Search

The study of activating mutations (NRAS,KRAS,FLT3,JAK2,CRLF2genes) of RAS/RAF/MEK/ERK and JAK/STAT signaling pathways in B-cell acute lymphoblastic leukemia (B-ALL) in adult patients which are included in Russian multicenter clinical trials.Within the multicenter study there were 119 adult patients included withde novoB-ALL. The study was considered as prospective and retrospective. The group withBCR-ABL1-negative B-ALL consisted of up to 93 patients (45 male and 48 female, at the age of 17 to 59, the median age 31), they were treated according to the protocols ALL-2009, ALL-2016. The median follow-up lasted for 19 months (1119). The group withBCR-ABL1-positive B-ALL with up to 26 patients (10 male and 16 female, at the age of 23 to 78, the median age 34 years) was included in the study as well. The treatment was carried out according to the protocols ALL-2009 and ALL-2012 in combination with tyrosine kinase inhibitors. The median follow-up lasted for 23 months (4120). The molecular analysis of activating mutations inNRAS,KRASgenes (RAS/RAF/MEK/ERK signaling pathway) andJAK2,CRLF2genes (JAK/STAT signaling cascade) was performed via Sanger sequencing. The internal tandem duplications (ITDs) inFLT3gene were studied by fragment analysis. The evaluation of CRLF2 expression was fulfilled via flow cytometry.Activating mutations inNRAS,KRAS,FLT3genes were found in 22 (23.6%) patients withBCR-ABL1-negative B-ALL. In total, 23 mutations were revealed in theNRAS(n=9),KRAS(n=12), andFLT3(n=2) genes, according to statistics that was significantly more frequent than withBCR-ABL1-positive B-ALL, these genes mutations were not identified in patients (p=0.007). The frequency of mutations detection inKRASandNRASgenes in patients withBCR-ABL1-negative B-ALL was comparable as 12.9% (12 of 93) to 9.7% (9 of 93), respectively (p=0.488). One patient was simultaneously revealed 2 mutations in theKRASgene (in codons 13 and 61).FLT3-ITD mutations were detected in 3.5% (2 of 57) cases ofBCR-ABL1-negative B-ALL. In patients withBCR-ABL1-positive B-ALLFLT3-ITD mutations were not assessed. Violations in the JAK/STAT signaling cascade were detected in 4 (4.3%) patients withBCR-ABL1-negative B-ALL. They were represented by the missense mutations ofJAK2gene (n=3) and the overexpression of CRLF2 (n=2); in one patient were detected the overexpression of CRLF2 and a mutation inJAK2gene simultaneously. No mutations were found inCRLF2gene. In patients withBCR-ABL1-positive B-ALL noJAK2mutations were detected. As long as analyzing demographic and clinical laboratory parameters between groups of patients with and without mutations, there were no statistically significant differences obtained. In the analyzed groups of patients, long-term therapy results did not differentiate according to the mutations presence inNRAS,KRAS,FLT3,JAK2genes. Also, substantive differences were not shown in the rate of the negative status achievement of the minimum residual disease between patients with and without activating mutations in the control points of the protocol (on the 70th, 133rd and 190th days).NRAS,KRAS,FLT3,JAK2activating mutations do not affect the long-term results of the therapy and the rate of the negative status achievement of the minimum residual disease in patients withBCR-ABL1-negative B-ALL treated by the Russian multicenter clinical trials.Цель.Изучение активирующих мутаций генов (NRAS,KRAS,FLT3,JAK2,CRLF2) сигнальных каскадов RAS/RAF/MEK/ERK и JAK/STAT при В-клеточном остром лимфобластном лейкозе (В-ОЛЛ) у взрослых больных, включенных в российские многоцентровые исследования. Материалы и методы.В многоцентровое исследование включены 119 взрослых пациентов с впервые установленным В-ОЛЛ. Исследование носило проспективный и ретроспективный характер. Группа сBCR-ABL1-негативным В-ОЛЛ составила 93 больных (48 женщин и 45 мужчин от 17 до 59 лет, медиана возраста 31 год), им проводили терапию по протоколам ОЛЛ-2009, ОЛЛ-2016. Медиана наблюдения составила 19 мес (1119). В группу сBCR-ABL1-позитивным В-ОЛЛ включены 26 пациентов (16 женщин и 10 мужчин от 23 до 78 лет, медиана возраста 34 года). Лечение проводили по протоколам ОЛЛ-2009 и ОЛЛ-2012 в сочетании с ингибиторами тирозинкиназ. Медиана наблюдения составила 23 мес (4120). Молекулярный анализ активирующих мутаций для геновNRAS,KRAS(сигнальный путь RAS/RAF/MEK/ERK) и геновJAK2,CRLF2(сигнальный путь JAK/STAT) проводился методом секвенирования по Сэнгеру. Внутренние тандемные повторы (ITD) генаFLT3 рецепторной внутриклеточной тирозинкиназы, приводящие к запуску целого каскада реакций, относящихся к различным сигнальным путям, включая RAS/RAF/MEK/ERK и JAK/STAT, исследованы методом фрагментного анализа. Экспрессию белка CRLF2 оценивали методом проточной цитофлуориметрии. Результаты.Активирующие мутации в генахNRAS,KRAS,FLT3обнаружены у 22 (23,6%) больныхBCR-ABL1-негативным В-ОЛЛ. В общей сложности выявлено 23 мутации в генахNRAS(n=9),KRAS(n=12),FLT3(n=2), что статистически значимо чаще, чем приBCR-ABL1-позитивном В-ОЛЛ, где мутации этих генов не выявлены ни у одного больного (р=0,007). Частота обнаружения мутаций в генахKRASиNRASу больныхBCR-ABL1-негативным В-ОЛЛ сопоставима 12,9% (12 из 93) и 9,7% (9 из 93) соответственно (р=0,488). У одного больного выявлено одновременно 2 мутации в генеKRAS(в кодонах 13 и 61). МутациюFLT3-ITD детектировали в 3,5% (2 из 57) случаевBCR-ABL1-негативных В-ОЛЛ. У больныхBCR-ABL1-позитивным В-ОЛЛ мутациюFLT3-ITD не оценивали. Нарушения в сигнальном каскаде JAK/STAT обнаружены у 4 (4,3%) больныхBCR-ABL1-негативным В-ОЛЛ. Они представлены миссенс-мутациями генаJAK2(n=3) и гиперэкспрессией CRLF2 (n=2), у одного больного обнаружены одновременно гиперэкспрессия CRLF2 и мутация в генеJAK2. В генеCRLF2мутации не выявлены. У больныхBCR-ABL1-позитивным В-ОЛЛ мутаций генаJAK2не выявлено. При анализе демографических и клинико-лабораторных показателей между группами больных с мутациями и без таковых статистически значимых различий не получено. В анализируемых группах больных долгосрочные результаты терапии в зависимости от наличия мутаций в генахNRAS,KRAS,FLT3,JAK2не различались. Также не показано значимых отличий в скорости достижения негативного статуса минимальной остаточной болезни между пациентами с активирующими мутациями и без в контрольные сроки протокола (на 70, 133 и 190-й день). Заключение.Активирующие мутации геновNRAS,KRAS,FLT3,JAK2не влияют на долгосрочные результаты терапии и скорость достижения негативного статуса минимальной остаточной болезни у больныхBCR-ABL1-негативным В-ОЛЛ при применении протоколов российского многоцентрового исследования.

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).

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.

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.

Breast implant-associated anaplastic large-cell lymphoma will be identified as a separate nosological entity in the 2017 adapted WHO classification due to differences in its clinical presentations, pathogenesis, and prognosis with those of nodal and cutaneous anaplastic large-cell lymphomas. The paper gives a review of the literature and describes the authors' own clinical case of common breast implant-associated anaplastic large-cell lymphoma involving breast tissue, axillary lymph nodes, anterior chest muscles, and bone marrow. The treatment policy chosen by the authors could achieve complete remission.Ассоциированная с имплантатом анапластическая крупноклеточная лимфома молочной железы будет выделена в отдельную нозологическую единицу в адаптированной классификации ВОЗ от 2017 г. в связи с различиями клинической картины, патогенеза и прогноза с нодальной и кожной анапластическими крупноклеточными лимфомами. В статье представлен обзор литературы и описано собственное клиническое наблюдение распространенной ассоциированной с имплантатом анапластической крупноклеточной лимфомы, протекающей с поражением ткани молочной железы, подмышечных лимфатических узлов, мышц передней грудной стенки и костного мозга. Выбранная нами тактика лечения позволила достигнуть полной ремиссии заболевания.

Double-hit lymphoma (DHL) is a rare aggressive B-cell lymphoma with concomitant c-MYC, BCL2 or BCL6 gene rearrangements, which is characterized by the high frequency of extranodal lesions and by resistance to chemotherapy. The median survival does not exceed 18 months in patients with this disease. The majority of DHL is represented by с-MYC/BCL2 cases. The combination of c-MYC/BCL6 occurs rarely (5-8%). The paper describes a case of DHL with concomitant c-MYC and BCL6 gene rearrangements, which mimics diffuse large B-cell lymphoma, leg-type.'Double-hit' лимфома (DHL) - редкая агрессивная В-клеточная лимфатическая опухоль с сочетанной перестройкой генов с-MYC, BCL2 или BCL6, характеризующаяся высокой частотой экстранодальных поражений и резистентностью к химиотерапии. Медиана продолжительности жизни при данном заболевании не превышает 18 мес. Большинство DHL представлено случаями с-MYC/BCL2. Сочетание с-MYC/BCL6 встречается редко (5-8%). Представлен случай DHL-лимфомы с сочетанной реаранжировкой генов c-MYC и BCL6, протекающей под маской ДВККЛ leg-type.

To characterize a group of patients with follicular lymphoma (FL) with leukemization and to evaluate the efficiency of different therapy options (R-CHOP/R-FMC/high-dose chemotherapy (HDCT)).18 (7.2%) out of 250 patients diagnosed with FL, who were examined and treated at the National Research Center for Hematology, Ministry of Health of the Russian Federation, were found to have leukemic FL (tumor cells in the peripheral blood smears were detected by cytology and flow cytofluorometry. Eight of the 18 patients had extranodal foci of involvement: lung, stomach, spleen, lumbar muscles, upper jaw, and vertebrae. Bone marrow was involved in 17 of the 18 patients. Tumor biopsy specimens displayed a morphological pattern of indolent FL in the majority of patients (10 of the 18 patients had cytological grade 1-2 tumors and 14 patients had a nodular or nodular-diffuse tumor growth pattern). The patients underwent R-CHOP/R-FMC) or HDCT cycles as first-line therapy, followed by autologous stem cell transplantation (auto-SCT).The median follow-up was 66 months (range 12-217 months). The 5-year overall survival (OS) and progression-free survival (PFS) rates were 70% (10% SEM) and 35% (15% SEM), respectively. The median OS was not reached; the median PFS was 3 years.Leukemic FL is characterized by low OS and PFS rates. The most effective chemotherapy regimens were R-CHOP, followed by HDCT and auto-SCT in first remission or R-FMC. These cycles can to a greater extent achieve a complete eradication of the bone marrow tumor clone. Due to the relapsing course of FL and the aggressiveness of leukemic FL, it is expedient to carry out auto-SCT in first remission.Цель исследования. Охарактеризовать группу больных фолликулярной лимфомой (ФЛ) с лейкемизацией и оценить эффективность разных вариантов терапии (R-CHOP/R-FMC/высокодозной химиотерапии - ВХТ). Материалы и методы. Из 250 пациентов с диагнозом ФЛ, которые обследовались и получали терапию в ФГБУ ГНЦ МЗ РФ, у 18 (7,2%) выявлен лейкемический вариант ФЛ (обнаружены опухолевые клетки в мазках периферической крови цитологически и методом проточной цитофлюориметрии - ПЦФМ). У 8 из 18 пациентов определялись экстранодальные очаги поражения: вовлечение легких, желудка, селезенки, поясничных мышц, верхней челюсти, позвонков. В 17 из 18 случаев вовлечен костный мозг. Морфологически в биоптате опухолей у большинства пациентов отмечалась картина индолентной ФЛ (у 10 из 18 I-II цитологический тип опухоли, у 14 из 18 нодулярный и нодулярно-диффузный характер опухолевого роста). В качестве терапии первой линии пациентам проводились курсы R-CHOP/R-FMC или ВХТ с последующей трансплантацией аутологичных стволовых клеток крови (ауто-ТСКК). Результаты. Медиана наблюдения составила 66 мес (12-217 мес). Пятилетняя общая выживаемость (ОВ) и выживаемость без прогрессирования (БПВ) составили 70% (стандартная ошибка 10%) и 35% (15%) соответственно. Медиана общей продолжительности жизни не достигнута, медиана продолжительности жизни без прогрессирования составила 3 года. Заключение. Лейкемический вариант ФЛ характеризуется низкими ОВ и БПВ. Наиболее эффективными оказались следующие химиотерапевтические режимы: R-CHOP c последующей ВХТ и ауто-ТСКК в первой ремиссии или R-FMC. Данные курсы позволяют в большей степени добиться полной эрадикации опухолевого клона в костном мозге. В связи с рецидивирующим течением ФЛ, а также агрессивностью лейкемического варианта ФЛ в первой ремиссии целесообразно проводить ауто-ТСКК.

To determine the prevalence of amp1q21 and its relationship to the clinical manifestations of multiple myeloma (MM).In December 2009 to March 2016, a total 134 patients aged 30 to 81 years (median 57 years) underwent a pretreatment FISH-study of bone marrow (BM) with centromeric and locus-specific DNA probes to identify amp1q21, t(11;14), t(4;14), t(14;16), t(14;20), t(6;14), trisomies of chromosomes 5, 9, 15, del13q14, del17p13/TP53, and t(8q24)/cMYC. Induction therapy with bortezomib-containing cycles was performed. Autologous stem cell transplantation was carried out in 48 patients. The median follow-up of patients was 19.3 months (3.2-77.4 months). Disease progression was diagnosed in 69 (51.5%) patients; 12 patients also underwent FISH study during disease progression.At the onset of MM, amp1q21 was detected in 53 (39.6%) patients. The overall 5-year survival rate in patients with amp1q21 was almost 2 times lower than that in those without amp1q21 (43.5 and 79.4%, respectively; p=0.07). The overall 5-year survival rate in patients with one extra copy of 1q21 (only 3 copies) was 67.3%, that in those with 2 or more extra copies of 1q21 (only 4-7 copies) was 20.9% (p=0.0016). Nine (75%) of the 12 patients examined during disease progression were found to have amp1q21: 2 cases were detected in the period of progression to have amp1q21 in its absence at disease onset; 7 cases had amp1q21 both at MM onset and progression; however, the number of copies of 1q21 was unchanged.Аmp1q21 is one of the most common chromosomal abnormalities in patients with new-onset MM and may appear in the course of disease progression. The presence of аmp1q21 is an important prognostic factor and must have to be included in the diagnostic study both at disease onset and progression.Цель исследования. Определить распространенность amp1q21 и ее связь с клиническими проявлениями множественной миеломы (ММ). Материалы и методы. C декабря 2009 г. по март 2016 г. 134 пациентам в возрасте от 30 лет до 81 года (медиана 57 лет) до начала лечения выполнено FISH-исследование костного мозга (КМ) с центромерными и локус-специфичными ДНК-зондами для выявления amp1q21, t(11;14), t(4;14), t(14;16), t(14;20), t(6;14), трисомий хромосом 5, 9, 15, del13q14, del17p13/TP53, t(8q24)/сMYC. Индукционная терапии выполнялась курсами, содержащими бортезомиб. Трансплантация аутологичных стволовых клеток выполнена 48 больным. Медиана наблюдения за больными составила 19,3 мес (3,2-77,4 мес). Прогрессирование заболевания диагностировано у 69 (51,5%) пациентов, 12 пациентам FISH-исследование также проведено в период прогрессирования заболевания. Результаты. В дебюте ММ amp1q21 обнаружена у 53 (39,6%) больных. Общая 5-летняя выживаемость у больных с amp1q21 почти в 2 раза ниже, чем у больных без нее, - 43,5 и 79,4% соответственно (р=0,07). Общая 5-летняя выживаемость у больных с одной дополнительной копией 1q21 (всего 3 копии) составила 67,3%, с 2 дополнительными копиями и более 1q21 (всего 4-7 копий) - 20,9% (р=0,0016). Из 12 пациентов, обследованных в период прогрессирования заболевания, amp1q21 выявлена у 9 (75%): в 2 случаях amp1q21 выявлена в период прогрессирования в отсутствие в дебюте; в 7 случаях amp1q21 обнаружена и в дебюте, и в период прогрессирования ММ, однако количество копий 1q21 не изменилось. Заключение. Аmp1q21 - одно из наиболее распространенных хромосомных нарушений у больных с впервые выявленной ММ и может появляться в ходе прогрессирования заболевания. Наличие аmp1q21 является важным прогностическим фактором и, вероятно, должна включаться в диагностические исследования как в дебюте, так и в период прогрессирования заболевания.

to evaluate the efficiency of high-dose chemotherapy (HDCT) with further autologous blood stem cell transplantation (auto-BSCT) in the first-line therapy of patients with follicular lymphoma (FL) and poor prognostic factors.In 2000 to 2015, the National Research Center for Hematology, Ministry of Health of the Russian Federation, performed therapy in 39 patients with FL and poor prognostic factors (a total of 215 patients with FL). The R-CHOP treatment was done as induction therapy. Sequential HCT and further auto-BSCT were performed in 29 (74%) of the 39 patients, who had shown a partial tumor response to the induction therapy or achieved partial remission after 4-6 cycles of CT, but had poor prognostic factors. 22 of the 29 patients underwent auto-BSCT in first-line therapy after induction R-CHOP regimens. Among them, there were 17 men with a median age of 46 years (31-68 years). 21 of the 22 patients were recorded to have Stage IV by the Ann Arbor staging classification. Bulky peritoneal and retroperitoneal tumors larger than 7 cm were detectable at disease onset in 14 of the 22 cases. Two patients were noted to have phenomena of leukemization. 16 patients had bone marrow (BM) involvement. According to the Follicular Lymphoma International Prognostic Index-1 (FLIPI-1), the patients were divided into 3 groups: 1) a low risk (n=5); 2) an intermediate risk (n=3); a high risk (n=14). B-symptoms were observed in 16 cases. 16 patients were diagnosed with cytological grade I-II FL and 6 had grade IIIA. According to the tumor proliferative pattern, the distribution turned out to be as follows: nodular (n=6), nodular-diffuse (n=13), and diffuse (n=3). The proliferative activity index averaged 30% (8-90%). Serum and urine proteins were immmunochemically assayed in 18 cases, out of them 8 patients were diagnosed as having serum β2-microglobulin concentrations above normal as a poor prognostic factor. In 14 of the 22 patients, the activity of lactate dehydrogenase was greater than normal (266-7806 U/l).Out of the 22 patients, 20 who have undergone auto-BSCT in first-line therapy are survivors and have remission of the underlying disease: 18 and 2 patients achieved complete and partial remission, respectively. The follow-up period was 7 to 178 months (median, 32 months). After auto-BSCT in the first remission, 2 patients developed disease recurrences: an early recurrence after 9 months in one case and a late recurrence 6 years after completion of therapy in the other.The first prospective study of intensive therapy for FL in Russia has demonstrated that HDCT with further auto-BSCT in first-line therapy allows complete remission in patients with poor prognostic factors and higher overall and progression-free survival rates.Цель исследования. Оценить эффективность высокодозной химиотерапии (ХТ) с последующей трансплантацией аутологичных стволовых клеток крови (ауто-ТСКК) в терапии первой линии у больных с фолликулярной лимфомой (ФЛ) и факторами неблагоприятного прогноза. Материалы и методы. В период с 2000 по 2015 г. в ФГБУ Гематологический научный центр МЗ РФ проводилась терапия 39 пациентам с ФЛ и факторами неблагоприятного прогноза (всего 215 больных с ФЛ). В качестве индукционной терапии проведено лечение по программе R-CHOP. У 29 (74%) из 39 пациентов в случае частичного ответа опухоли на индукционную терапию или достижения частичной ремиссии после 4-6 курсов ХТ, но при наличии факторов неблагоприятного прогноза, выполнена последовательная высокодозная химиотерапия (ПВХТ) с последующей ауто-ТСКК. Из 29 больных ауто-ТСКК в терапии первой линии после индукционных режимов по программе R-CHOP выполнена 22 больным. Из них 17 мужчин с медианой возраста 46 (31-68) лет. У 21 из 22 больных констатирована IV стадия заболевания по классификации Ann Arbor. В 14 из 22 случаев в дебюте заболевания определялись опухолевые конгломераты более 7 см внутрибрюшной или забрюшинной локализаций (bulky). У 2 больных отмечались явления лейкемизации. У 16 пациентов имелось поражение костного мозга (КМ). По критериям FLIPI-1 пациентов разделили на 3 группы: в 1-й группе риска было 5 больных, во 2-й - 3, в 3-4-й - 14. В 16 случаях наблюдалось наличие В-симптомов. У 16 пациентов диагностирован I-II цитологический тип ФЛ, у 6 - IIIА. По характеру пролиферации опухоли распределение оказалось следующим: нодулярный у 6 больных, нодулярно-диффузный - у 13, диффузный - у 3. Индекс пролиферативной активности в среднем составил 30% (8-90%). Иммунохимическое исследование белков сыворотки крови и мочи проведено в 18 случаях, из них концентрация β2-микроглобулина в сыворотке выше нормы, как фактор неблагоприятного прогноза, диагностирована у 8 из 18 больных. Активность лактатдегидрогеназы превышала норму (266-7806 ед/л) у 14 из 22 пациентов. Результаты. Из 22 пациентов 20, перенесшие ауто-ТСКК в терапии первой линии, живы и находятся в ремиссии по основному заболеванию: полная ремиссия достигнута у 18, частичная - у 2. Период наблюдения составляет от 7 до 178 (медиана 32) мес. У 2 пациентов после ауто-ТСКК в первой ремиссии развились рецидивы заболевания: в одном случае - ранний спустя 9 мес, во втором случае - поздний спустя 6 лет от окончания терапии. Заключение. Результаты первого проспективного исследования интенсивной терапии у больных ФЛ в России демонстрируют, что ПВХТ с последующей ауто-ТСКК в терапии первой линии позволяет достичь полной ремиссии заболевания у пациентов с факторами неблагоприятного прогноза, а также увеличить общую и беспрогрессивную выживаемость.

Myeloproliferative disease associated with FGFR1 rearrangement (8p11), which is included in the 2008 WHO Classification of Myeloid Neoplasms, is a rare and extremely aggressive abnormality. The paper describes a clinical case of a 39-year-old female patient who was detected to have leukocytosis (as high as 47.2·109/l), absolute eosinophilia (as high as 3.1·109/l), and enlarged peripheral lymph nodes during her visit to a doctor. The bone marrow (BM) showed the changes typically encountered in myeloproliferative disease with eosinophilia. The patient was found to have t(8;13)(p11;q12) translocation associated with the rearrangement of the FGFR1 gene located at the 8p11 locus. Molecular and cytogenetic examinations failed to reveal BCR-ABL chimeric transcript, Jak2 V617F mutation, and deletions and translocations involving PDGFRA (4q12) and PDGFRB (5q32-33). The similar changes in the karyotype were also found in the lymph node cells. The undertaken treatment with hydroxyurea and the tyrosine kinase inhibitor dasatinib turned out to be ineffective. The patient underwent allogeneic BM transplantation from a HLA-identical sibling. Graft rejection occurred 6 months later. Allogeneic BM transplantation from the same donor (100% donor chimerism; FGFR1/8р11 translocation was not detected), which was complicated by the development of chronic graft-versus-host reaction, was performed again in March 2015. The patient is being followed up and continues to receive immunosuppressive therapy.Миелопролиферативное заболевание, ассоциированное с реаранжировкой гена FGFR1 (8р11), включенное в классификацию миелоидных новообразований ВОЗ, 2008 г., - редко встречающаяся патология, протекающая чрезвычайно агрессивно. Приведено клиническое наблюдение 39-летней пациентки, у которой при обращении к врачу выявлены лейкоцитоз (до 47,2·109/л), абсолютная эозинофилия (до 3,1·109/л), увеличение периферических лимфатических узлов. В костном мозге (КМ) наблюдались изменения, характерные для миелопролиферативного заболевания с эозинофилией. У больной выявлена транслокация t(8;13)(p11;q12), связанная с перестройкой гена FGFR1, расположенного в локусе 8p11. При молекулярном и цитогенетическом исследованиях химерный транскрипт BCR-ABL, мутация V617F гена Jak2, делеции и транслокации с вовлечением локусов генов PDGFRA (4q12) и PDGFRB (5q32-33) не обнаружены. Аналогичные изменения кариотипа выявлены и в клетках лимфатического узла. Предпринятое лечение больной гидроксимочевиной и ингибитором тирозинкиназ дазатинибом оказалось неэффективным. Выполнена трансплантация аллогенного КМ от сиблинга, совместимого по HLA. Спустя 6 мес произошло отторжение трансплантата. В марте 2015 г. проведена повторная аллотрансплантация КМ от того же донора (100% донорский химеризм, транслокация FGFR1/8р11 не выявляется), осложнившаяся развитием хронической реакции трансплантат против хозяина. Пациентка остается под наблюдением, продолжает получать иммуносупрессивную терапию.

The term mastocytosis (MC) encompasses a group of rare diseases characterized by the tumorous proliferation of clonal mast cells and the infiltration of one or several organs. The clinical picture of MC is extremely diverse from skin lesions that can spontaneously regress to the aggressive disease forms associated with organ dysfunction and short survival. Nowadays, the 2008 WHO classification identifies 7 MC subtypes. The disease is diagnosed on the basis of its clinical manifestations and detection of tumorous mast cell infiltrations via morphological, immunohistochemical, immunophenotypic, genetic, and molecular examinations. Abnormal mast cells are characterized by the atypical morphology and pathological expression of CD25 and CD2 antigens. Enhanced serum tryptase activity is a common sign in all MC subtypes. More than 90% of the patients have D816V KIT mutations in the mast cells. This paper reviews the literature. Three cases are described as a clinical example in patients with different MC subtypes.

Double-hit (DH) lymphoma, an extremely aggressive variant of B-cell lymphoma, is accompanied by chromosomal abnormalities leading to the activation of a few oncogenes, one of which is the c-MYC gene in conjunction with BCL2 or BCL6 gene rearrangements. There are most common cases of MYC/8q24 and BCL2/18q21 gene rearrangements (MYC/BCL-2 DH lymphoma). The tumor is characterized by an aggressive clinical course and a poor response to chemotherapy (CT). The median survival in patients with DH lymphomas varies from 4.5 to 18 months. Such patients are generally resistant to CHOP-21 and R-CHOP-21 therapy regimens. For the treatment of patients with DH lymphoma, the Hematology Research Center, Ministry of Health of the Russian Federation, chose an original BL-M-04 polychemotherapy (PCT) protocol in combination with rituximab, followed by autologous stem cell transplantation (allo-SCT). The paper describes the experience in successfully treating a patient with two hematologic tumors: 1) MYC/BCL-2 DH lymphoma with high-dose PCT cycles, followed by allo-SCT, and 2) a metachronously developed second tumor (acute myelomonoblastic leukemia (AMML)) with CT cycles, followed by auto-SCT. The incidence of tumors induced by the previous high-dose CT for aggressive lymphomas for 10 years is 0.7 to 10%. As a rule, the development of secondary AMML is preceded by a history of myelodysplastic syndrome (MDS); characteristic chromosomal abnormalities (deletions of the long arm of chromosomes 5 and 7) are detectable. In this case, the follow-up was 3 months before the development of AMML, during this period the patient was not found to have laboratory signs of MDS (anemia, thrombocytopenia) or chromosomal abnormalities associated with secondary MDS/AML. The presence of a leukemic stem cell is associated with the occurrence and development of hemoblastosis; that of the similar cell populations that may cause B-cell lymphomas remains uncertain. The described case may have defect in a hematopoietic stem cell that gives rise to both germs of hematopoiesis, as well as complete donor chimerism of bone marrow hematopoiesis, which gives hope to long-term remission in both DH lymphoma and AMML.

To make a randomized comparison of 2 consolidation treatment options (two patient groups): 2 cycles of cytarabine in average (Ig/m2 in Group 2) and standard (100 mg/mi2 in Group 1) doses in combination with idarubicin (8-12 mg/m2) and mitoxantrone (10 mg/m2), after two 7+3 induction cycles of daunorubicin (60 mg/mi2) and subsequent 6 cycles of maintenance therapy.In January 2010 to October 2013, a Russian multicenter trial was conducted to treat patients with acute myeloid leukemias (AML) in accordance with the AML-01.10 protocol (ClinicalTrials.gov Identifier: NCT01587430). The trial enrolled 243 AML patients from 21 centers, including 71 patients (median age 38 years) from the State Hematology Center, Ministry of Health of the Russian Federation; 35 and 36 patients were randomized to Groups 1 and 2, respectively. The randomized groups were balanced by basic clinical and laboratory parameters. Favorable, intermediate, and high cytogenetic prognoses were in 14 (21.9%), 40 (62.5%), and 10 (15.6%) patients, respectively.Prior to treatment, 2 patients died; one patient refused treatment. Fifty-eight (85.3%) of the 68 patients achieved complete remission (CR); early deaths was in 2 (2.9%) and resistance in 8 (11.8%). Four (6.9%) patients died during CR. Protocol deviations (doses, intervals, and the number of cycles) were recorded in 12 (20.7%) of the 58 patients. Other 8 (11.8%) patients were switched to low-dose cytarabine because of complications, withdrawn from the protocol and not included into the analysis of randomized comparison. Twenty allogeneic bone marrow transplantations (allo-BMT) (7 related, 12 unrelated, and 1 haploidentical) were performed; of them 15 allo-BMTs were done during first CR. In the 68 patients, 3-year overall survival (OS) was 45.6%; relapse-free survival (RFS) was 41.5%. OS was 64.6% in Group 1 and 58.3% in Group 2; RFS was 62 and 38.8% in Groups 1 and 2, respectively (p0.5). In the favorable, intermediate, and high prognosis groups, OS was 79.5, 60, and 31.1% and RFS was 81.8, 41.3, and 33.3%, respectively (p=0.1). The consolidation treatment option unchanged survival rates in the above risk groups. Unachieved CR after the first cycle considerably decreased RFS (33.9% versus 60%) and served as an indication for allo-BMT during first CP (RFS without BMT was 0; that with BMT was 78%).No differences were found between both consolidation options according to long-term results. Protocol deviations were recorded in one-third of the patients. While implementing the protocol, the efficiency of treatment was high. Allo-BMT during first CR substantially increased RFS if CP was not achieved after the first cycle.

Myeloid sarcoma (MS) is a rare malignant solid tumor presented with myeloid blast cells showing varying degrees of maturation. MS may have an extramedullary site, precede, or develop simultaneously with the clinical manifestations of acute myeloid leukemia (AML); it may also occur as an AML relapse. Besides AML, MS may be a manifestation of chronic myeloid leukemia or other chronic myeloproliferative diseases. Due to the fact that this disease is rare, the bulk of the literature on MS is presented with single descriptions of retrospective studies and clinical cases. The paper describes 3 cases of MS with inversion of chromosome 16 and small bowel lesion.

To evaluate the efficiency of intensive polychemotherapy (PCT) in adult patients having diffuse large B-cell lymphoma (DLBL) of bones and soft tissues with and without poor prognostic factors (PPF).Out of 58 enrolled patients, 51 were diagnosed as having DLBL. Burkitt's lymphoma (BL) was diagnosed in 6 patients. One patient had marginal zone B-cell lymphoma. Thirty-five patients with DLBL (10 patients with PPF and 25 without PPF) and 3 patients with BL were treated with the CHOP/R-CHOP regimen. The NHL-BFM-90 program was used in 3 patients with BL and 16 with DLBL (15 patients with PPF and 1 patient without PPF).After radiotherapy, the patient with marginal zone B-cell lymphoma achieved a 20-month remission; three BL patients receiving CHOP died. All the BL patients receiving NHL-BFM-90 achieved complete remissions of 48 to 72 months. In 9 patients having DLBL without PPF, who received CHOP, five-year overall and event-free survival rates were 100%; in 22 patients with PPF, these were 50 and 45%, respectively. In the patients with and without PPF, who received CHOP/R-CHOP, the survival rates differed statistically significantly (p = 0.01; logrank test). In the group of 15 patients having DLBL with PPF, who were treated with the NHL-BFM-90 protocol, 14 achieved an average remission of 17 months. In the patients having DLBL with PPF who used NHF-BFM-90, therapeutic efficiency was significantly higher (p = 0.05; Fisher's exact test).Differential therapy for primary lymphomas of bones and soft tissues indicated that the NHL-BFM-90 protocol used in the PPF group was significantly more effective than the CHOP regimens.

To characterize clinical and epidemiological features of adult Berkitt's lymphoma (BL).The trial enrolled 72 patients (51 males and 21 females, age 14-69, mean age 27 years) treated in 1995-2008.Stage I BL (by S.B. Murphy) was diagnosed in 5 patients, stage II--in 9, stage III--in 25, IV--in 14 patients, B-cell acute lymphoblastic leukemia (ALL) (L3)--in 19 patients. Intoxication was seen in 56 (78%) patients, 38% patients had severe cachexia. Elevated concentration of lactatedehydrogenase (LDG) was detected in 57 (79%) patients. In all the cases clinical symptoms developed for 1-3 months, median 6 weeks. Bone marrow involvement was diagnosed in 22 (31%) patients, CNS was affected in 17 (24%) patients, of them 14 were males. Fifty two (72%) patients had abdominal, retroperitoneal and/or small pelvis tumors. Intestinal, hepatic, renal and gastric tumors occurred most frequently. Specific ascitis was detected in 25 (48%), tumor pleuritis--in 11 (15%) patients. BL of the facial skeleton, Waldeyer's ring, oro- and nasopharynx was in 12 (17%) patients. Seven patients had concomitant involvement of the CNS. Eight (38%) and 2 (10%) women had tumors of the ovaries and uterus, respectively.BL is characterized by the following clinical features: young age of the patients, most of them are males, B-symptoms, short history, generalized stages, extranodal lesions, firequent involvement of the bone marrow and CNS.

To evaluate efficacy of intensive modified program NHL-BFM-90 (mNHL-BFM-90) in adult poor-prognosis patients with diffuse large B-cell lymphosarcoma (DLBCL) of the bones and soft tissues.The mNHL-BFM-90 program was used in the treatment of 3 male and 2 female patients aged 17-69 years (median 42 years). Four patients had DLBCL of the bones and one patient--DLBCL of the soft tissues. All the patients had tumors more than 10 cm in size. B-symptoms, a high concentration of lactate dehydrogenase (LDG) were registered in 3 patients. One patient had stage IE by Ann-Arbor, two--stage IIE (involvement of regional lymph nodes), two--stage ME (multiple bone lesions). A total of 4-6 blocks of polychemotherapy according to mNHL-BFM-90 program were performed.Complete remissions were achieved in all the patients. They had no recurrences after 6 to 20 month (median 13 months) follow-up.Positive results of the program mNHL-BFM-90 in poor-prognosis patients with DLBCL of the bones and tissues necessitate further studies of this therapy.

To analyse efficacy and tolerance of high-dose polychemotherapy (PCT) of Berkitt's lymphoma (BL) in patients aged over 40 years.High-dose PCT was given to 6 BL patients aged 41-56 years (median 48.1 years).Complete clinicohematological remissions were achieved in 4 patients. In two of them the treatment was discontinued after three blocks of PCT because of severe infectious complications. According to 4-12 month follow-up, remission continues. Remission was not achieved in two patients: one patient had primary resistance, the other died of sepsis after the second PCT course before remission. The time to remission did not correlate with age. Duration of myelotoxic agranulocytosis varied from 2 to 24 days. Duration of agranulocytosis did not correlate with age. Infections complicated 19 of 20 PCT blocks. Severity of complications caused withdrawal of three patients.BL is biologically heterogenous as it demonstrates different responses to BL-M-04 program. Causes of slow regression of tumor mass in some patients need further investigations. In spite of a great number of infectious complications high-dose therapy has no alternative.

In the past decade, a notable advance has been made in the understanding of the pathogenesis of NK/T-cell lymphomas; however, their diagnosis remains difficult because of their rarity and clinical and morphological variabilities. The paper generalizes the ten-year experience of the Hematology Research Center, Ministry of Health of Russia, in diagnosing and treating hepatosplenic T-cell lymphoma (HSTL), considers the problems of differential diagnosis with other hematological diseases occurring with similar clinical and laboratory symptoms, and lays down current approaches to the diagnosis and treatment of this condition. A clinician's view of the problem of diagnosis and treatment of this disease is given. HSTL is shown to be a heterogeneous group of diseases differing in a T-cell receptor chain gene rearrangement, the clinical course of the disease, and overall survival (OS). According to our data, 3-year OS was 12%; the median survival was 26 months. Two-year OS for γδ and αβ HSTL was equal to 25 and 70%, respectively. The difference in OS for the variants of HSTL failed to reach statistical significance (because the sample might be insufficient).За последнее десятилетие достигнуты значительные успехи в понимании патогенеза NK/Т-клеточных лимфом, однако их диагностика остается затруднительной вследствие их редкости и клинико-морфологического разнообразия. В статье обобщен десятилетний опыт диагностики и лечения гепатолиенальной Т-клеточной лимфомы (ГЛТЛ) в ФГБУ 'Гематологический научный центр' Минздрава России, рассмотрены вопросы дифференциальной диагностики с другими гематологическими заболеваниями, протекающими со сходными клинико-лабораторными симптомами, сформулированы современные подходы к диагностике и лечению. Представлен взгляд клинициста на проблему диагностики и лечения данного заболевания. Показано, что ГЛТЛ - гетерогенная группа заболеваний, различающихся по реаранжировкам генов цепей Т-клеточного рецептора, клиническому течению заболевания, общей выживаемости (ОВ). По нашим данным, 3-летняя ОВ составила 12%, медиана продолжительности жизни - 26 мес. Для вариантов γδ и αβ ГЛТЛ 2-летняя ОВ равна 25 и 70% соответственно. Различие ОВ для вариантов ГЛТЛ не достигало статистической значимости (возможно, в силу недостаточного объема выборки).

to analyze well-known risk factors (RFs), such as age, immunophenotype, baseline leukocytosis, enhanced lactate dehydrogenase (LDH) activity, time to achieve complete remission, a risk group, and cytogenetic abnormalities) in patients with acute lymphoblastic leukemia (ALL) in the use of the ALL-2009 protocol.The protocol covered 298 patients (137 women (including 13 pregnant women) and 161 men) aged 15 to 55 years (median age 28 years) with Ph-negative ALL. The phenotype was unknown in 6 patients. Three (1%) were ascertained to have a biphenotypic variant. 182 (62.4%) patients were found to have B-cell ALL (early pre-B ALL (n=51); common ALL (n=92), and pre-B ALL (n=39); 107 (36.6%) patients had T-cell ALL (early T-ALL (n=56); thymic T-ALL (n=41), and mature T-ALL (n=10). According to the baseline clinical and laboratory parameters (leukocytosis of 30·109/l and more for B-ALL; and that of 100·109/l and more for T-ALL; phenotype В-I for B-ALL, phenotype Т-I-II-IV for T-ALL; LDH activity was more than twice the normal values; the presence of translocation t(4;11)), the high-risk group included most patients with B-ALL (n=110 (72.8%)) and T-ALL (n=76 (76%)). Thirty-five patients with T-ALL underwent autologous bone marrow transplantation (BMT). Allogeneic BMT was performed in 18 (7%) of the 258 patients who had undergone an induction phase.Five-year overall survival for all the patients included in the investigation was 59%; relapse-free survival was 65%, which was significantly different in the patients with B-ALL and in those with T-ALL: the overall survival rates were 53.3 and 67.5% (p=0.1); the relapse-free survival was 56 and 79% (p=0.005), respectively. Multivariate analysis including the well-known RFs demonstrated that the latter for T-ALL were of no independent prognostic value and only the patient's age was identified for B-ALL (p=0.013).A lower chemotherapeutic load and a small number of allogeneic BMTs did not affect total positive treatment results in adult patients with ALL, by complying with the principle achieving the continuity of cytostatic effects and by preserving the total cytostatic loading dose. The results of the Russian investigation casts some doubt on the necessity of using very intensive consolidation cycles and performing a large number of allogeneic BMTs in adult patients with ALL.Цель исследования - проанализировать общеизвестные факторы риска - ФР (возраст, иммунофенотип, исходный лейкоцитоз, повышенная активность лактатдегидрогеназы - ЛДГ, время достижения полной ремиссии, группа риска, цитогенетические аномалии) у больных острыми лимфобластными лейкозами (ОЛЛ) при использовании протокола ОЛЛ-2009. Материалы и методы. В протокол включили 298 больных Ph-негативным ОЛЛ в возрасте от 15 до 55 лет, медиана 28 лет, 137 женщин (среди них 13 беременных) и 161 мужчина. У 6 фенотип неизвестен. У 3 (1%) установлен бифенотипический вариант. У 182 (62,4%) пациентов определен В-клеточный (у 51 ранний пре-В ОЛЛ, у 92 common-ОЛЛ, у 39 пре-В ОЛЛ) и у 107 (36,6%) Т-клеточный вариант ОЛЛ (у 56 ранний Т-ОЛЛ, у 41 тимический Т-ОЛЛ, у 10 зрелый Т-ОЛЛ). К группе высокого риска на основании исходных клинико-лабораторных параметров (лейкоцитоз для В-ОЛЛ 30·109/л и более, для Т-ОЛЛ 100·109/л и более, фенотип В-I для В-ОЛЛ, фенотип Т-I-II-IV для Т-ОЛЛ, активность ЛДГ более чем в 2 раза выше нормы, наличие транслокации t(4;11)) отнесено большинство больных с В-ОЛЛ (n=110, 72,8%) и с Т-ОЛЛ (n=76, 76%). У 35 пациентов с Т-ОЛЛ осуществлена аутологичная трансплантация костного мозга (ТКМ). Аллогенная ТКМ (алло-ТКМ) выполнена лишь 18 (7%) из 258 больных, переживших индукционную фазу. Результаты. Пятилетняя общая выживаемость для всех больных, включенных в исследование, составила 59%, безрецидивная - 65%, что достоверно отличается у больных с В-ОЛЛ и Т-ОЛЛ: общая 53,3 и 67,5% (р=0,1), безрецидивная 56 и 79% (р=0,005) соответственно. Многофакторный анализ, выполненный с включением общеизвестных ФР, продемонстрировал, что для Т-ОЛЛ общеизвестные ФР не имели независимой прогностической значимости, а для В-ОЛЛ выделялся как значимый только возраст больного (р=0,013). Заключение. Снижение химиотерапевтической нагрузки и малое число алло-ТКМ не влияли на общие положительные результаты лечения взрослых больных ОЛЛ, при соблюдении принципа непрерывности цитостатического воздействия и сохранении общей дозы цитостатической нагрузки. Результаты российского исследования ставят под сомнение необходимость использования у взрослых больных ОЛЛ очень интенсивных курсов консолидации и выполнения большого количества алло-ТКМ.

To test feasibility of detection of translocations which are diagnostic for Berkitt's lymphoma with the method of fluorescence in situ hibridization (FISH) on histological sections of paraffin blocks.FISH on histological sections for detection of t(8;14)(q24;q32) and variant t(2;8)(p12;q24) and t(8;22)(q24;q11) was performed on the material obtained from 53 patients with typical clinical, morphological and immunological picture. DNA probe LSI IgH/MYC, CEP 8 Tri-color, Dual Fusion Translocation Probe (Vysis, USA), for variant translocations DNA-probe LSI MYC, Dual color, Break Apart Rearrangement Probe (Vysis, USA) were used.Histological material from 31 patients contained translocations characteristic for LB: in 29 (93.5%)--t(8;14)(q24;q32), in 2--variant rearrangements of locus of gene c-myc. Translocation t(8;14)(q24;q32) and its variants were not detected in 22 patients, the diagnosis was changed for diffuse large B-cell lymphoma (DLBCL).Typical for BL clinical, morphological and immunological picture may present in extra-nodal diffuse large B-cell lymphoma with high proliferative activity. Differential diagnosis between BL and the latter lymphoma is possible only basing on detection of translocation t(8;14)(q24;q32) or its variants. If it is impossible to obtain native material, FISH on histological sections of parasffin blocks is the only possible method of differential diagnosis.

To investigate characteristics of the course and efficacy of treatment of diffuse large B-cell lymphosarcoma (DLBL) with primary lesion of the spleen.From 1998 to 2006, primary splenic lesion was registered in 15 of 120 patients with DLBL and affected lymph nodes (LN), spleen and Waldeyer's ring. The diagnosis was made according to WHO criteria. Of them 14 patients had splenectomy as the first stage of therapy. The operation was followed with 6 to 8 courses of CHOP-21 (8 patients), 4 courses of R-CHOP-21 and radiotherapy (one patient). One patient received 7 courses of CHOP-21 followed by splenectomy. Because of the presence of several signs of unfavourable prognosis 5 patients under 60 years were given intensive therapy: 4-6 courses of the modified program NHL-BFM-90, 2 of 5 patients received radiotherapy.All the patients with primary DLBL of the spleen had two and more signs of unfavourable prognosis: elevated concentration of serum LDG, size of the tumor more than 10 cm, high proliferative activity of tumor cells, B-symptoms, severe condition. Seven patients had centroblastic, 8--anaplastic variants of DLBL. Tumor cells in primary DLBL of the spleen had no specific immunophenotype. Complete remission of the disease was achieved in 9 (90%) of 10 patients treated on programs CHOP-21, R-CHOP-21, in 4 of 4 patients on the modified program NHL-BFM-90. Mean follow-up was 39.3 months (from 7 to 103 months).For primary DLBL of the spleen characteristic are long-term remissions on first line therapy according to CHOP-21 program irrespective of morphology and immunophenotype.

To study a relationship between cytogenetic disorders, clinicobiological characteristics and prognosis in chronic B-cell lymphoid leukemia (B-CLL).Cytogenetic examination of blood, bone marrow and lymph node cells from 135 patients (90 males and 45 females aged 23-84 years) with chronic B-CLL was made. The patients were followed up from 1 month to 25 years. Before the cytogenetic examination specific therapy was not given. B-CLL was staged by K. Rai, forms--by A.L. Vorobyev and M.D. Brilliant. All the patients have undergone standard cytogenetic examination, FISH with multicolor probe to loci with possible frequent aberrations (del3q14, del11q23, del17p13, trisomia 12), determination of CD38 antigen expression on circulating tumor cells. Mutation status of the genes of immunoglobulins variable region (IgVH) was defined in 61 patients.Del13q14 was detected in 34 cases, del11q23--in 26, trisomia of chromosome 12--in 17 cases, del 17p13--in 8, absence of q-arm of chromosome 13--in 3 cases. 61 patients had no karyotype defects. Three prognostic groups of the patients were identified: favourable prognosis--patients without disorders of karyotype and one chromosomal aberration--del13q14; intermediate prognosis patients with dell1q23 and trisomia of chromosome 12; poor prognosis--patients with del17p13 and complex disorders of karyotype. CONCLUSION. Cytogenetic study help determine prognosis of B-CLL and detect patients in need of early therapy.

To compare programs of chemotherapy used in adult Berkitt-like lymphoma (ABLL); to assess efficacy and toxicity of the protocol AblL-M-04.31 ABLL patients (23 males, 8 females, mean age 27 years) participated in the study performed in Hematological Research Center in 1995-2004. ABLL stage I, II, III and IV was diagnosed in 3, 5, 8 and 15 patients, respectively. 10 patients had diffuse large B-cell lymphoma. 9 patients received 2 to 6 courses of CHOP, 1 patient--6 courses of Pro-Mace-Cytabom, 11 patients with newly diagnosed ABLL and 5 pretreated with CHOP--NHL-BFM-90. The modified protocol ABLL-M-04 of intensive short-term therapy included 10 patients, 2 of them pretreated.Of 10 patients given CHOP or CHOP-like courses 9 were resistant to therapy, 2 died of rapid progression, 7 were converted to the program therapy. 5 patients on the protocol NHL-BFM-90 died after short-term improvement. None of them achieved remission. Of 10 patients with newly diagnosed ABLL treated according to NHL-BFM-90 protocol, remission was achieved in 4 patients, follow-up median--34 months (2-56). Six patients died: 4 of progression, 2 of chemotherapy complications. BLL-M-04 therapy was made in 9 patients: 7 patients persisted on the first remission, 2 patients died of chemotherapy complications. Overall duration of the treatment was 3-3.5 months.The protocol ABLL-M-04 seems to be more effective than a classic NHL-BFM-90, but this must be supported by more cases. CHOP therapy cannot be recommended for patients with ABLL because of poor efficacy (all the CHOP patients died).

To determine the type and rate of secondary chromosomal aberrations and role in pathogenesis of mantle cell lymphoma (MCL).Standard cytogenetic examination (SCE) and fluorescent in situ hybridization (FISH) with tests for 11q22/ATM, 13q14, 17p13/p53, 9p21/p16 and chromosome 12 centromere were made in 28 patients.Secondary chromosomal aberrations were detected in 22 patients. Chromosomal abnormalities occurring in more than 2 cases include deletions 6q15-q23 (53% cases); 11q22/ATM (50%); 9p21 (36%, in half the cases deletion 9p21 was biallele); 13q14 (32%); trisomy 3/3q, monosomy 20 and deletions/translocations 1q and 1p (27% and 20%) and deletion 17p13/p53 (18%). Trisomies 12/12q, 6 and 18/18q, monosomies 2 and 16, deletions/translocations 2p and 16p were found in 2 cases each. The FISH technique identified 9 chromosomal anomalies missed at SCE. Deletions 6q15-q23 were seen in patients with privalent lesions of lymph nodes. Deletions 11q, 13q14, 9p21 and 17p13 occur more frequently in transformation and the blastoid variant. Monosomy 20 was found only in patients with large cell transformations. This was the only cytogenetic defect characteristic for transformed cases, in contrast to denovoblastoid ones. Thus, deletions 6q, 11q23, 13q14 and 9p21 are typical for MCL. Deletions 9p21 and 17p13 are more characteristic for large cell variants of the tumor. Deletion 17p13 occurs at the terminal stage of the disease in rapidly growing tumor mass and resistance to chemotherapy. FISH technique is effective in detection of submicroscopic rearrangements especially small deletions. No significant differences were found between transformed and de novo blastoid cases. This shows that the blastoid variant is not a specific biological form, it is rather a less typical manifestation of the disease due to some preclinical cytogenetic disorders.Progression and transformation of MCL are related to mutation of proapoptotic genes and genes proteins of which are inhibitors of active complexes of D1 cycline. Specification of these mechanisms requires further investigations in patients with different clinicomorphological forms of the disease at various stages of the disease.

To assess factors of an unfavourable prognosis in a group of intermediate risk of B-cell chronic lymphoid leukemia (BCCLL).206 BCCLL patients (mean age 55.5 years, male/female = 1.66) entered the study conducted by Hematological Research Center in 1992-2000.Nine patients under 35 years of age did not survive 5 years except one female who achieved a complete remission on fludarabin. The type of bone marrow infiltration (diffuse vs interstitial and nodular), the time of lymphocyte count doubling (under or over 12 months) discriminate the patients by prognosis in the group of intermediate risk: medians of overall survival 65 months vs 148 months and 72 vs 133 months, respectively (p0.005 for both curves, log-rank criterion). Survival medians in groups with low (50% cells) and high (50% cells) expression of CD38+ cells in the group of intermediate BCCLL risk comprise 55 and 106 months (p = 0.005). The type of bone marrow infiltration and time of doubling of lymphocyte count overlap:70% patients with a diffuse type of bone marrow infiltration have the time of doubling under 12 months and vice versa while expression of CD38 do not overlap with these values. Combination of two signs (type of bone marrow infiltration and CD38 expression or time og lymphocyte count doubling and CD38 expression) allows more precise identification of prognostically unfavourable groups. Medians of survival for combination of the first two signs (two positive against two negative) comprise 51 months vs 169 months (p0.0001), for combination of the latter two signs 55 months vs 106 months was not reached (p0.001). Although most patients with a tumor form of BCCLL are referred to stage II, the prognosis in this form is much worse than in stage II, survival medians are 44 and 69 months, respectively (p0.05). A mutation status of the genes of a variable region of immunoglobulins enable identification of the group of patients with a relatively benign course of BCCLL (survival medians 61 and 289 months, p0.0001).In patients under 35 years of age BCCLL runs unfavourably and seems to require intensive polychemotherapy. Usage of a combination of the signs (CD38, time of doubling of lymphocyte count and type of bone marrow infiltration) is a simple and reliable method of identification of prognostically different categories of patients in the group of an intermediate BCCLL risk. Prognosis in patients with a tumor form of BCCLL is unfavourable: medians of survival in patients with a tumor form and stage III-IV are comparable. Mutational status of the genes of immunoglobulin variable region may serve a marker of a long-term prognosis.