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Background. Primary cutaneous T-cell lymphomas are rare heterogeneous group of lymphoproliferative diseases characterized by primarily involving skin and subcutaneous adipose tissue. Half of these cases are mycosis fungoides (MF), for about 25% are cutaneous CD30+ lymphoproliferative diseases (CD30+ LPD): primary cutaneous anaplastic large cell lymphoma (pcALCL) and lymphomatoid papulosis (LyP). During the initiating treatment of patients with MF and Szary syndrome (SS), carried out on the territory of the Russian Federation, for about 30% of patients are resistant to various therapeutic effects, especially in the later stages. The problem of the treatment of CD30+ LPD is extracutaneous dissemination in case of pcALCL, steadily relapsing course of LyP without symptom-free intervals. These characteristics of the therapy of cutaneous lymphomas demand for the need to search for new treatment options. Brentuximab vedotin, according to the results of the international randomized ALCANZA trial, has shown high efficiency in the treatment of cutaneous T-cell lymphoproliferative diseases. Aim. To evaluate the efficacy of brentuximab vedotin application in patients with cutaneous T-cell lymphomas in adverse risk group received at least one line of systemic therapy. Materials and methods. The study included 21 patients: 16 men and 5 women. The diagnosis of MF was verified in 8 patients, SS in 5 patients, cutaneous CD30+ LPD in 6 patients (5 patients pcALCL, 1 patient LyP) and a primary cutaneous peripheral T-cell lymphoma, unspecified in 2 patients. The diagnosis of cutaneous T-cell lymphoma was verified on the basis of the anamnesis of the disease, on the character of cutaneous lesions, on histological, immunohistochemical and in some cases on molecular genetic testing of the biopted sample of the skin (the assessment of T-cell receptor gene rearrangement). Results. The late stages of the disease were diagnosed in 12 of 13 patients with MF/SS. Extracutaneous lesions were diagnosed in 57% of cases. The median of prior lines therapy was 3 (18 variants of treatment). The overall response to the treatment was achieved in 91% of cases (in 19 of 21 patients): the complete remission was obtained in 53% of cases, very good partial remission in 31% of cases and partial remission in 16% of cases. The progression of the disease was determined in 2 patients (after the first and fourth cycles). Some patients with partial remission as a result of therapy using brentuximab vedotin had the additional therapy (radiation therapy, interferon , the cycles of systemic therapy) and these acts gave an option of achieving deeper antitumor response. The early relapse was diagnosed in 2 of 19 patients who had responded to the treatment. The treatment tolerability was acceptable, and the toxicity did not exceed the already known one described in earlier studies. Thus, the stable overall antitumor response had been persisting in 89% of patients (the median of the observation was 10 months). Conclusion. The use of targeted therapy with brentuximab vedotin gave an option of achieving high treatment results in group of patients with advanced stages of the disease and inefficiency of several lines of therapy.

Introduction. Kaposi’s sarcoma (КS) is a multi-focal malignant tumor of vascular origin with a predominant lesion of the skin, involving internal organs and lymph nodes. Epidemic and immunosuppressive variants of the disease are considered to be the most studied and common. The main reason for the development of the immunosuppressive variant is the use of immunosuppressive drugs in patients after transplantation of solid organs. Descriptions of the development of Kaposi’s sarcoma in patients with diseases of the hematopoietic system are rare.Aim — to describe a rare combination of a malignant tumor of vascular origin (Kaposi’s sarcoma) and a chronic myeloproliferative disease: primary myelofi brosis.Main findings. To verify the diagnosis of Kaposi’s sarcoma in a patient with primary myelofi brosis, the following were used: histological, immunohistochemical studies of skin biopsies and the polymerase chain reaction method with detection of a fl uorescent signal in “real time” in biological material samples (peripheral blood, smear from the mucous membrane of the oropharynx, skin biopsies from lesions) with quantitative determination of the activity of the human herpes virus 8. A comprehensive examination made it possible to establish the fi nal diagnosis of multiple malignant neoplasms and recommend treatment.

Dyskeratosis congenita (DC) is a hereditary syndrome of bone marrow failure, which develops because of telomeres defects and combines with cancer predisposition. Its classical clinical features are skin pigmentation, nail dystrophy, oral leukoplakia (skin-mucosa triad). The goal is to describe the algorithm of diagnosis, clinical specificities of DC and specific treatment for cases of DC in one family. The present report includes descriptions of diagnosis and treatment of family members diagnosed for the first time as having a DC. The report shows an importance of all diagnostic stages: from a medical history and clinical picture to an application of modern high-tech diagnostic methods (flow-FISH, NGS). The report underlines an importance of diagnosis of all family members for excluding an asymptomatic form after a case of DC has been already detected in that family. A high frequency of a toxicity and secondary neoplasia makes it necessary to realize an individual approach at treatment of each patient with DC (the earliest start of androgen treatment, prompt decision of implementation of allogenic hematopoietic stem cell transplantation). The knowledge of pathogenesis, clinical features and principles of diagnosis and therapy of this disease is relevant to pediatricians and hematologists.Врожденный дискератоз (ВД) наследственный синдром недостаточности костномозгового кроветворения, развивающийся вследствие нарушения биологии теломер и сочетающийся с предрасположенностью к опухолевым заболеваниям. Классическими клиническими признаками болезни (кожно-слизистая триада) являются ретикулярная пигментация кожи, дистрофические изменения ногтевых пластин, лейкоплакия слизистой оболочки полости рта. Цель описать алгоритм диагностики, особенностей клинического течения и выбора терапии семейного случая ВД. Представлено клиническое наблюдение диагностики и лечения членов семьи с впервые выявленным ВД. Данное наблюдение демонстрирует важность всех этапов обследования: от сбора анамнеза и клинической картины до применения высокотехнологичных современных диагностических методов (flow-FISH, NGS). Подчеркивается, что при выявлении ВД у больного показано обследование членов семьи на наличие бессимптомного течения болезни. Высокая частота органной токсичности и развития вторичных неоплазий диктует необходимость индивидуального подхода к лечению каждого больного с этим заболеванием (раннее начало приема андрогенов, своевременное рассмотрение возможности выполнения трансплантации аллогенных гемопоэтических стволовых клеток). Знание патогенеза, клинической картины, принципов диагностики и терапии этой нозологии актуальны как для врачей педиатрической практики, так и для гематологов.

Thrombotic complications are the most significant factors determining the prognosis in myeloproliferative neoplasms. Markers for assessing the risk of thrombosis are the number of leukocytes, platelets, hemoglobin level, hematocrit, age, molecular status, history of thrombosis, obesity, arterial hypertension, hyperlipidemia, hereditary or acquired thrombophilia. The pathogenesis of thrombosis in patients with myeloproliferative neoplasms is complex and multifactorial. In most cases, the etiological factor remains unknown. Currently, antiplatelet and anticoagulant therapy is carried out on an individual basis. The algorithm for primary and secondary (after thrombosis) prevention requires development and testing. We present a clinical case of repeated arterial and venous thrombotic complications in a patient with primary myelofibrosis.Тромботические осложнения значимые факторы, определяющие прогноз при миелопролиферативных новообразованиях. Маркерами, позволяющими оценить риск развития тромбозов, являются количество лейкоцитов, тромбоцитов, уровень гемоглобина, гематокрит, возраст, молекулярный статус, тромбозы в анамнезе, ожирение, артериальная гипертензия, гиперлипидемия, наследственная или приобретенная тромбофилия. Патогенез тромбозов у больных с миелопролиферативными новообразованиями сложный и многофакторный. В большинстве случаев этиологический фактор остается неизвестным. В настоящее время терапия антиагрегантами и антикоагулянтами проводится в индивидуальном порядке. Алгоритм первичной и вторичной (после состоявшегося тромбоза) профилактики требует разработки и апробации. Мы представляем клиническое наблюдение повторные артериальные и венозные тромботические осложнения у больного с первичным миелофиброзом.

Indications of allogeneic hematopoietic stem cell transplantation (allo-HSCT) in patients with primary myelofibrosis are intermediate-2 and high-risk group of DIPSS (Dynamic International Prognostic Scoring System), beginning of the disease in childhood. The other adverse factors affect engraftment and survival after allo-HSCT, example partialy matched donor. But the result of allo-HSCT from matched related donors and result of allo-HSCT from haploidentical donors are comparable. The method for haploidentical hematopoietic stem cell transplantation is T-cell-depletion. This is clinical case of T-cell-depleted haploidentical hematopoietic stem cell transplantation in patient with primary myelofibrosis, the diagnosis was established in childhood.Показанием к трансплантации аллогенных гемопоэтических стволовых клеток (алло-ТГСК) у пациентов с первичным миелофиброзом является их принадлежность к группе промежуточного-2 и высокого риска. Пациентам с низким или промежуточным-1 риском с дебютом заболевания в детском возрасте также целесообразно рассмотреть включение алло-ТГСК в программу терапии. Перед алло-ТГСК необходимо учитывать наличие других неблагоприятных факторов, которые могут повлиять на приживление трансплантата и выживаемость после алло-ТГСК, например выполнение алло-ТГСК от частично-совместимого донора. При этом результаты нескольких исследований свидетельствуют о том, что алло-ТГСК от родственных полностью совместимых и гаплоидентичных доноров сопоставимы. Одним из подходов к выполнению трансплантации гаплоидентичных гемопоэтических стволовых клеток является T-клеточная/CD19-деплеция. Представлен клинический случай алло-ТГСК с T-клеточной/CD19-деплецией больному первичным миелофиброзом, у которого диагноз установлен в детском возрасте.

Hodgkin’s lymphoma is a tumor characterized by predominant lesions in lymph nodes. Primary extranodal lesions are exceedingly rare. In the now available world literature, there are only single observations of classical Hodgkin’s lymphoma with ovary involvements. The present paper reports the diagnosis and treatment of a patient with classical Hodgkin’s lymphoma with ovary involvements confirmed by histological and immunohistochemical analyses.

The development of National clinical guidelines on diagnosis and treatment of Ph-negative myeloproliferative neoplasms comes in response to the need to standardize the approach to diagnosis and treatment. The availability of clinical guidelines can facilitate the choice of adequate treatment strategy, provides practicing physicians with exhaustive and up-to-date information on advantages and shortcomings of different treatment methods as well as lets health professionals better assess expected extents of treatment required by patients. In 2013 a working group was formed to develop and formulate clinical guidelines on the treatment of myeloproliferative neoplasms. These guidelines were first published in 2014, afterwards they were revised and republished. The dynamic development of current hematology presupposes constant updating of knowledge and implementation of new diagnosis and treatment methods in clinical practice. In this context clinical guidelines present a dynamic document to be continuously amended, expanded, and updated in accordance with scientific findings and new requirements of specialists who deal directly with this category of patients. The present edition is an upgraded version of clinical guidelines with updated information on the unification of constitutional symptoms assessment using MPN-SAF TSS questionnaire (MPN10), on applying prognostic scales in primary myelofibrosis, assessing therapy efficacy in myeloproliferative neoplasms, revising indications for prescription, on dose correction, and discontinuation of targeted drugs (ruxolitinib). The guidelines are intended for oncologists, hematologists, healthcare executives, and medical students.

The application of highly effective tumor treatment protocols in children and increasing number of patients healed resulted in a growing focus on long-term effects of chemotherapy. One of the most dangerous complications of a first malignant neoplasm (MN) is the development of second MNs. Cytostatic drugs of the epipodophyllotoxin group and alkylating agents contribute to secondary acute myeloid leukemias (AML), the rare and prognostically very unfavorable second MNs. The present article provides a review of literature on risks of secondary hematological MNs associated with the therapy of first tumors. It also contains a case report of successful treatment of AML which occurred after Burkitt’s lymphoma therapy.

Background. Splenic marginal zone lymphoma (SMZL) is an indolent non-Hodgkin’s B-cell lymphoma. It presents morphologically by mature lymphoid B-cells. They conform to these immunological characteristics of marginal zone lymphocytes from secondary follicles. The tumor B-cells of SMZL do not have specific markers of immunophenotype and requires the exclusion of other non-Hodgkin’s B-cell lymphomas. There is an annual increase in the incidence of SMZL. There are refractory forms and progressive course of the SMZL. There is a huge variety of the mechanisms of evading tumor cells from immunological control. Unlike solid tumors, B-lymphoproliferative diseases are characterized by the expression of HLA I/II and co-stimulatory molecules (CD80 and CD86). Therefore, tumor B-lymphocytes can act as antigen-presenting cells (APC) for T lymphocytes. The T-cell immune response is known to play an important role in antitumor control. It is known that effective activation of T-lymphocytes requires the formation of an immunological synapse and the presence of two activation signals (antigen recognition and co-stimulation of CD28-CD80/86). According to the modern concept of tumor development, there is a gradual selection of tumor clones. As a result, only tumor cells that are invisible to the immune system remain. Mechanisms of evasion of tumor B-cells of SMZL from immune surveillance are currently not fully understood and are being actively studied.Objective: to study the expression features of antigens involved in the formation of immunological synapse in patients with SMZL in peripheral blood.Materials and methods. The study includes 10 primary SMZL patients; all patients have stage IV according to the Ann Arbor classification. Splenectomy was performed for all patients as a first stage of treatment. Two patients had progression of SMZL after splenectomy, which required chemotherapy. The control group included 25 healthy donors. Peripheral blood was used as a material for analysis. The study was conducted on a 6-color BD FACS Canto II flow cytometer (BD Biosciences, USA) immediately after diagnosis.Results. Tumor B-cells of SMZL are different from B-cells of healthy donors with a greater proportion of CD80+, FAS+, PD-1+-cells, which may correspond to activated B-cells. The proportion of CD4+PD-1+ and CD8+PD-1+ T-cells in patients with SMZL was higher in comparison with the control group. There was a large proportion of T-cells expressing PD-1 in the group of patients with SMZL progression after splenectomy in comparison with the group of patients with indolent course of SMZL. Conclusion. Thereby, tumor B-cells of the SMZL retains the features of non-tumor analogues. The most significant mechanism for evading immune surveillance in an SMZL is inhibition of the T-cell immunity via the PD-1–PD-L1 pathway. The most pronounced inhibition of T-cell immunity causes an uncontrolled tumor process.

Chronic lymphocytic leukemia/small lymphocytic lymphoma. Clinical recommendations

Background Myelodysplastic syndromes (MDS) can present a challenge for clinicians. Multicolor flow cytometry (MFC) can aid in establishing a diagnosis. The aim of this study was to determine the optimal MFC approach for MDS. Methods The study included 102 MDS (39 low-grade MDS), 83 cytopenic patients without myeloid neoplastic disorders (control group), and 35 healthy donors. Bone marrow was analyzed using a six-color MFC. Analysis was conducted according to the "Ogata score," "Wells score," and the integrated flow cytometry (iFC) score. Results The respective sensitivity and specificity values were 77.5% and 90.4% for the Ogata score, 79.4% and 81.9% for the Wells score, and 87.3% and 87.6% for the iFC score. Specificity was not 100% due to deviations of MFC parameters in the control group. Patients with paroxysmal nocturnal hemoglobinuria (PNH) had higher levels of CD34+ CD7+ myeloid cells than donors. Aplastic anemia and PNH were characterized by a high proportion of CD56+ cells among CD34+ precursors and neutrophils. The proportion of MDS-related features increased with the progression of MDS. The highest number of CD34+ blasts was found in MDS with excess blasts. MDS with isolated del(5q) was characterized by a high proportion of CD34+ CD7+ cells and low granularity of neutrophils. In 39 low-grade MDS, the sensitivities were 53.8%, 61.5%, and 71.8% for Ogata score, Wells score, and iFC, respectively. Conclusion The results support iFC as a useful diagnostic tool in MDS.

Reveal morphological and immunohistochemical predictors of reversibility of dialysis-dependent acute kidney injury (AKI) in patients with myeloma cast nephropathy (MCN) based on the study of kidney biopsy.Renal pathological findings were studied in 36 patients with MCN and dialysis-dependent stage 3 AKI (AKIN, 2012). The study of biopsy samples was performed by a semi-quantitative and quantitative analysis using computer morphometry. The expression of E-cadherin, vimentin and-smooth muscle actin was determined immunohistochemically in the tubular cells and interstitium. Induction therapy for 26 patients was carried out to bortezomib-based programs; in 10 patients other schemes were used. A comparative analysis of morphological changes in nephrobiopathy depending on the renal response was performed in patients with achieved hematologic remission.Improved renal function was observed only in patients with hematologic response to therapy. There were no differences in the number of sclerotic glomeruli, protein casts, the area of inflammatory interstitial infiltration, and the degree of acute tubular damage in patients with and without renal response. In patients with renal response compared with patients without improving renal function, the area of interstitial fibrosis was less (24.9% and 45.9%, respectively;p=0.001), and the area of E-cadherin expression was larger (15.9% and 7.1%, respectively;p=0.006). Interstitial fibrosis of 40% or more and/or the area of expression of E-cadherin less than 10% of the area of tubulo-interstitium have an unfavorable prognostic value in achieving a renal response in MCN.If the interstitial fibrosis area is 40% or more and the expression area of E-cadherin is less than 10%, the probability of the absence of a renal response is 93.3% (OR=24.5) even when a hematological response to induction therapy is achieved. The number of protein casts, the prevalence of acute tubular damage and inflammatory interstitial infiltration have not prognostic value.Цель.Выявить морфологические и иммуногистохимические предикторы обратимости острого повреждения почек (ОПП) с потребностью в диализе у больных миеломной каст-нефропатией (МКН) на основании исследования биоптатов почек. Материалы и методы.Проведено исследование нефробиоптатов 36 пациентов с МКН и 3-й стадией ОПП (AKIN, 2012) с потребностью в диализе. Исследование биоптатов выполняли полуколичественным и количественным методом с применением компьютерной морфометрии. Иммуногистохимически в клетках эпителия канальцев и интерстиции определяли экспрессию Е-кадгерина, виментина,-гладкомышечного актина. Индукционная терапия 26 пациентам проводилась по бортезомибсодержащим программам, 10 больным использовали другие схемы. Сравнительный анализ морфологических изменений в нефробиоптатах в зависимости от почечного ответа выполнен у пациентов с достигнутой гематологической ремиссией. Результаты.Улучшение функции почек наблюдалось только у пациентов с гематологическим ответом на терапию. Не выявлено различий в количестве склерозированных клубочков, белковых цилиндров, площади клеточной воспалительной инфильтрации, а также степени острого повреждения канальцев у пациентов с почечном ответом и без него. У больных с почечным ответом по сравнению с пациентами без улучшения функции почек площадь интерстициального фиброза меньше (соответственно 24,9 и 45,9%;р=0,001), а площадь экспрессии E-кадгерина больше (соответственно 15,9 и 7,1%;p=0,006). Фиброз интерстиция 40% и более и/или площадь экспрессии Е-кадгерина менее 10% от площади тубулоинтерстиция имеют неблагоприятное прогностическое значение в достижении почечного ответа при МКН. Заключение.При площади фиброза интерстиция 40% и более и площади экспрессии Е-кадгерина менее 10% вероятность отсутствия почечного ответа составляет 93,3% (отношение шансов 24,5) даже при достижении гематологического ответа на индукционную терапию. Количество белковых цилиндров, распространенность острого повреждения канальцев и воспалительной инфильтрации интерстиция не имеют прогностического значения.

Our case demonstrates severe bone disease in primary AL-amyloidosis without concomitant multiple myeloma. A 30-year-old man had spontaneous vertebral fracture Th8. A computed tomography scan suggested multiple foci of lesions in all the bones. In bone marrow and resected rib werent detected any tumor cells. After 15 years from the beginning of the disease, nephrotic syndrome developed. Based on the kidney biopsy, AL-amyloidosis was confirmed. Amyloid was also detected in the bowel and bone marrow. On the indirect signs (thickening of the interventricular septum 16 mm and increased NT-proBNP 2200 pg/ml), a cardial involvement was confirmed. In the bone marrow (from three sites) was found 2.85% clonal plasma cells with immunophenotype СD138+, СD38dim, СD19-, СD117+, СD81-, СD27-, СD56-. FISH method revealed polysomy 5,9,15 in 3% of the nuclei. Serum free light chain Kappa 575 mg/l (/44.9) was detected. Multiple foci of destruction with increased metabolic activity (SUVmax 3.6) were visualized on PET-CT, and an surgical intervention biopsy was performed from two foci. The number of plasma cells from the destruction foci was 2.5%, and massive amyloid deposition was detected. On CT scan foci of lesions differed from bone lesions at multiple myeloma. Bone fragments of point and linear type (button sequestration) were visualized in most of the destruction foci. The content of the lesion was low density. There was no extraossal spread from large zones of destruction. There was also spontaneous scarring of the some lesions (without therapy). Thus, the diagnosis of multiple myeloma was excluded on the basis based on x-ray signs, of the duration of osteodestructive syndrome (15 years), the absence of plasma infiltration in the bone marrow, including from foci of bone destruction by open biopsy. This observation proves the possibility of damage to the skeleton due to amyloid deposition and justifies the need to include AL-amyloidosis in the spectrum of differential diagnosis of diseases that occur with osteodestructive syndrome.Представлено клиническое наблюдение, доказывающее, что AL-амилоидоз без сопутствующей множественной миеломы может быть причиной тяжелого остеодеструктивного синдрома. В 2004 г. у 30-летнего мужчины развился патологический перелом VIII грудного позвонка. На компьютерной томографии выявлены множественные крупные очаги деструкции во всех костях скелета. При исследовании костного мозга и резецированного ребра опухолевых клеток не обнаружено, диагноз не установлен. Через 15 лет от начала заболевания развился нефротический синдром. В биоптате почки подтверждено отложение AL-амилоида. Амилоид выявлен также в толстой кишке и костном мозге. На основании косвенных признаков (утолщение межжелудочковой перегородки до 16 мм и повышения предсердного натрийуретического пептида NT-proBNP до 2200 пг/мл) диагностировано вовлечение сердца. В пунктате костного мозга (из 3 различных локализаций) обнаружено 2,85,6% клональных плазматических клеток с иммунофенотипом СD138+, СD38dim, СD19-, СD117+, СD81-, СD27-, СD56-. При цитогенетическом исследовании методом FISH (флуоресцентная гибридизация in situ) в 3% ядер выявлена полисомия 5, 9, 15. В сыворотке повышение свободных легких цепей -типа 575 мг/л ( 44,9). На позитронно-эмиссионной томографии, совмещенной с компьютерной томографией (18F-фтордезоксиглюкоза), визуализированы множественные очаги деструкций с повышенной метаболической активностью (SUVmax 3,6). Из 2 очагов деструкций в костях таза с повышенным накоплением радиофармпрепарата выполнена биопсия методом открытого оперативного вмешательства. В биоптатах количество плазматических клеток не превышало 2,5%, отмечалось массивное отложение амилоида. Выявлены рентгенологические отличия поражения костей при AL-амилоидозе от остеодеструкций при множественной миеломе. У пациента в большинстве очагов деструкций визуализировались костные фрагменты точечного и линейного вида (button sequestration), содержимое очагов деструкций низкой плотности. Отсутствовало экстраоссальное распространение из больших зон деструкции. Отмечалось также спонтанное рубцевание отдельных участков деструкции при отсутствии терапии. Таким образом, диагноз множественная миелома исключен на основании рентгенологических признаков, длительности остеодеструктивного синдрома, отсутствия плазматической инфильтрации в костном мозге, в том числе из очагов костных деструкций методом открытой биопсии. Это наблюдение доказывает возможность поражения костей вследствие отложения AL-амилоида и обосновывает необходимость включения AL-амилоидоза в спектр дифференциальной диагностики заболеваний, протекающих с остеодеструктивным синдромом.

Treatment programs for patients with acquired aplastic anemia include two main therapeutic options: allogeneic bone marrow transplantation and combined immunosuppressive therapy (IST). However, combined IST remains the method of choice for most adult AA patients. This study included 120 AA patients who received IST at the National Research Center for Hematology in 20072016. The analysis was applied to 120 patients. Median age was 25 (1765) years, M/F: 66/54, SAA/NSAA: 66%/34%. Effectiveness of IST was carried out in 120 patients with AA. This group did not include 8 SAA patients who died during the first 3 months from the start of treatment from severe infectious complications (early deaths 6.2%) and 2 AA patients who dropped out of surveillance. The observation time was 55 (6120) months. Paroxysmal nocturnal hemoglobinuria (PNH clone) was detected in 67% of AA patients. The median PNH clone size (granulocytes) was 2.5 (0.0199.5)%. The treatment was according to the classical protocol of combined IST: horse antithymocytic globulin and cyclosporin A. Most of patients (87%) responded to combined immunosuppressive therapy. To achieve a positive response, it was sufficient to conduct one course of ATG to 64% of patients, two courses of ATG 24% of patients and 2% of patients responded only after the third course of ATG. A positive response after the first course was obtained in 64% of patients included in the analysis. Most of the responding patients (93%) achieve a positive response after 36 months from the start of treatment. Therefore, the 3rd6th months after the first course of ATG in the absence of an answer to the first line of therapy can be considered the optimal time for the second course of ATG. This tactic allows to get an answer in another 58% of patients who did not respond to the first course of ATG. The probability of an overall 10-year survival rate was 90% (95% confidence interval 83.696.2).Современные программы лечения больных апластической анемией (АА) включают два основных терапевтических направления: трансплантацию аллогенного костного мозга и комбинированную иммуносупрессивную терапию (ИСТ). Методом выбора для большинства взрослых больных АА остается комбинированная ИСТ. В данную работу первоначально включены 130 пациентов с АА, получавших ИСТ в ФГБУ НМИЦ гематологии в 20072016 гг., анализ эффективности ИСТ проводился у 120 больных. Медиана возраста составила 25 (1765) лет, 70 мужчин и 50 женщин, у 66% больных диагностирована тяжелая АА и у 34% нетяжелая. Анализ эффективности ИСТ выполнялся у 120 больных АА. В группу анализа не включены 8 больных тяжелой АА, умерших в течение первых 3 мес от начала лечения от тяжелых инфекционных осложнений (ранние смерти 6,2%), и 2 больных АА, течение заболевания которых неизвестно. Медиана продолжительности наблюдения 55 (6120) мес. Клон пароксизмальной ночной гемоглобинурии выявлен у 67% больных АА, медиана его размера по гранулоцитам 2,5 (0,0199,5)%. Лечение проводилось по классическому протоколу комбинированной ИСТ: лошадиный антитимоцитарный глобулин (АТГ) и циклоспорин А. У 87% больных достигнут положительный ответ на комбинированную ИСТ. Для получения положительного ответа оказалось достаточным проведение одного курса терапии АТГ 74% больных, 2 курсов АТГ 24%, и 2% потребовалось 3 курса АТГ. У большинства больных (93%) гематологический ответ получен через 36 мес от начала лечения. Поэтому 36-й месяцы после 1-го курса АТГ при отсутствии ответа на 1-ю линию терапии можно считать оптимальным сроком проведения 2-го курса АТГ. Такая тактика позволяет получить ответ еще у 58% больных, не ответивших на 1-й курс терапии АТГ. Вероятность 10-летней общей выживаемости составила 90% (95% доверительный интервал 83,696,2).

Clinical recommendations.

Introduction. BCR-ABL tyrosine kinase inhibitors are currently used to successfully treat chronic myeloid leukemia (CML). Drug therapy is carried out in a continuous daily mode throughout the patient’s life. Treatment with this group of drugs is associated with specific dermatological adverse events (dAE), which can lead to a change in the regimen of effective, vital therapy for CML patients.Purpose. To study the characteristics of dermatological adverse events, the severity and influence on the quality of life of BCR-ABL tyrosine kinase inhibitors.Patients and methods. The observational study included 93 patients. The clinical manifestations of dAE, their severity were evaluated, their photographs and pathomorphological studies of skin biopsy samples were performed, cases of dose reduction or drug withdrawal due to dAE were recorded. The quality of life of patients with dAE was determined based on the assessment of the dermatological index of quality of life.Results. Imatinib therapy was accompanied by a maculopapular rash in 43.3 % of patients, nilotinib caused follicular keratosis in 12.9 % of patients. In 3.2 % of patients, dasatinib caused hyperpigmentation, in 2.2 % of patients lichenoid rashes of the II degree occurred during treatment with bosutinib. Ponatinib treatment was followed by dAE in 9.7 % of patients. All dAE have an impact on the quality of life of patients, but the maculopapular rash and dyskeratotic changes are most pronounced. In a pathomorphological study, these dAE have specific features corresponding to immuno-mediated dermatitis.Conclusions. The most frequent and pronounced dAE that significantly affect the quality of life of patients with CML are a maculopapular rash and dyskeratotic skin changes: psoriasiform and lichenoid dermatitis. Clinical and pathomorphological characteristics of skin reactions make it possible in the future to determine effective methods of supportive therapy for dAE.

Hairy cell leukemia. Clinical recommendations

Relevance. Cutaneous T-cell lymphomas (CTCL) are not common diseases which are associated with a decrease in quality of life. Currently available systemic therapy rarely provides a stable and long-termed response. In Russia, current CTCL therapy is a big issue due to the limited access to modern targeted therapy, an absence of a National CTCL registry, and the difficulties in morphological diagnosis of these rare diseases. Since June 17, 2019, a new indication of brentuximab vedotin as a new treatment option for patients with CD30+ CTCL after at least one line of previous systemic therapy was registered. Brentuximab vedotin is a conjugate of a CD30 directed monoclonal antibody and an antitumor agent. Brentuximab vedotin is a CD30-directed monoclonal antibody conjugated to an antitumor agent. Aim. To identify the unresolved issues of current clinical practice and to adapt available approaches to the treatment and diagnosis of CD30 + CTCL given new therapeutic opportunities. Results. The available approaches to the systemic CTCL therapy in Russia routine clinical practice have been discussed, the unresolved issues of therapy and diagnosis have been identified, the routing of patients with CD30 + CTCL in Russia has been discussed, the importance of CD30 testing has been established, the profiles of patients with CTCL for treatment with brentuximab vedotin have been determined.

Aim. Based on our own materials to characterize the clinical manifestations of hypereosinophilic states distinguishing between reactive eosinophilia (RE), clonal myeloproliferative neoplasms with eosinophilia (MPN-eo), and myeloproliferative variant of hypereosinophilic syndrome (MP-HES); to evaluate treatment results. Materials & Methods. The trial included 188 patients with primary HES (132 men and 56 women, aged 19-72 years) having been followed-up at the National Research Center for Hematology since 2001. The main entry criteria were blood eosinophilia > 1.5 x 109/L and clinical symptoms resulting sometimes from hypereosinophilia. All patients received complete physical examination, immunomorphological, standard cytogenetic, and molecular genetic testing. Treatment was provided to 73 patients (63 men and 10 women) including those with MPN-eo PDGFRA+ (п = 39), PDGFRB+ (п = 2), FGFR1+ (п = 1), chronic eosinophilic leukemia not otherwise specified (п = 8), systemic mastocytosis (п = 1), and MP-HES (п = 22). Complete hematological response (CHR) was the criterion for treatment efficacy. In the MPN-eo PDGFRA+ and PDGFRB+ groups molecular response (MR) rate was also estimated in cases of imatinib treatment. MR was considered as no expression of the FIP1L1-PDGFRA and ETV6-PDGFRB transcripts in RT-PCR. Results. The trial yielded the cause of eosinophilia in 117 (62.2 %) out of 188 patients. RE was diagnosed in 60 (32 %) out of 117 patients, various types of clonal MPNs were reported in 57 (30 %) patients. In 71 (38 %) out of 188 patients HES was still present at the first trial stages. Later within this group MP-HES was identified in 22 (30.9 %) out of 71 patients. Among imatinib recipients CHR was achieved in 37 (90 %) out of 41 patients within 1-3 months: in 36 patients with MPN-eo FIP1L1-PDGFRA+ and in 1 patient with MPN-eo ETV6-PDGFRB+. MR was achieved in 88 % of cases. In the absence of molecular markers characteristic of MPN-eo CHR was achieved in 26 % of cases. Among the recipients of treatments other than imatinib nobody achieved CHR. Conclusion. The diagnosis approach in patients with HES should be complex and individualized. Development and enhancement of molecular genetic diagnostic techniques are regarded as ones of the highest priority areas in modern hematology. The use of imatinib mesylate in MPN-eo therapy commonly results in long-term hematological and molecular remissions. On achieving CHR to imatinib treatment of patients without molecular markers characteristic of MPN-eo early use of this drug (or other tyrosine kinase inhibitors) can be recommended in acute forms of HES.

Aim. To compare NHL BFM-90 and CHOEP efficacy in adult patients with ALK-positive anaplastic large-cell lymphoma (ALK+ ALCL). Materials & Methods. Within the period from June 2014 to December 2019 the prospective randomized comparative study at the National Research Center for Hematology in Moscow included 23 ALK+ ALCL patients. In one study arm (n = 11) CHOEP was administered, whereas the other one (n = 12) received high-dose chemotherapy (CT) according to NHL BFM-90 protocol. The median age of patients in both arms was 33 and 40 years, respectively. Results. Overall survival (OS) and event-free survival (EFS) within 3 years were 91 % in the arm receiving CHOEP (this protocol was administered to all 11 patients), and 100 % in the arm receiving NHL BFM-90 (complete remission was achieved in all patients). Due to its toxicity NHL BFM-90 was fully implemented in 9 out of 12 patients. The 3-year OS and EFS in the CHOEP and NHL BFM-90 arms are comparable, and the difference between them is not significant. Conclusion. In ALK+ ALCL treatment high-dose CT according to NHL BFM-90 protocol has no advantage in terms of the 3-year OS and EFS compared to less toxic regimen CHOEP. A larger sample of patients is required to achieve significant results, which will further lead to a final judgement on feasibility of high-dose regimens in the treatment of adult patients with ALK+ ALCL.

Aim. To study the structure of Ph-negative myeloproliferative diseases (Ph- MPD) and to identify morphological markers for diagnosing masked polycythemia vera (PV). Materials & Methods. Bone marrow core biopsy samples from the database of pathology department of National Research Center for Hematology within the period from January 2014 to June 2017 provided the basis for analyzing the diagnosed Ph- MPD cases. The trial included the bone marrow core biopsy samples of the patients treated and fol-lowed-up not only at the National Research Center for Hematology but also at other medical centers in the Russian Federation in the context of clinical, laboratory and molecular data. Results. In 1611 Ph- MPD patients PV prevailed corresponding to 40.6 % of all cases. In the PV group the masked form was diagnosed in 29 % of patients. Primary myelofibrosis (PMF) was diagnosed in 26.6 % of all patients including 10 % of cases with pre-fibrosis/early stage. The 3d most frequent disorder was essential thrombocythemia (ET) which corresponded to 16 %. JAK2 driver mutation was identified in all 654 PV patients. In 4 cases out of them exon 12 mutation was detected. A similar mutation was found out in PMF (53 %) and ET (60 %). In 36 % of PMF patients and 27 % of ET patients CALR mutation was detected. MPL mutation was identified in 4 % of PMF cases and was not discovered in ET. Triple negative patients were identified in 7 % of PMF and 13 % of ET cases. The designation of “myeloproliferative disease unclassifiable” can be applied to 16.8 % of cases. The trial deals with morphological criteria for diagnosing masked PV during examination of bone marrow core biopsy samples. In 30 % of patients with masked PV (according to the 2017 WHO classification) and splenomegaly (> 14 cm) portal vein thrombosis was identified. Conclusion. In the Ph- MPD group PV diagnosis prevailed (40.6 %). The histological analysis of bone marrow core biopsy samples of the patients with the masked PV accounting for 29 % of all PV cases, revealed morphological features typical of overt PV. Histological analysis of bone marrow is a reliable method for diagnosing overt and masked PV. Among morphological characteristics of the bone marrow of patients with masked PV and portal vein thrombosis special attention should be paid to the MF-1 grade of reticulin fibrosis (29 % of cases) and loose clusters of megakaryocytes (71.4 %).

IgG4-associated disease (IgG4-RD) is a systemic inflammatory disease characterized by tumorlike sclerosing masses in different organs. Differential diagnosis in orbital IgG4-RD includes majority of conditions, such as thyroid eye disease (TED), sarcoidosis, granulomatosis with polyangiitis, idiopatic orbital inflammation, limphoproliferative diseases and others. A case of IgG4-RD with different organs involvement and complicated differential diagnosis is presented. This case demonstrates very uncommon manifestation of IgG4-RD, when orbital involvement was very similar with TED. Systemic process was not recognized during a long period of time and diagnosis of IgG4-RD was established only after biopsy of abnormally increased lacrimal gland. Differential diagnosis included other systemic diseases, first of all sarcoidosis, GPA, and lymphoma. Biopsy results were consistent with the gold standard of diagnosis, e. g. more than 40% of plasma cells were IgG4 positive. This case demonstrates the necessity of orbital biopsy before starting immunosuppression to avoid inappropriate treatment strategy.IgG4-ассоциированное заболевание (IgG4АЗ) это системное воспалительное заболевание, которое, как правило, характеризуется формированием опухолеподобных склерозирующих очагов. Дифференциальный диагноз при поражении орбиты при IgG4АЗ довольно обширный и включает такие заболевания, как эндокринная офтальмопатия, саркоидоз, гранулематоз с полиангиитом, идиопатическое воспаление орбиты, лимфопролиферативные заболевания и др. В статье представлен клинический случай IgG4АЗ с поражением нескольких органов-мишеней и сложным дифференциальным диагнозом. Этот клинический пример является демонстрацией достаточно необычной манифестации IgG4АЗ, при которой ведущим проявлением было поражение орбит, схожее с таковым при эндокринной офтальмопатии. В течение длительного времени системный процесс не был распознан, и только после проведения биопсии аномально увеличенной слезной железы было диагностировано IgG4АЗ. Дифференциальный диагноз проводили с другими системными заболеваниями, в первую очередь гранулематозом с полиангиитом и саркоидозом, а также с лимфомой. Данные биопсии в представленном случае соответствовали золотому стандарту диагноза IgG4АЗ, т.е. более 40% плазматических клеток были IgG4-позитивны. Этот случай демонстрирует необходимость проведения биопсии патологически измененных тканей орбиты до назначения иммуносупрессивного лечения во избежание ошибок в выборе тактики лечения пациента.

In chronic lymphocytic leukemia, the risk of second tumors including hematological malignancies, with which the use of purine nucleosides and alkylating agents in treatment of chronic lymphocytic leukemia is most often associated, is significantly increased. Concurrent detection of this disease and various hematological tumors is a rare occurrence in hematological practice. Use of cytogenetic method or analysis allows to differentiate between 2 tumors and confirm differences in genetic abnormalities in different clones and on different levels of cell differentiation. This article presents a clinical case of simultaneous chronic lymphocytic leukemia and myelodysplastic syndrome with 2 clones with different cytogenetic abnormalities: partial trisomy of chromosome 12 and deletion of the long arm of chromosome 5 formed at different levels of cell differentiation.

Aim. To study immunohistochemical parameters of tumor plasma cells in bone marrow and to assess how the expression of adhesion molecule CD56 impacts overall survival (OS) of multiple myeloma (MM) patients. Materials & Methods. The trial included 35 patients (19 men and 16 women) aged 23 to 73 years (with median age of 58 years) with newly diagnosed MM. At disease onset plasmacytoma was diagnosed in 21 patients. In all patients bone marrow core biopsy was performed followed by histologic and immunohistochemical (IHC) examinations. IHC examination was based on the panel of CD56, CD166, CXCR4, Ki-67, and c-MYC/CD138 antibodies. Kaplan-Meier survival curves and significance assessment by means of Cox's F-Test were used. Results. Expression mean values of most of studied markers (CD56, CXCR4, c-MYC, and Ki-67) in bone marrow of patients without plasmacytoma (n = 14) appeared to be higher than in patients with plasmacytoma at MM onset. Expression mean value is understood as percentage ratio of plasma cells expressing a studied marker to total cell count of tumor substrate. High expression of chemo-kine receptors (CXCR4), and adhesion molecules (CD56) probably inhibits plasma cell migration and impedes ex-tramedullary tumor progression. Comparison of protein expression by tumor plasma cells in bone marrow in the groups with bone extramedullary plasmacytoma shows a distinct regularity referring to CD56 adhesion molecule. For example, CD56 expression is significantly (р < 0.05) lower in terms of the count of tumor plasma cells with marker expression in bone marrow of MM patients with extramedullary plasmacytoma compared with patients with bone plasmacytoma (1 ± 1 % vs. 65.71 ± 12.12 %). Comparison of MM patients' OS depending on CD56 expression by tumor plasma cells in bone marrow showed that 4-year OS of patients with CD56 expression in bone marrow was significantly higher being 80 % vs. 38 % in the group with CD56 expression less than in 10 % of tumor cells. Conclusion. Expression of adhesion molecule CD56 in tumor plasma cells in bone marrow can be regarded as a prognostic factor in MM. Probably, when at disease onset CD56 expression is identified in less than 10 % of tumor cells in bone marrow, more detailed additional examination of patients should be carried out to rule out extramedullary lesions in different organs and tissues.

The paper focuses on Epstein-Barr virus (EBV)-associated inflammatory pseudotumor in the spleen, an extremely rare disease which so far remained undefined in the Russian literature. The morphology of it is not characterized by any specific features and is represented by a spindlecell component with pronounced inflammatory infiltration which complicates differential diagnosis. Previously this nosology was regarded within a group of the so-called inflammatory pseudotumors due to the similarity of the clinical course and radiological presentation with tumor processes. Today the term “inflammatory pseudotumor” is considered obsolete, since as pathogenesis was being studied within this disease group, the individual forms with similar morphology and different histogenesis were identified. Differential diagnosis in the context of additional diagnostic techniques is based in such cases on a wide range of reactive states, benign and malignant tumors.

Aim of the issue was to compare clinical characteristics and treatment results of patients with follicular lymphoma (FL) with translocations involving loci of c-MYC/8q24, BCL2/18q21 and/or BCL6/3q27 genes and patients with high - grade B-cell lymphoma [High - grade B-cell lymphoma (HGBL), double - hit (DH)]. Materials and methods. Since 2004 to 2017 years in National Research Center for Hematology 12 patients with high - grade B-cell lymphoma double - hit (HGBL DH) and 6 FL patients with translocations involving c-MYC and BCL2 and/or BCL6 had been treated. We performed a comparative analysis of clinical characterisctics in both groups. As primary endpoints was assessed frequency of complete remission (CR) or progressive disease (PD); as secondary endpoints - overall (OS) and event - free survival (EFS). Results. 5 patients with HGBL DH had c-MYC/BCL6, 7 - c-MYC/BCL2 rearrangements; 2 patients with FL had c-MYC/BCL2, 3 - c-MYC/BCL6, 1 - c-MYC/BCL2/BCL6 rearrangements. FL was represented by grade 3A in 2, grade 3B - in 4 cases, 3 of them had large - cell transformation. In HGBL DH and FL patients had no significant differences in clinical characteristics. The majority of patients had a widespread tumour, increased LDH activity, high frequency of extranodal and bone marrow involvement. Ki-67 expression level was lower in patients with FL (p.Цель работы: сопоставить клинические характеристики и результаты терапии больных фолликулярной лимфомой (ФЛ) с транслокациями с участием локусов генов с-MYC/8q24, BCL2/18q21 и/или BCL6/3q27 и больных В-клеточной лимфомой высокой степени злокачественности [high-grade B-cell lymphoma (HGBL)], double-hit (DH). Материалы и методы. С 2004 по 2017 г. в ФГБУ «НМИЦ гематологии» Минздрава России наблюдались 12 больных с диагнозом HGBL DH и 6 больных ФЛ с транслокациями с участием локусов генов c-MYC, BCL2 и/или BCL6. Мы выполнили сравнительный ретроспективный анализ клинических характеристик в обеих группах пациентов. В качестве первичных конечных точек оценена частота полных ремиссий (ПР) и прогрессирования заболевания (Прогр), в качестве вторичных - общая (ОВ) и бессобытийная выживаемость (БСВ). Результаты. У 5 больных с HGBL DH выявлены транслокации с участием локусов генов c-MYC/BCL6, у 7 - c-MYC/BCL2; у 2 с диагнозом ФЛ - c-MYC/BCL2, у 3 - c-MYC/BCL6, у 1 - c-MYC/BCL2/BCL6. Цитологический тип ФЛ представлен ФЛ 3А с бластоидной морфологической картиной в 2 случаях, ФЛ 3В в 4 случаях, 3 из которых имели признаки гистологической трансформации. Больные HGBL DH и ФЛ не имели значимых различий по клиническим характеристикам. Так, большинство из них имели распространенную стадию заболевания, повышенную активность лактатдегидрогеназы, высокую частоту вовлечения экстранодальных областей и костного мозга. Уровень пролиферативной активности Ki-67 был значимо выше у больных HGBL DH (p.

to determine molecular diagnostics routine for different tissue samples in angioimmunoblastic T-cell lymphoma.Molecular studies were performed for 84 primary AITL patients. The median age was 61 year (29-81); the male to female ratio was 48/36. T-cell and B-cell clonality was assessed by GeneScan analysis of rearranged T-cell receptor (TCRG, TCRB) and immunoglobulin heavy chain genes. For the quantitative determination of cells with RHOA G17V mutation real - time polymerase chain reaction (PCR) with allele - specific LNA modified primers was used.In lymph nodes rearrangements of T-cell receptor genes were determined in 76 (90.5%) of 84 patients and were absent in 8 (9.5%) cases. Identification of the same clonal products of the TCRG and TCRB genes in the lymph node and in peripheral blood and/or bone marrow indicated the prevalence of the tumor process and was observed in 64.7% of patients. Clonal products in peripheral blood and/or bone marrow different from those in the lymph node indicated reactive cytotoxic lymphocyte population and were noted in 58.8% of AITL cases. Simultaneous detection of T- and B-cell clonality in the lymph node was observed in 20 (24.7%) of 81 patients. Cells with RHOA G17V mutation were detected in lymph node in 45 (54.9%) of 82 patients. The use of allele - specific PCR with LNA modified primers revealed presence of the tumor cells in peripheral blood in 100% and in bone marrow in 93.9% of patients with G17V RHOA mutation in the lymph nodes.The validity of different molecular assays performed on certain tissue samples for the diagnosis of angioimmunoblastic T-cell lymphoma has been evaluated. Quantitative allele - specific PCR assay for RHOA G17V mutation based on LNA modified primers possesses sufficient sensitivity for tumor process prevalence evaluation and minimal residual disease monitoring.Цель: определить показания и последовательность проведения молекулярных исследований при ангиоиммунобластной Т-клеточной лимфоме (АИТЛ) в различном биологическом материале. Материалы и методы. Молекулярные исследования проведены у 84 первичных больных АИТЛ. Медиана возраста составила 61 (29-81) год, соотношение мужчины/женщины - 48/36. Оценку T-клеточной и В-клеточной клональности проводили по реаранжировкам генов цепей T-клеточного рецептора и тяжелых цепей иммуноглобулинов. Для количественного определения клеток с мутацией G17V гена RHOA применяли полимеразную цепную реакцию (ПЦР) в реальном времени с аллель - специфичными LNA модифицированными праймерами. Результаты. В биоптатах лимфатических узлов реаранжировки генов цепей Т-клеточных рецепторов определены у 76 (90,5%) из 84 больных и отсутствовали в 8 (9,5%) случаях. Выявление одинаковых клональных продуктов амплификации генов TCRG и TCRB в биоптате лимфатического узла и в образцах периферической крови и/или костного мозга свидетельствовало о лейкемизации опухолевого процесса и наблюдалось у 64,7% больных. Определение в образцах периферической крови и/или костного мозга клональных продуктов, отсутствующих в лимфатическом узле, обусловлено реактивной цитотоксической популяцией лимфоцитов и наблюдалось в 58,8% случаев АИТЛ. Одновременное выявление Т- и В-клеточной клональности в биоптате лимфатического узла отмечалось у 20 (24,7%) из 81 больного. Клетки с мутацией G17V гена RHOA выявлены в биоптатах лимфоузлов у 45 (54,9%) из 82 пациентов. Применение метода аллель - специфичной ПЦР с LNA модифицированными праймерами позволило выявить лейкемизацию опухолевого процесса у 100% и поражение костного мозга - у 93,9% пациентов с выявленной мутацией в лимфоузлах. Заключение. В результате выполненной работы определены показания и последовательность проведения молекулярных исследований при АИТЛ в различном биологическом материале. Количественная аллель - специфичная ПЦР с LNA модифицированными праймерами для определения мутации G17V гена RHOA обладает высокой чувствительностью, позволяет верифицировать лейкемизацию опухолевого процесса и проводить мониторинг минимальной резидуальной болезни во время терапии.

to propose diagnostic algorithm of IgG4-related disease (IgG4-RD).One center retrospective research. 52 pts with IgG4-RD were included. The diagnosis was proved histologically and immunohistochemically. 48 out of 52 pts received treatment. Treatment included one of the following schemes (along with low oral glucocorticoids): rituximab monotherapy, cyclophosphamide monotherapy or their combination.The mean age was 47.4±5.9 years, the mean age of the disease onset was 43.9±16.0 years. Median time before the diagnosis was 24 months. The most often sites of IgG4-RD were lacrimal (63.5%), salivary (46.2%) glands, lungs (48%), lymph nodes (34.6%) and retroperitoneum (17.3%). In clinical picture the leading complain was organ enlargement, but not its dysfunction. Pain was characteristic for retroperitoneum localization. In 56.8% of pts with IgG4-related syalo - and/or dacryoadenitis there was association with ear - nose - throat organs affection. In 4 pts (7.7%) IgG4-RD was combined with some malignant disease, including MALT-lymphoma of lacrimal glands. Irreversible organ damage as an IgG4-RD outcome had 15.4% of pts. The main laboratory markers of IgG4-RD were ESR elevation (38.5%), blood eosinophilia (9.6%), immunological disturbances (serum total IgG and IgG4 elevation, IgE elevation, antinuclear antibodies, rheumatoid factor detection, hypocomplementemia). Serum IgG4 level1.35 g/l was elevated in 88% of pts and correlated with the number of affected organs (Spearman correlation coefficient 0.39, Student's test, р=0.0056). Monoclonal serum secretion and B-cell clonality in the tissue was detected in 4 (23.5%) out of 17 pts, but not all of them had both signs.Based on the analysis of clinical and laboratory characteristics of IgG4-RD a diagnostic algorithm was proposed that enhances the detection and examination of the patients with suspected IgG4-RD.Цель: предложить алгоритм диагностики IgG4-связанного заболевания (IgG4-СЗ). Материалы и методы. Одноцентровое ретроспективное исследование, в которое включено 52 пациента с IgG4-CЗ. Диагноз верифицирован гистологически и иммуногистохимически. Из 52 пациентов 48 лечились медикаментозно. Лечение проводилось по одной из схем (на фоне низких доз пероральных глюкокортикоидов): монотерапия ритуксимабом (РТМ); монотерапия циклофосфамидом (ЦФ); комбинированная терапия РТМ и ЦФ. Результаты. Средний возраст пациентов составил 47,4±15,9 года, средний возраст дебюта заболевания 43,9±16,0 лет. Медиана времени с момента дебюта до постановки диагноза - 24 мес. Наиболее часто поражались слезные (63,5%), слюнные (46,2%) железы, легкие (48%), лимфатические узлы (34,6%) и забрюшинное пространство (17,3%). В клинической картине преобладали жалобы на увеличение органов, а не на снижение их функции. Наличие болевого синдрома характерно для пациентов с ретроперитонеальным фиброзом. У 56,8% пациентов с IgG4-связанным сиало - и/или дакриоаденитом имелась ассоциация с поражением ЛОР-органов. У 4 (7,7%) пациентов IgG4-СЗ сочеталось с онкологическим заболеванием, в том числе с MALT-лимфомой слезных желез. Необратимые поражения органов как исход IgG4-СЗ были у 15,4% пациентов. Основными лабораторными отклонениями у пациентов с IgG4-СЗ были повышение скорости оседания эритроцитов (38,5 %), эозинофилия в крови (9,6%), иммунологические нарушения (повышение уровня общего IgG и IgG4 сыворотки, повышение IgE, выявление антинуклеарных антител, ревматоидного фактора и снижение уровня компонентов комплемента). Уровень IgG41,35 г/л повышен у 88% пациентов и положительно коррелировал с числом пораженных органов (коэффициент корреляции Спирмена 0,39, критерий Стьюдента, р=0,0056). Наличие моноклональной секреции в сыворотке крови и наличие В-клеточной клональности в ткани выявлено у 4 (23,5 %) из 17 исследованных, однако они не всегда сочеталась у одного пациента. Заключение. На основании анализа клинико - лабораторных проявлений IgG4-СЗ предложен алгоритм диагностики данного заболевания, который улучшит выявление и качество обследования пациентов с подозрением на IgG4-СЗ.

Background. Primary bone lymphomas (PBL) are rare extranodal lymphomas. In more than 90 % of cases they are reported as diffuse large B-cell lymphomas (DLBCL). At local (IE) stage of PBL the standard R-CHOP immunotherapy demonstrates efficacy over 90 %. If, however, such poor prognostic factors (PPF) as multiple bone lesions (IVE stage), increased lactate dehydrogenase (LDH) activity, B-symptoms, and large tumor mass are identified, R-CHOP efficacy tends to decrease. There is currently no optimal regimen for treatment of PBL patients with PPF. We suggest intensified multiagent chemotherapy for this category of patients. Aim. To assess long-term results of prospective single-center trial on the use of high-dose mNHL-BFM-90 program in patients with primary bone DLBCL and PPF. Materials & Methods. The trial included 33 patients with primary bone DLBCL followed-up at the National Medical Hematology Research Center from 2006 to 2018. The median age of patients was 44 years (range 16-78 years). The spectrum of assessed data included main clinical, laboratory, X-ray and MRI tumor characteristics as well as survival rates and prognostic factors. Results. PPF were identified in 29 (88 %) patients, out of them 20 (61 %) patients had an advanced stage (> IE), 20 (59 %) patients showed an increased LDH activity, B-symptoms were identified in 15 (45 %) patients, and large tumor mass was reported in 23 (71 %) patients. High-dose antitumor treatment (mNHL-BFM-90) was administered in 27 out of 33 patients. Overall and progression-free survival within the period of 5 years was 92 %. None of PPF significantly influenced survival rates. Conclusion. The use of high-dose mNHL-BFM-90 program in PBL with poor prognosis achieves long-term remissions in 92 % patients. We recommend mNHL-BFM-90 as a therapy of choice for PBL patients with poor prognosis.

Background. Primary mediastinal (thymic) large B-cell lymphoma (PMBCL) is a malignant tumor with large atypical lymphoid cells expressing post-germinal differentiation markers. Rearrangements of immunoglobulin genes in PMBCL are revealed in 30-65 % of cases. Immunoglobulin molecules, however, are expressed neither on the surface, nor in cytoplasm of tumor cells. Aim. To assess cell clonality rate on the basis of rearrangements of immunoglobulin heavy/light chain genes; to determine rearrangement stability at the time of relapse development; to study the range of rearrangements and clonal relationship with primary tumor in metachronous development of mediastinal gray zone lymphoma. Materials & Methods. The assessment of rearrangements of immunoglobulin heavy/light chain genes was based on molecular analysis of 29 primary tumor biopsies and 4 tissue samples with histologically and immunohistochemically verified relapses or metachronous lymphoma development. Results. In 16 (55.2 %) out of 29 cases a rearrangement of immunoglobulin heavy chain genes was reported, in 7 (24.1 %) cases a rearrangement of light chain genes was identified, in 6 (20.7 %) cases no rearrangements of immunoglobulin heavy/light chain genes were found. On the basis of immunoglobulin gene analysis in 2 patients with early relapse a tumor clone was detected that was identical with the one identified at the onset of the disease. In 2 patients with complete remission a metachronous development of mediastinal gray zone lymphoma was reported, whereas molecular genetic analysis revealed a change/disappearance of initial clonal rearrangements of immunoglobulin genes. Conclusion. Total detection rate of B-cell clonality in PMB-CL was 79.3 %. Molecular genetic analysis confirmed that initial clonal rearrangements of immunoglobulin genes were preserved in early relapses, and invalidated tumor clonal relationship in a metachronous development of mediastinal gray zone lymphoma.

Background. TP53 gene mutations impede cell apoptosis and lead to additional oncogenic events contributing to tumor progression. Aim. To assess TP53 gene mutation rate in patients with high-grade B-cell lymphoma double-hit (HGBCL DH) and not otherwise specified (HGBL NOS); to analyse its relationship with disease prognosis. Materials & Methods. Retrospective materials from medical data of 10 HGBL DH and 26 HGBL NOS patients were analyzed. Median follow-up was 26.5 months (range 0.6-160.9 months). Selection was based on the presence of available biological materials (paraffin blocks) for Sanger sequencing of TP53 gene from exon 5 to exon 8 (encoding DNA-binding domain of TP53 gene). FISH analysis of the tumor was performed in all patients to identify translocations involving c-MYC/8q24, BCL2/18q21, and BCL6/3q27 gene locus. To analyze differences between groups χ2 and Mann-Whitney tests were applied. Univariate event analysis (Kaplan-Meier and log-rank tests) and Cox regression analysis were used to assess the influence of molecular markers on the disease prognosis. Results. TP53 gene mutations in lymphoma cells were found in 13 (36 %) out of 36 patients, 10 (77 %) out of 13 mutations were pathogenic. In 8 out of 10 patients with TP53 mutations c-MYC/8q24 gene translocation was identified. Groups with wild (TP53-WT) and mutant (TP53-MUT) types of TP53 gene were similar in terms of main clinical characteristics. Patients with TP53-MUT in tumor cells showed worse 3-year overall survival (OS) compared with the group without TP53-MUT (30 % vs. 73 %; p = 0.026) as well as higher probability of disease progression in the period of 3 years (66 % vs. 15 %; p = 0.004). In multivariate analysis significant OS predictor was the presence of TP53 mutation (p = 0.006). Relapse/ progression probability was higher in combined cases of TP53 mutation and translocation involving c-MYC gene locus (p = 0.0003). Conclusion. Translocation involving c-MYC gene along with TP53 gene mutation in tumor cells can serve as a criterion for dividing HGBL DH and HGBL NOS patients into different lymphoma relapse/progression risk groups.

The prevalence of multiple primary tumors has significantly increased last time. The question of choosing the optimal tactics of therapy today not fully resolved. Particular interest is the simultaneous detection of two neoplasms of similar origin in one study biopsy material. This publication presents a case of simultaneous diagnosis of myeloid sarcoma and mantle cell lymphoma in a 65-year-old patient, which required use of two different chemotherapy protocols. This example shows the need to use an extended diagnostic approach at all stages of the therapy, which allows choosing right tactics of therapy and achieving complete remission of two neoplasms.Распространенность первично-множественных опухолей в последнее время значимо выросла, но вопрос выбора оптимальной тактики терапии при данной нозологии по-прежнему остается нерешенным. Особый интерес представляет одномоментное, или симультанное, выявление двух новообразований родственного происхождения в одном и том же очаге или очагах поражения. В данной публикации представлен случай одномоментной диагностики миелоидной саркомы и лимфомы из клеток мантийной зоны у больной 65 лет, потребовавший последовательного применения двух различных подходов и схем химиотерапии. Этот пример демонстрирует необходимость внедрения расширенного диагностического подхода с применением гистологических, иммуногистохимических, цитогенетических, молекулярных методов исследования на всех этапах диагностики и лечения, что позволяет своевременно выбрать правильную тактику терапии и достичь полной ремиссии при длительных сроках наблюдения по двум новообразованиям при первично-множественных опухолях.

This study conducted the possibilities of diffusion-weighted magnetic resonance imaging of the whole body diffusion WB-MRI (in comparison with positron emission tomography with computed tomography PET/CT) in assessing the volume and prevalence of the tumor, as well as determining bone marrow (BM) damage (for various cytological types) in the diagnosis and staging of the disease in patients with FL.A prospective comparative search study included 15 patients (4 men and 11 women, with a median age of 53 years) with newly diagnosed FL. Patients have not received antitumor chemotherapy previously. After the diagnosis was established, all patients (with the blindness of both the cases themselves and some specialists regarding the results of other specialists) were examined by PET/CT and diffusion WB-MRI, after which a BM examination was performed (histological examination and determination of B-cell clonality in BM puncture by PCR). Using the diffusion WB-MRI method, the prevalence of tumor lesion (nodal and extranodal foci) in each patient was estimated, and the total tumor volume was calculated, BM lesion was detected, and BM lesion volume was calculated. For lesions of different localization, the measured diffusion coefficient (DC) of the diffusion WB-MRI and the standardized rate of accumulation of the radiopharmaceutical in tissues (SUV) of the PET/CT method were determined and compared with each other (for the same areas). Statistical analysis was performed using the estimate of agreement (by Cohens kappa coefficient and asymptotic test) of the results of the compared methods.Estimates of the prevalence of tumor damage (lymph nodes and extranodal foci) using the diffusion WB-MRI and PET/CT methods were the same. High DC and SUV were observed in the peripheral lymph nodes, extranodal foci and bulky, low DC and SUV in the foci of BM. All 4 methods successfully determined BM damage, however, the diffusion WB-MRI had comparatively less negative results. The highest values of SUV and CD were noted in cases of the 3 grade of FL. Using the diffusion WB-MRI method, the prevalence of tumor lesion was assessed in each patient (nodal and extranodal foci were detected) and the total tumor volume was calculated, BM lesion detection was performed, and the volume of BM lesion was calculated. It is important to note that with the help of diffusion WB-MRI, it was possible to measure separately the total tumor volume (462025 cm3) and separately the volume of bulky (251358 cm3). The diffusion WB-MRI allowed us to differentiate the volume of tumor tissue (reduced as a result of treatment) and residual (fibrous-adipose) tissue in residual formations (which averaged 21% of the initial volume). The predictors of a poor antitumor response were the maximum SUV values (more than 14.0) and the minimum DC values (0.510-3mm2/s) in the BM foci.The diffusion WB-MRI allows for detailed visualization of BM lesions and surrounding soft tissues both in the debut of the FL and in the process of tracking the effectiveness of chemotherapy, which makes it possible to use it along with PET/CT. Diffusion WB-MRI allows to separately evaluate the volume of true tumor tissue and residual tissue. Cases of the 3 grade of FL (including the transformation of FL into diffuse B-large cell lymphoma) are isolated due to low DC values (and high SUV values) in the tumor tissue. BM foci of FL lesion also have (in comparison with nodal and extranodal foci) lower DC values. The predictors of a poor antitumor response were high (from 14.0 or more) SUV valuesin the tumor (and especially in bulky), and low (about 0.5103mm2/s) DC values of BM foci. The PET/CT and diffusion WB-MRI have proven to be reliable diagnostic tools for establishing the stage of FL and detecting BM damage. Diffusion WB-MRI for FL is an informative first-line diagnostic method that allows regular monitoring of the disease and early detection of foci of relapse and disease progression.Цель.Изучение возможностей диффузионно-взвешенной магнитно-резонансной томографии всего тела МРТ-ДВИ-ВТ (в сравнении с позитронно-эмиссионной томографией с компьютерной томографией ПЭТ/КТ) в оценке объема и распространенности опухоли, а также определении поражения костного мозга (при различных цитологических типах) при диагностике и стадировании заболевания у больных фолликулярной лимфомой (ФЛ). Материалы и методы.В проспективное сравнительное поисковое исследование включены 15 пациентов (медиана возраста 53 года) с впервые диагностированной ФЛ. Противоопухолевую химиотерапию пациенты ранее не получали. После установления диагноза все пациенты обследованы методами ПЭТ/КТ и МРТ-ДВИ-ВТ, им также выполнено исследование костного мозга (гистологическое исследование, определение В-клеточной клональности в пунктате костного мозга методом полимеразной цепной реакции). Методом МРТ-ДВИ-ВТ у каждого пациента оценена распространенность опухолевого поражения, подсчитан суммарный объем опухоли, выполнена детекция поражения костного мозга и подсчитан объем костномозгового поражения. Для очагов поражения разной локализации определены и сопоставлены друг с другом (для одних и тех же зон) измеряемый коэффициент диффузии (ИКД) метода МРТ-ДВИ-ВТ и стандартизированный показатель накопления радиофармпрепарата в тканях (SUV) метода ПЭТ/КТ. Статистический анализ проведен c использованием оценки согласия (с коэффициентом каппа Коэна и асимптотическим тестом) результатов сравниваемых методов. Результаты.Оценки распространенности опухолевого поражения методами МРТ-ДВИ-ВТ и ПЭТ/КТ совпали. Высокие значения ИКД и SUV отмечались в периферических лимфатических узлах, экстранодальных очагах и bulky, низкие значения в очагах поражения костного мозга. Все 4 метода успешно определяли поражение костного мозга, однако у метода МРТ-ДВИ-ВТ отмечено сравнительно меньше отрицательных результатов. Самые высокие значения SUV (метод ПЭТ/КТ) и ИКД (метод МРТ-ДВИ-ВТ) отмечались в случаях 3-го цитологического типа ФЛ. Методом МРТ-ДВИ-ВТ у каждого пациента оценена распространенность опухолевого поражения и подсчитан суммарный объем опухоли, выполнена детекция поражения костного мозга и подсчитан объем костномозгового поражения. С помощью МРТ-ДВИ-ВТ удалось измерить отдельно общий объем опухоли (462025 см3) и отдельно объем опухолевых конгломератов bulky (251358 см3). Метод МРТ-ДВИ-ВТ позволил провести дифференциальную диагностику объема опухолевой ткани (редуцировавшей в результате лечения) и резидуальной (фиброзно-жировой) ткани в остаточных образованиях, который составил в среднем 21% от исходного объема. Предикторами плохого противоопухолевого ответа оказались максимальные значения SUV (более 14,0) и минимальные значения ИКД (0,510-3мм2/с) в костномозговых очагах. Заключение.Метод МРТ-ДВИ-ВТ позволяет получать детализированную визуализацию костномозговых очагов поражения и окружающих мягких тканей как в дебюте ФЛ, так и в процессе мониторирования эффективности полихимиотерапии; позволяет раздельно оценивать объем истинной опухолевой ткани и остаточного образования. Случаи 3-го цитологического типа ФЛ вычленяются благодаря низким значениям ИКД (и высоким значениям SUV) в опухолевой ткани. Костномозговые очаги поражения ФЛ также имеют более низкие значения ИКД. Предикторами плохого противоопухолевого ответа оказались высокие (от 14,0 и более) значения SUV в опухоли (и особенно в bulky) и низкие (около 0,5103мм2/с) значения ИКД костномозговых очагов. Методы ПЭТ/КТ и МРТ-ДВИ-ВТ показали себя как надежные диагностические инструменты для установления стадии ФЛ и детекции поражения костного мозга. МРТ-ДВИ-ВТ при ФЛ является информативным диагностическим методом первой линии, позволяющим проводить регулярный мониторинг заболевания и обеспечивать раннее выявление очагов рецидивирования и прогрессирования заболевания.

Background . Myelodysplastic syndromes (MDS) are a heterogeneous group of clonal diseases of the hematopoiesis system characterized by dismyelopoiesis and cytopenia, the presence of cytogenetic aberrations and a high risk of transformation into acute myeloid leukemias. Diagnosis of MDS requires a comprehensive approach and mandatory performance of cytological, cytochemical and cytogenetic studies of bone marrow aspirate, as well as histological examination of trephine biopsy. However, in some cases it is necessary to undergo a diagnostic test that would allow verification of the MDS. The study of bone marrow aspirate by multicolor flow cytometry (MFC) can be considered as an additional diagnostic criterion in the diagnosis of MDS.The objective of the study was to estimate the incidence of myelodysplastic features in patients with various forms of MDS by the MFC method. Materials and methods . The study included 79 patients with MDS: 8 with MDS with 5q deletion, 33 with MDS without excess blast cells and 38 with excess of blasts. A bone marrow aspirate test was performed by 6-color flow cytometry. The control group included 35 donors of allogeneic bone marrow. The analysis resulted in a conclusion on the Ogata score scale, the Wells prognostic scale and the combined Ogata–Wells scale. When using the screening method, the presence of two or more cytometric signs of MDS was detected in 60 (75.9 %) of 79 MDS patients. Wells score was higher in MDS group with an excess of blast than in others. Using the combined Ogata–Wells scale, cytometric aberrations were found in 70 (88.6 %) of 79 MDS patients. In patients with MDS with an excess of blasts, the incidence of increased CD34+ and/or CD117+ myeloid cells was higher than in MDS patients without an excess of blasts and an MDS with a 5q deletion. The frequency of abnormal cytometric parameters (anomalous expression of CD34, CD117, CD56+ myeloblasts) in these groups did not differ. In patients with isolated 5q deletion and MDS without excess of blasts, an increased proportion of CD7+CD34+ cells was more often detected than in MDS with an excess of blasts.Conclusion . Thus, cytometric abnormalities in MDS are common, even in patients without excess of blasts. The MFC method can be used as an additional diagnostic method in the initial diagnosis of MDS.

Background. Nodular lymphocyte-predominant Hodgkin's lymphoma (NLPHL) is a rare Hodgkin's lymphoma subtype with a variable growth pattern and immune tissue architecture of tumor. Clustering of patients into subgroups based on immunohistochemical (IHC) tumor subvariants is essential for prognosis assessment and development of new differentiated treatment approaches. Aim. To study clinical course of NLPHL in patients with different IHC-subvariants of the disease and identify a poor prognosis subgroup. Materials & Methods. From 2010 to 2017 the Department of Anatomic Pathology at the National Medical Hematology Research Center undertook morphological and IHC-analysis of lymph node and bone marrow core biopsies of 60 NLPHL patients: 47 men and 13 women (male/female ratio of 3.6:1) aged 17-68 years (median 37 years). IHC-analysis with expanded panel of antibodies was performed in all cases of determining IHC-subvariants in accordance with WHO-2017 classification. Results. The clinical and immunomorphological comparative study of NLPHL with variant immune tissue architecture allowed to divide the patient population into three subgroups with differently manifested areas similar to T-cell/ histiocyte-rich large B-cell lymphoma (THRLBCL) in lymph node sections or other site biopsies. These subgroups are characterized by different clinical course of the disease. The subgroup with ≥ 50 % THRLBCL-like areas was marked by the prevalence of clinical stage IV and significantly larger amount of extranodal lesions. Conclusion. In NLPHL the most unfavorable clinical course is typical of the patients whose biopsies contain ≥ 50 % THRLBCL-like areas. Semi-quantification of THRLBCL-like areas allowed to define a spectrum of NLPHL IHC-subvariants correlating with the clinical course of the disease. The true transformation into diffuse large B-cell lymphoma is a rare event, it occurred in 2 (3 %) out of 60 patients.

Background To study the histological structure and immunohistochemical (IHC) parameters of the plasmacytoma tumour substrate in patients with multiple myeloma (MM). Methods The study included 21 patients (10 men/11 women) aged 23 to 73 years old with newly diagnosed MM complicated by plasmacytoma. Bone plasmacytoma was diagnosed in 14 patients, and extramedullary plasmacytoma was diagnosed in 7 patients. Plasmacytoma tissue specimens were examined using a LEICA DM4000B microscope. Anti-CD56, anti-CD166, anti-CXCR4, anti-Ki-67, and anti-c-MYC antibodies were used for IHC study of plasmacytoma biopsies. Results When comparing the morphology of bone and extramedullary plasmacytoma, no significant differences were revealed; however, the substrate of extramedullary plasmacytoma was more often represented by tumour cells with an immature morphology than was the bone plasmacytoma substrate (57.1% vs. 28.6%, respectively). We revealed a significant difference in the expression of CD166 between bone and extramedullary plasmacytoma. The mean values ​​of CD166 expression in bone plasmacytoma cells were significantly higher (36.29 ± 7.61% versus 9.57 ± 8.46%, respectively; p = 0.033) than those in extramedullary plasmacytoma cells. We noticed that in extramedullary plasmacytoma cells, there were higher values for the Ki-67 index than in bone plasmacytoma cells, and this result was independent of cell morphology. Conclusion The mechanisms involved in the dissemination of tumour plasma cells are currently unexplored. Even in such a small sample, some differences in expression could be identified, which may indicate that different mechanisms lead to the formation of bone and extramedullary plasmacytomas. Specifically, the expression of CD166 in extramedullary plasmacytoma cells was almost 4 times lower than that in bone plasmacytoma cells, which may indicate the involvement of CD166 in the mechanisms of bone destruction. The proliferative activity of extramedullary plasmacytoma cells was shown to be higher than that of bone plasmacytoma cells.

The aim of the study is to present a successful case in treating primary cutaneous anaplastic large cell lymphoma (PCALCL) occurring with common lesions of the skin and lung tissue.Materials and methods. For the verification of the diagnosis in a patient with three types of skin elements (spot, thin plaque with and without ulceration), differential diagnosis was performed between ulcerative pyoderma gangrenosum, PCALCL, large-cell transformation of mycosis fungoides, and secondary skin lesions under the nodal ALK-negtaive ALCL. A complex of studies, including histological, immunohisto - chemical, cytogenetic studies of skin tumor biopsy, allowed the verification of the PCALCL diagnosis. For the treatment of the patient, intensive induction chemotherapy was used followed by high-dose consolidation and autologous transplantation of hematopoietic stem cells.Results. The selected treatment tactics allowed a long-term complete remission of the disease to be achieved in a patient from the poor prognosis group.Conclusion. An algorithm for the differential diagnosis and tactics of treating is presented for a patient with primary anaplastic large cell lymphoma with a widespread skin lesion and extradermal foci.

Background. Follicular lymphoma (FL) is the most common type of indolent lymphomas and accounts for 20–30 % of all non-Hodgkin’s lymphomas detected. High risk of recurrence and elderly patients make it difficult to choose induction therapy for FL. The R–B course in comparison with the R–CHOP course increases the progressive free survival (PFS) of FL patients and is less toxic. International studies have not studied the efficacy and toxicity of the R–B course due to various cytological types of FL. Aim of the study – assessment of the effectiveness and toxicity of the R–B course (with R support) in general and depending on the different cytological types of FL, the assessment of overall survival (OS) and PFS (adverse events: progression, relapse, death); identification of risk factors for an adverse event in general and death, in particular. The main endpoint of this study is selected BPV. Materials and methods. We performed a prospective, multicenter, open-label trial in Russia since June 1, 2013 till June 1, 2018. The study included 74 patients with FL. Median age of patients was 59 years (from 30 to 78 years). Treatment was completed in 66 patients, so this group of patients was analyzed. Ratio between men and women was 1:2. 32/66 of patients (48 %) were older than 60 years old. Patients received rituximab 375 mg/m2 on day 1 and bendamustine 90 mg/m2 on days 1 and 2 of a 4-week cycle (6 cycles). 49/66 (74 %) of patients were diagnosed with FL grade 1, 10/66 (15 %) – grade 2, 7/66 (11 %) – grade 3A. 34/66 (52 %) patients had nodular tumor growth type, 28/66 (42 %) – nodular-diffuse, 4/66 (6 %) – diffuse. High risk according to FLIPI had 25/59 (42 %) of patients with cytologic grade of FL 1–2 and 7/7 (100 %) of patients with FL grade 3A. Extranodal lesions were revealed in 26/66 (39 %) of cases: in 4/66 of cases – orbit, in 2/66 – parotid gland, in 5/66 – lungs, in 4/66 – intestines, in 2/66 – stomach, 2/66 – pancreas, 2/66 – uterus, 2/66 – skin, 1/66 – subcutaneous tissue, 3/66 – vertebrae, in 1/66 – latticed maze and nasal passages, 1/66 – kidneys, 1/66 – root of the tongue. In 23/26 (88 %) of cases extranodal lesion was revealed in generalized stage of FL (including lymph nodes and bone marrow). Extranodal lesions were found in 37 % of patients with FL grade 1–2, and 57 % with FL grade 3A. Bulky also was observed more frequently in pts with FL grade 3 3/7 (43 %) than in patients with FL grade 1–2 20/59 (34 %). (The risk factors of an adverse event are also its predictors in this study.) Results. Complete remission of disease was achieved in 40/66 (61 %) patients, partial remission – 13/66 (19 %) patients. Tumor progression observed in 11/66 (17 %) cases, patients were withdrawn from the protocol. А partial tumor response was achieved in 2/66 cases (3 %) and patients received high-dose therapy after 4 courses of R–B. Five-year (as well as the 3-year) overall survival (OS) of all patients (n = 66) in R–B was 90 % (95 % confidence interval (CI) 78–96), 5-year PFS – 70 % (95 % CI 55–85) and a 3-year PFS – 75 % (95 % CI 60–89). The cumulative incidence of relapse (considering competing risks of progression and death) at the 3th year after initiation of treatment was 11 % (95 % CI 3–19). The following independent statistically significant (p ≤0.05) predictors of PFS (measured in the onset of the disease) were determined (as a result of a stepwise multivariate cox regression analysis): 1) cytological type of tumor (only type 3A is significant); 2) involvement of nodal zones (more than 4); 3) presence of a conglomerate of tumor lymph nodes larger than 6 cm (bulky); 4) Ki-67 protein expression (more than 35 %). The first 3 characteristics (as well as the sign «presence of extranodal foci», close to the level of significance) are independent statistically significant predictors of OS. In the single factor analysis the following characteristics (besides the above) were significant: index FLIPI (significant only 5 points against all others), bone marrow damage, β2-microglobulin (more than 2.2 mg/L), age (over 68 years) and hemoglobin (less than 110 g/dL). Conclusion 1. The independent negative predictors of OS and PFS in follicular lymphoma were determined. 2. Of the predictors of an adverse event identified, the greatest risk (as a result of a multivariate analysis) is associated with a 3A cytological type of tumor. 3. The FLIPI index has a predictive value not only for the determination of OS, but also for the PFS (moreover, in reduced dichotomous form: 5 points against all the others combined). 4. An increase in the time interval between the first manifestations of follicular lymphoma (lymph node enlargement / appearance of a tumor formation) and the start of therapy beyond a certain threshold value (estimated to be approximately 22 months) is associated (according to the results of univariate analysis) with an increased risk of an adverse event. One of the reasons for the increase in this time interval is associated with expectant medical tactics adopted during the slow development of the clinical picture of the disease. The obtained result shows that the low rate of development of the clinical picture of the disease does not correlate with the low risk of adverse events, and, therefore, cannot be a determining factor when deciding whether to start treatment. 5. The morphology of the tumor is the determining factor in the choice of induction therapy. 6. After achieving full/partial remission of FL, there is a constant risk of recurrence of the disease (by the age of 3 from the termination of treatment, the risk is 11 % (95 % CI 3–19)). 7. The R–B course effectively sanitizes the bone marrow. 8. The R–B allows performing stem cells mobilization and autoSCT that is actual in FL patients with bone marrow involvement. 9. The treatment regimen of R–B is effective and has a relatively low toxicity, so it is advisable in the treatment of elderly patients.

Background. MALT-lymphoma is usually characterized with an indolent course. The factors underlying the effectiveness of the standard chemotherapy in patients with MALT-lymphomas include MALT-IPI risk group and a high SUVmax according to the results of positron emission tomography (PET). All well-known MALT-lymphoma risk factors indirectly indicate a high risk of transformation to large cell lymphoma. The search for an effective chemotherapy continues. Aim. To evaluate the effectiveness of the R-EPOCH/R-BAC escalated immunochemotherapy for MALT-lymphoma patients with poor prognosis factors. Materials & Methods. In the period of 2016-2017 the study included 5 female MALT-lymphoma patients (the mean age of 41 years), of which 1 patient had an early relapse after surgery and 4 patients were newly diagnosed. Prior to therapy 4 patients were evaluated with PET. The mean SUVmax was 10.04. According to MALT-IPI 2 patients belonged to a high-risk group and 3 belonged to a middle-risk group. All the patients received R-EPOCH/R-BAC regimen therapy. A month after completing the treatment all the patients were again evaluated with PET. Results. In 4 patients with 10-24 months follow-up complete remission was reported, which was confirmed by the results of histology and PET. The treatment of 1 patient was not completed. The immunotherapy was well tolerated by the patients. Hematological toxicity grade 3-4 occurred only after completing R-BAC treatment regimens. No severe infectious complications were reported. Conclusion. MALT-lymphoma patients need to be evaluated in terms of all prognostic factors to identify the high-risk patients for whom escalated therapy is to be used already in the first line treatment. This pilot study of the use of R-EPOCH/R-BAC for treatment of MALT-lymphoma patients with poor prognosis factors yielded positive results and showed its acceptable tolerance.

Mucosis fungoidea (МF) belongs to the class of epidermotropic T-cell lymphomas. MF is represented by over 10 sub-types only in terms of its clinical manifestations, with one of them being erythrodermic MF (EMF). This disease is characterized by diverse symptomatology in the form of erythroderma and intense skin itch, aggressive сlinical course and unfavorable prognosis. The disease prognosis also correlates with age, previous history of long-term systemic gluco-corticosteroid treatment (GCS), increased activity of lactate dehydrogenase (LDH) and hypereosinophilia. The choice of MF treatment is determined by the disease stage and somatic status of the patient. In EMF, a therapy combining various effective preparations and taking into account the specifics of the given case is required. Extracorporeal photopheresis (ECP) is frequently an approach of choice; however, it has demonstrated the highest efficacy in Sezary disease or in EFM associated with leucemization. Application of new pharmaceuticals (monoclonal antibodies, epigenetic agents) in combination or in sequence with immune therapy is a promising direction, particularly for treating patients older than 75 years. In this paper, we describe the clinical case of an elderly patient suffering from EMF without peripheral blood leukemia with multimodal factors of unfavorable prognosis, such as age, increased lactate dehy drogenase activity, history of prolonged inefficient treatment with gluco-cortecosteroid preparations and eosinophilia. A long-term positive response to the treatment using sequential immune epigenetic therapy has not been achieved, although the treatment tolerability and the patient's life quality were satisfactory.

Diffuse large B-cell lymphoma is categorized by gene expression profiling into germinal center (GCB) and activated B-cell (ABC) subtype, also referred to as non-germinal center B-cell (non-GCB) by immunohistochemistry. ABC DLBCL is characterized by NF-κB pathway activation and high expression of IRF4/MUM1, a key transcription factor in B cell differentiation. Patients with ABC DLBCL have a significantly worse outcome when treated with standard chemotherapy (R-CHOP). Lenalidomide have shown activity in the ABC-DLBCL in combination with R-CHOP. But about 40% of patients remain resistant. We present the experience of treatment of a patient with generalized non-GCB-DLBCL using the intensive protocol R-mNHL-BFM-90 with lenalidomide.

Nodal anaplastic ALK-negative large cell lymphoma (nALCL, ALK-) is a Т-cell lymphoma that is characterized by aggressive clinical course and low sensitivity to СНОР (cyclophosphamide, doxorubicin, vincristine, prednisolone) and other chemotherapy regimen. In the article we present a literature review and describe our clinical case of nALCL, ALK-. For the first time a combination of Brentuximab vedotin with modified program NHL-BFM-90 was used as a first-line therapy. As a result of immunochemotherapy a complete antineoplastic effect was obtained. For consolidation of this effect high-dose chemotherapy with following autologous blood stem cell transplantation was performed. The chosen treatment tactics allowed to achieve a complete remission in a medium risk group patient.

Objective. To study the histological structure of bone marrow (BM) and plasmacytoma tumor substrate in patients with multiple myeloma (MM). Materials and methods. The study included 35 patients (19 men and 16 women) aged 23 to 73 years with newly diagnosed MM. At the first onset of the disease plasmacytoma was diagnosed in 21 patients: bone plasmacytoma, associated with skeletal bones – in 14 patients; extramedullary plasmacytoma, emerging in various organs not connected with bone tissue – in 7 patients. All patients underwent BM trephine biopsy and plasmacytoma biopsy with subsequent histological examination. BM and plasmacytoma histological specimens were studied using LEICA DM4000B microscope. Frequency domain analysis (cross tables, Fisher–Freeman test) was used for data statistical analysis.Results. The analysis showed that the histological features of BM in MM patients with extramedullary plasmacytoma statistically significantly differed from that in MM patients with bone plasmacytoma and without plasmacytoma. As a result of the analysis, the relationship between BM morphological variant and tumor advancement became apparent. When comparing the morphological pattern of the bone and extramedullary plasmacytomas, no significant differences were found, however, the substrate of the extramedullary plasmacytoma was more often represented by tumor cells with immature morphology as compared to the substrate of the bone plasmacytoma.Conclusion. The established differences in the histological structure of the BM in MM patients with extramedullary plasmacytoma suggest that this type of the disease stands apart and requires further detailed pathomorphological study.

Background: Angioimmunoblast T-cell lymphoma (AITL) is a rare T-cell lymphoproliferative disease that is accompanied by generalized lymphadenopathy, hepatosplenomegaly, intoxication symptoms and extranodal lesions. The extranodal manifestations of the disease frequently involve various skin changes. One of the first such manifestations is maculopapular rashes observed in about half of AITL patients and usually preceding the appearance of lymphadenopathy. Other forms of skin lesions accompany the disease considerably less frequently.Aim: To characterize the range of skin changes in patients suffering from AITL, to establish a correspondence between the nature of skin changes and their histological picture.Materials and methods: 54 AITL patients were being treated at the National Research Centre for Hematology from 2000 to 2017, with the male/female ratio being 30/24. The median age was 61 (29–81) years.Results: Changes in the skin were observed in 24 (44.4 %) of 54 AITL patients, out of whom 18 (75 %) and 6 (25 %) were male and female patients, respectively. Maculopapular rash was observed in 22 (91.7 %) out of 24 patients. The morphological and molecular investigations of skin biopsy specimens exhibiting maculopapular rash demonstrated nonspecific reactive changes. Patients with maculopapular rash demonstrated an increase in the level of total (polyclonal) IgE. Specific skin lesions detected in 8 (14.8 %) cases were represented by a ‘livedo reticularis’, focal skin hyperpigmentation, erythroderma, left eyelid tumour and tumour in 3, 2, 1, 1 and 1 cases, respectively.Conclusion: Maculopapular rash frequently observed in AITL patients is a reactive process not associated with a specific skin lesion. Specific skin lesions in AITL are much less common and can be represented by various forms. In some AITL cases, skin changes of the reactive and tumour nature can be simultaneously observed.

Background. Chronic lymphocytic leukemia (CLL) is a lymphoproliferative disease that manifests by the accumulation of tumor monoclonal B-lymphocytes in the bone marrow, peripheral blood and secondary lymphoid organs. Recently it was found that CLL cells are able to form immunological synapses with microenvironment cells, directly and indirectly affecting their function. Therefore, it became clear that the pathogenesis of CLL is not only escape of apoptosis but also the ability of CLL cells to cause T-lymphocyte anergy, thereby avoiding immune surveillance. Objective: to study the expression of FAS, co-stimulatory molecules CD80 and CD86, PD-1, PD-L1 on CLL cells, and also to study the basic subpopulations of T-cells (naїve, memory, effector cells). Materials and methods. The study included 46 CLL patients: 16 patients with disease progression after chemotherapy and 30 patients with newly diagnosed CLL. “Primary” patients are categorized according to J. Binet’s CLL stages. Stage A was established in 14 patients, B – 10, C – 6. The control group included 29 healthy donors. Peripheral blood was used as a material for analysis. The study was performed on a 6-color flow cytometer BD FACS Canto II (BD Biosciences, USA). Results. In CLL patients, the proportion of CD80+, CD86+, FAS+ B-cells was significantly lower than in donors. In “primary” patients the proportion of CD80 + CLL cells was higher than in patients with CLL progression. Among “primary” patients the proportion of CD80+ and CD86+ was lower in advanced stages of the disease. In patients with CLL progression the proportion of FAS+ B cells was higher than in “primary” patients. The proportion of PD-1+ B cells in CLL patients was higher than in donors and “primary” patients. The proportion of PD-1+ tumor cells was significantly lower in advanced stages of the disease. The proportion of PD-L1+ B cells in CLL patients was lower than in donors. Among the “primary” patients, the proportion of PD-L1+ B-lymphocytes was higher in stage A. The proportion of PD-1+ Thelpers was higher in CLL patients than in donors, and among “primary” patients it was higher in advanced stages of the disease. The proportion of PDL1+ T-helpers and cytotoxic T-cells in CLL patients was lower than in donors. The proportion of naїve cells (CD95-CD28+) in patients compared with donors was lower and the proportion of effector cells (CD95+ CD28–), memory cells (CD95 + CD28 +) was higher, a proportion of CD8+ memory T-cells was higher among patients in the advanced stage of CLL. Conclusion . Therefore, a decline the CD80/CD86+ B-cells in CLL can cause ineffectiveness of an immunological synapse between tumor cells and T-cells, which leads to anergy of T-lymphocytes. Decline expression of the FAS receptor allows tumor CLL cells to avoid FAS-mediated apoptosis. A change in the T-cell pool toward memory cells and effectors, the acquisition of a CD4+PD-1+ (“exhausted”) phenotype impaired antitumor immunity and possible leads to disease progression.

Background. Extramediastinal and bone marrow involvement in PMBCL patients in the onset of the disease is an exception to the rules and complete information, except for the word “rare”, in Russian and international literature is not available. Objective : to characterize PMBCL patients with extramediastinal involvement. Materials and methods. From 2007 to 2017 diagnosis of PMBCL was established in 157 patients according to WHO criteria with extramediastinal involvement in 16 (10.2 %) patients, 3 of them were at different stages of pregnancy. The median age was 27 years (23–69). Patients received different therapy protocols: m-NHL-BFM-90, R-DA-EPOCH и VACOP-B. Results . One extramediastinal lesion was verified in 11/16 (68.7 %) patients, multiple – in 5/11 (31.3 %). The most common localizations were: pancreas – 6 (37.5 %), kidneys – 5 (31.2 %), ovaries – 3 (18.7 %), liver – 3 (18.7 %), bone marrow – 3 (18.7 %) and breast – 2 (12 %) cases. Involvement of stomach, bones, soft tissues, spleen, pelvis, adrenal gland was revealed in one case each. In 15/16 cases, extramediastinal lesions were combined with antero-superior mediastinum involvement and only in 1 cases an isolated lesion of the soft thorax tissues without involvement of mediastinal structures was revealed. Five-year overall survival in the group of patients with classical PMBCL who received R-DA-EPOCH, m-NHL-BFM-90 and cohort of patients with extramediastinal lesions was comparable and was 93 %. As a result of the analysis, in 10.2 % (16/157) of cases extramediastinal involvement was revealed. In all cases, there is involvement of organs and tissues, but not the lymph nodes. In 18.7 % (3/16) of cases there was bone marrow involvement, confirmed by molecular and histological studies. Conclusion. Involvement of the antero-superior mediastinum and the presence of extramediastinal lesion, bone marrow involvement is not excluding criterion for PMBCL, but requires differential diagnosis with DBCL, including standard and molecular methods. Is isolated extramediastinal involvement in PMBCL a poor prognostic factor, is uncertain because of the small number of observations.

Angioimmunoblastic T-cell lymphoma is a rare T-cell lymphoproliferative disease with generalized lymphadenopathy, hepatosplenomegaly, intoxication and polyclonal hypergammaglobulinemia. The persistence of plasma cells in peripheral blood can be a manifestation of both tumor and reactive processes. In our article, we described the case of angioimmunoblastic T-cell lymphoma with an increase in the number of peripheral blood plasma cells to 28 %, and in bone marrow to 9 %. The complex diagnostics, including plasma cells immunophenotyping, morphology of the lymph node biopsy and bone marrow samples, made it possible to verify the diagnosis of angioimmunoblastic T-cell lymphoma with polyclonal plasmacytosis.

Hydroxycarbamide is an antitumor agent mainly used for treatment of Ph-negative myeloproliferative disorders and sickle cell disease. The development of skin ulcers is a rare but serious adverse event in long-term antitumor therapy. Hydroxycarbamide-induced ulcers are often multiple and bilateral, and usually occur in the lower legs, although they can occur in other regions of the body. The ulcers are smallsized and shallow with sharp margins and yellow fibrine-covered base. They cause constant severe, difficult to treat pain which is a characteristic sign. The drug withdrawal usually leads to spontaneous healing of ulcers. Regular dermatologic screening must be obligatory for all the patients receiving hydroxycarbamide. The present paper provides a literature review on dermatological toxicity of hydroxycarbamide and a clinical case description.

Background: Follicular lymphoma (FL) is characterized by clinical and morphological heterogeneity. It is based on the pathogenetic mechanisms of the development of tumor cells. The identification and assessment of risk factors associated with the course of the disease and treatment outcome in FL is an important task, as it allows to evaluate and predict the effectiveness of therapy. Objective: Identify and estimate risk factors for overall survival (OS) and progression free survival (PFS) in FL. Patients and Methods: The prospective exploratory study conducted at National Research Center for Hematology (Moscow) from 01/2017 to 04/2021 included patients (pts)(in total, 80) with FL. Morpho-immunohistochemical, cytogenetic and molecular studies were performed on biopsies of lymph nodes taken before the start of therapy. The mutational status of exon 16 and intron polymorphism rs_2072407 of the EZH2 gene were investigated by Sanger sequencing. 18q21/BCL-2 rearrangements were determined by conventional cytogenetic analysis and/or FISH study. The results obtained in a blind study were compared with the effect of the therapy. Results: Of the 80 pts 34 were male: Me (median) age 50 years (range 30-72) and 46 were female: Me 56 (range 21-81). The median follow-up (FU) time was 53 months. As a result of the study in the multivariate Cox regression model (likelihood-ratio test, p=0.01) of significant factors, selected in the previously univariate analysis, the following statistically significant (Wald test) risk factors for OS and PFS (the events: progression, relapse, or death) were obtained: • BCL-2 gene rearrangements (no vs yes) • EZH2 gene genotypes (AA/AG vs GG) • proliferation index Ki-67 (>35%) • morphological grade (3А vs 1/2) • tumor size (>6 cm /bulky/) (Tab. 1, Fig. 1) The BCL-2 rearrangements were found in 45 from 80 pts (56%; 95 % CI 45-66). The probability of BCL-2 rearrangements is estimated to be about 0.5 (50%). According to the results of Cox-regression analysis (by OS) in the absence of BCL-2 rearrangements, the risk of death in FL was generally significantly (p = 0.01) higher than in the group with its presence: HR = 4.3 (95 % CI 1.5-13.0) (Fig. 2) Mutations in the 16th exon of the EZH2 gene (mutEZH2) were found in 10/80 (13%) pts. Analysis of EZH2 gene mutations with BCL-2 rearrangements revealed that in the mutEZH2 group with the presence of BCL-2 rearrangements, the number of deaths associated with progression is significantly less than in the control initial groups (mutEZH2 with BCL-2 rearrangements - 0/6, mutEZH2 without BCL-2 rearrangements - 2/4, wEZH2 with BCL-2 rearrangements - 3/39 (8%), wEZH2 without BCL-2 rearrangements - 11/31 (35%)) . The prognostic significance of EZH2 genotypes in lymphomas was studied for the first time in this study. The frequencies of rs_2072407 genotypes were: AA - 24% (19), AG - 42% (34), and GG - 34% (27). AA and AG genotypes of the EZH2 gene in pts with FL were associated with an increased risk of death (compared to the GG genotype) : HR = 2.9 (95% CI: 1.2-10.6), p = 0.01 (Fig. 3). The GG variant in most cases was associated with wEZH2 (26/27 (96%)) with BCL-2 rearrangements (16/26 (62%)) and a favorable prognosis (26/27 (96%)) (p = 0.01). Index of proliferative activity Ki-67> 35% (n = 40) and Ki-67 ≤ 35% (n = 40) were equally common in the study group. With a Ki-67> 35%, the probability of death is 2.9 (95% CI 1.1-9.7) times higher. The frequency distribution of morphological grade was as follows: grade 3A - 53% (n = 43) and grade 1-2 - 47% (n = 37). At grade 3A, the probability of death is 2.5 (95% CI 1.1-7.8) times higher. The number of pts with tumor size >6 cm (bulky) and ≤ 6 cm in the sample is approximately the same (41 and 39, respectively), the presence of bulky increased the mortality risk by 2.1 (95% CI 1.0-6.5) times. A short time from the manifestation of the disease to appeal to medical care is a predictor of poor prognosis, but this result we received earlier on a large sample of pts was not significant on a smaller sample. Conclusions: As a result of the multivariable Cox regression analysis, we identified and confirmed the previously obtained factors (bulky, grade 3A, Ki-67 > 35%, short medical history), and discovered new biogenetic factors (BCL-2 rearrangements and the GG rs2072407 genotype of the EZH2 gene). The model based on these independent risk factors improves the accuracy of predicting adverse events and allows to use more personalized treatment options for patients with FL. Figure 1 Figure 1. Disclosures No relevant conflicts of interest to declare.