Department of Hematology and Chemotherapy of Lymphoproliferative Diseases

Head of the department — hematologist- Sergey K. Kravchenko, Associate Professor, Candidate of Medical Sciences

The department was established by Academician of the Russian Academy of Sciences and the Russian Academy of Medical Sciences Andrey I. Vorobyov on 26 February 1990. The original name was the Department of Hematology and Intensive Care with a functional biochemical group, later — the Department of Intensive High-dose Therapy of Hemoblastoses with Round-the-clock and Day Hospital.

The department was headed by Honored Doctor of Russia, Alexandra M. Kremenetskaya and Doctor of Medical Sciences, Professor Alexander V. Pivnik (Head of the Clinical Department and Scientific Supervisor), who previously worked at the Central Clinical Hospital No. 2 in the Department of Hematology and Intensive Care of the Russian Medical Academy of Continuous Professional Education (Head of the Department - Academician Andrey I. Vorobyov). In 1987, with the appointment of Vorobyov to the post of director of the State Scientific Center of the Russian Academy of Medical Sciences, the Institute became the second base of the Department of Hematology and Intensive Care, and the department became a structural unit in which the ideas of the department's staff and the staff of the newly created department were cultivated and brought into fruition.

Andrey Vorobyov supervised the scientific and clinical work of the department, directly participating in the planning and strategy of the scientific research. Clinical reviews by the Academician were a daily practice of the department. Scientific seminars initiated by Vorobyov were carried out following the example of the famous seminars of I.M. Gelfand, in which Vorobyov was a participant. These seminars cultivated openness, a creative atmosphere and a drive for discovery.

The department continued the development of scientific directions that were instituted at the Department of Hematology and Intensive Care on the pathology of red blood and the diagnosis and treatment of tumors of the lymphatic system. Together with the laboratories of Karyology, headed by Elena V. Domracheva, and Hemocytology, headed by Gennady I. Kozinets, the department studied changes in the blood, chromosomal abnormalities, and biological dosimetry by taking into account unstable chromosomal aberrations in peripheral blood lymphocytes (the dissertation of Tatyana N. Moiseeva: “Clinical and hematological indicators in liquidators and residents of the Chernobyl region, taking into account the received dose of ionizing radiation”, 1994, heads - A. I. Vorobyov, G. I. Kozinets).

In real practice, the department became a center for consultative and therapeutic care for patients with acute porphyria, hemolytic anemia, and partial red cell aplasia of the bone marrow. Research on the pathology of red blood, previously conducted at the department by Lev I. Idelson -  “head of the hematological school of red blood pathology, which has no equal" (quote by A. I. Vorobyov) -Alexander V. Pivnik continued (doctoral dissertation “Autoimmune depressions of the red germ of hematopoiesis: clinic, diagnosis, treatment”, consultant A.I. Vorobyov, 1997, in which, according to Pivnik, the results of work with outstanding scientists V.S. Ter-Grigorov, employees of the laboratory of G.I. Abeleva, E.S. Ievleva on the discovery of the interspecific antigen of mammalian erythroblasts). Subsequently, the scientific direction in the diagnosis and treatment of acute porphyrias was headed by Yaroslav S. Pustovoit, who, together with a team of co-authors, created the country's first Russian register of drugs used in patients with porphyrin metabolism disorders.

Since the mid-1990s, the diagnosis and therapy of tumors of the lymphatic system has become the main scientific duty of the department. The development and improvement of the immunophenotyping techniques has made it possible to expand the possibilities of diagnosis and classification of lymphomas. At the same time, understanding the applied value of immunophenotyping, the staff of the department under the leadership of A.I. Vorobyov, A.M. Kremenetskaya and A.V. Pivnik developed the concept of the "image of the disease," postulating that the criteria for diagnosis are a set of signs, and in addition to laboratory parameters (immunophenotype, genetic abnormalities), it is important to take into account the features of the clinical picture and the response of the tumor to specific therapy (Andrey I. Vorobyov, Elena I.Yakhnina (Gitelzon), Rimma S. Samoilova. "Principles of differential diagnosis of mature cell lymphatic tumors" ("Therapeutic Archive", No. 7, 1995)).

The concept of forming the image of the disease in the conceptualization of the diagnosis was further developed in the Candidate of Medical Sciences thesis of Igor A. Ascaturov "Immunophenotyping in the diagnosis of chronic lymphoproliferative diseases" (1997, scientific supervisors — A. I. Vorobyev, R. S. Samoylova), the first conclusion of which states that none of the immunological markers are "unique" for the nosological form, and when making a diagnosis, it is necessary to take into account the combination of all immunological markers characteristic to the disease in combination with morphology and clinical picture.

The department treated both patients with common lymphoproliferative diseases and rare forms of lymphomas, and each clinical case was subjected to in-depth analysis in order to most accurately verify the diagnosis and identify new forms of pathology. One of the first dissertation works that reflected the general ability of the department to find the unusual, in the seemingly ordinary, was the study of Lyubov S. Al-Radi "Hairy cell leukemia: features of the course, modern tactics of therapy" (head A.V. Pivnik, work started in 1995).

Despite the problems caused by external factors that the State Scientific Center of the Russian Academy of Medical Sciences experienced in the early 90s, the enormous scientific authority of A.I. Vorobyov as well as the brightness, erudition and enthusiasm of his closest associates, A.M. Kremenetskaya, A.V. Pivnik, N.E. Shklovsky-Kordy, the department expanded and formed and maintained active scientific contacts with foreign colleagues. In particular a close scientific relationship was formed with Volker Diehl, one of the leading hematologists in Germany, awarded the John Georg Zimmermann Prize for merit in the field of hematology, who provided invaluable assistance to the State Research Center of the Russian Academy of Medical Sciences by organizing the delivery from Germany as a charitable gift of a large number of medicines, medical supplies and food.

Nikita E. Shklovsky, being Andrey Vorobyov’s personal secretary, with the support of the department staff, created a video and audio archive of lectures and speeches by Academician A. I. Vorobyov, as well as a website where everyone can get acquainted with the archive materials.

In the early 2000s, largely due to the principled position of Alexandra M. Kremenetskaya, who consistently defended the course of searching for new methods of therapy for aggressive lymphomas, the team of the department developed protocols for high-dose therapy for Burkitt's lymphoma that have no analogues in the world (dissertation by Baryakh E. A., supervisors - S. K. Kravchenko, T. N. Obukhova, the study was supported by the Grant of the President of the Russian Federation), diffuse B-cell large cell lymphoma (dissertation of Magomedova A. U., scientific consultant -Academician A. I. Vorobyov). The protocols of high-dose chemotherapy with m-NHL-BFM-90 blocks, created by the staff of the department, proved their effectiveness in the treatment of DLBCL (A. U. Magomedova), DLBCL of the stomach (E. E. Zvonkov), primary bone DLBCL(dissertation by A. K. Smolyaninova , leader - E. E. Zvonkov).

The program of high-dose therapy for Burkitt's lymphoma, LB-M-04, developed and tested by Elena A. Baryakh along with the staff of the department, is based on the intensification of treatment and reduction of its duration. In the course of the work, it was found that in most patients, remission is achieved after two courses of chemotherapy. It was decided to use a total of four blocks: A-C-A-C (Diagnostics and Treatment of Burkitt's Lymphoma, 2007), while maintaining a high efficiency of treatment (95% 3-year disease-free survival was achieved). Thus, the dissertation was the first work that substantiated the possibility of reducing the total number of chemotherapy courses, contrary to the dogma that existed in oncohematology about the need for at least six chemotherapy courses to achieve complete remission, and it was shown that the duration of treatment should be determined by the speed of achieving complete remission.

The dissertation work of A.U. Magomedova, defended in 2008, still retains its scientific and clinical relevance, and the conclusions drawn serve as an ideological source for planning and conducting modern scientific research. Thus, within the framework of the dissertation work, the NHL-BFM-90 program was first applied and modified for the treatment of adult patients with DLBCL, a significant advantage in its effectiveness over the "foreign standard" therapy (CHOP-21) was proven. For the first time it was proven that "sarcoma" damage to the bone marrow in DLBCL is an independent sign of a poor prognosis, and also "it was noted that lymphosarcoma with the presence of focal mature cell lesions of the bone marrow and translocation t (14; 18) (q31; q21) is a separate form of the tumor and can be regarded as sarcoma transformation of follicular lymphoma."

Aminat U. Magomedova directly oversees the clinical direction of high-dose DLBCL therapy and is the leading specialist in this field in Russia. On the initiative and under the direct supervision of the leading researcher of the department, A.U. Magomedova is conducting the first multicenter randomized study in Russia to compare the effectiveness of therapy in DLBCL patients with signs of an unfavorable prognosis, the preliminary results of which confirm both the high effectiveness of the R-m-NHL-BFM-90 program and its advantage over R-Da-EPOCH courses (the frequency of achieving complete remissions on R-mNHL-BFM therapy-90 — 100%, on R-DA-EPOCH therapy — 71.4% (p=0.0094)), as well as the pharmaco-economic advantage (the cost of a unit of efficiency is lower and also the cost of achieving one case of complete remission, dissertation by Madina Olegovna Bagova, supervisor A. U. Magomedov).

One of the pioneering works that determined the tactics of treating the splenic form of lymphoma from cells of the marginal zone for years was the dissertation of Hunan L. Julhakyan (“Lymphocytoma of the spleen (lymphoma from the cells of the marginal zone of the spleen): diagnosis, treatment”, 2011, supervisor A.I. Vorobyov), who proved the advantage of using splenectomy as a first-line therapy for splenic lymphocytoma. Three-year progression-free survival in the group of patients with splenectomy in the first line was 85%, against chemotherapy in the first line - 0%.

The innovative concept of patient-specific immunochemotherapy, which assumed a decrease in the intensity of the chemotherapeutic load in the case of high drug toxicity, was first reflected in the dissertation work of Vladimir I. Vorobyov “High-dose program risk-adapted therapy for mantle cell lymphoma” ( supervisor — S.K. Kravchenko, E. V. Domracheva).

Later, the concept of patient-specific therapy found a new interpretation in terms of adjusting the volume of chemotherapy depending on the sensitivity of the tumor to the treatment (effectiveness of therapy), which was reflected in a pilot clinical study on the treatment of follicular lymphoma ( author - S. K. Kravchenko, protocol curator- E. S. Nesterova).

Unlike aggressive lymphomas, indolent lymphoproliferative diseases such as follicular lymphoma, are characterized by a relapsing course, and the use of high-dose chemotherapy regimens does not lead to an increase in overall survival. Differences in the chemosensitivity of DLBCL and follicular lymphoma indirectly confirm the presence of significant differences in the pathogenesis of diseases, the identification of which may contribute to the development of new approaches to therapy. In this regard, in 2010-2011 a series of studies on the pathogenesis of follicular lymphoma was initiated in the department, the promising goal of which was to search for new methods of treatment (E.S. Nesterova, "Morphoimmunohistochemical characteristics of the tumor substrate in patients with follicular lymphoma", 2013; L. V. Plastinina, heads - S.K. Kravchenko, A.M. Kovrigina).

The heterogeneity of large-cell lymphomas of mediastinal localization was characterized in the dissertation work of Y. K. Mangasarova, which showed the expediency of using JAK2, PDL1, PDL2, MAL, TRAF1 gene expression indicators as differential diagnostic criteria for DLBCL with a primary lesion of mediastinal lymph nodes and primary mediastinal lymphoma. The effectiveness of high-dose polychemotherapy according to the m-NHL-BFM-90 program was also determined in DLBCL patients with primary lesion of mediastinal lymph nodes and PMBCL ("Molecular diagnostics of DLBCL with primary involvement of mediastinal lymph nodes and primary mediastinal B—large cell lymphoma", 2012, heads - A. U. Magomedova, A.V. Misyurin).

Together with Andrey Misyurin, Head of the Laboratory of Genetic Engineering, the diagnostics of minimal residual and disseminated disease in patients with anaplastic large cell ALK-positive lymphoma was developed and introduced into clinical practice (dissertation by L.G. Gorenkova, supervisors — S. K. Kravchenko, A. V. Misyurin).

The department owes much to the development of the diagnostics of T-cell lymphoproliferative diseases, primarily T-cell cutaneous lymphomas, to the initiative and teachings of Yulia E. Vinogradova, who initiated a study to evaluate the effectiveness of prolonged treatment of angioimmunoblastic lymphoma according to the protocol of therapy for acute lymphoblastic leukemia (therapy is based on the principle of prolonged exposure to the tumor, not short—pulse exposure).

This initiative was continued and developed by Natalia G. Chernova. Chernova’s Candidate of Medical Sciences thesis is devoted to the study of Hodgkin's lymphoma ("Lymphogranulomatosis: clinical and morphological comparisons and the effectiveness of first-line therapy", supervisor — A. I. Vorobyev). Continuing the development of the idea of the formation of the "image of the disease" as a tool for identifying new forms, the concept of "Hodgkin's sarcoma" was introduced in the dissertation and atypical forms of Berezovsky—Sternberg cells were described as one of the factors of an unfavorable prognosis.

Before the advent of positron emission tomography, the assessment of the completeness of remission of Hodgkin's lymphoma was a difficult task, since often, despite chemotherapy and radiation therapy, mediastinal residual tumor formation persists. Morphologically, Hodgkin's lymphoma, in most cases, is represented by a small number of tumor cells, compared with a significantly predominant reactive cellular component. The residual tumor-like formation consists mainly of fibroblasts, reactive T cells and macrophages. Oleg V. Margolin in his dissertation, "Radiation diagnostics of residual mediastinal formations in patients with lymphogranulomatosis" proposed a progressive algorithm for examining patients with residual conglomerates of lymph nodes to detect the presence of tumors in them, without resorting to biopsy, associated with a high risk of life-threatening complications, using complementary instrumental techniques: ultrasound, computed tomography with contrast enhancement according to a modified method, by radioisotope research with 67Ga-citrate (2000, heads — A.V. Pivnik, L. N. Gotman).

The study of the effectiveness of various skin lymphoma treatment programs was continued by Ekaterina A. Penskaya (Ilyushkina) and Lilia G. Gorenkova.

Currently, the department conducts a wide range of clinical studies on the treatment of nodal T-cell lymphomas (L.G. Gorenkova):

• a randomized prospective study comparing the efficacy of high-dose chemotherapy and CHOEP courses in the treatment of ALCL in ALK-positive lymphoma;
• a prospective study evaluating the effectiveness of high-dose treatment programs for ALCL in ALK-negative lymphoma;
• alternative treatment regimens for peripheral T-cell lymphoma (including transplantation of autologous hematopoietic stem cells), angioimmunoblastic T-cell lymphoma, extranodal NK/T-cell lymphoma.

L.G. Gorenkova also oversees the direction of cutaneous lymphomas, being a leading expert in this field of orphan pathologies, the author of the T-cell lymphomas section of the Russian Clinical Guidelines 2016, 2018, 2021. Since 2019 she has been a member of the International Society of Cutaneous Lymphomas (ISCL) .

The department conducts several scientific works in the field of modern diagnostics of cutaneous lymphomas, the development of the latest, relevant and effective algorithms for the treatment of late stages of mycosis fungoides, primary cutaneous CD30-positive lymphoproliferative diseases, and B-cell lymphomas of the skin.

The department initiated the first multicenter study in Russia to evaluate the effectiveness of follicular lymphoma therapy according to the R-B protocol (S.K. Kravchenko, E.S. Nesterova).

The department tested highly effective protocols for the treatment of primary mediastinal lymphoma ( curator — Yana K. Mangasarova) and developed tactics for managing pregnant women with lymphoproliferative diseases, designed to save the life of the mother and fetus (curator — Y.K. Mangasarova).

Currently, one of the most difficult directions in the development of tactics for the treatment of high-grade B-cell lymphomas is supervised by Anna E. Misyurina, who developed the concept of the pathogenetic commonality of doublehit lymphomas with rearrangements of the c-Myc/BCL2 and c-Myc/BCL6 genes with follicular lymphoma and lymphoma from marginal zone cells, respectively (report and abstracts at the EAFO conference, January 2022). 

Main scientific directions:

• study of pathogenesis
• improvement of diagnostics
• creation of new and improvement of existing methods for the treatment of tumors of the lymphatic system: Burkitt's lymphoma, diffuse large B-cell lymphoma, high-grade lymphoma, follicular lymphoma, mantle cell lymphoma, primary mediastinal and gray zone lymphoma, Hodgkin's lymphoma, marginal zone lymphoma, T-cell lymphomas

A.M. Kremenetskaya and A.I. Vorobyov gave the first and only description of cytological features of peripheral blood lymphocytes in indolent lymphomas in the world.

The team of the department prepared and published the first in Russia atlas "Tumors of the lymphatic system", the uniqueness of which lies in the comparison of the morphological features of lymphomas with the cytological characteristics of tumor cells. The software processing of digital photographs of the morphological and cytological picture of lymphomas was carried out to a large extent thanks to Elena A. Gilyazitdinova.

With the direct participation of the staff, chapters on lymphoma therapy were created in the publication of the "Guidelines on Hematology" edited by A.I. Vorobyov, the collection "Diagnostic algorithms and treatment protocols for diseases of the blood system" edited by V.G. Savchenko, in the Russian Clinical Guidelines edited by I.V. Poddubnaya, V.G. Savchenko.

The staff of the department initiated a number of fundamental scientific works carried out thanks to the close collaboration of the laboratories and the clinical department.

Scientific work on the development of alternative methods for the treatment of resistant and refractory forms of lymphoproliferative diseases was reflected in the dissertation work of Fatima E. Babaeva "Clinical and laboratory characteristics of B-cell lymphoproliferative diseases in relation to sensitivity to oncolytic viruses" (scientific supervisors - Doctor of Biological Sciences, Professor, Corresponding Member of the Russian Academy of Sciences P.M. Chumakov,Candidate of Medical Sciences, Associate Professor S.K. Kravchenko). The study was carried out on live cultures of tumor cells obtained from patients with various types of lymphomas who underwent therapy in the department. The dissertation work has no analogues in the world.

In the work of E.A. Fastova, led by A.U. Magomedova and N.A. Petinati, "Study of the stromal microenvironment of the bone marrow in patients with diffuse B-cell large-cell lymphoma without bone marrow damage at the onset of the disease and after chemotherapy", the presence of humoral influence of tumor cells on stromal precursor cells of the bone marrow was proven for the first time in the world (the work was carried out in Laboratory of Physiology of Hematopoiesis, head — Doctor of Biological Sciences N. I. Drize).

An example of an unusually deep knowledge of the problem, the brightness of the presentation of the material and the abundance of the author's innovative proposals for improving diagnostic techniques (algorithms for laboratory diagnostics of violations of microsatellite loci significant in B-cell lymphomas of chromosomal regions, namely the region of the long arm of chromosome 6 were developed; microsatellites of the SESN1 gene, whose role was proven in the pathogenesis of FL, are described and studied) is the dissertation work of Ksenia A. Sychevskaya "Clinical significance of molecular markers of instability of the genome of tumor cells in patients with B-cell lymphomas", in which, in addition to applied goals aimed at identifying additional molecular criteria for the expected effectiveness of new therapies based on the analysis of the occurrence of MSI variants, in particular EMAST, and LOH on a large cohort of patients with FL of various morphological types, DLBCL, HGBL, the fundamental issues of tumor progression were studied and it was established that in the relapse/progression of the disease, it is possible both to acquire additional events of the MSI type, in particular EMAST, and/or LOH, and a complete change in the microsatellite profile, which indicates the possibility of different variants of the development of primary and secondary tumor clones from an earlier progenitor cell, and the dynamics of mutations of the IGH genes are observed independently of the pathogenesis of MSI and LOH. This dissertation research has no analogues in the world.

In 2022 , as a result of restructuring , two independent structures were created on the basis of the department:

The department provides training for residents, postgraduates, doctors of primary specialization and advanced training.

The staff of the department gives lectures, conducts practical classes, and compiles training materials for advanced training for hematologists of the country.

The doctors of the department are included in the Problem Commission, the Academic Council, the Dissertation Council, and the Ethics Committee.

Many of the residents and postgraduates who have worked in the department habe become department heads, professors, scientific secretaries, and representatives of Russian medicine in other countries.

PATENTS OF INVENTION:

1.      "Method of differentiated treatment of diffuse B-large-cell lymphosarcomas of lymphoid organs of adults", A. U. Magomedova with co-authors, 2011;

2.      "Method for identifying patients with first-time attacks of acute porphyria", Y.. S. Pustovoit with co-authors, 2016;

3.      "Method for culturing cells of malignant lymphoid organs", F. E. Babaeva and co-authors, 2019,

4.      "Test system and method for detecting deletions of the long arm of chromosome 6", K.A. Sychevskaya and co-authors;

5.      "Test system and method for detecting SESN1 gene deletions", K.A. Sychevskaya and co-authors.

Photo 2017: Sitting (from left to right): Marina N. Shipilova (nurse), Nina A. Chabaeva (housekeeper), S. K. Maslennikova (nurse), Sergey K. Kravchenko (Head of the department, Candidate of Medical Sciences, Associate Professor), Andrei I. Vorobyov (Academician of the Russian Academy of Sciences), Aminat U. Magomedova (Doctor of Medical Sciences, Leading Researcher), Nikita E. Shklovsky-Kordi (Candidate of Biological Sciences, Leading Researcher), Oleg V. Margolin (Candidate of Medical Sciences., doctor), Yana K. Mangasarova (Candidate of Medical Sciences). Standing (from left to right): Yury Y. Polyakov (resident), Olga P. Meshcheryakova (nurse), Tatyana A. Bushmeleva (nurse), Tatyana A. Morkovina (nurse), Lyubov V. Plastinina (Candidate of Medical Sciences, doctor), Svetlana S. Sushchevskaya (nurse), Ekaterina S. Nesterova (Candidate of Medical Sciences, doctor, researcher), Valentina A. Gorshkova (senior nurse), Evgeniya V. Zakharova (medical registrar), Alexandra M. Kremenetskaya (Honored Doctor of Russia, Deputy Head of the department), Lilia G. Gorenkova (Candidate of Medical Sciences, doctor), Ekaterina A. Penskaya (doctor), Fatima E. Babaeva (Candidate of Medical Sciences, doctor), Yana Dvornikova (resident), Elena I. Dorokhina (Candidate of Medical Sciences, doctor), Alice I. Zhilenko (resident), Yaroslav S. Pustovoit (Candidate of Medical Sciences, researcher, doctor), Muhammad M. Zakaryaev (resident), Vitaly N. Yakimets (resident).

Andrei I. Vorobyov , Nikita E. Shklovsky-Kordi

Sergey K. Kravchenko, Alexandra M. Kremenetskaya

Ekaterina A. Fastova, Aminat U. Magomedova, Madina O. Bagova