Russian Research Institute of Hematology and Transfusiology

Saint Petersburg, Russia

Russian Research Institute of Hematology and Transfusiology

Saint Petersburg, Russia

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Robak T.,Medical University of Lódz | Warzocha K.,Institute of Hematology and Transfusion Medicine | Govind Babu K.,Kidwai Memorial Institute of Oncology | Kulyaba Y.,Makiivka City Hospital and 2 of Donetsk Region | And 15 more authors.
Leukemia and Lymphoma | Year: 2016

In this multicenter, open-label, phase III study, patients with relapsed chronic lymphocytic leukemia (CLL) were randomized (1:1) to receive ofatumumab plus fludarabine and cyclophosphamide (OFA + FC) or FC alone; the primary endpoint being progression-free survival (PFS) assessed by an independent review committee (IRC). Between March 2009 and January 2012, 365 patients were randomized (OFA + FC: n = 183; FC: n = 182). Median IRC-assessed PFS was 28.9 months with OFA + FC versus 18.8 months with FC (hazard ratio = 0.67; 95% confidence interval, 0.51–0.88; p = .0032). Grade ≥3 adverse events (≤60 days after last dose) were reported in 134 (74%) OFA + FC-treated patients compared with 123 (69%) FC-treated patients. Of these, neutropenia was the most common (89 [49%] vs. 64 [36%]). OFA + FC improved PFS with manageable safety for patients with relapsed CLL compared with FC alone, thus providing an alternative treatment option for patients with relapsed CLL. Trial registration: www.clinicaltrials.gov (NCT00824265). © 2016 Informa UK Limited, trading as Taylor & Francis Group


Sipol A.A.,Saint Petersburg State University | Babenko E.V.,Saint Petersburg State University | Borisov V.I.,Alexion Pharma | Naumova E.V.,Moscow Medical Academy | And 9 more authors.
Hematology | Year: 2015

Objectives: Paroxysmal nocturnal hemoglobinuria (PNH) is an acquired clonal stem cell disorder characterized by partial or absolute deficiency of glycophosphatidyl-inositol (GPI) anchor-linked surface proteins on blood cells. A lack of precise diagnostic standards for flow cytometry has hampered useful comparisons of data between laboratories. We report data from the first study evaluating the reproducibility of high-sensitivity flow cytometry for PNH in Russia.Methods: PNH clone sizes were determined at diagnosis in PNH patients at a central laboratory and compared with follow-up measurements in six laboratories across the country. Analyses in each laboratory were performed according to recommendations from the International Clinical Cytometry Society (ICCS) and the more recent ‘practical guidelines’. Follow-up measurements were compared with each other and with the values determined at diagnosis.Results: PNH clone size measurements were determined in seven diagnosed PNH patients (five females, two males: mean age 37 years); five had a history of aplastic anemia and three (one with and two without aplastic anemia) had severe hemolytic PNH and elevated plasma lactate dehydrogenase. PNH clone sizes at diagnosis were low in patients with less severe clinical symptoms (0.41–9.7% of granulocytes) and high in patients with severe symptoms (58–99%). There were only minimal differences in the follow-up clone size measurement for each patient between the six laboratories, particularly in those with high values at diagnosis.Conclusions: The ICCS-recommended high-sensitivity flow cytometry protocol was effective for detecting major and minor PNH clones in Russian PNH patients, and showed high reproducibility between laboratories. © 2015 W. S. Maney & Son Ltd.


Moreau P.,University of Nantes | Karamanesht I.I.,Kiev Center | Domnikova N.,State Novosibirsk Regional Clinical Hospital | Kyselyova M.Y.,Crimean Republic Clinical Oncology Dispensary | And 14 more authors.
Clinical Pharmacokinetics | Year: 2012

Background and Objectives: The proteasome inhibitor bortezomib is approved for the treatment of multiple myeloma (MM) and, in the US, for the treatment of mantle cell lymphoma following at least one prior therapy; the recommended dose and schedule is 1.3 mg/m2 on days 1, 4, 8 and 11 of 21-day cycles, and the approved routes of administration in the US prescribing information are by intravenous and, following a recent update, subcutaneous injection. Findings from a phase III study demonstrated that subcutaneous administration of bortezomib, using the same dose and schedule, resulted in similar efficacy with an improved systemic safety profile (including significantly lower rates of peripheral neuropathy) versus intravenous bortezomib in patients with relapsed MM. The objectives of this report were to present a comprehensive analysis of the pharmacokinetics and pharmacodynamics of subcutaneous versus intravenous bortezomib, and to evaluate the impact of the subcutaneous administration site, subcutaneous injection concentration and demographic characteristics on bortezomib pharmacokinetics and pharmacodynamics. Patients and Methods: Data were analysed from the pharmacokinetic substudy of the randomized phase III MMY-3021 study and the phase I CAN-1004 study of subcutaneous versus intravenous bortezomib in patients aged ≥18 (MMY-3021) or ≤75 (CAN-1004) years with symptomatic relapsed or refractory MM after 1-3 (MMY-3021) or ≥1 (CAN-1004) prior therapies. Patients received up to eight 21-day cycles of subcutaneous or intravenous bortezomib 1.3 mg/m2 on days 1, 4, 8 and 11. Pharmacokinetic and pharmacodynamic (20S proteasome inhibition) parameters of bortezomib following subcutaneous or intravenous administration were evaluated on day 11, cycle 1. Results: Bortezomib systemic exposure was equivalent with subcutaneous versus intravenous administration in MMY-3021 [mean area under the plasma concentration-time curve from time zero to the last quantifiable timepoint (AUClast): 155 vs. 151 ng·h/mL; geometric mean ratio 0.992 (90 % CI 80.18, 122.80)] and comparable in CAN-1004 (mean AUC last: 195 vs. 241 ng·h/mL); maximum (peak) plasma drug concentration (Cmax) was lower with subcutaneous administration in both MMY-3021 (mean 20.4 vs. 223 ng/mL) and CAN-1004 (mean 22.5 vs. 162 ng/mL), and time to Cmax (tmax) was longer with subcutaneous administration in both studies (median 30 vs. 2 min). Blood 20S proteasome inhibition pharmacodynamic parameters were also similar with subcutaneous versus intravenous bortezomib: mean maximum effect (Emax) was 63.7 versus 69.3 % in MMY-3021 and 57.0 versus 68.8 % in CAN-1004, and mean area under the effect-time curve from time zero to 72 h was 1,714 versus 1,383 %·h in MMY-3021 and 1,619 versus 1,283 %·h in CAN-1004. Time to Emax was longer with subcutaneous administration in MMY-3021 (median 120 vs. 5 min) and CAN-1004 (median 120 vs. 3 min). Concentration of the subcutaneous injected solution had no appreciable effect on pharmacokinetic or pharmacodynamic parameters. There were no apparent differences in bortezomib pharmacokinetic and pharmacodynamic parameters between subcutaneous administration in the thigh or abdomen. There were also no apparent differences in bortezomib exposure related to body mass index, body surface area or age. Conclusion: Subcutaneous administration results in equivalent bortezomib plasma exposure to intravenous administration, together with comparable blood 20S proteasome inhibition pharmacodynamic effects. These findings, together with the non-inferior efficacy of subcutaneous versus intravenous bortezomib demonstrated in MMY-3021, support the use of bortezomib via the subcutaneous route across the settings of clinical use in which the safety and efficacy of intravenous bortezomib has been established. © 2012 Springer International Publishing Switzerland.


PubMed | Russian Research Institute of Hematology and Transfusiology, University of Houston, Hospital Britanico, Jagiellonian University and 11 more.
Type: Journal Article | Journal: The Lancet. Haematology | Year: 2016

Optimal management of patients with chronic myeloid leukaemia in chronic phase with suboptimal cytogenetic response remains undetermined. This study aimed to investigate the safety and efficacy of switching to nilotinib vs imatinib dose escalation for patients with suboptimal cytogenetic response on imatinib.We did a phase 3, open-label, randomised trial in patients with chronic myeloid leukaemia in chronic phase with suboptimal cytogenetic response to imatinib according to the 2009 European LeukemiaNet criteria, in Latin America, Europe, and Asia (59 hospitals and care centres in 12 countries). Eligible patients were aged 18 years or older with Philadelphia chromosome-positive chronic myeloid leukaemia in chronic phase and Eastern Cooperative Oncology Group performance status of 0-2. Before enrolment, all patients had received 3-18 months of imatinib 400 mg once daily and had a suboptimal cytogenetic response according to 2009 ELN recommendations, established through bone marrow cytogenetics. By use of an interactive response technology using fixed blocks, we randomly assigned patients (1:1) to switch to nilotinib 400 mg twice per day or an escalation of imatinib dose to 600 mg once per day (block size of 4). Investigators and participants were not blinded to study treatment. Crossover was allowed for loss of response or intolerance at any time, or for patients with no complete cytogenetic response at 6 months. The primary endpoint was complete cytogenetic response at 6 months in the intention-to-treat population. Efficacy endpoints were based on the intention-to-treat population, with all patients assessed according to the treatment group to which they were randomised (regardless of crossover); the effect of crossover was assessed in post-hoc analyses, in which responses achieved after crossover were excluded. We present the final results at 24 months follow-up. This study is registered with ClinicalTrials.gov (NCT00802841).Between July 7, 2009, and Aug 29, 2012, we enrolled 191 patients. 96 patients were randomly assigned to nilotinib and 95 patients were randomly assigned to imatinib. Complete cytogenetic response at 6 months was achieved by 48 of 96 patients in the nilotinib group (50%, 9518% CI 40-61) and 40 of 95 in the imatinib group (42%, 32-53%; difference 79% in favour of nilotinib; 95% CI -62 to 220, p=031). Excluding responses achieved after crossover, 48 (50%) of 96 patients in the nilotinib group and 34 (36%) of 95 patients in the imatinib group achieved complete cytogenic response at 6 months (nominal p=0058). Grade 3-4 non-haematological adverse events occurring in more than one patient were headache (nilotinib group, n=2 [2%, including 1 after crossover to imatinib]; imatinib group, n=1 [1%]), blast cell crisis (nilotinib group, n=1 [1%]; imatinib group, n=1 [1%]), and QT prolongation (nilotinib group, n=1 [1%]; imatinib group, n=1 [1%, after crossover to nilotinib]). Serious adverse events on assigned treatment were reported in 11 (11%) of 96 patients in the nilotinib group and nine (10%) of 93 patients in the imatinib group. Seven (7%) of 96 patients died in the nilotinib group and five (5%) of 93 patients died in the imatinib group; no deaths were treatment-related.While longer-term analyses are needed to establish whether the clinical benefits observed with switching to nilotinib are associated with improved long-term survival outcomes, our results suggest that patients with suboptimal cytogenetic response are more likely to achieve improved cytogenetic and molecular responses with switching to nilotinib than with imatinib dose escalation, although the difference was not statistically significant when responses achieved after crossover were included.Novartis Pharmaceuticals.


Hollenbach J.A.,Childrens Hospital Oakland Research Institute | Augusto D.G.,Federal University of Paraná | Alaez C.,Institute Diagnostico y Referencia Epidemiologicos InDRE | Bubnova L.,Russian Research Institute of Hematology and Transfusiology | And 15 more authors.
International Journal of Immunogenetics | Year: 2013

In the last fifteen years, published reports have described KIR gene-content frequency distributions in more than 120 populations worldwide. However, there have been limited studies examining these data in aggregate to detect overall patterns of variation at regional and global levels. Here, we present a summary of the collection of KIR gene-content data for 105 worldwide populations collected as part of the 15th and 16th International Histocompatibility and Immunogenetics Workshops, and preliminary results for data analysis. © 2012 Blackwell Publishing Ltd.


Kudryavtsev I.V.,Far Eastern Federal University | Borisov A.G.D.,St. Petersburg State Medical University | Krobinets I.I.,Russian Research Institute of Hematology and Transfusiology | Savchenko A.A.,Russian Academy of Sciences | And 2 more authors.
Medical Immunology (Russia) | Year: 2016

Expression of chemokine receptors (CCR4, CCR6, CXCR3 and CXCR5) on T-helper (Th) cells at various levels of differentiation in a group of healthy volunteers (n = 52) was assessed on the basis of CD45RA and CD62L expression, using the eight-color flow cytometry. It was found that the "naive" T helper cells (N) with CD45RA+CD62L+ phenotype express CXCR3 (4.94±0.39%), and CXCR5 (3.63±0.25%). About 50% of central memory T helpers (CD45RA-CD62L+, CM) were CXCR3 positive, and 43.72±1.27% of CM cells expressed CCR6, whereas CXCR5 and CCR4 levels were about 30%. Furthermore, CXCR3 was expressed by 76.76±0.75% of the CD3+CD4+CD45RA-CD62L- (EM) population, and similar values were obtained for CCR6, while the relative abundance of CXCR5+ cells decreased to 13.68±0.50%, and CCR4 levels did not change and accounted for 33.26±1.13% positive cells. Likewise, co-expression of the chemokine receptors was studied for the abovementioned subpopulations of T helper cells. Among the CXCR5- Th, Th1 cells were identified as CXCR3+CCR6-CCR4- (this subset also contained Th9), and CXCR3+CCR6+CCR4- subsets, referred to as Th1/Th17. Th2 were detected on the basis of CCR4 expression in absence of all other chemokine receptors. In addition to the mentioned Th1/Th17 populations, Th 17 cells were found in the subsets of Th17 CXCR3-CCR6+CCR4- And CXCR3-CCR6+CCR4+. The latter also contained a Th22 population. Follicular Th cell populations (CXCR5+) consisted of, at least, six different subsets: CXCR3-CCR6-CCR4- (Tfh/Tfh2), CXCR3-CCR6-CCR4+ (Tfh2), CXCR3-CCR6+CCR4- (Tfh17), CXCR3-CCR6+CCR4+ (Tfh17), CXCR3+CCR6-CCR4- (Tfh1) and CXCR3+CCR6+CCR4- (Tfh1/ Tfh17). The cells with Th1/Th9 and Th1/Th17 phenotypes dominated among CM (about 13%), whereas their relative abundance within EM increased to 22.37±1.69% and 31.69±1.52%, respectively. The amounts of Th2 were 8.15±0.46% within CM, and only 1.72±0.15% for EM population. For the cells with Th17/Th22 phenotype, these values are 8.07±0.30% and 12.03±0.57%, respectively. The main Tfh subsets were represented among the CM T-helpers: The relative content of Tfh/Tfh2 was 5.79 0.26%, Tfh2, 1.34±0.07%; Tfh17 with CXCR3-CCR6+CCR4- and CXCR3-CCR6+CCR4+ phenotypes made up to 6.22±0.28% and 3.28±0.16%, as well as Tfh1 (7.68±0.31%), and Tfh1/Tfh17 (4.02±0.17%), respectively. Relative content of the mentioned Tfh subsets was decreased > 2-fold within effector memory Th subpopulation. The data obtained may be applied for diagnostics of different immunopathological conditions and could be used as a comparison group in further studies. © 2016, SPb RAACI.


Gritsaev S.V.,Russian Research Institute of Hematology and Transfusiology | Martynkevich I.S.,Russian Research Institute of Hematology and Transfusiology | Martynenko L.S.,Russian Research Institute of Hematology and Transfusiology | Ivanova M.P.,Russian Research Institute of Hematology and Transfusiology | And 4 more authors.
Terapevticheskii Arkhiv | Year: 2011

Aim. To study distribution of some karyotype variants among patients of different age with acute myeloid leukemia (AML). Material and methods. Distribution of balanced, normal, unbalanced, complex and monosomic karyotype among 244 patients with de novo AML in age groups 16-20, 21-30, 31-40, 41-50, 51-60, 61 and older was analysed. Results. There Is difference in frequency of balanced and complex karyotype in patients under and over 60 years. Number of AML patients with balanced aberrations including favourable variants t(8;21), t(15;17) and inv( 16) falls after 60 years of age (6.7% versus 15.0% in patients aged 16-20 years; p < 0.001), while a complex karyotype occurs more frequently in AML patients at the age of 61 and older (56.8% versus 2.7% in the group 16-20 years; p < 0.001). With age, more frequently detected is the most unfavourable monosomic karyotype with aberrations similar to those in myelodysplastic syndrome (57.1% in patients aged 16-60 years and in 80.0% in the group of 61 years of age and over). Conclusion. Age-specific karyotype features detected may be explained by different biological mechanisms involved in leukosogenesis in young and elderly AML patients.


Gritsaev S.V.,Russian Research Institute of Hematology and Transfusiology | Martynkevich I.S.,Russian Research Institute of Hematology and Transfusiology | Petrova E.V.,Russian Research Institute of Hematology and Transfusiology | Martynenko L.S.,Russian Research Institute of Hematology and Transfusiology | And 5 more authors.
Terapevticheskii Arkhiv | Year: 2013

Aim. To analyze the prevalence of chromosome aberrations presented in the revised International Prognostic Scoring System (R-IPSS) in patients with de novo myelodysplastic syndrome (MDS). Subjects and methods. Chromosome aberrations were analyzed in 197 patients aged 14 to 86 years (median age 64 years) with de novo MDS. Results. Karyotype abnormalities were revealed in 129 (65.5%) patients with de novo MDS. According to the IPSS criteria, the karyotypes found 52 (26.4%) patients were assigned to an intermediate prognostic group whereas in accordance with the R-IPSS guidelines, an intermediate karyotype group included chromosome abnormalities in 32 (16.2%) patients. Out of 5 R-IPSS prognostic types, the favorable karyotype group was the largest (48.2%). The very favorable and unfavorable karyotype groups comprised few patients with MDS: 3 and 3.6%, respectively. Despite the fact that it was not mentioned in the R-IPSS, a monosomal karyotype was verified in 24 (12.2%) patients There was a correlation of the (normal and complex) karyotype with bone marrow blast counts (r=0.469; p=0.000), but not with age. Conclusion. A variety of cytogenetic damages cannot identify the prognostic potential of all chromosome aberrations occurring in patients with MDS even if prognostic factors increased up to 5.


Selivanov E.A.,Russian Research Institute of Hematology and Transfusiology | Rugal V.I.,Russian Research Institute of Hematology and Transfusiology
Cellular Transplantation and Tissue Engineering | Year: 2011

The regulation development of haemopoietic stem cells by rabbit anti-human CD34 + stem cells immune globulin has been established. It was showed by experimental investigation on rats with cytostatic haemo-immunosuppression and in culture human CD34 + stem cells. Thus, in animals which received anti-CD34 + immune globulin the recovery of blood and immunity values occurred earlier than in the control animals. The experimental animals recovered haemolymphocytopoiesis after one month while control group normalized haemopoietic function after two months. In vitro colony-forming ability human haemopoietic stem cells are increased in 30 per cent by the addition specific CD34 + immune globulin in counditioned medium. Our preliminary date suggest that rabbit anti-human mesenchymal stem cells immune globulin can stimulate the differentiation of mesenchymal cells in osteoblasts and endotheliocytis the cells that form haemopoietic niche.


PubMed | Russian Research Institute of Hematology and Transfusiology
Type: Journal Article | Journal: European journal of pharmacology | Year: 2011

It has been found that dinitrosyl iron complexes with glutathione (DNIC-GS) injected into the blood flow of rats at a dose of 0.05 moles/kg prior to hemorrhage significantly improve cardiac function under conditions of hemorrhagic shock manifested in increased stroke volume, left ventricular work and cardiac output to a level exceeding control values 1.5-fold. Enhanced myocardial contractile activity leads to a situation where mean arterial pressure does not decrease further despite the significant decrease of total peripheral resistance. The decrease of total peripheral vascular resistance of the vascular system under vasodilating effects of DNIC-GS used as nitric oxide donors improves microcirculation in experimental rats judging from increased rates of blood flow and low degree of erythrocyte aggregation. Pretreatment of rats with the complexes significantly increases survival (by 21%) under conditions of hemorrhagic shock. It is suggested that beneficial effects of DNIC-GS on systemic circulation parameters under conditions of hemorrhagic shock are determined by their antioxidant activity and the ability to induce S-nitrosylation of proteins.

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