Leukemia. Innovations and therapeutic breakthroughs

- an oncological disease accompanied by the accumulation of atypical mature B-lymphocytes in the peripheral blood, liver, spleen, lymph nodes and bone marrow. In the initial stages, it is manifested by lymphocytosis and generalized lymphadenopathy. With the progression of chronic lymphocytic leukemia, hepatomegaly and splenomegaly are observed, as well as anemia and thrombocytopenia, manifested by weakness, fatigue, petechial hemorrhages and increased bleeding. There are frequent infections due to a decrease in immunity. The diagnosis is established on the basis of laboratory tests. Treatment - chemotherapy, transplantation bone marrow.

General information

Chronic lymphocytic leukemia is a disease from the group of non-Hodgkin's lymphomas. Accompanied by an increase in the number of morphologically mature, but defective B-lymphocytes. Chronic lymphocytic leukemia is the most common form of hemoblastoses, accounting for one third of all leukemias diagnosed in the US and Europe. Men are affected more often than women. The peak incidence occurs at the age of 50-70 years, in this period about 70% of the total number of chronic lymphocytic leukemias are detected.

Young patients rarely suffer, up to 40 years the first symptom of the disease occurs in only 10% of patients. AT last years experts note some "rejuvenation" of the pathology. The clinical course of chronic lymphocytic leukemia is very variable, ranging from a prolonged absence of progression to an extremely aggressive variant with a fatal outcome within 2-3 years after diagnosis. There are a number of factors that can predict the course of the disease. Treatment is carried out by specialists in the field of oncology and hematology.

Etiology and pathogenesis of chronic lymphocytic leukemia

The causes of occurrence have not been fully elucidated. Chronic lymphocytic leukemia is considered the only leukemia with an unconfirmed relationship between the development of the disease and adverse environmental factors (ionizing radiation, contact with carcinogens). Experts believe that the main factor contributing to the development of chronic lymphocytic leukemia is hereditary predisposition. Typical chromosomal mutations that cause damage to oncogenes at the initial stage of the disease have not yet been identified, however, studies confirm the mutagenic nature of the disease.

The clinical picture of chronic lymphocytic leukemia is due to lymphocytosis. The cause of lymphocytosis is the appearance of a large number of morphologically mature, but immunologically defective B-lymphocytes, incapable of providing humoral immunity. It was previously believed that abnormal B-lymphocytes in chronic lymphocytic leukemia are long-lived cells and rarely undergo division. Subsequently, this theory was refuted. Studies have shown that B-lymphocytes multiply rapidly. Every day, 0.1-1% of the total number of atypical cells is formed in the patient's body. In different patients, different clones of cells are affected, so chronic lymphocytic leukemia can be considered as a group of closely related diseases with a common etiopathogenesis and similar clinical symptoms.

When studying cells, a great variety is revealed. The material may be dominated by wide-plasma or narrow-plasma cells with young or wrinkled nuclei, almost colorless or brightly colored granular cytoplasm. Proliferation of abnormal cells occurs in pseudofollicles - clusters of leukemic cells located in the lymph nodes and bone marrow. The causes of cytopenia in chronic lymphocytic leukemia are autoimmune destruction of blood cells and suppression of stem cell proliferation due to an increase in the level of T-lymphocytes in the spleen and peripheral blood. In addition, in the presence of killer properties, the destruction blood cells can cause atypical B-lymphocytes.

Classification of chronic lymphocytic leukemia

Given the symptoms morphological features, rates of progression and response to therapy, the following forms of the disease are distinguished:

• Chronic lymphocytic leukemia with a benign course. The patient's condition remains satisfactory for a long time. There is a slow increase in the number of leukocytes in the blood. From the moment of diagnosis to a stable increase in lymph nodes, it can take several years or even decades. Patients retain their ability to work and their usual way of life.
• Classical (progressive) form of chronic lymphocytic leukemia. Leukocytosis builds up over months, not years. There is a parallel increase in lymph nodes.
• Tumor form of chronic lymphocytic leukemia. Distinctive feature this form is mildly pronounced leukocytosis with a pronounced increase in lymph nodes.
• Bone marrow form of chronic lymphocytic leukemia. Progressive cytopenia is detected in the absence of an increase lymph nodes, liver and spleen.
• Chronic lymphocytic leukemia with enlarged spleen.
• Chronic lymphocytic leukemia with paraproteinemia. Symptoms of one of the above forms of the disease are noted in combination with monoclonal G- or M-gammapathy.
• Prelymphocytic form X chronic lymphocytic leukemia. A distinctive feature of this form is the presence of lymphocytes containing nucleoli in blood and bone marrow smears, tissue samples of the spleen and lymph nodes.
• Hairy cell leukemia. Cytopenia and splenomegaly are detected in the absence of enlarged lymph nodes. Microscopic examination reveals lymphocytes with a characteristic "youthful" nucleus and "uneven" cytoplasm with breaks, scalloped edges and sprouts in the form of hairs or villi.
• T-cell form of chronic lymphocytic leukemia. It is observed in 5% of cases. Accompanied by leukemic infiltration of the dermis. Usually progresses quickly.

There are three stages of the clinical stage of chronic lymphocytic leukemia: initial, advanced clinical manifestations and terminal.

Symptoms of chronic lymphocytic leukemia

At the initial stage, the pathology is asymptomatic and can only be detected by blood tests. Within a few months or years, a patient with chronic lymphocytic leukemia has 40-50% lymphocytosis. The number of leukocytes is close to the upper limit of the norm. In the normal state, peripheral and visceral lymph nodes are not enlarged. During the period of infectious diseases, the lymph nodes can temporarily increase, and after recovery they decrease again. The first sign of the progression of chronic lymphocytic leukemia is a stable increase in lymph nodes, often in combination with hepatomegaly and splenomegaly.

First, the cervical and axillary lymph nodes are affected, then the nodes in the mediastinum and abdominal cavity, then - in the inguinal region. Palpation reveals mobile, painless, densely elastic formations that are not soldered to the skin and nearby tissues. The diameter of the nodes in chronic lymphocytic leukemia can range from 0.5 to 5 or more centimeters. Large peripheral lymph nodes may swell with a visible cosmetic defect. With a significant increase in the liver, spleen and visceral lymph nodes, compression of the internal organs can be observed, accompanied by various functional disorders.

Patients with chronic lymphocytic leukemia complain of weakness, unreasonable fatigue and decreased ability to work. According to blood tests, there is an increase in lymphocytosis up to 80-90%. The number of erythrocytes and platelets usually remains within the normal range, in some patients minor thrombocytopenia is detected. In the later stages of chronic lymphocytic leukemia, weight loss, night sweats and fever to subfebrile numbers are noted. Immune disorders are characteristic. Patients often suffer colds, cystitis and urethritis. There is a tendency to suppuration of wounds and the frequent formation of abscesses in the subcutaneous fatty tissue.

The cause of death in chronic lymphocytic leukemia is often severe infectious diseases. Possible inflammation of the lungs, accompanied by a collapse of the lung tissue and gross violations of ventilation. Some patients develop exudative pleurisy, which may be complicated by rupture or compression of the thoracic lymphatic duct. Another common manifestation of advanced chronic lymphocytic leukemia is herpes zoster, which in severe cases becomes generalized, capturing the entire surface of the skin, and sometimes the mucous membranes. Similar lesions can be seen in herpes and chickenpox.

Among others possible complications chronic lymphocytic leukemia - infiltration of the vestibulocochlear nerve, accompanied by hearing disorders and tinnitus. In the terminal stage of chronic lymphocytic leukemia, infiltration of the meninges, medulla and nerve roots can be observed. Blood tests reveal thrombocytopenia, hemolytic anemia, and granulocytopenia. It is possible to transform chronic lymphocytic leukemia into Richter's syndrome, a diffuse lymphoma that manifests itself rapid growth lymph nodes and the formation of foci outside lymphatic system. About 5% of patients survive to develop lymphoma. In other cases, death occurs from infectious complications, bleeding, anemia and cachexia. Some patients with chronic lymphocytic leukemia develop severe kidney failure due to infiltration of the renal parenchyma.

Diagnosis of chronic lymphocytic leukemia

In half of the cases, the pathology is discovered by chance, during examination for other diseases or during a routine examination. When making a diagnosis, complaints, anamnesis, objective examination data, results of blood tests and immunophenotyping are taken into account. Diagnostic criterion chronic lymphocytic leukemia is an increase in the number of leukocytes in the blood test up to 5 × 109 / l in combination with characteristic changes in the immunophenotype of lymphocytes. Microscopic examination of a blood smear reveals small B-lymphocytes and Gumprecht shadows, possibly in combination with atypical or large lymphocytes. Immunophenotyping confirms the presence of cells with an aberrant immunophenotype and clonality.

The determination of the stage of chronic lymphocytic leukemia is carried out on the basis of the clinical manifestations of the disease and the results of an objective examination of the peripheral lymph nodes. To draw up a treatment plan and assess the prognosis for chronic lymphocytic leukemia, cytogenetic studies are carried out. If Richter's syndrome is suspected, a biopsy is prescribed. To determine the causes of cytopenia, a sternal puncture of the bone marrow is performed, followed by a microscopic examination of the punctate.

Treatment and prognosis for chronic lymphocytic leukemia

At the initial stages of chronic lymphocytic leukemia, expectant management is used. Patients are scheduled for examination every 3-6 months. In the absence of signs of progression, they are limited to observation. An indication for active treatment is an increase in the number of leukocytes by a factor of two or more within six months. The main treatment for chronic lymphocytic leukemia is chemotherapy. The combination of rituximab, cyclophosphamide, and fludarabine is usually the most effective drug combination.

In the persistent course of chronic lymphocytic leukemia, large doses of corticosteroids are prescribed, bone marrow transplantation is performed. In elderly patients with severe somatic pathology, the use of intensive chemotherapy and bone marrow transplantation may be difficult. In such cases, monochemotherapy with chlorambucil is carried out or this drug is used in combination with rituximab. In chronic lymphocytic leukemia with autoimmune cytopenia, prednisolone is prescribed. Treatment is carried out until the patient's condition improves, while the duration of the course of therapy is at least 8-12 months. After a stable improvement in the patient's condition, treatment is stopped. The indication for resuming therapy is clinical and laboratory symptoms, indicating the progression of the disease.

Chronic lymphocytic leukemia is considered as a practically incurable long-term disease with a relatively satisfactory prognosis. In 15% of cases, an aggressive course is observed with a rapid increase in leukocytosis and progression of clinical symptoms. Lethal outcome in this form of chronic lymphocytic leukemia occurs within 2-3 years. In other cases, slow progression is noted, the average life expectancy from the moment of diagnosis ranges from 5 to 10 years. With a benign course, the life span can be several decades. After the course of treatment, improvement is observed in 40-70% of patients with chronic lymphocytic leukemia, but complete remissions are rarely detected.

Chronic lymphocytic leukemia (CLL) is an oncological disease of the hematopoietic system. This is the most common type of leukemia in adults. Therefore, the treatment of such patients is a serious social problem. At the same time, a serious problem is the treatment of those patients who are no longer susceptible to traditional chemotherapy. Meanwhile, use as a second line therapy modern drugs allows you to achieve remission and well control chronic lymphocytic leukemia. At the same time, the life expectancy of patients increases and, most importantly, its good quality is maintained. With questions about such modern methods of treating this life-threatening disease, we turned to the head of the hematology department of the Pavlodar regional hospital them. G. Sultanov, chief freelance hematologist of Pavlodar region, hematologist the highest category J.B. SEYSENBEKOVA and hematologist of the Kostanay regional hospital S.F. SHARNEVSKAYA.

- Tell us about chronic lymphocytic leukemia in general. How common is this disease and what are the symptoms?

- J.B. Seisenbekov: Chronic lymphocytic leukemia is one of the most common oncohematological diseases in adults and belongs to the group of lymphoproliferative diseases. It is characterized by the uncontrolled formation and accumulation of atypical monoclonal mature B-lymphocytes in the blood, bone marrow, lymph nodes, liver and spleen, multiplying and accumulating in the bone marrow, they interfere with the production and functioning of normal blood cells.

- S.F. Sharnevskaya: Chronic lymphocytic leukemia is a sluggish indolent, i.e. slowly progressive, a disease that in the initial stages may not manifest itself at all. But still his characteristic symptoms are fever, night sweats, lymphadenopathy (enlarged lymph nodes and spleen), susceptibility to infections, weight loss.

Now approaches to the treatment of chronic lymphocytic leukemia have changed. Previously, treatment began immediately after the diagnosis was made, now, if the patient is not bothered by anything and there is no sharp progression, then therapy is postponed. Those. The tactics are such that early treatment of this disease does not affect life expectancy, treatment is started when there are symptoms that interfere with the patient's quality of life.

Zhannur Baltabaevna, what methods are used in the treatment of this disease? How was CLL treated before and how is it treated today?

Standard chemotherapy for chronic lymphocytic leukemia usually includes one or more drugs. The choice of treatment program depends on age, physical health and other factors. At the same time, the treatment of chronic lymphocytic leukemia has made great strides in recent years. Deep studies of etiology and pathogenesis this disease made it possible to differentiate at the molecular level various forms. This opened up opportunities for the development of targeted drugs, antibodies that specifically destroy only tumor cells without affecting healthy organs and tissues. In recent years, a wide range of such drugs has appeared. They are used in standard chemotherapy.

- Today, in relation to malignant neoplasms we often talk about personalized therapy. Do hematologists have such drugs for the treatment of chronic lymphocytic leukemia?

- J.B. Seisenbekov: In the first line of therapy for chronic lymphocytic leukemia, chemotherapeutic agents are used. Of course, they are very toxic and such treatment changes the patient's quality of life so much that he can no longer be an active member of society and receives only in a hospital due to tumor intoxication, anemia of varying depth and other problems. Chemotherapy can be supplemented with targeted biological agents, such as rituximab. Then the patient goes into the category of outpatients and at this stage he no longer receives such aggressive therapy, the patient is observed and other drugs are prescribed to him. This tactic of treatment is accepted all over the world.

- Are there new approaches to treatment that can save the patient's quality of life?

- J.B. Seisenbekov: Today, an innovative drug, ibrutinib, has appeared at the disposal of oncohematologists. It is a Bruton's tyrosine kinase inhibitor that plays an important role in maintaining the viability of malignant cells. By blocking tyrosine kinase
Bruton, ibrutinib reduces the manifestations of chronic lymphocytic leukemia. The drug has proven itself very well in clinical practice and has shown effectiveness in the treatment of even refractory patients who do not respond to standard treatment. Those. it is a second-line drug, it is used when first-line drugs are no longer effective.

- Do Kazakh patients have the opportunity to be treated with this highly effective drug?

- S.F. Sharnevskaya: In the Kostanay region, two patients receive it. They were completely immune to the previous treatment. Therefore, the drug helped not only save their lives, but also had a positive effect on its quality. The reason is good tolerability, outpatient reception. In addition, the drug, unlike traditional chemotherapy drugs, does not cause the development of secondary solid tumors. We received a complete hematological response, the blood picture was completely restored, there is no immunodeficiency, the lymph nodes have decreased in volume, there are no foci of proliferation. Patients returned to normal life.

- J.B. Seisenbekov: More than 30 patients with CLL are registered in Pavlodar region. These are the patients different ages with various comorbidities, different stages and the severity of the disease, etc. Two patients were selected to participate in the Early Access Therapy Program with
the minimum number of comorbidities and already receiving first-line drugs.
They were treated with oral ibrutinib on an outpatient basis. They had a good response to therapy, while it was accompanied by a minimum amount of side effects. Patients noted less toxicity of the drug, in comparison with chemotherapeutic agents. The treatment did not disturb their habitual way of life, and, therefore, did not affect its quality. At the same time, they improved psychological condition the patient himself and his whole family, they remained efficient, there was a belief in a prosperous future. I note that ibrutinib is the first drug for the treatment of CLL, which makes it possible to treat a patient on an outpatient basis.

- Tell us more about the program of early access to ibrutinib therapy.

- J.B. Seisenbekov: In 2016, as part of corporate social responsibility, the ibrutinib manufacturing company initiated an early access program to therapy with this drug in our country. It is primarily intended for patients with relapsed or refractory chronic lymphocytic leukemia who require ibrutinib as a second and subsequent line of therapy.

Under the terms of the program, the patient is provided with treatment free of charge at the expense of the company until the state can take over the provision of ibrutinib. This is very important, since in this case we are talking about long-term and continuous treatment with an expensive drug, which the patient will definitely not be able to pay for at his own expense.

What are the benefits of ibrutinib treatment? How effective is outpatient treatment compared to conventional hospitalization?

- J.B. Seisenbekov: Ibrutinib is available in oral form, has a very convenient reception scheme and a good safety profile. It can be applied at the outpatient level, i.e. for treatment with the drug there is no need to go to the hospital. Its inclusion in the list of drugs for drug provision at the outpatient level (absent in the order of the Ministry of Health of the Republic of Kazakhstan dated November 4, 2011 No. 786 "On approval of the List medicines and products medical purpose for free provision of the population within the guaranteed volume of free medical care at an outpatient level with certain diseases (conditions) and specialized therapeutic products") will not only open access to highly effective therapy for those patients with B-cell leukemia who are no longer responding to standard treatment, but and save financial resources. After all, this eliminates the need for hospitalization of the patient, reduces the cost of treating complications of toxic chemotherapy. In addition, the patient himself does not come off work and family. He remains socially active, fully capable and continues to benefit the state and society.

Prepared by Olga BAIMBETOVA

May 22, 2017 Within the framework of the XII All-Russian Forum "New Horizons" a lecture was held by the assistant of the Department of Oncology of the First Moscow State Medical University named after A.I. THEM. Sechenov Ministry of Health of the Russian Federation, Ph.D. THOSE. Bialik on the topic of chronic lymphocytic leukemia.

The lecturer highlighted the main aspects that a patient with a diagnosis of chronic lymphocytic leukemia should know.

Chronic lymphocytic leukemia is a clonal lymphoproliferative disease characterized by proliferation and an increase in the number of mature lymphocytes in the peripheral blood against the background of lymphocytic infiltration of the bone marrow, lymph nodes, spleen and other organs. The most common type of leukemia in the adult population. The incidence is 3-3.5 per 100,000 population per year. The median age ranges from 58 to 72 years and only 10% of patients are under 40 years of age.

Unlike other oncological diseases, the relationship of chronic lymphocytic leukemia with "classic" carcinogenic factors has not yet been established. Also, this disease is the only leukemia, the origin of which is not associated with ionizing radiation.

In the early stages of the disease, there are practically no symptoms. The disease can develop for years asymptomatically, with only some changes. general analysis blood. The number of leukocytes in the early stages of the disease fluctuates within the upper limit of normal.

Symptoms of the disease:

• Increased lymphocytes in peripheral blood;
• Enlarged lymph nodes;
• Enlargement of the spleen;
• Enlargement of the liver;
• Decreased hemoglobin level;
• Decreased platelet levels;
• Increase in body temperature;
• Weight loss;
• Fast fatiguability;
• Tendency to infections.

Required examinations:

• Clinical blood test with counting of formed elements;
• Blood chemistry;
• Analysis of urine;
• Puncture and trepanobiopsy of the bone marrow;
• Immunophenotypic analysis of bone marrow lymphocytes;
• Cytogenetic study of bone marrow lymphocytes;
• Molecular study of peripheral blood and bone marrow lymphocytes;
• CT scan chest, abdominal cavity, small pelvis;
• ECG, ultrasound of the heart.

Disease stages:

Stage A - lymphocytosis with damage to no more than 2 groups of lymph nodes or the absence of their defeat, anemia and thrombocytopenia are absent;

Stage B - lesions of 3 or more groups of lymph nodes, liver, spleen; anemia, thrombocytopenia are absent;

Stage C - lymphadenopathy, the presence of anemia and / or thrombocytopenia.

Unfortunately, chronic lymphocytic leukemia is not a curable disease, however, with timely diagnosis and properly selected therapy, the duration and quality of life of patients can be significantly improved. However, even with the highest quality treatment, this disease retains the ability to slowly progress.

The initial stages of the disease do not require special treatment. At this stage, the patient's condition is under the constant supervision of a hematologist. With a stable slow course, the patient may feel well without taking any drugs.

Indications for starting drug therapy:

• Doubling time of lymphocytes (less than 6 months);
• Progressive growth of lymph nodes, spleen, liver;
• The appearance of anemia;
• The appearance of thrombocytopenia;
• Autoimmune complications;
• The appearance of complaints - an increase in the frequency of infectious diseases, increased weakness, sweating, hyperemia.

Treatment: alkylating agents (leukeran, cyclophosphamide), purine analogues (fludarabine, cladribine), combined preparations(bendamustine), monoclonal antibodies.

New drugs for the treatment of chronic lymphocytic leukemia: monoclonal antibodies, inhibitors of the BCR complex signal, proapoptotic drugs.

As a result of the report, the forum participants were able to ask questions, which were immediately answered.

The material was prepared on the basis of a lecture by T.E. Bialik.

Photos of the event:

1 GBOU VPO KrasGMU named after. professor V.F. Voyno-Yasenetsky

2 KGBUZ "Regional Clinical Hospital"

3 Federal State Budgetary Institution Hematological Research Center of the Ministry of Health of Russia

4 N.I. Pirogov National Medical and Surgical Center of the Ministry of Health of Russia

B-cell chronic lymphocytic leukemia is a heterogeneous disease in terms of clinical manifestations and biological features. At the time of diagnosis of the disease, almost 70% of patients are over 65 years old, most of them have several concomitant diseases by this time. The effect of treatment depends on the individual sensitivity of tumor cells, the toxicity of chemotherapy, and comorbidity. The goal of therapy is to ensure the best quality of life for the patient, and to start treatment only when the patient has symptoms of the disease. Despite the fact that chronic lymphocytic leukemia (CLL) remains an incurable disease, over the past decade there have been significant advances in understanding the pathophysiology and approaches to the treatment of CLL. This article describes the issues of diagnosis and modern methods of treatment of this disease.

chronic lymphocytic leukemia

diagnostic criteria

poor prognostic factors

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Chronic lymphocytic leukemia (CLL)/small lymphocyte lymphoma is a lymphoproliferative disease, the morphological substrate of which is tumor clonal lymphoid cells that have the size and morphology of a mature lymphocyte and an immunophenotype corresponding to B-lymphocytes of late stages of differentiation.

In Europe and North America, CLL is the most common type of leukemia. In these countries, it accounts for about 30% of all leukemias. The annual incidence is 3-3.5 per 100,000 population, increasing to 20 per 100,000 after age 70. CLL is extremely rare among Uzbeks. Among residents of Japan, no more than one new case per year is recorded annually.

CLL is more common in men, with a male to female ratio of 2:1. average age 72 years old. Almost 70% of patients are over 65 years of age, most of them by this time have several concomitant diseases. This is especially important to consider when, after chemotherapy, numerous complications develop, worsen chronic diseases. The median age of patients who died from CLL is 79 years. Infectious complications are the main cause of death in patients with CLL. Mortality from infections is 30-50% of all fatal cases.

Despite significant progress in therapy, CLL remains an incurable disease. The current treatment goal is to increase overall survival (OS) and progression-free survival (PFS) while minimizing toxicity. This is especially important in older people with comorbidities.

CLL is the most common form of leukemia in blood relatives. The median age at diagnosis of the disease among familial cases is 58 years.

During the study of the course of the disease in 16367 patients with CLL from 1973 to 1996, an increase in the frequency of second tumors by 1.2 times was revealed. A higher risk of developing melanoma, Hodgkin's lymphoma and acute myeloid leukemia among patients treated with alkylating drugs, and was not increased among untreated patients and those treated with fludarabine alone.

The criteria for the diagnosis of CLL are the detection of B-lymphocytes in the peripheral blood in an amount exceeding 5 × 10 9 /l, the presence of at least 30% of lymphocytes in the bone marrow aspirate, and the detection of specific markers by flow cytometry. CLL cells co-express CD5 antigen and B-cell markers CD19, CD20, CD23. The level of surface immunoglobulins CD20 and CD79b on tumor cells is lower than on normal B-lymphocytes.

Lymphoma from small lymphocytes is diagnosed in the presence of lymphadenopathy, splenomegaly, cytopenia, provided that the number of B-lymphocytes in the blood does not exceed 5×10 9 /l. A prerequisite for establishing a diagnosis is biopsy of the lymph node.

By clinical course CLL is extremely heterogeneous. The prognosis of the disease depends on the presence or absence of adverse clinical, morphological and molecular genetic features. The heterogeneity of clinical and laboratory manifestations formed the basis for the classification of CLL developed by Vorobyov A.I. and Brilliant M.D. There are eight forms of the disease: 1) benign, 2) tumor, 3) progressive, 4) splenic, 5) bone marrow, 6) abdominal, 7) prolymphocytic and 8) lymphoplasmacytic.

Clinical and laboratory prognostic markers include peripheral blood leukocytosis at the start of therapy, lymphocyte doubling time, clinical stage of the disease, type of bone marrow lesion, gender, age, patient status on the ECOG scale, and general somatic status. Tumor biology is reflected by chromosomal aberrations determined by the FISH method, the mutational status of VH genes, the expression level of CD 38, ZAP 70. The most common chromosomal changes are del 13q14 (40-60%), trisomy 12 chromosomes (15-30%), del 17p13 (ten%) .

Analysis of the karyotype, clinical manifestations and duration of the disease showed that with an isolated 13q deletion, a stable condition and slow progression with a good response to therapy are observed. The prognostic value of trisomy 12 is still a matter of debate. The presence of 17p is often associated with a mutation in the tumor suppressor gene TP53 and is associated with an unfavorable course of the disease. The median survival of patients with trisomy 12 is 114 months, with a deletion of 11q - 79 months, and with a deletion of 17p - 32 months.

The mutational status of JgVH genes in CLL reflects the most significant biological features of the disease. Several studies have found that the median survival for modern therapy ranges from 79 to 119 months in the absence of mutations, while in their presence it is 200-300 months.

CD38+ was the first marker to correlate with mutational status. The threshold level of CD38+ expression on peripheral blood lymphocytes in CLL is 30%. The median survival in the CD38-positive group was 109 months, in the CD38-negative group - 293 months. A direct relationship was found between the absence of mutations in IgVH genes and the expression of tyrosine kinase ZAP-70, lipoprotein lipase (LPL), and metalloprotease (ADAM29) . In addition to the above factors, there are at least a dozen other prognostic factors, which include BCL6 gene mutation, BCL2 gene expression, lactate dehydrogenase (LDH) level, serum β2-microglobulin, expression of cytokines (IL-4, IL-6) and factor vascular endothelial growth (VEGF).

The choice of therapy and the time of initiation of treatment depends on age, comorbidities, and the presence of unfavorable prognosis factors.

In turn, the effectiveness of therapy largely depends on compliance with the dose and mode of administration of chemotherapy drugs. The goal of therapy in CLL is to achieve remission. Clinical and hematological criteria for response to treatment in B-CLL do not allow one to judge the depth of remission, i.e., the number of remaining B-CLL lymphocytes in the patient's blood and bone marrow. It has been proven that the lower the level of remaining B-CLL tumor cells, as determined by flow cytometry or polymerase chain reaction(PCR), the better the prognosis of the disease (longer PFS and OS). It has been proven that semi-quantitative methods for determining minimal residual disease (MRD) are not suitable for the clinic. Currently, four-color flow cytometry has become the most accessible and widely used method for determining MRD.

The first drugs for the treatment of chronic lymphoid leukemia were urethane, arsenic salts. From 1905 and the next 50 years, the main method of treatment was local X-ray therapy. Currently, radiation therapy is practically not used. In 1953, alkylating drugs appeared, the first of which was embiquine, currently chlorambucil is used. According to the results of studies, there was no difference in survival between early and delayed administration of chlorambucil. Following chlorambucil, new alkylating agents were synthesized, so far only cyclophosphamide (C) has been used. The third major step in the treatment of CLL was the creation of purine analogues. Fludarabine (F) was one of the first to be synthesized. Almost simultaneously, other purine analogs were obtained - pentostatin, cladribine.

The first clinical trials were conducted in previously treated patients and showed high efficacy of fludarabine. In 45% of patients refractory to all therapy, remission was obtained: 13% had a complete remission (PR) lasting 21 months, 32% had a partial remission (PR) lasting 13 months. The International Working Group on CLL, which studied 695 patients, evaluated the efficacy of CHOP, CAP, and fludarabine in patients in stages B and C. CR and PR were achieved in 66% of patients treated with CAP, in 77% of patients who received CHOP, and in 81% after fludarabine treatment. The number of PRs was 13, 28 and 37%, respectively. Median survival was 70 months with CAP, 68 months with CHOP, and 74 months with fludarabine.

Since the late 1990s, a monoclonal antibody to the CD20 antigen, rituximab (R), has been actively used in clinical practice. In previously untreated patients, the overall response (OR) from rituximab monotherapy is 51-86%, the frequency of CR is 4-19%. In the group that received treatment earlier, the overall response was obtained in 25-45% of patients, CR only in 3%.

The results of the second phase of a randomized study of the efficacy of fludarabine with rituximab (RF) in various regimens proved that the combined use of RF in previously untreated patients allows achieving complete and partial clinical and hematological remissions in 90% of cases, of which 47% - PR. When treated with fludarabine for 6 months, followed by the appointment of rituximab for 2 months, only 77% of remissions were obtained, of which 28% were CR. With a median follow-up of 23 months, both groups failed to reach the median of both relapse-free and overall survival.

Combinations of fludarabine with mitoxantrone (M) (77% remissions, 20% of them - PR), epirubicin (92% of remissions, 40% - PR) and cyclophosphamide (88-100% of remissions, 35-50% - PR) turned out to be highly effective.

Mitoxantrone was added to fludarabine and cyclophosphamide in a Spanish study of 69 patients under 65 years of age with newly diagnosed CLL. The overall response was 90%, MRD-negative complete response was 26%, MRD-positive complete response was 38%, PR was 26%. Severe neutropenia (grade 3 or 4) developed in 10% of patients. Infectious complications were reported in 9% of cases, respectively. The median duration of response was 37 months. In patients with a 17p deletion, CR was not achieved.

One study evaluated the combined use of fludarabine in combination with different doses of cyclophosphamide and mitoxantrone in 60 patients with relapsed or resistant CLL. A complete response was obtained in 30 patients (50%), of which 10 cases (17%) were with MRD-negative, and 17 (28%) with a partial response. The mean duration of response was 19 months. The main complications were infections - 8%, neutropenia, nausea and vomiting. On the background of treatment, lethality from infectious complications was 5%.

Some investigators have attempted to obtain a higher remission rate by adding dexamethasone (D) to fludarabine and cyclophosphamide. A large number of works devoted to the FMD regimen, the use of which allows you to get up to 94% of responses (47% of CR), even in patients treated previously intensive care. And when using this protocol as first-line therapy, the frequency of achieving CR was even higher (79%) with an overall response in 95% of patients. It is extremely important to pay attention to the fact that when PR was achieved, molecular remissions were recorded in 82% of cases and PR was maintained for 2 years in 84% of cases. Of the side effects of this combination, only opportunistic infections were noted.

A group of researchers from Barcelona used a combination of chemotherapy drugs fludarabine, cyclophosphamide, mitoxantrone, rituximab (R-FSM). Six courses of therapy were carried out. Patients who achieved response received rituximab every 4 months as maintenance therapy. OS, PR in the absence of MRD, PR in the presence of MRD, CR - amounted to 93%, 46%, 36% and 11%, respectively. Severe neutropenia developed in 13% of patients. Major and minor infections were reported in 8% and 5% of patients, respectively. Later stages, 17p deletion, or high serum beta-2-microglobulin levels have been found to correlate with a lower likelihood of achieving CR.

In 2010, Russian scientists published data that evaluated the effectiveness of various CLL therapy regimens, including fludarabine (RFC, FCM, FC). The study included 229 patients, of whom 78 received the RFC program, 72 - FCM, 79 - FC. As a result of the combination of RFCs, a clinically significant healing effect obtained in 96% of patients, PR in 80% of primary patients and in 53% of previously treated patients. When prescribing the FCM program, a positive response was noted in 93% of patients, PR - in 75% of primary and 42% of previously treated patients. In the treatment of FC, the overall effect was 80%, CR was observed in 41% of primary and 14% of previously treated patients. A comparative analysis of the response to therapy showed that the effectiveness of the RFC combination significantly exceeds the effectiveness of the FCM and FC programs without increasing toxicity, which allows us to consider the RFC regimen as the program of choice in the treatment of CLL.

Combination therapy with fludarabine, cyclophosphamide, and rituximab (FCR) is currently the standard first-line treatment for CLL. However, due to toxicity, the FCR regimen can only be used in patients without significant comorbidities.

It should not be forgotten that CLL is a disease of the elderly and often comorbidities and severe complications can become an obstacle to the appointment of RFC therapy. When choosing a course, a balanced approach is needed, because at the moment this disease is not curable, it is necessary to strike a balance between toxicity and effectiveness.

One of the approaches to the treatment of elderly patients suffering from CLL is the use of a course of RFC in reduced doses (RFClite). In one study, RFC lite was administered to 50 patients aged 58 years. The mean duration of response was 22.3 months (5.2-42.5). Grade III-IV neutropenia was noted in 13% of cases during PCT cycles. In addition, for elderly patients, leukeran (chlorambucil) therapy in combination with rituximab can be used. The study of this scheme included 100 patients, mean age 70 years (43-86), median follow-up 30 months. The overall response was 84%, PR achieved in 10%. Therapy with R-chlorambucil increases the response rate to a greater extent than chlorambucil alone, although remissions are achieved to a lesser extent than with RFC.

A large number of works are devoted to the appointment of interferons for chemotherapy, which contributes to an increase in relapse-free survival in patients with indolent lymphomas, which include lymphoma from small lymphocytes. The overall response in patients who had not previously received therapy for the underlying disease was 75%, in previously treated patients - 76%. Median to disease progression was 12 months. Grade III toxicity was manifested by neutropenia in 39% of patients, anemia - in 17%, thrombocytopenia - in 5%.

Since 2008, the United States approved for use the drug bendamustine, which has bifunctional alkylating activity and antimetabolic properties of purine analogues. During treatment with bendamustine, there was an improvement in objective response rates (68% vs. 31%) and complete response (31% vs. 2%) compared with chlorambucil. Also, during therapy with bendamustine, a significant increase in PFS was noted compared with chlorambucil (21.6 versus 8.3 months).

The high efficiency of bendamustine in combination with Rituximab (CLL2M protocol) has been proven. The overall response to therapy was 90.9%: 36 (32.7%) patients had PR, 61 (55.5%) had PR, and 3 (2.7%) had nodal PR. Stabilization of the disease was registered in 10 (9.1%) patients. However, among 7 patients with a 17p deletion, only 3 (42.9%) developed PR.

An extension of this work is the CLL10, a multicenter, open-label, randomized, phase III trial comparing the BR combination with the standard of first-line FCR therapy. A total of 688 patients without a 17p deletion were included in the study. This work confirmed the efficacy advantage of FCR therapy, where there were higher rates of CR, progression-free and event-free survival. The advantage of the BR program was a lower number of infectious complications, which is especially important for debilitated and elderly patients.

Fludarabine refractoriness remains a serious problem in CLL therapy, which is associated with resistance to other cytostatics and a low median OS, not exceeding 1-2 years.

Alemtuzumab (Campas), which is an anti-CD52 antibody, has been used in the treatment of resistant forms of CLL. Alemtuzumab induces a clinical response in 40% of patients with refractory CLL and in 80% of patients when used in first line therapy. Unlike most other regimens for CLL, alemtuzumab was equally effective in patients with a 17p chromosome deletion compared to other cytogenetic subgroups. The addition of alemtuzumab to the FCR program contributed to the achievement of a rapid response in patients with relapsing CLL, but was accompanied by a large number of infectious complications both during and after therapy.

Over the past five years, monoclonal anti-CD20 antibodies of a new generation have appeared. Good results in the treatment of CLL have been obtained with the use of ofatumumab. Ofatomumab is a fully human anti-CD20 monoclonal antibody that has the ability to inhibit early activation of B-lymphocytes. In an international study, 138 patients were divided into two groups: 59 people resistant to fludarabine and alemtuzumab (FA-ref.), 79 - resistant to fludarabine (BF-ref.), and the presence of contraindications to the appointment of alemtuzumab. Group BF-ref. was characterized by a large tumor mass (lymph nodes over 5 cm). The overall response rate was 58% in the first group and 47% in the second. Complete regression of disease symptoms and improvement in general well-being were achieved in 57% and 48% of cases, respectively. Median progression-free survival and OS were 5.7 and 13.7 months in the FA-ref. group, and 5.9 and 15.4 months in BF-ref. group, respectively. Obinutuzumab is a glyco-engineered humanized type II monoclonal antibody that specifically binds to a specific CD20 antigen protein on the surface of malignant B-lymphocytes.

The open-label, randomized, 2-stage, 3-arm CLL11 (Phase III) trial compared the safety and efficacy of obinutuzumab + chlorambucil (G-Clb) with chlorambucil alone (Clb; stage 1a) and evaluated the efficacy of G- Clb versus rituximab plus Clb (R-Clb; stage 2) in patients with previously untreated CLL and at least one comorbidity and/or creatinine clearance< 70 мл/мин. Согласно полученным результатам на всех этапах медиана ВБП была значимо больше в группе G-Clb .

All young, somatically intact primary patients with a 17p deletion are advised to search for a donor for allogeneic hematopoietic stem cell transplantation. The use of transplantation of autologous blood stem cells has not justified itself due to the development of a large number of relapses.

Despite the emergence of new drugs, patients with a (17p)/TP53 deletion mutation represent a group with a poor prognosis. A promising direction in the treatment of high-risk patients is targeted therapy - the use of drugs aimed at BCR-associated kinases. These include fostamatinib, a Syk inhibitor, PCI-32765 (ibrutinib), a Btk inhibitor, and CAL-101 (Idelalisib), a PI3K inhibitor. These drugs show a fairly high efficiency. A characteristic feature of the action of drugs is the rapid regression of lymph nodes in combination with transient lymphocytosis, which is probably associated with the mobilization of cells from tissues into the bloodstream. According to the recommendations of a group of researchers from Germany, if a (17p)/TP53 mutation is detected in the first line, it is necessary to prescribe PCI-32765 or CAL-101 in combination with rituximab. The use of CAL-101 was accompanied by the development of a large number of infectious complications, in some patients with a fatal outcome. To date, due to increased complications, some studies have been closed.

According to the results of observations of patients taking ibrutinib for three years, a decrease in hematological toxicity and the number of infectious complications was found, while an increase in the overall response rate to therapy and the duration of remissions were noted.

Recently, studies have been actively conducted on the use of inhibitors of the Bcl-2 (AT-101), ABT-263 (navitoxlax) and ABT-199 (venetoclax) family proteins. Initially, the use of AVT-199 in monotherapy seemed promising, but later an important side effect was revealed - thrombocytopenia. In one treatment protocol, a single dose of ABT-199 in three patients with resistant CLL resulted in tumor lysis within 24 hours. Despite the good results associated with the use of new drugs, their mechanism of action and the potential benefit of their combination with traditional drugs still require more thorough study.

Immunotherapy and chemotherapy exacerbate the hypogammaglobulinemia present in CLL patients. Moreover, chemotherapy leads to the suppression of all links of the immune response, which is fraught with an increase in the risk of developing infectious complications, which significantly limit the possibilities of specific treatment and, in most cases, serve as one of the links of thanatogenesis. The prognosis for recovery depends on a number of reasons, such as the course of the underlying disease, the state of the granulocytic germ of hematopoiesis, the causative agent of an infectious disease, its prevalence, the location of the infection, the sensitivity of the causative agent of an infectious disease to medicines and the presence of comorbidities. To determine the role of comorbidity in patient survival, the German Lymphoma Group conducted two multicentre studies including a total of 555 patients with CLL. Patients were divided into three groups depending on the ongoing chemotherapy: treated with fludarabine with cyclophosphamide, fludarabine monotherapy, and chlorbutine. Studies have shown that the most effective first-line therapy is combined application fludarabine with cyclophosphamide, and comorbidity is an independent negative prognostic factor. Thus, the OS of patients with two or more comorbidities was 71.7 versus 90.2 months in the group of patients with one disease or no comorbidities. PFS in the first and second groups was 21% and 31.5%, respectively. I would like to draw attention to such a combination of data, namely, the low overall and progressive survival of patients in the first group with a comorbidity index ≥2 Special attention, since the high incidence of CLL progression in this group is associated with a reduction in doses of anticancer drugs due to comorbidities in order to minimize complications. The desire to reduce lethality due to drug toxicity led to an increase in the frequency of relapses and progression of CLL, which ultimately affected the overall survival of patients and led to its reduction.

Thus, the development of algorithms for the treatment of chronic lymphocytic leukemia should be based on the following main points: first, the most effective antitumor regimens should be used; secondly, in the treatment it is necessary to take into account not only the cytogenetic features of CLL, but also the age of patients and comorbidities; thirdly, it is necessary to improve the accompanying therapy, designed to minimize drug-related mortality.

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Significant progress has been made in the treatment of various kinds cancer of the blood and lymph. Our new article is all about treating blood cancer as part of Cancer Awareness Month. Only good news for you today.

In addition to traditional chemotherapy, which has shown good results in treating most types of cancer, including leukemia, many advanced biologics have been approved in recent years and have shown high cure rates in patients with leukemia. These drugs not only increase the life expectancy of patients, but also provide prospects for the treatment of many cancer, including lymphocytic leukemia.

Innovative biological therapies are based on the use of two main mechanisms:

1. Targeted Therapy , which consists in a unique mechanism of action of drugs, which consists in a selective effect on cancer cells and does not cause significant damage to healthy cells.
2. Procedures based on the activation and stimulation of the immune system patient against cancer cells. It is known that cancer cells are able to "deceive" the immune system, but new drugs can disrupt this mechanism, so the body itself is able to fight the disease.

New drugs for the treatment of blood cancer.

CML is chronic myelogenous leukemia.

The first breakthrough in the biological treatment of chronic myeloid leukemia was recorded in the early 2000s. Until this time, all patients had a transition chronic form acute, followed by death of the patient.

The disease is fixed as a rule in people 50-60 years old, but it also occurs in young people. Worldwide, about 100,000 people are diagnosed each year. Several hundred patients diagnosed with blood cancer are under observation in Israeli hospitals.

Blood cancer is caused by a genetic mutation of cells in the bone marrow, which causes the activation of the tyrosine kinase protein in the cell, which leads to its damage and rapid division.

Ten years ago, the drug imatinib Glivec was successfully used for the first time, which inhibited the activity of protein tyrosine kinases, which led to a cure in 90% of patients, and also eliminated a genetic mutation in 80% of patients.

Since 2004, imatinib has been added to the basket of drugs for the treatment of blood cancer, and more advanced generations of tyrosine kinase inhibitors such as Nilotinib (Tsignh), Dstinib (Sfriisl) and Fontinib (Aiklosig) have been developed later.

These drugs are more effective in fighting cancer cells, even in cases where patients develop resistance to imatinib treatment. It is thanks to them that the life expectancy of patients with blood cancer is almost equal to the life of healthy people.

CLL, chronic lymphocytic leukemia; and NHL, non-Hodgkin's lymphoma.

Chronic lymphocytic leukemia is the most common type of leukemia in adult B-lymphocytes, cells belonging to immune system and protect the body from harmful cells.

The disease occurs in 2-4 people per 100 thousand patients, and its prevalence is much higher among people over 70 years of age. The disease tends to develop slowly and recur after diagnosis and treatment. Because traditional chemotherapy does not give good indicators for a cure, then to some extent this is what prompted scientists to develop new biological drugs.

Non-Hodgkin's lymphoma is a cancer of the lymph nodes that also damages other organs in the body. In most cases, the source of the disease is B-lymphocytes, which are life threatening, especially in the case of aggressive lymphoma and a moderate form of the disease, also called indolent lymphoma.

A breakthrough in the treatment of CLL and NHL began over a decade ago with the launch of MabThera (Ritoksimb). The combination of the drug with chemotherapy significantly improved the response of patients to treatment. Moreover, this combination greatly contributes to the cure of the patient.

MabThera is a monoclonal antibody directed against a protein called CD-20. The antibody binds to cancer cells and causes their death by directly entering the cell membrane and activating lymphocytes of the immune system against cancer.

Subsequently, several more antibodies have been developed that work against CD-20, including Aofatomomb (Arzrh) for the treatment of patients with CLL. In combination with chemotherapy, the use of the drug led to a significant improvement in response to treatment.

The second generation of drugs, Belvedere, has shown high efficiency in patients who, for one reason or another, cannot receive chemotherapy. To date, it has been shown to be effective in treating other types of lymphoma, and its use is expected to increase, especially in adult patients with CLL.

Scientific advances in understanding the structure of cancer cells and the functions of a cancerous tumor have made a huge breakthrough in oncology medicine and have made a great contribution to the development of a number of innovative smart drugs for the treatment of CLL. One such drug is Aibrotinib.

This drug blocks the protein BTK (Bruton's tyrosine kinase), which is important for the survival and proliferation of B cells. Accordingly, thanks to the drug, the protein is inhibited, which causes the neutralization and destruction of cancer cells. In this case, significant harm to other cells of the body is not applied.

In early 2014, the drug was approved by the FDA for the treatment of CLL in patients with relapsed or resistant disease who had already received at least one line of treatment. results medical examination showed that the disease returned in 60% of patients who responded well to the drug.

At the same time, patients who, as a rule, do not respond to treatment, responded well to drug therapy. As a result, the drug has been introduced into the treatment regimen since 2014 for patients suffering from blood cancer with a mutation in chromosome 17.

In 2015, the use of the drug became available for all patients with recurrent CLL, as well as for those patients who did not fit the standard treatment regimens. To date, most treatments have been successful, and the drug itself is effective and approved for use in a basket of patients with mantle cell lymphoma, an aggressive form of relapsing lymphoma.

Notoklast is another new drug that inhibits a protein called BCL2 and causes cancer cells to die. The drug is approved by the FDA for the treatment of CLL and is effective in the treatment of other types of lymphomas.

Multiple myeloma.

Multiple myeloma is a cancer of the blood in which the plasma cells of the bone marrow become malignant. In fact, these are cells that produce antibodies that help the body fight various infections. With such blood cancer, cells begin to divide uncontrollably and form tumors, but also affect other organs due to the spread of blood flow.

Multiple myeloma is a rather painful disease that causes concomitant pathologies. These are kidney failure, and repeated infections, and bone fractures, as well as anemia. The average life expectancy of patients with multiple myeloma used to be only 2-3 years. Now, thanks to the development of biological drugs, which today are an integral part of the treatment of multiple myeloma, the life expectancy of patients has increased to 7-9 years.

Biological treatments for multiple myeloma are usually divided into two groups, each of which represents an addition to advanced biological therapies.

The first group is "aimidin", which affects the blood flow to tumor cells, activates the immune system against cancer cells, and suppresses factors responsible for cancer cell proliferation. These drugs include Lnlidomid (Rblimid) and Fomlidomid (Aimnobid).

Lnlidomide is given to elderly patients during first-line treatment. Fomlidomid is included in the health basket of all patients with multiple myeloma. Drugs are of particular importance for patients with poor diagnostic performance.

The second group of myeloma treatments is "frotaozom". Such treatment leads to the destruction of cancer cells by interfering with their activity. Bortizomib (Velcade) is the first drug in this group. It is approved and available for all patients with multiple myeloma, used alone or in combination with other biologics or chemotherapeutic agents. Krfilzomib (Kifrolis) is a new generation drug for third-line patients. It is especially effective for patients with a relapse of the disease.

It should be noted that multiple myeloma remains an incurable disease. Moreover, it is a disease with an inevitable recurrence, and each time the disease becomes more aggressive and more difficult to treat. However, the use of biological drugs not only makes it possible to replace chemotherapy, which has many side effects, but also significantly prolongs the life of patients. Especially in cases where patients have received other multiple myeloma treatments.

In 2015, a list of food and drug products was approved for use in the treatment of multiple myeloma.

Daratomomab is an immunotherapy drug that is a monoclonal antibody that is active against the CD-38 protein in the myeloma cell membrane. The drug triggers several mechanisms, including activating the immune system, as well as blocking the signals of cancer cells for their uncontrolled division. The drug kills cancer cells and a protein that targets the expression of myeloma cancer cells.

Clinical trials of these drugs are being conducted around the world, including in medical centers Israel. The results are being published in prestigious journals and, most recently, presented at medical conferences around the world, defining major research for the near future as having the greatest implications for the treatment of cancers, including multiple myeloma.

Hodgkin's lymphoma.

Today, Hodgkin's lymphoma has a high degree of curing due to a combination of chemotherapy and radiation. However, at least 10-30% of patients do not respond to chemotherapy or have a relapse of the disease after treatment.

New biological methods of treatment show better results, and therefore their use is gaining more and more popularity in leading clinics, including Israeli clinics.

Among them is Brntoksimb (Adtztris), a drug that is an antibody against the CD-30 protein found in the tumor cells of patients with Hodgkin's lymphoma. The drug showed its effectiveness in 75% of cases of patients in whom the disease returned after bone marrow transplantation. At the same time, the duration of remission increased by 2 times.

Currently, the drug is used in the treatment of patients whose disease has returned after bone marrow transplantation and in patients with relapse of the disease who are not candidates for bone marrow transplantation.

The PD-1 anti-inhibitor (Aofdibo / Nibolomab, Kitrodh / Fmbrolizomab) is another group of drugs that cause the activation of T cells in the body's immune system that are suppressed by cancer. The treatment produces a 78% positive response rate in patients with Hodgkin's lymphoma who have undergone a bone marrow transplant.

As you can see, medicine is on the verge of a revolution in the treatment of cancer. We have seen significant advances in the biological clearance of most blood and lymph cancers, greatly improving the chances of survival and recovery from these diseases. We think that in the near future we will announce significant improvements in drugs, their greater effectiveness and safety of treatment.