Background. Primary immune thrombocytopenia (ITP) is an orphan disease characterized by decreased platelet count in the peripheral blood which in some cases can cause bleeding of varying severity. Currently, the use of thrombopoietin receptor agonists (TPO-RAs) is recommended as the second line therapy for ITP as it allows to achieve high platelet response (PR), including complete, in 73 % of cases of chronic ITP and in 87 % of cases of newly diagnosed disease. The mechanism of action differs for different TPO-RAs. Given this fact, in cases of resistance or intolerance to therapy with one TPO-RA, attempts are made to switch to another. The effectiveness of this approach for overcoming ITP resistance varies from 50 to 93 % according to various publications. Aim. To assess the ability to achieve and maintain PR by switching from one TPO-RA to another in cases of resistance to the previous TPO-RA used in the second or subsequent lines of therapy. Materials and methods. The analysis included 59 patients who were resistant (in 2 cases intolerance was also noted) to TPO-RA therapy (received after standard therapy) who were prescribed TPO-RA treatment with a different mechanism of action: switch from romiplostim to eltrombopag (25 patients) or vice versa (34 patients). Both groups were comparable in terms of demographic characteristics and median platelet level at the time of TPO-RA switching. Results. PR was obtained in 76 % of cases, including complete response in 54 %, as a result of switching from one TPO-RA to another in 59 patients. Among 34 patients switched from eltrombopag to romiplostim, PR was achieved in 31 (91 %) patients, including complete response in 22 (65 %). Romiplostim was switched to eltrombopag in 25 patients, PR was achieved in 14 (56 %) with complete response in 10 (40 %). Conclusion. The study showed that PR can be achieved and maintained through switching from one TPO-RA to an alternative.

Эпидемиология хронических онкогематологических заболеваний в условиях интенсивного появления инновационной терапии требует тщательного наблюдения и изучения. Понимание эпидемиологических тенденций различных нозологий имеет первостепенное значение для развития фармакоэкономики и системы здравоохранения, определяет соответствие производственных и клинико-диагностических мощностей уровню потребности. Высокая стоимость таргетных препаратов и рост числа пациентов, нуждающихся в них, оказывают существенное влияние на увеличение социальных бюджетов. Формирование сбалансированной стратегии и тактики клиническо-терапевтического обеспечения должно быть обосновано реальной эпидемиологической практикой. В настоящей работе представлен обзор международных и отечественных данных, касающихся основных эпидемиологических параметров (заболеваемость, распространенность, смертность, общая выживаемость, гендерно-возрастные характеристики) ряда хронических гемобластозов, таких как множественная миелома, хронический лимфолейкоз, диффузная В-крупноклеточная лимфома, лимфома мантийной зоны, фолликулярная лимфома, лимфома Ходжкина, хронический миелоидный лейкоз, миелопролиферативные Ph-негативные новообразования. Продемонстрированы общемировая динамика и отличия показателей в разных популяциях. Литературные данные убедительно показывают тенденцию к постепенному росту заболеваемости и распространенности рассмотренных гемобластозов в последние десятилетия. Статья послужит важным информационным источником для специалистов системы здравоохранения. The epidemiology of chronic oncohematological diseases in the context of intensive emergence of innovative therapy requires careful monitoring and study. Understanding the epidemiological trends of various nosologies is of paramount importance for the development of pharmacoeconomics and the healthcare system and determines the compliance of production and clinical diagnostic capacities with the level of demand. The high cost of targeted drugs and the growing number of patients in need of them have a significant impact on the increase in social budgets. The formation of a balanced strategy and tactics of clinical and therapeutic support must be justified by real epidemiological practice. The paper presents an overview of international and national data concerning the main epidemiological parameters (incidence, prevalence, mortality, overall survival, gender and age characteristics) of chronic hematological malignancies: multiple myeloma, chronic lymphocytic leukemia, diffuse large B-cell lymphoma, mantle zone lymphoma, follicular lymphoma, Hodgkin lymphoma, chronic myeloid leukemia, myeloproliferative Ph-negative neoplasms. World dynamics and variety of parameters in different populations are demonstrated. Literary data convincingly show a trend towards a gradual increase in the incidence and prevalence of the considered hemoblastoses in recent decades.

Background. Currently, targeted therapy is the most promising for the treatment of myelofibrosis (MF). Today, the results of many years of experience with the use of ruxolitinib, including outside randomized trials and the identification of predictors of its effectiveness are important.Aim. To evaluate the results of long-term ruxolitinib therapy in patients with primary and secondary MF resistant to standard treatment and compare the effectiveness of MF targeted therapy in patient groups depending on age, gender, clinical, laboratory and morphological parameters.Materials and methods. The prospective study included 206 patients (95 (46 %) men and 111 (54 %) women aged 18–84 (mean 64) years) with MF in the chronic phase who received ruxolitinib: 154 (75 %) with primary MF, 39 (19 %) – with post-polycythemic, 13 (6 %) – with post-thrombocythemic. The median duration of chronic myeloproliferative disease from diagnosisto prescription of ruxolitinib was 75 (1–432) months. According to DIPSS (Dynamic International Prognostic Scoring System), 15 % of patients were classified as high risk, 35 % as intermediate-2, 33 % as intermediate-1, and 17 % as low-risk. 44 % of patients had MF3, 49 % – MF2, 7 % – MF1. 71 % of patients had JAK2 V617F mutation, 3 % – MPL, 19 % – CALR, and in 7 % triple negative status was detected.Results. The median duration of ruxolitinib therapy was 24 (1–116) months. Clinical and hematological response at 1 month: complete and partial response – 14 %, clinical improvement – 20 %, stabilization – 57 %; at 3 months – 21, 34, 36 %, at 1 year – 34, 21, 34 %, respectively. No response was obtained in 18 % of patients. The median allele burden of JAK2 V617F during observation decreased more than twice from the initial value in half of the patients. The median of progression-free survival (PFS) from the start of ruxolitinib therapy was 28 months, the median of overall survival (OS) has not been achieved. PFS at 1 year of treatment was 68 %, at 2 years – 56 %, at 3 years – 46 %, at 5 years – 32 %, OS – 87, 75, 68, and 54 %, respectively. Among many factors analyzed before starting ruxolitinib therapy, the following ones had statistically proofed significance for PFS: age, DIPSS risk level,therapy with hydroxycarbamide, interferon, white blood cell count, platelet count, hemoglobin level, and degree of fibrosis. For OS,the following factors were significantly important: age, risk level according to DIPSS,type of MF, interferon therapy, white blood cell count, platelet count, hemoglobin level, and degree of fibrosis.Conclusion. The long-term effectiveness of ruxolitinib therapy for primary and secondary MF has been demonstrated. Gender, age, clinical, laboratory, and morphological prognostic factors of ruxolitinib therapy efficiency in MF have been identified.

Background. Thrombopoietin receptor agonists (TORAs), which can imitate the biological effect of thrombopoietin, have shown high efficacy in a number of clinical studies and real clinical practice in patients with resistant primary immune thrombocytopenia (IT). It seems extremely relevant to evaluate the success of using various TORAs in a longterm nonrandomized study and their comparative effectiveness.Aim. To evaluate the longterm efficacy of TORAs (romiplostim and eltrombopag) in patients with primary IT who are resistant to standard therapy, and to determine the clinical and hematological factors predicting the efficacy of TORAs therapy.Materials and methods. The study included 456 patients with primary IT (127 (28 %) men and 329 (72 %) women) who were resistant to standard therapy. atients received TORAs therapy at the otkin Hospital. The median age at the start of TORAs therapy was 59 (9–91) years. Romiplostim was received by 339 patients (95 (28 %) men and 244 (72 %) women), eltrombopag – 117 (32 (27 %) men and 85 (73 %) women).Results. The median duration of TORAs therapy was 78 (1–583) weeks for romiplostim and 59 (1–572) weeks for eltrombopag. uring the TORAs therapy the platelet response was obtained in 89 % (n = 405) of cases in total group of IT patients, in the romiplostim group – in 90 % (n = 306), in the eltrombopag group – in 85 % (n = 99). y the time of data analysis in the total cohort of IT patients, 55 % (n = 253) of patients maintained a sustained platelet response, with a median duration of 159 (2–655) weeks. Among patients receiving romiplostim, these parameters were 59 % (n = 200) and 149 (2–655) weeks, for eltrombopag – 45 % (n = 53) and 240 (24–565) weeks, respectively. The 10‑year overall survival rate with TORAs therapy, regardless of the drug chosen, was 86 %. Negative predictors of achieving a platelet response to romiplostim therapy were identified: ≥2 lines of previous therapy (p = 0.03), a history of splenectomy (p = 0.02). No negative predictors of platelet response to eltrombopag therapy were identified.Conclusion. The longterm efficacy of 2 drugs of the same therapeutic class (TORAs), romiplostim and eltrombopag, in patients with resistant IT was demonstrated in a direct comparative analysis in a nonrandomized study. Clinical and hematological factors predicting the longterm effectiveness of romiplostim were identified.

Aim. To assess the stability of clinical remission in patients with primary immune thrombocytopenia (ITP) after withdrawal of thrombopoietin receptor agonists (TPO-RAs). Materials & Methods. The study enrolled 456 patients with primary ITP who received second- and subsequent-line TPO-RA treatment. Complete platelet response (PR) was achieved in 338 patients, the therapy was discontinued in 116 of them. The present prospective clinical study started in 2014 and focused on the data of these 116 patients. Among them, there were 27 (23 %) men and 89 (77 %) women. By the time of TPO-RA therapy onset, the median age of the patients was 60 years (range 13–87 years), on ITP diagnosis date it was 52 years (range 1–80 years). Results. By the time of data analysis, 59 % of patients sustained PR after TPO-RA withdrawal. The median PR duration after TPO-RA withdrawal was 230 weeks. Romiplostim and eltrombopag recipients showed no significant differences in the survival rates without PR-loss after TPO-RA withdrawal. In the present study, the maximum PR duration achieved 9.5 years. The mid-term assessment of PR status was carried out in 3, 6, 12, 24, and 30 months after TPO-RA withdrawal and showed 99 %, 94 %, 83 %, 72 %, and 70 %, respectively. The number of previous therapy lines significantly affected the survival rates without PR-loss (p = 0.011). The age of patients, prior splenectomy, TPO-RA treatment duration, time to different PR levels on therapy, PR duration on TPO-RA therapy, and platelet count upon TPO-RA withdrawal showed no significant effect on this parameter. After PR-loss, TPO-RAs were administered again to 31 (27 %) patients. Repeated PR was achieved in 26 (84 %) of them. Conclusion. TPO-RA administration yields multi-year off-treatment remission in some patients with primary ITP. Upon therapy discontinuation, 59 % of patients with complete PR sustained PR for 3 months to 9.5 years. Stable PR after TPO-RA withdrawal significantly correlated with only one of the studied prognostic parameters, i.e., the number of previous therapy lines.

Background. Mastocytosis is a heterogeneous group of diseases that are characterized by excessive proliferation and accumulation of clonal (neoplastic) mast cells in one or more organs. Advanced variants of systemic mastocytosis (aggressive systemic mastocytosis, systemic mastocytosis associated with hematological neoplasm, and mast cell leukemia) are characterized by infiltration of organs by mast cells, which leads to organs dysfunction. Such patients require a more active approach and the use of cytoreductive therapy. Available therapeutic options include imatinib, interferon-alpha, cladribine. Only one of the targeted drugs is registered in Russia – midostaurin. Midostaurin is a potent multikinase inhibitor that is active against KIT regardless of mutation status. Midostaurin has shown its effectiveness in clinical trials, however, we know that data from real clinical practice often differ from clinical studies due to the characteristics of patients (preserved comorbid status, stable disease parameters) traditionally included in clinical trials. Aim. To evaluate the effectiveness and safety of midostaurin in patients with advanced variants of systemic mastocytosis in real clinical practice. Materials and methods. This work analyzed 13 patients (7 (54 %) men and 6 (46 %) women) who received midostaurin therapy for systemic mastocytosis (aggressive systemic mastocytosis – 9 (69 %), systemic mastocytosis associated with a hematological neoplasm – 4 (31 %)). The median age of patients when the diagnosis was verified was 73 (61–87) years, the median age when midostaurin was prescribed was 74 (61–88) years. According to the International prognostic scoring system for mastocytosis (IPSM) based on clinical variables, patients are classified as follows groups: SM1 – 1 (8 %) patient, SM2 – 3 (23 %), SM3 – 8 (61 %), SM4 – 1 (8 %). Results. As a result of therapy, clinical improvement was achieved in 10 (77 %) patients, and stabilization in 3 (23 %) patients. During midostaurin therapy, grade I–II adverse events were noted from the gastrointestinal tract: nausea in 5 patients (38 %), vomiting in 2 (15 %), diarrhea in 6 (46 %). Hematological toxicity of grade I–II was also observed: anemia in 6 (46 %) patients, thrombocytopenia in 5 (38 %) patients. The median overall survival in the group was not achieved. The 2-year overall survival rate was 75 %. Conclusion. The study results suggest the potential efficacy and safety of midostaurin in patients with aggressive systemic mastocytosis and systemic mastocytosis associated with hematological malignancies.

Background. Targeted therapy is the most promising in the treatment of myelofibrosis, but it is necessary to search for the reasons limiting its effectiveness. There are known factors negatively affecting the development of myelofibrosis, but data on their negative impact in the context of targeted therapy are scarce.Aim. Assessing the impact of cytogenetic and genetic abnormalities on the course and therapy results for primary and secondary myelofibrosis during ruxolitinib therapy.Materials and methods. The prospective study included 106 patients with myelofibrosis in the chronic phase (53 (50 %) men and 53 (50 %) women) who received ruxolitinib at the Moscow City Hematology Center, S.P. Botkin City Clinical Hospital. The median age of patients was 62 (18–84) years. The median disease duration before initiation of ruxolitinib therapy was 79 (1–432) months. Before therapy, genetic studies were performed, including next-generation sequencing. The median duration of ruxolitinib therapy was 33 (1–111) months. The influence of the cytogenetic landscape, driver mutations, allele burden of JAK2 (over time) and CALR, additional mutations on the dynamics of symptoms, spleen size, achievement of hematological response, overall survival, progression-free survival, survival without blast crisis and without progression of myelofibrosis with targeted therapy was assessed.Results. The studied genetic factors did not have a significant correlation with hemogram parameters. The hematological response in patients with JAK2 and CALR mutations compared favorably with the response in the groups with the MPL mutation and triple negative status (TNS). Higher hematological response rate was obtained in the group with initially low allele burden <50 % of JAK2 or CALR. Significant differences in 5-year overall survival were found between groups of patients with TNS and JAK2 and CALR mutations (p <0.05); with CALR allele burden <50 % and ³50 % before initiation of ruxolitinib therapy (p = 0.01); the presence or absence of positive dynamics of the JAK2 allele burden during treatment (p <0.05); additional mutations assigned to different pathogenicity groups (p <0.05); with different number of pathogenic mutations (1 or ³2), the presence or absence of pathogenic mutations in the ASXL1 (p = 0.002) and SETBP1 (p = 0.00001) genes. The 5-year progression-free survival was significantly different in cohorts of patients with or without positive dynamics of the JAK2 allelic load during treatment (p <0.05); additional mutations assigned to different pathogenicity groups (p <0.05); with a different number of pathogenic mutations (1 or ³2), the presence or absence of a pathogenic mutation of the SETBP1 gene (p = 0.003). Progression-free survival did not correlate with the type of driver mutation or its absence; however, all patients with TNS died from myelofibrosis progression. Significant differences in 5-year blast crisis-free survival were observed between groups with JAK2 and MPL mutations (p = 0.001), JAK2 and TNS (p = 0.002); difference in 5-year survival without progression of fibrosis – between groups with pathogenic and benign (p = 0.031); uncertain and benign (p = 0.001) mutations.Conclusion. The study identified genetic markers associated with decreased efficacy of ruxolitinib therapy.

Background. For many years the primary aim of treatment strategy for ph-negative myeloproliferative neoplasms has been to restrain disease progression, with lasting relief and management of symptoms to improve patients’ quality of life. Generally, this did not lead to a significant increase in life expectancy with primary myelofibrosis and didn’t decrease the risk of fibrosis in patients with polycythemia vera and essential thrombocythemia. To date a new class of targeted drugs has been developed, it is JAK2 inhibitors with pathogenetic effects. The results of clinical trials showed the high efficacy of the first registered drug of this its kind – ruxolitinib – that includes a faster reduction in the symptoms of tumor intoxication and in symptoms associated with the development of splenomegaly and increase in the overall survival rates. It is known that the data obtained during clinical trials of medicines may differ from the results obtained in routine clinical practice. In actual practice drugs are used in a much wider heterogeneous population of patients, less limited first of all by age and comorbid characteristics. It is possible to analyze cohorts of patients including a larger number of clinical cases with a longer follow-up period. In this regard of great interest is the actual clinical experience of long-term use of ruxolitinib in patients whose set is limited only by clinical contraindications for prescribing the drug.Aim. To present our own actual experience of targeted therapy of myelofibrosis and compare the results obtained with the data of clinical trials.Materials and methods. Our analysis includes data from 141 patients (67 (47.5 %) men and 74 (52.5 %) women) in a chronic phase myelofibrosis. All patients received ruxolitinib. Of these, 109 (69 %) patients had primary myelofibrosis, 26 (16 %) – postpolycythemia myelofibrosis, 6 (4 %) – postessential thrombocythemia myelofibrosis. The median age at the start of therapy was 62 (18–84) years. The median disease duration before ruxolitinib was prescribed – 79 (1–401) months. According to the dIpSS (dynamic International prognostic Scoring System) criteria, 13 % of patients were assigned to the low risk group, 38 % – to the intermediate-1, 36 % – to the intermediate-2, 13 % – to the high risk group. Most patients (52 %) had grade 3 bone marrow fibrosis.Results. The median duration of treatment was 18 (range from 1 to 115) months. Symptoms of intoxication were relieved 74 (81 %) of 91 patients, the spleen size decreased in 81 % of patients (the spleen size returned to normal in 25 % of patients). The increase in the median hemoglobin level was 15 %. The proportion of patients requiring blood transfusion decreased by 4 times (from 39 to 9 %). Mean platelet levels normalized in most patients with baseline high and low platelet levels. A complete clinical and hematological response was achieved in 16 % (n = 23) of cases, a partial response – in 26 % (n = 37) of cases, clinical improvement – in 21 % (n = 30), disease stabilization – in 33 % (n = 46) of cases. No response was received in 1 (1 %) patient and in 3 (3 %) cases there was progression of the disease. At the time of analysis, 81 (57 %) of 141 patients were continuing the ruxolitinib treatment. The fatal outcome in 33 (22 %) patients was associated with concomitant diseases, among which 20 (14 %) died from proven COvId-19 infection. Overall survival: 1-year 81 %, 2-year 73 %, 5-year 50 %. Overall survival excluding deaths due to COvId-19: 1-year 92 %, 2-year 85 %, 5-year 70 %. Massive splenomegaly and a high degree of fibrosis were unfavorable predictors of prognosis of overall survival.Conclusion. Target therapy with Janus kinase inhibitor ruxolitinib has demonstrated high efficacy in patients with myelofibrosis in routine clinical practice. The most rapid effect ruxolitinib had on the spleen size and the symptoms of intoxication. Tolerability of ruxolitinib therapy was generally satisfactory. The overall and progression-free survival rates in patients with myelofibrosis, receiving ruxolitinib in the clinical setting was consistent with the results of international multicenter clinical trials.

The additional molecular and chromosomal abnormalities (ACA) in Phositive cells usually considered as a genetic marker of chronic myeloid leukemia (CML) progression. 457 patients in different CML phases received tyrosine kinase inhibitors (1st and 2nd generation) were studied. During therapy 50 cases with additional chromosomal abnormalities in Ph+ clone (22 of them in chronic CML phase) were revealed (median follow-up from CML diagnosis – 117 months, median imatinib therapy – 62 months). 86 % of patients in chronic phase with Ph+- cell abnormalities were cytogenetic resistance, and their 5-years overall survival was 80 % which was significantly lower than in patients without ACA (p < 0.005). The treatment results depend on chromosomal abnormalities detected. In patients with additional chromosome 8 imatinib therapy is effective, although complete cytogenetic response (CCR) is achieved only in the later therapy stages. In patients with additional translocations CCR also achieved with imatinib or 2nd generation TKI. Only a third of patients with additional Ph-chromosome or BCR/ABL amplification achieved complete suppression of Ph+ clone using 2nd generation TKI. The presence of additional chromosome 7 abnormalities and complex karyotype disorders involving isochromosome i(17)(q10) are poor prognostic factors of TKI treatment failures.

AIM:To assess the main epidemiological characteristics of chronic myeloid leukemia (CML) in the Russian Federation.SUBJECTS AND METHODS:A planned epidemiological prospective study was conducted in 2009-2012 in 6 Russian regions with the total number of 10.1 million inhabitants, which notified all new CML cases.RESULTS:The unstandardized (unnormalized, baseline) recorded incidence of CML in the examined regions was 0.58 per 100,000 annually. Its standardized (normalized) incidence was 0.70 for the WHO standard population and 0.72 for the European standard population. The regional variations in the incidence were 0.44 to 0.69. The structural analysis of the incidence in the age strata indicated that the overall morbidity was less due to the decreased rate of registration in old age groups. The morbidity rates in patients aged less than 60 years were nearly similar to the European rates; those in patients aged over 70 years were almost 10 times lower. The lower rate of detection and screening diagnosis of CML in pensioners in primary health care is discussed.CONCLUSION:The data obtained in this study may serve as the starting point for monitoring the CML epidemiological situation.

This article reviews the role of both exogenous factors (such as antineoplastic therapy) and genetic predisposition in the development of secondary acute myeloblastic leukemia in patients with tumors after antineoplastic therapy of the primary tumor. Data on genetic polymorphisms of enzymes of DNA repair and xenobiotic detoxification/biotransformation systems, and their potential association with secondary AML is reported. The combined influence of polymorphic proteins of repair and detoxification/biotransformation systems in modulating the individual's risk of secondary AML and the complexity of genetic context interpretation is discussed.

The results of the analysis of multiaberrant cells (MAC) obtained in the course of long-term investigation of cytogenetic effects in human peripheral blood lymphocytes are presented. MAC were discovered in different groups of the population exposed to the radiation factor. No such cells were found in the control groups. The greatest number of MAC "carriers" was registered among employees of radiochemical plants who had contacts with plutonium salts. The highest frequency of MAC (2.49 +/- 0.59 per 1000 cells) was also revealed in the same group. It exceeded by an order of magnitude the analogous values in other examined groups. In the groups of radiochemical workers, cosmonauts, and miners from Tselinograd the frequency of dicentrics and centric rings was also the highest as compared to that in other groups. The character of chromosome aberrations observed in MAC suggests that they are formed under the action of the radiation factor, and their frequency among different groups of people exposed to radiation makes it possible to assume that the formation of MAC is a result of the action on lymphocytes of alpha-particles emitted by radionuclides incorporated in the organism. Classical MAC was observed in routine studies (FPG staining) are only an extreme manifestation of cell damage. To elucidate the true picture of chromosome rearrangements induced by radiation and the role of MAC in the tumor process, it is necessary to use methodical potentialities of modern molecular cytogenetics, including the FISH method.

AIM:To determine the type of chimerism in patients with chronic myeloid leukemia (CML) in various periods after allogenic transplantation of bone marrow (TBM) and its association with subsequent relapse.MATERIALS AND METHODS:Ten patients were examined after allogenic TBM, which was performed during the chronic phase of CML in 9 patients and during acceleration phase in 1. Two patients received therapy with donor lymphocytes during relapse after transplantation. Time course of chimerism and minimum residual illness was studied by standard cytogenetic methods, fluorescent in situ hybridization (FISH) with DNA probes to centromer sites of X and Y chromosomes and BCR and ABL genes. The studies were carried out 30, 60, 90, 180 days, 9 months, 1 year, and then every 6 months after transplantation.RESULTS:Mixed chimerism was observed in all patients during 9 months after TBM. The count of host cells was 0.1-5.8% in 8 patients; later the count of autologous cells was less than 1% in 5 patients, and in 3 patients complete donor chimerism was observed. Clinical hematological remission was stable in these patients. Relapses of leukemia with 40 and 83.1% host cells occurred in 2 patients 13 and 23 months after transplantation, respectively. Donor lymphocytes were transfused in order to induce the graft versus host effect, and in patient No. 2 restoration of donor hemopoiesis was attained.CONCLUSION:Highly sensitive FISH method with DNA probe to centromer sites of X and Y chromosomes detects early relapse of the disease and demonstrates the time course of donor hemopoiesis recovery after transfusion of donor lymphocytes. The data indicate that 9 months after transplantation molecular cytogenetic studies should be carried out more often (once a month), particularly in patients with poor prognosis, for earlier detection of the relapse and beginning of immunotherapy.