolerance to physical activity increased, and general condition improved. In October 2021, another inpatient treatment was carried out at the faculty therapy clinic, which included extracorporeal hemocorrection (3 sessions of plasmapheresis). The basic therapy was also adjusted (metipred 4 mg/day, azathioprine 150 mg/day). Since November 2021, pain in the left half of the abdomen began to bother me. The patient received treatment at the military field surgery clinic of the Military Medical Academy for diverticular disease of the large intestine. Despite the treatment, high immunological activity of the disease remained (ANF titer 1:10000–1:20000), as well as clinical manifestations of the disease in the form of increasing dryness of the eyes, mouth, and skin. Complications of the glucocorticoid therapy were added in the form of the development of osteoporosis with compression fracture of the thoracic vertebrae, and a low-energy fracture of the left ankle. It should also be noted that the patient had an extensive comorbid background, which did not allow intensification of the therapy.

Laboratory tests observed in the patient included the following changes: Clinical blood test on 10/07/2017: erythrocytes - 4.11×1012/l, hemoglobin - 132 g/l, platelets - 380×109/l, ESR - 34 mm/h, leukocytes - 5, 09×109/l, eosinophils - 0%, basophils - 1%, p/i - 1%, c/i - 49%, lymphocytes - 40%, monocytes - 9%, CRP - 15.88 mg/l. Coagulogram: prothrombin - 120%, fibrinogen - 5.72 g/l, INR - 0.90. Immunological blood test: IgM - 0.94 g/l, IgG - 16.32 g/l, IgA - 1.88 g/l, circulating immune complexes - 13 units, ANF titer >1:10000. Immunoblot of antinuclear antibodies: Ro-52 +++, CENT B +++. Detailed immunogram 11/16/2017. Analysis of B cell subpopulations indicates an increase in the relative/absolute content of total B cells, activated B cells, memory B cells, B-2 cells and B-1 cells associated with the production of autoantibodies. Signs of a decrease in the main subpopulations of T cells (mostly T helper cells) were identified, characterized by a decrease in the relative/absolute number of total T cells, activated CD25+ T cells, activated HLA-DR+ T lymphocytes and a significant imbalance in the content of the main T subpopulations -cells. Along with this, there is an increase in the relative and absolute number of NK cells expressing the α-chain of the CD8 antigen and having the ability to repeatedly perform their cytolytic function.

Due to the progression of the disease against the background of combined basic cytostatic and glucocorticoid therapy, in particular the increase in clinical symptoms, the high immunological activity of the disease (according to a detailed immunogram and immunoblot of antinuclear antibodies), in April 2018, a decision was made to initiate HIBT with the use of rituximab. The drug was administered at a dose of 1000 mg at intervals of 2 weeks. Subsequently, repeated administrations of the drug continued after 6 months. with an interval of 2 weeks. (1st year of therapy). From the 2nd year of treatment, due to the positive clinical effect, it was decided to reduce the dose to 1000 mg once every 6 months. As a result of rituximab therapy, the patient showed significant positive clinical dynamics in the form of a significant reduction in dryness of the mucous membranes of the mouth and eyes, exercise tolerance also increased, and abdominal pain and shortness of breath were relieved. Laboratory tests also showed positive dynamics in the form of a decrease in the acute phase and immunological activity of the disease.

Clinical blood test 02/07/2019: erythrocytes - 4.5x1012/l, hemoglobin - 140 g/l, platelets - 220x109/l, ESR - 13 mm/h, leukocytes - 5.09x109/l, eosinophils - 2%, basophils - 1%, p/i - 1%, s/i - 59%, lymphocytes - 30%, monocytes - 7%, CRP - 5.6 mg/l. Coagulogram: prothrombin - 110%, fibrinogen - 3.75 g/l. Immunological blood test: ANF titer >1:1000. Immunoblot of antinuclear antibodies: Ro-52+, CENT B+.

Contraindications

The use of rituximab if you are allergic to it is excluded.

It should not be used in patients with immune deficiency because the drug destroys already insufficient B lymphocytes.

In acute inflammatory and infectious processes, a temporary taboo is placed on treatment, since suppression of the immune system can lead to generalization of the infection.

The medicine is used very carefully when the levels of leukocytes - neutrophils and platelets are reduced, which is usually due to the consequences of chemotherapy.

The administration of the drug is often complicated by shortness of breath and swelling of the lung tissue, so patients with pulmonary metastases or respiratory failure can have very unpleasant health consequences. However, this is not considered an absolute contraindication; treatment simply needs to be carried out with a certain amount of caution.

Clinical studies are not conducted in minors, so the pitfalls of therapy are unknown, which is why the drug is not licensed for this age category. Do not use in pregnant or lactating mothers.

Introduction

The emergence of genetically engineered biological drugs has opened up wide opportunities for rheumatologists in the treatment of autoimmune diseases.
The rapid development of biotechnology has led to the fact that now more and more new molecules for so-called biological therapy appear every year. These molecules are capable of specifically blocking certain inflammatory mediators (anti-cytokine therapy) or immunocompetent cells, such as CD20 lymphocytes (anti-B cell therapy). Rituximab, originally developed for the treatment of B-cell lymphomas, has subsequently proven itself well in the treatment of rheumatic diseases associated with the production of a large number of autoantibodies. First of all, this is rheumatoid arthritis (RA), which is a registered indication for the use of rituximab (both the original drug and a number of its biosimilars), then diseases such as ANCA-associated vasculitis have appeared in the indications for therapy with the original drug. A good effect in achieving disease control in RA was demonstrated, which made it possible to expand the scope of use of the drug in other autoimmune diseases. There are reports of the successful use of rituximab in the treatment of such nosologies as systemic lupus erythematosus (SLE), dermato- and polymyositis, systemic scleroderma (SSc) and Sjögren's disease (SD), however, rituximab in these cases is still used off-label, according to the decision medical commission. The team at our clinic also has extensive experience in the use of rituximab both in RA and in ANCA vasculitis (granulomatosis with polyangiitis and eosinophilic granulomatosis with polyangiitis), SLE, and SSc. In this article, we would like to pay special attention to the use of the drug in BS and describe our own observation of a patient who successfully received rituximab therapy for this disease for 2 years.

Side effects

Any antitumor treatment is fraught with complications, and rituximab is no exception; the range of complications is quite wide, some adverse reactions are common, and some are not avoided by most patients. With combination chemotherapy, the toxicity of rituximab is superimposed by adverse reactions from other drugs in the regimen.

Very often during treatment with rituximab the following develops:

• local swelling of the skin - angioedema, when the area rises like a “cushion” next to completely unchanged tissues;
• the development of infection is associated with the mechanism of action and the main strength of the drug - the destruction of lymphocytes;
• various rashes with itching;
• headaches and often with fever;
• nausea.

After the course, blood test results and G-immunoglobulin levels decrease, but grade 4 drop in level is observed in hardly 1-2%. The decrease in the number of B-lymphocytes is not fatal, but is very long-lasting - up to a year.

With very high sensitivity to rituximab and massive destruction of tumor nodes, the development of tumor lysis syndrome is possible, which must be predicted in advance and preventive measures taken.

Experience with the use of rituximab in the treatment of rheumatoid arthritis

Rheumatoid arthritis (RA) is a chronic inflammatory disease of the joints, which primarily affects the synovium, as well as articular cartilage and marginal areas of the bone. RA is characterized by a steadily progressive, relapsing course and a sharp decline in quality of life with early disability.

The pathogenesis of RA is complex and not fully understood: it is known that provoking factors in the development of the disease are the activation and proliferation of immunocompetent cells (macrophages, T- and B-lymphocytes), the release of cytokines, growth factors, as well as the synthesis of autoantibodies (for example, anti-citrullinated antibodies) and the formation of immune complexes (rheumatoid factor).

To treat RA, a wide range of drugs are used that have a symptomatic effect or affect individual parts of the pathogenesis of the disease (disease-modifying therapy). Early initiation and duration of basic therapy are considered to be favorable signs of prognosis in RA. The rational use of these drugs in the early stages of the disease significantly improves the immediate, long-term functional and even life prognosis, but in many cases their use does not control the progression of the disease, the development of life-threatening complications, or is associated with severe side effects.

In recent years, the view of RA as a potentially incurable and prognostically unfavorable disease has been revised. This is largely due to the expansion of opportunities for early diagnosis of RA, which makes it possible to begin active therapy at the onset of the disease, and the development of a new class of basic anti-inflammatory drugs (DMARDs), the so-called “biological agents”, which selectively block important stages of immunopathogenesis.

Until recently, the pathogenetic mechanisms of RA development were considered mainly from the point of view of defects in T-cell immunoregulation and overproduction of “pro-inflammatory” cytokines, primarily tumor necrosis factor-a (TNF-α), as well as interleukins (IL-1 and IL-6 ). This served as the basis for the widespread introduction into clinical practice of TNF-α inhibitors, which include chimeric (infliximab) and fully human (adalimumab) antibodies to TNF-α.

However, there is evidence that approximately a quarter of patients with RA do not respond to therapy with TNF-a inhibitors. Some patients, more often than not, after 5-6 injections, and sometimes even at later stages of infliximab therapy, do not notice further clinical improvement (the “escape” effect).

But, as is known, RA is a very heterogeneous disease from the point of view of pathogenetic mechanisms, and hyperproduction of TNF-α is, although the most important, but far from the only mechanism of inflammation and tissue destruction in RA.

Until recently, it was believed that antibody-producing B cells play a secondary role in RA, producing IgM, IgG, and IgA rheumatoid factor (RF). Today, the role of B cells as antigen-presenting cells is undeniable. Differentially capturing the antigen using immunoglobulin on the cell surface, the B cell presents it to the T lymphocyte. B cells that synthesize RF have a unique ability to interact with immune complexes and “present” a wide range of autoantigens, and activated B cells express costimulatory molecules (B7 and CD40) necessary for full activation of T cells. The effector role of B cells in the development of joint destruction in RA is also discussed, which is realized through the synthesis of “pro-inflammatory” cytokines (TNF-α, IL-1 and lymphotoxin), as well as IL-6 and IL-10, which have an additional stimulating effect on B lymphocytes.

The use of anti-B-cell drugs is considered a fairly new method of treating RA - namely, the only drug of this group registered to date - rituximab. Rituximab is a genetically engineered chimeric high-affinity monoclonal antibody to the surface receptor of B lymphocytes - CD20. CD20 is a cell membrane antigen, the expression of which is characteristic of “early” and mature B lymphocytes, but is not expressed on stem, “early” pre-B and plasma cells. Therefore, deletion of CD20 B cells does not impair the B cell immune response. Rituximab is believed to act by removing B cells through a combination of several mechanisms—complement-dependent cellular cytotoxicity, antibody-dependent cellular cytotoxicity, and induction of B-cell apoptosis.

The official indication for rituximab is active RA in adults in combination with methotrexate in the setting of intolerance to or inadequate response to current regimens containing one or more tumor necrosis factor-alpha (TNF-a) inhibitors.

This study is devoted to the use of this drug as part of the creation of a national register of the Republic of Tatarstan.

Materials and methods

The study included six patients whose diagnosis of RA was confirmed according to the 1987 American College of Rheumatology (ACR) criteria. The characteristics of the patients are presented in the table.

All patients received basic therapy for RA: methotrexate at a dose of 7.5–10 mg per week; three patients, in addition, received 7.5–10 mg of glucocorticosteroids per day. All patients also received nonsteroidal anti-inflammatory drugs (NSAIDs) in adequate daily doses. However, despite the therapy, consistently high disease activity was observed. One patient received infliximab infusions, which also had no effect - after the seventh infusion there was about. After stopping infliximab, it was decided to prescribe rituximab. All patients during treatment with rituximab continued to receive basic therapy with methotrexate.

All patients had extra-articular manifestations (rheumatoid nodules - 1, polyneuropathy - 2, keratoconjunctivitis sicca - 1, weight loss and low-grade fever - 4, Raynaud's syndrome - 1 patient).

Rituximab was administered twice with an interval of two weeks: 1000 mg in 500 ml of physiological solution intravenously over 6 hours. Treatment was carried out according to the standard regimen.

Evaluation of clinical and laboratory indicators of the therapeutic effect was carried out before the start of rituximab administration, before the second administration of the drug and 8, 16, 24 and 48 weeks after the first infusion.

The effectiveness of treatment was assessed using the clinical criteria of ACR and the DAS 28 disease activity index (EULAR).

results

All 6 patients included in the registry received 2 infusions of rituximab and were followed for 24–48 weeks.

A positive effect of rituximab therapy was noted in all patients. By the 8th week of treatment, a significant improvement occurred, reaching a maximum by the 16th week. There was a decrease in pain on a visual analogue scale (VAS, mm), duration of morning stiffness, number of painful and swollen joints, and a decrease in the need for NSAIDs until complete withdrawal (p < 0.05). Two patients completely stopped taking glucocorticosteroids, one patient reduced the dose to 5 mg per day. A significant (p < 0.05) decrease in ESR and C-reactive protein was revealed. The effectiveness of therapy according to ACR criteria was 50% in 3 and 70% in 3 patients; according to DAS 28, the effect was considered satisfactory in two, good in three patients; one patient achieved complete clinical and laboratory remission by week 16.

By the 24th week, in two patients the effect weakened, which was reflected in the deterioration of clinical and laboratory parameters. In this regard, a second course of drug therapy was carried out - two infusions with an interval of 2 weeks. By the 32nd week of observation, one patient showed a significant improvement in clinical and laboratory data, the second patient noted the lack of effect after the second course of treatment (the observation period was 4 weeks).

We observed no adverse events during rituximab therapy. The drug's tolerability is assessed as good.

Thus, the use of rituximab in patients with RA, including those with an inadequate response to basic drugs, has a pronounced long-term clinical and laboratory effect. Such therapy can reduce the risk of early disability, improve the quality of life of patients and the long-term prognosis of the disease.

Literature

1. Nasonov E. L. New directions in the treatment of rheumatoid arthritis: prospects for the use of monoclonal antibodies to B-lymphocytes (rituximab) // Russian Medical Journal. 2006. 25; 1778–1782.
2. Nasonov E. L. Pharmacotherapy of rheumatoid arthritis - a look into the 21st century. Klin: Medicine. 2005. 6: 8–12.
3. Nasonov E. L. Treatment of rheumatoid arthritis: current state of the problem // Breast cancer. 2006. 14 (8); 573–577.
4. Browning JL B cell move to center stage: novel opportunities for autoimmune disease treatment // Nature Rev. 2006. 5: 564–576.
5. Bizzaro N., Tozzoli R., Shoenfeld Y. Are we at stage to predict autoimmune rheumatic diseases? // Arthritis Rheum. 2007. 56: 1736–1744.
6. Hansen A., Lipsky PE, Dorner T. B cell lymphoproliferation in chronic inflammatory rheumatic diseases // Nature Clin Pracr Rheumatol. 2007; 3:561.
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I. G. Salikhov , Doctor of Medical Sciences, Professor L. I. Myasoutova M. Yu. Badeeva E. R. Kirillova , Candidate of Medical Sciences S. A. Lapshina , Candidate of Medical Sciences R. D. Abdrakipov KSMU , Kazan

special instructions

Every second person during a drip, especially during the first injections, develops an unpleasant condition - an infusion reaction, when the patient feels a sudden surge of weakness to the point of “shaking”, with nausea and headache, the skin begins to itch in some places and a rash can quickly appear, causing It is difficult to breathe due to spastic contractions of the respiratory tract.

If, despite the preliminary administration of drugs - premedication, a severe infusion reaction has developed, then the administration of rituximab is stopped for a while, additional auxiliary drugs are administered intravenously, and when the condition normalizes, the drip administration of rituximab is continued, but the rate of droplet fall is halved.

As a rule, the intensity of the reaction decreases by the next dropper, and 99% of patients tolerate the last 8th dropper without a reaction. However, before administering rituximab, drugs are always administered prophylactically to prevent allergic manifestations, pain and fever.

Rituximab

The incidence of side effects is classified according to the recommendations of the World Health Organization: very often (≥ 1/10); often (≥1/100 and <1/10); uncommon (≥ 1/1000 and < 1/100); rare (≥1/10000 and <1/1000); very rare (<1/10000), frequency unknown (cannot be calculated based on available data).

The drug Rituximab in the treatment of low-grade or follicular non-Hodgkin lymphoma - monothepapia / maintenance therapy

Adverse reactions were reported up to 12 months after monotherapy and up to 1 month after maintenance therapy with Rituximab.

Infectious and parasitic diseases: very often - bacterial and viral infections; often - respiratory tract infections*, pneumonia*, sepsis, herpes zoster*, infections accompanied by fever*, fungal infections, infections of unknown etiology.

Disorders of the blood and lymphatic system: very often - leukopenia, neutropenia; often - thrombocytopenia, anemia; uncommon - lymphadenopathy, bleeding disorder, transient aplastic anemia, hemolytic anemia.

Disorders of the respiratory system, chest and mediastinal organs: often - rhinitis, bronchospasm, cough, respiratory diseases, shortness of breath, chest pain; uncommon - hypoxia, impaired pulmonary function, bronchiolitis obliterans, bronchial asthma.

Immune system disorders: very often - angioedema; often - hypersensitivity reactions.

Metabolic and nutritional disorders: often - hyperglycemia, weight loss, peripheral edema, facial edema, increased LDH activity, hypocalcemia.

General disorders and disorders at the injection site: very often - headache, fever, chills, asthenia; often - pain in tumor foci, flu-like syndrome, hot flashes, weakness; Uncommon: pain at the injection site.

Gastrointestinal disorders: very often - nausea; often - vomiting, diarrhea, dyspepsia, lack of appetite, dysphagia, stomatitis, constipation, abdominal pain, sore throat; infrequently - abdominal enlargement.

Disorders of the cardiovascular system: often - decreased blood pressure, increased blood pressure, orthostatic hypotension, tachycardia, arrhythmia, atrial fibrillation*, myocardial infarction*, cardiac pathology*; uncommon - left ventricular heart failure*, ventricular and supraventricular tachycardia*, bradycardia, myocardial ischemia*, angina*.

Nervous system disorders: often - dizziness, paresthesia, hypoesthesia, sleep disturbance, anxiety, agitation, vasodilation; infrequently - perversion of taste.

Mental disorders: infrequently - nervousness, depression.

Musculoskeletal and connective tissue disorders: often - myalgia, arthralgia, muscle hypertonicity, back pain, neck pain, pain.

Disorders of the skin and subcutaneous tissues: very often - itching, rash; often - urticaria, increased sweating at night, sweating, alopecia*.

Visual disturbances: often - lacrimation disorders, conjunctivitis.

Hearing and labyrinthine disorders: often - pain and tinnitus. Laboratory and instrumental data: very often - a decrease in the level of immunoglobulins G (IgG).

* - frequency is indicated only for adverse reactions ≥ grade 3 in accordance with the National Cancer Institute toxicity criteria (NCI-CTC).

The drug Rituximab in combination with chemotherapy (R-CHOP, R-CVP, R-FO for non-Hodgkin's lymphoma and chronic lymphocytic leukemia

The following are severe adverse reactions in addition to those observed with monotherapy/maintenance therapy and/or occurring at a higher frequency.

Infectious and parasitic diseases: very often - bronchitis; often - acute bronchitis, sinusitis, hepatitis B* (reactivation of the hepatitis B virus and primary infection).

Disorders of the blood and lymphatic system: very often - neutropenia**, febrile neutropenia, thrombocytopenia; often - pancytopenia, granulocytopenia.

Disorders of the skin and subcutaneous tissues: very often - alopecia; often - skin diseases.

General disorders and disorders at the injection site: often - fatigue, chills.

* — frequency is indicated based on observations during the treatment of relapsing/chemoresistant chronic lymphocytic leukemia according to the R-FC regimen.

** - prolonged and/or delayed neutropenia was observed after completion of R-FC therapy in previously untreated patients or in patients with relapsed/chemoresistant chronic lymphocytic leukemia.

The following are adverse events occurring during rituximab therapy with equal frequency (or less frequently) compared to the control group: hematotoxicity, neutropenic infections, urinary tract infections, septic shock, pulmonary superinfections, implant infections, staphylococcal septicemia, pulmonary infection, mucous discharge from nose, pulmonary edema, heart failure, sensory disturbances, venous thrombosis, incl. deep vein thrombosis of the extremities, mucositis, influenza-like illness, edema of the lower extremities, decreased left ventricular ejection fraction, increased temperature, deterioration of general health, fall, multiple organ failure, bacteremia, decompensation of diabetes mellitus. The safety profile of Rituximab in combination with MCP, CHVP-IFN chemotherapy is no different from that of Rituximab in combination with CVP, CHOP or FC in appropriate populations.

Infusion reactions

Monotherapy with Rituximab (for 4 weeks)

More than 50% of patients experienced events resembling infusion reactions, most often during the first infusions. Infusion reactions include chills, trembling, weakness, shortness of breath, nausea, rash, hot flashes, low blood pressure, fever, itching, urticaria, tongue irritation or swelling of the larynx (angioedema), rhinitis, vomiting, tumor pain, headache, bronchospasm . The development of signs of tumor lysis syndrome has been reported.

The drug Rituximab in combination with chemotherapy according to the following regimens: R-CVP for non-Hodgkin's lymphoma: R-CHOP for diffuse large B-cell non-Hodgkin's lymphoma: R-FC for chronic lymphocytic leukemia

Grade 3 and 4 infusion reactions during infusion or within 24 hours after infusion of Rituximab were observed during the first cycle of chemotherapy in 12% of patients. The incidence of infusion reactions decreased with each subsequent cycle and by the 8th cycle of chemotherapy, the incidence of infusion reactions decreased to less than 1%. Infusion reactions, in addition to those mentioned above (with monotherapy with Rituximab), included: dyspepsia, rash, increased blood pressure, tachycardia, signs of tumor lysis syndrome, in some cases - myocardial infarction, atrial fibrillation, pulmonary edema and acute reversible thrombocytopenia.

Infections

Monotherapy with Rituximab (for 4 weeks)

Rituximab causes depletion of the B cell pool in 70-80% of patients and a decrease in serum immunoglobulin concentrations in a small number of patients. Bacterial, viral, fungal infections and infections of unspecified etiology (all, regardless of cause) develop in 30.3% of patients. Severe infections (grades 3 and 4), including sepsis, were noted in 3.9% of patients.

Maintenance therapy (non-Hodgkin's lymphoma) up to 2 years

During therapy with Rituximab, an increase in the overall incidence of infections was observed, including grade 3-4 infections. There was no increase in the incidence of infectious complications with maintenance therapy lasting 2 years. Fatal progressive multifocal leukoencephalopathy (PML) has been reported in patients with non-Hodgkin's lymphoma after disease progression and re-treatment.

The drug Rituximab in combination with chemotherapy according to the following regimens: R-CVP for non-Hodgkin's lymphoma; R-CHOP for diffuse large B-cell non-Hodgkin lymphoma; R-FC for chronic lymphocytic leukemia

There was no increase in the incidence of infections or infestations when treated with Rituximab according to the R-CVP regimen. Upper respiratory tract infections were the most common (12.3% in the R-CVP group). Serious infections occurred in 4.3% of patients receiving R-CVP chemotherapy; No life-threatening infections were reported. The proportion of patients with grade 2-4 infections and/or febrile neutropenia in the R-CHOP group was 55.4%. The overall incidence of grade 2–4 infections in the R-CHOP group was 45.5%. The incidence of grade 2-4 fungal infections in the R-CHOP group was higher than in the CHOP group due to a higher incidence of local candidiasis and amounted to 4.5%. The frequency of herpetic infections of grade 2-4 severity was higher than in the CHOP group due to a higher frequency of local candidiasis and amounted to 4.5%. The incidence of grade 2-4 herpes infection was higher in the R-CHOP group than in the CHOP group and was 4.5%. In patients with chronic lymphocytic leukemia, the incidence of hepatitis B (hepatitis B virus reactivation and primary infection) of grade 3-4 in the R-FC group was 2%.

From the blood system

Monotherapy with Rituximab (for 4 weeks)

Severe thrombocytopenia (grades 3 and 4) was observed in 1.7% of patients, severe neutropenia in 4.2% of patients, and severe anemia (grades 3 and 4) in 1.1% of patients.

Maintenance therapy (non-Hodgkin's lymphoma) up to 2 years

Leukopenia (grades 3 and 4) was observed in 5% of patients, and neutropenia (grades 3 and 4) in 10% of patients receiving Rituximab. The incidence of thrombocytopenia (grade 3-4 severity) was low and amounted to <1%. Approximately 50% of patients for whom B-cell recovery data were available took 12 months or more to recover B-cell counts to normal levels after completion of induction therapy with Rituximab.

The drug Rituximab in combination with chemotherapy according to the following regimens: R-CVP for non-Hodgkin's lymphoma; R-CHOP for diffuse large B-cell non-Hodgkin lymphoma; R-FC for chronic lymphocytic leukemia

Severe neutropenia and leukopenia: in patients receiving Rituximab in combination with chemotherapy, grade 3 and 4 leukopenia were observed more often than in patients receiving chemotherapy alone. The incidence of severe leukopenia was 88% in patients receiving R-CHOP and 23% in patients receiving R-FC. The incidence of severe neutropenia was 24% in the R-CVP group, 97% in the R-CHOP group, and 30% in the R-FC group in previously untreated chronic lymphocytic leukemia. The higher incidence of neutropenia in patients receiving Rituximab and chemotherapy was not associated with an increased incidence of infections and infestations compared with patients receiving chemotherapy alone. In patients with recurrent or chemoresistant chronic lymphocytic leukemia and in previously untreated patients after treatment with the R-FC regimen, in some cases neutropenia was characterized by a long course and later manifestations.

Severe anemia and thrombocytopenia (grades 3 and 4): there was no significant difference in the incidence of anemia of grades 3 and 4 between groups. In the R-FC group, in the first line of treatment for chronic lymphocytic leukemia, anemia of grades 3 and 4 occurred in 4% of patients, thrombocytopenia of grades 3 and 4 - in 7% of patients. In the R-FC group with recurrent or chemoresistant chronic lymphocytic leukemia, anemia of grades 3 and 4 occurred in 12% of patients, thrombocytopenia of grades 3 and 4 - in 11% of patients.

From the cardiovascular system

Monotherapy with Rituximab (for 4 weeks)

Side effects from the cardiovascular system were noted in 18.8%. The most common occurrences are increases and decreases in blood pressure. In isolated cases, cardiac arrhythmias of grade 3 and 4 were observed (including ventricular and supraventricular tachycardia) and angina pectoris.

Maintenance therapy (non-Holzhkin lymphoma) up to 2 years

The incidence of grade 3 and 4 cardiovascular events was similar in patients receiving Rituximab and those not receiving it. Serious cardiovascular events occurred in less than 1% of patients not receiving Rituximab and in 3% of patients receiving Rituximab (atrial fibrillation in 1%, myocardial infarction in 1%, left ventricular failure in <1%, myocardial ischemia in <1%). %).

The drug Rituximab in combination with chemotherapy according to the following regimens: R-CVP for non-Hodgkin's lymphoma; R -CHOP for diffuse large B-cell non-Hodgkin lymphoma; R-FC for chronic lymphocytic leukemia

The incidence of grade 3 and 4 cardiac arrhythmias, mainly supraventricular arrhythmias (tachycardia, atrial flutter and atrial fibrillation), was higher in the R-CHOP group and amounted to 6.9%. All arrhythmias developed either in connection with the infusion of Rituximab or were associated with predisposing conditions such as fever, infection, acute myocardial infarction, or concomitant diseases of the respiratory and cardiovascular systems. The R-CHOP and CHOP groups did not differ in the incidence of other grade 3 and 4 cardiac adverse events, including heart failure, myocardial disease, and manifestation of coronary artery disease.

The overall incidence of grade 3 and 4 cardiovascular events was low both in first-line treatment of chronic lymphocytic leukemia (4% in the R-FC group) and in the treatment of relapsed/chemoresistant chronic lymphocytic leukemia (4% in the R-FC group).

Nervous system

The drug Rituximab in combination with chemotherapy according to the following regimens: R-CVP for non-Hodgkin's lymphoma; R-CHOP for diffuse large B-cell lymphoma; R-FC for chronic lymphocytic leukemia

Patients (2%) in the R-CHOP group with cardiovascular risk factors developed cerebroembolic events during the first cycle of therapy, in contrast to patients in the CHOP group who developed cerebroembolic events during the observation period without treatment. There was no difference between groups in the incidence of other thromboembolism.

The overall incidence of grade 3 and 4 neurological impairment was low both in the first-line treatment of chronic lymphocytic leukemia (4% in the R-FC group) and in the treatment of relapsed/chemoresistant chronic lymphocytic leukemia (3% in the R-FC group).

IgG concentration

Maintenance therapy (non-Hodgkin's lymphoma) up to 2 years

After induction therapy, IgG concentrations were below the lower limit of normal (<7 g/L) in the Rituximab-treated and untreated groups. In the group not receiving Rituximab, the median IgG level consistently increased and exceeded the lower limit of normal, while the median IgG level did not change in the group receiving Rituximab. In 60% of patients treated with Rituximab for 2 years, IgG concentrations remained below the lower limit. In the group without treatment with Rituximab, after 2 years the IgG concentration remained below the lower limit in 36% of patients.

Special categories of patients

Monotherapy with Rituximab (for 4 weeks)

Elderly age (≥65 years): the frequency and severity of all adverse reactions and grade 3 and 4 adverse reactions does not differ from that in younger patients.

Combination therapy

Older age (65 years and older): In first-line therapy and in treatment of relapsed/chemoresistant chronic lymphocytic leukemia, the incidence of grade 3 and 4 side effects from the blood and lymphatic system was higher compared to younger patients.

High tumor load (diameter of single lesions more than 10 cm): increased frequency of grade 3 and 4 adverse reactions.

Repeated therapy: the frequency and severity of adverse reactions do not differ from those during initial therapy.

Information on the post-registration use of Rituximab for non-Hodgkin's lymphoma and chronic lymphocytic leukemia

From the cardiovascular system: severe cardiovascular events associated with infusion reactions, such as heart failure and myocardial infarction, mainly in patients with a history of cardiovascular disease and/or receiving cytotoxic chemotherapy; very rarely - vasculitis, mainly cutaneous (leukocytoclastic).

From the respiratory system: respiratory failure and pulmonary infiltrates caused by infusion reactions; In addition to pulmonary adverse events due to infusion reactions, interstitial lung disease, in some cases fatal, has been observed.

From the circulatory and lymphatic system: reversible acute thrombocytopenia associated with infusion reactions.

From the skin and its appendages: rarely - severe bullous reactions, toxic epidermal necrolysis and Stevens-Johnson syndrome, in some cases with death.

From the nervous system: rarely - neuropathy of the cranial nerves in combination with peripheral neuropathy or without it (marked decrease in visual acuity, hearing, damage to other sense organs, paresis of the facial nerve) during various periods of therapy up to several months after completion of the course of treatment with the drug Rituximab.

Cases of posterior reversible encephalopathy (PRE8)/posterior reversible leukoencephalopathy syndrome (PRLS) have been reported in patients treated with Rituximab. Symptoms included visual disturbances, headache, seizures and mental disturbances, with or without increased blood pressure. The diagnosis of PRES/PRLS can be confirmed using brain imaging techniques. In the reported cases, patients had risk factors for developing PRES/PRLS, such as underlying disease, hypertension, immunosuppressive therapy and/or chemotherapy.

From the body as a whole, reactions at the injection site: rarely - serum sickness.

Infections: reactivation of hepatitis B virus (in most cases with a combination of rituximab and cytotoxic chemotherapy); as well as other severe viral infections (primary infection, viral reactivation or exacerbation), some of which were fatal. Most patients received rituximab in combination with chemotherapy or in combination with hematopoietic stem cell transplantation. Examples of such severe viral infections are infections caused by herpes viruses (cytomegalovirus, Varicella zoster, Herpes simplex), JC polyomavirus (PML), hepatitis C virus. When prescribing rituximab for indications not covered by the instructions for medical use in patients with previously diagnosed Kaloshi sarcoma progression of sarcoma was observed (most patients were HIV positive).

From the gastrointestinal tract: perforation of the stomach and/or intestines (possibly fatal) when Rituximab is combined with chemotherapy for non-Hodgkin's lymphoma.

From the blood and lymphatic system: rarely - neutropenia that occurred 4 weeks after the last administration of Rituximab; a transient increase in IgM levels in patients with Waldenström's macroglobulinemia, followed by a return to its original value after 4 months.

Interaction

Rituximab is included in many drug combinations that are being studied in clinical trials not only for effectiveness, but also for safety for patients. For the treatment of oncohematological processes, certain standard combinations are recommended, in which the toxicity is minimally identical with the maximum effectiveness of each drug individually. For drip administration of rituximab, special systems are used, since the drug molecules are combined with the material of conventional droppers.

Fertility, pregnancy and lactation

Antitumor drugs are not studied in pregnant and lactating women, as well as in children. In preclinical studies, of course, experiments can be carried out with pregnant animals, but the coincidence of reactions in animals and humans is absolutely not guaranteed.

Immunoglobulins G are able to pass into breast milk and the fetus; in those who accidentally became pregnant during MAB treatment, newborn blood tests showed a decrease in the number of B lymphocytes.

Women of reproductive age are strongly recommended to use contraception during therapy and for at least a year after its completion.

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Introduction

Chronic lymphocytic leukemia (CLL) is one of the most common diseases in the field of oncohematology. Every year, 11.5% of cases of CLL are registered in the world out of the total number of cases of hematological malignancies [1]. This is the most common type of leukemia in Europe and North America. In these countries, it accounts for about 30% of all leukemias. [2]. The five-year survival rate is approximately 70% [1]. The annual incidence of CLL is 3–3.5 per 100,000 thousand population, increasing to 20 per 100,000 for people over 65 and to 50 per 100,000 after 70 years. Thanks to modern therapy, the life expectancy of patients with CLL is steadily increasing and currently often reaches 20–25 years [1].

CLL is mainly a disease of older people. More than 70% become ill over the age of 60 years, the average age of those affected is 65–69 years. Less than 10% develop the disease before the age of 40. [1].

Clinical picture and diagnosis

The clinical picture and course of the disease are very diverse. Some patients experience a smoldering process of disease development and this group does not require therapy for decades. The other part, on the contrary, requires immediate initiation of treatment [3].

The diagnosis of CLL is described in detail by the International CLL Study Group [4]. To make a diagnosis of CLL, a blood test and immunophenotypic study must be performed. The presence of at least 5000/μl B-lymphocytes in the peripheral blood with a characteristic immunophenotype, of which the most prognostically important are the expression of the CD 5 antigen (CLL cells) and B-cell markers CD 19, CD 20, CD 5, CD 23, allows the diagnosis of CLL to be made . [5]. When using the fluorescent hybridization method, at least one chromosomal abnormality is detected in this group of patients, including deletion of 17p (8%) and 11q (15%) [1], which is an unfavorable prognosis factor.

Classification

To determine the stage of the disease, the classification of KR Rai et al is used throughout the world. (1975), reflecting the course of CLL and dividing it into stages depending on clinical manifestations. Another classification of CLL, published in 1981 by JL Binet et al., is based on the level of hemoglobin and platelets in the peripheral blood combined with the number of affected lymphatic areas [5].

Classification of CLL according to A.I. Vorobyov (2007)

Treatment of CLL

The group of patients who have stage A according to JL Binet at the onset of the disease do not require therapy for many years; observation tactics are preferable until signs of indications for starting therapy appear.

There are the following clear indications for starting therapy:

1. signs of intoxication (weight loss of 10% over 6 months, night sweats, low-grade fever without signs of infection)

2. increasing anemia or thrombocytopenia

3. splenomegaly (> 6 cm below the costal margin)

4. massive lymphadenopathy

5. increase in lymphocytosis >2 times in 2 months.

The standard first-line therapy for healthy patients is the FCR regimen (fludarabine, cyclophosphamide, rituximab); in the presence of contraindications to fludarabine therapy, the BR regimen (bendamustine, rituximab) is optimal [5].

According to Russian clinical guidelines for the diagnosis and treatment of lymphoproliferative diseases, 2nd line therapy involves FCR, R-HDMP, BR, FCR-lite regimens. The choice of regimen is based on the first-line therapy used, the time of relapse, and the clinical picture. The choice of the 3rd and subsequent lines is not regulated by these recommendations.

Characteristics of patients and treatment method

Taking into account the above, as well as literature data, we identified and treated 5 patients with relapsed CLL.

The age of the patients ranged from 45 to 67 years, the average age was 59-+2 years. On average, patients were in complete remission for 2.5 years. Each of them received fludarabine-containing regimens as 1st line of therapy.

Before starting treatment, all patients underwent standard methods for diagnosing relapse of CLL: complete blood count, immunophenotyping of bone marrow lymphocytes - high expression of CD 19, CD 20, CD 5, CD 23 was revealed. Additional examination methods were also carried out: CT scan of the neck, thoracic and abdominal organs , small pelvis, according to the results of which all patients had severe lymphadenopathy, hepato- and splenomegaly. Biochemical analysis of blood serum, echocardiography. No pronounced pathology of organs and systems was identified. 2 patients had anemia (80 and 95 g/l)

As a second-line polychemotherapy regimen, patients received 6 courses of BR (bendamustine, rituximab) on an outpatient basis. The dose of bendamustine was 70 mg/m2 on days 1 and 2 of the 28-day cycle. Rituximab was used at a dosage of 375 mg/m2 on day 1 of cycle 1, then 500 mg/m2 on day 1 of each subsequent cycle. The administration of bendamustine was accompanied by infusion therapy in a volume of 1500 ml, rituximab 1000 ml.

Antiemetogenic drugs and glucocorticosteroids were used as premedication 30 minutes before the start of bendamustine administration. In accompanying therapy, drugs that affect tumor lysis syndrome and hepatoprotectors were prescribed.

The duration of bendamustine infusion was 1 hour, and rituximab infusion averaged 4 hours. No adverse reactions were detected during administration. The dose of drugs was not reduced.

After the 3rd course of therapy, patients again underwent a CT scan of the neck, chest, abdominal cavity, and pelvis, according to the results of which all patients showed positive dynamics in the form of a reduction in the size of the tumor mass by more than 50% (in 4 patients) and the absence of new targeted lymphatic nodes, which allowed us to note a partial response to therapy in 4 patients. Stabilization of the process was observed in 1 patient.

When analyzing laboratory data in 2 patients after the 2nd course of therapy, blood counts worsened, anemia (up to 50 g/l) and thrombocytopenia (4 million) increased, and therefore replacement therapy with blood components was carried out. In 3 patients, after 4 courses, severe leukocytopenia (up to 3.5 thousand) was observed, which required the introduction of a colony-stimulating factor. Against the background of agranulocytosis, 1 patient developed polysegmental pneumonia, which was managed with broad-spectrum antibiotics in a hospital setting.

After completing 6 courses of therapy and assessing the response to therapy, all patients experienced clinical and hematological remission. The duration of observation of disease-free survival to date has averaged 4 months.

Conclusions:

1. After analyzing the data obtained, we can conclude that it is possible to conduct a course of BR on an outpatient basis, which leads to a reduction in in-hospital complications and reduces the cost of a patient’s hospital stay.
2. The 100% remission achieved demonstrates the effectiveness of using this regimen in the amount of 6 courses of therapy in the proposed dosages of drugs.
3. Further monitoring of the duration of relapse-free and overall survival of patients is necessary in order to assess the effectiveness of therapy.