Aplastic anemia (AA) is a non-neoplastic hematological disease closely associated with bone marrow failure which is typical of paroxysmal nocturnal hemoglobinuria (PNH) and myelodysplastic syndrome (MDS). The PNH clones can be detected in more than a half of AA patients at onset of the disease, and there is a probability for AA/PNH co-variants to progress to classic hemolytic PNH. At the same time, the AA patients treated by immunosuppressive therapy undergo the risk of disease transformation to MDS and acute myeloid leukemia. Currently known risk factors and possible precursors of such transformation are considered in the brief literature review. In addition to that, the paper provides a case report of AA/PNH transformation to MDS during complete AA remission after immunosuppressive therapy combined with a successful haploidentical transplantation of hematopoietic stem cells.

In this article mechanisms of anaemia development in patients with lymphatic tissue malignant diseases are presented. Therapy efficacy of erythropoiesis-stimulating agents (EPO) in patients with lymphoproliferative disorders and anaemia (n = 21) is studied. Study group included patients with a chronic lymphoid leukemia (n = 5), indolent lymphomas (n = 7) and multiple myeloma (n = 9). Patients were 49–80 years of age (63.6 ± 8.2 years). The positive response to EPO therapy was considered if hemoglobin level increased on 20 g/l or its rising to 120 g/l. With given therapy hemoglobin level was increased from 86.8 ± 18.5 g/l to 111.4 ± 26.5 g/l (p < 0.001). EPO therapy efficacy was 61.9 % for total group of patients. Importance of TNF-alpha detection as the prognosis factor of EPO therapy efficacy was studied. Patients with low level of TNF-alpha (less than 15 pg/ml) achieved the positive response in 92.9 %, with a high level of TNF-alpha (more than 15 pg/ml) – the positive response was not observed. Inversely proportional correlation between initial TNF-alpha level and therapy response has been established (r = -0.487; p < 0.03; n = 21). Thus, detection of TNF-alpha level in patients with lymphoproliferative disorders before EPO therapy allows to predict therapy response with high degree of significance.

Апластическая анемия (АА) — неопухолевое заболевание системы крови, имеющее тесную связь с заболеваниями, характеризующимися костномозговой недостаточностью, такими как пароксизмальная ночная гемоглобинурия (ПНГ) и миелодиспластический синдром (МДС). Клоны ПНГ могут быть выявлены более чем у половины больных АА в дебюте заболевания, и существует вероятность перехода сочетанных вариантов АА/ПНГ в классическую гемолитическую ПНГ. В то же время у пациентов с АА, получавших курсы иммуносупрессивной терапии, имеется риск трансформации болезни в МДС и острый миелоидный лейкоз. Известные к настоящему времени факторы риска и возможные предвестники такой трансформации рассматриваются в кратком обзоре литературы. Кроме того, представлено клиническое наблюдение трансформации АА/ПНГ в МДС на фоне полной ремиссии АА после проведения комбинированной иммуносупрессивной терапии с успешной гаплоидентичной трансплантацией гемопоэтических стволовых клеток.

Aim. To study the features of the pathogenesis of anemia in patients with colorectal cancer and metastatic liver damage, as well as to evaluate the effectiveness of etiological correction of anemia in the preoperative period. Methods. 90 patients with colorectal liver metastases and anemia (hemoglobin content 7595 g/L), who were observed at the City Clinical Oncological Center of St. Petersburg between 2014 and 2020, were included. The patients were divided into two groups. The first group consisted of prospectively assessed patients with the preoperative correction of anemia by iron supplements (intravenously 7 mg/kg once a week) and recombinant erythropoietin (subcutaneously 150 IU/kg 3 times a week). The second group included retrospectively assessed patients with the correction of anemia only by red blood cell (RBC) transfusion (13 doses). The groups were comparable for gender [sex ratio (male/female) was 17:31 and 16:26 for the first and the second groups, respectively; p 0.5], age (63.31.4 and 60.21.2 years, respectively; p 0.1) and hemoglobin content (87.41.0 and 86.70.9 g/l, respectively; p 0.2). Results. In studying the causes of anemia, a decrease in the mean serum endogenous erythropoietin level was revealed in most patients (36.71.9 mIU/ml with the required 70 mIU/ml). A decrease in the concentration of serum iron (6.60.3 versus 15.10.8 mol/l) and ferritin (15.51.9 versus 102.48.4 g/ml) levels were revealed. At the same time, there was no difference in the concentration of pro-inflammatory cytokines in patients with anemia and healthy controls (tumor necrosis factor , interleukin-1, interleukin-6; p 0.2), which indicates a low activity of the immune system in response to a tumor, due to conducted chemotherapy. In the preoperative correction of anemia, a positive effect was achieved with both iron supplementation with erythropoietin preparation (the hemoglobin level increased from 87.61.0 to 108.10.9 g/l; p 0.01) and RBC transfusion (from 86.70.9 to 114.60.6 g/l; p 0.01). Conclusion. In patients with colorectal liver metastases, the most common causes of anemia were low levels of erythropoietin and iron deficiency; also for this group of patients, the prescription of erythropoietin and intravenous iron preparations are effective for the preoperative correction of anemia.

Cytokines are an integral part of normal hematopoiesis and affect virtually all of its stages, causing and regulating the processes of cell proliferation, differentiation and apoptosis. According to recent studies, it has been shown that cytokines also mediate complex interactions between hematopoietic, immune systems and a growing tumor. On the one hand, cytokines take part in the activation of antitumor immunity aimed at eliminating malignant cells; on the other hand, they are synthesized by tumor cells and participate in the progression and metastasis of tumors. The article summarizes the data of modern literature on the characteristics of changes in the cytokine profile in patients with acute myeloid leukemia (AML). The role of cytokines in leukemogenesis is shown: in activation of signal transmission pathways, interaction with bone marrow microenvironment, implementation of antitumor immunity and maintenance of persistence of clonal blast cells. The connection of cytokines with the results of treatment and the prognosis of the disease, taking into account the presence in the patient’s genotype of various allelic variants of cytokine genes encoding high or low production of these factors, is highlighted. The data presented in the review on the participation of cytokines in the formation, development and elimination of tumor cells in hemoblastoses are sometimes contradictory. However, these contradictions may be explained by the concept of tumor immunoediting, according to which the cells of the immune system can be transformed by a tumor in the process of carcinogenesis and start actively promoting its growth.

Background & Aims. Paroxysmal nocturnal hemoglobinuria (PNH) is a disease caused by an acquired clonal disorder of hematopoietic stem cells with clone cell membrane hypersensitivity to the complement. PNH can exist as an independent disease and can also be associated with other pathological conditions characterized by bone marrow deficiency, first of all with aplastic anemia (AA). In PNH-associated AA (AA/PNH) pathological clones may be initially of different size. In some patients a gradual growth of PNH clone is observed together with occurring signs of intravascular hemolysis and transformation into classical hemolytic PNH. In this case it is important to assess the clinical situation and determine eligibility for complement inhibitor therapy. During targeted therapy it is necessary to assess the efficacy of treatment based on monitoring of complement-mediated hemolysis and to identify probable reasons for insufficient effect. Materials & Methods. The paper deals with 1 clinical case. A female patient born in 1964, with initial diagnosis of AA was followed-up from 1989 till present at the Russian Research Institute of Hematology and Transfusiology. Her treatment included blood-component therapy, the use of antilymphocyte immunoglobulin, cyclosporine, plasmapheresis, eculizumab, and symptom-relieving drugs. Results. The study deals with the case of transformation of non-severe AA with remission after immune-suppressive therapy into classical hemolytic PNH. The case report describes the characteristic features, AA/PNH diagnosis and treatment issues at different stages of the disease, and the reasons for incomplete effect of targeted therapy. Conclusion. The case under discussion confirms the relevance of current methods of detecting PNH clone at early stages of AA diagnosis and dynamic follow-up with respect to a probable growth of clone with PNH phenotype, especially at the stage of hematopoietic recovery. Determination of PNH clone size and lactate dehydrogenase serum level is required for timely amendment of treatment strategy with a switch to long-term targeted monitoring of hemolysis which allows to prevent irreversible visceral changes and severe complications. In case of insufficient effect of targeted therapy with ongoing anemia Coombs test is recommended because of probability of C3-mediated extravascular hemolysis.

Cytokines are an integral part of normal hematopoiesis and affect virtually all of its stages, causing and regulating the processes of cell proliferation, differentiation and a poptosis. According to recent studies, it has been shown that cytokines also mediate complex interactions between hematopoietic, immune systems and a growing tumor. On the one hand, cytokines take part in the activation of antitumor immunity aimed at eliminating malignant cells; on the other hand, they are synthesized by tumor cells and participate in the progression and metastasis of tumors. The article summarizes the data of modern literature on the characteristics of changes in the cytokine profile in patients with acute myeloid leukemia (AML). The role of cytokines in leukemogenesis is shown: in activation of signal transmission pathways, interaction with bone marrow microenvironment, implementation of antitumor immunity and maintenance of persistence of clonal blast cells. The connection of cytokines with the results of treatment and the prognosis of the disease, taking into account the presence in the patient's genotype of various allelic variants of cytokine genes encoding high or low production of these factors, is highlighted. The data presented in the review on the participation of cytokines in the formation, development and elimination of tumor cells in hemoblastoses are sometimes contradictory. However, these contradictions may be explained by the concept of tumor immunoediting, according to which the cells of the immune system can be transformed by a tumor in the process of carcinogenesis and start actively promoting its growth.

Resistance to transfusions of blood components is caused by production of antibodies to donor platelet and leukocyte surface antigens. The incidence of HLA and HPA antibodies was significantly higher in patients with a history of transfusions. These antibodies were detected in 93% patients with aplastic anemia, 75% patients with hematological malignancies, and 65.6% patients with hemostasis disorders. Various combinations of antibodies were found in 56.7, 46.7, and 38.1% cases, respectively. Antibodies were rare detected in just solitary cases - in patients without history of transfusions, mainly in women with a history of pregnancy. These data indicated high probability of allosensitization to leukocyte and/or platelet antigens after transfusions of blood components. This fact suggests the selection of the donor-recipient pair with consideration for their compatibility.

Исследованы показатели иммунитета и образование антител к антигенам HLA I и II класса и НРА у пациентов с апластической анемией (АА, n=54), часть из которых (38,9 %) получала трансфузии гемокомпонентов (ГК) — эритроцитной массы и/или тромбоцитного концентрата, а другая часть не получала трансфузий. При отсутствии различий между выделенными группами в относительном содержании общей популяции Т-лимфоцитов, их основных иммунорегуляторных субпопуляций (Т-хелперов и Т-цитотоксических клеток) и В-клеток, установлено опосредованное иммуносупрессирующее влияние гемокомпонентной терапии на показатели клеточного иммунитета, проявляющееся в изменении относительного содержания ряда минорных популяций: возрастании числа иммунокомпетентных клеток с фенотипом CD8+/CD3и снижении числа активированных лимфоцитов с фенотипом CD3+/ DR+ и НКТ-клеток (CD3+/CD16/56+). У больных АА, получавших гемокомпонентную терапию, выявлено более высокое содержание ИЛ-6 (в 1,3 раза) и более низкое содержание ИЛ-1b (в 2,1 раза) и ИФНg (в 2,5 раза) по сравнению с группой больных, которым не проводились трансфузии гемокомпонентов. У подавляющего большинства больных (93,3 %), получавших ГК, присутствовали те или иные из изученных аллоантител. При этом чаще всего выявляли HLA антитела II класса — у 70 % обследованных и НРА антитела — у 61 % обследованных пациентов; HLA антитела I класса были обнаружены у 50 % больных, получавших трансфузии ГК. Полученные результаты свидетельствуют, во-первых, что пациентов с многократными трансфузиями гемокомпонентов в анамнезе следует относить к группе повышенного риска развития вторичного иммунодефицита, что целесообразно учитывать при назначении иммуносупрессивных препаратов трансфузионнозависимым больным. Во-вторых, наличие алосенсибилизации следует принимать во внимание при выборе тактики гемокомпонентной терапии.

In this review article, we present current clinical data about the effects of transfused hemocomponents upon immune system of the recipients, and about transfusion-related immunomodulation, with emphasis on the role of T-regulatory (Treg) cells in these events. The article describes a role of Treg’s in development of tolerance to self-antigens, in decrease of anti-neoplastic and anti-infection immune response, and their proposed role in transfusion-related immunomodulatory effects.

В настоящее время основной метод лечения больных апластической анемией (АА), которым не проводится трансплантация гемопоэтических стволовых клеток — иммуносупрессивная терапия (ИСТ) с использованием антитимоцитарного иммуноглобулина (АТГ) и циклоспорина-А (ЦсА). Такая терапия позволяет получить стойкие ремиссии у 70 % больных и более. Для улучшения результатов терапии ведётся поиск возможностей применения дополнительных иммуносупрессивных препаратов. К таким средствам терапии относятся и препараты микофеноловой кислоты. Несмотря на литературные данные об отсутствии существенного положительного эффекта при добавлении препаратов данного ряда к комбинированной терапии АТГ/ ЦсА, их применение может быть целесообразным, когда не имеется возможности проведения ИСТ в полном объёме «традиционными» средствами. Для оценки эффективности МФК, как альтернативы лечении больных АА с токсическими осложнениями на фоне приема ЦсА, проанализированы результаты использования препаратов Селлсепта и Майфортика в у 14 больных: 5 больных с НАА и 9 — с ТАА. Положительный клинико-гематологический эффект отмечен у 10 больных. Препараты были эффективны в группе пациентов с хорошим результатом начальной стандартной ИСТ при невозможности её продолжения из-за побочных действий ЦсА. Полученные данные позволяют включать препараты МФК во вторую-третью линии терапии больных АА, у которых не имеется возможности проведения стандартной ИСТ в полных дозах.

Abstract. The capacity of mononuclear cells of peripheral blood and bone marrow of 36 patients with aplastic anemia to produce multi-colony-stimulating factor - IL-3 have been studied. It was established that the cells of immune system produce the amount of cytokine comparable to normal values, and the depression of hemopoesis in this disease is not connected with insufficient synthesis of IL-3 by mononuclear cells and is possibly due to other factors.

AIM To clarify the prognostic value of the baseline blood levels of endogenous erythropoietin (EE) and tumor necrosis factor-a (TNF-a) involved in the key components of the pathogenesis of anemia in lymphoproliferative diseases (LPD), the counts of reticulocytes and platelets (hematopoietic preservation indicators) in the use of erythropoiesis-stimulating agents (ESAs) to correct anemia syndrome (AS) in patients with LPD. SUBJECTS AND METHODS The results of AS treatment with ESAs were analyzed in 48 patients with LPD. A study group comprised patients with chronic lymphocytic leukemia (n=1 3), indolent lymphomas (n=14), and multiple myeloma (n=21). Their hemograms (hemoglobin concentration, red blood cells, packed cell volume, reticulocytes, and platelets) and blood EE and TNF-alpha levels were examined before using ESAs. The hemogram was monitored during treatment. ESAs (eralfon (epoietin alpha) in 21 patients and epres in 27) were subcutaneously injected in a dose of 150 IU/kg thrice weekly (for not more than 16 weeks). A control group included 21 anemic patients with multiple myeloma who did not receive ESAs. Increasing hemoglobin concentrations up to 120 g/l was regarded as a positive response to ESA treatment. RESULTS By and large, the efficacy of epoietin alpha was 62.5% (61.9% for eralfon and 63.0% for epres), which was significantly higher than that in the control group (23.4%; p<0.05). A number of blood laboratory parameters were found to be of value in predicting the efficacy of ESAs. The patients with the decreased baseline concentrations o EE ( <130 mlU/ml) and TNF- alfa (,15 pg/ml) were ascertained to show a positive response more frequently (80 and 92.9%, respectively; p<0.05) than those with thepredicting the efficacy of ESAs. The patients with the decreased baseline concentrations of EE (<130 mlU/ml) and TNF-a (<15 elevated concentrations of the enzymes in question. In addition, a positive response was more often recorded in patients with reticulocyte counts of more than 1% (77.4%; p<0.05) and platelets of 100-10(9)/1 (70%; p=0.05). CONCLUSION Estimating the baseline blood levels of EE and TNF-a and the counts of reticulocytes and platelets prior to the use of ESAs enables prediction of the efficiency of erythropoiesis-stimulating therapy in anemic patients with LPD.