Publications by authors named "Kazimierz Kuliczkowski"

139 Publications

IDH2 mutations in patients with normal karyotype AML predict favorable responses to daunorubicin, cytarabine and cladribine regimen.

Sci Rep 2021 May 11;11(1):10017. Epub 2021 May 11.

Department of Cancer Prevention, School of Public Health, Silesian Medical University, Katowice, Poland.

Mutations in isocitrate dehydrogenase 1 and 2 (IDH1/2) genes occur in about 20% patients with acute myeloid leukemia (AML), leading to DNA hypermethylation and epigenetic deregulation. We assessed the prognostic significance of IDH1/2 mutations (IDH1/2) in 398 AML patients with normal karyotype (NK-AML), treated with daunorubicine + cytarabine (DA), DA + cladribine (DAC), or DA + fludarabine. IDH2 mutation was an independent favorable prognostic factor for 4-year overall survival (OS) in total NK-AML population (p = 0.03, censoring at allotransplant). We next evaluated the effect of addition of cladribine to induction regimen on the patients' outcome according to IDH1/2 mutation status. In DAC group, 4-year OS was increased in IDH2 patients, compared to IDH-wild type group (54% vs 33%; p = 0.0087, censoring at allotransplant), while no difference was observed for DA-treated subjects. In multivariate analysis, DAC independently improved the survival of IDH2 patients (HR = 0.6 [0.37-0.93]; p = 0.024; censored at transplant), indicating that this group specifically benefits from cladribine-containing therapy. In AML cells with R140Q or R172K IDH2 mutations, cladribine restrained mutations-related DNA hypermethylation. Altogether, DAC regimen produces better outcomes in IDH2 NK-AML patients than DA, and this likely results from the hypomethylating activity of cladribine. Our observations warrant further investigations of induction protocols combining cladribine with IDH1/2 inhibitors in IDH2-mutant.
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http://dx.doi.org/10.1038/s41598-021-88120-yDOI Listing
May 2021

Comparing radioactive tracers 18F-FDG and 18F-FLT in the staging of diffuse large B-cell lymphoma by PET/CT examination: A single-center prospective study.

Adv Clin Exp Med 2019 Aug;28(8):1095-1099

Department of Hematology, Blood Neoplasms and Bone Marrow Transplantation, Wroclaw Medical University, Poland.

Background: Positron emission tomography in combination with computer tomography (PET/CT) is a very important method of imaging patients with non-Hodgkin lymphomas (NHLs). It is used to define the initial grade of the disease and to assess early response to treatment and after chemotherapy. The most commonly used radioactive tracer is 18F-FDG, but 18F-FLT seems to be more specific.

Objectives: The aim of our study was to compare the staging of diffuse large B-cell lymphoma (DLBCL) with PET/CT examination using 18F-FLT and 18F-FDG.

Material And Methods: The study included 33 patients with newly diagnosed DLBCL (17 women and 16 men). The median age of the patients was 57 years. In each patient, 2 PET/CT examinations were performed before treatment, one using 18F-FLT and the second using 18F-FDG.

Results: The average maximum 18F-FDG uptake in the whole group of patients was higher than the average maximum of 18F-FLT. This was also true of individual patients; however, 3 patients with an aggressive disease course had greater FLT uptake than the other patients.

Conclusions: Our analysis suggests that PET/CT exams using 18F-FLT may be a useful diagnostic tool in patients with DLBCL.
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http://dx.doi.org/10.17219/acem/104558DOI Listing
August 2019

Significance of apoptosis and autophagy of leukemic blasts for the outcomes of acute myeloid leukemia patients.

Adv Clin Exp Med 2019 Jul;28(7):861-869

Department of Hematology, Blood Cancers and Bone Marrow Transplantation, University Hospital No. 1, Wrocław, Poland.

Background: Cytostatic treatment induces apoptosis or other types of cell death like autophagy, necrosis, mitotic catastrophe, etc. Autophagy can play a role in the drug resistance of neoplastic cells, allowing the survival of blast cells under stressful conditions, such as the use of cytostatics. Studies on apoptosis and autophagy 12-24 h after the start of treatment have not been conducted until now.

Objectives: The study aimed to investigate the predictive and prognostic significance of autophagy and apoptosis in patients with acute myeloid leukemia (AML).

Material And Methods: The study included 38 patients. Blood was collected before and 12-24 h after the start of treatment, since at that time point, the appropriate blast cell count was still available. Autophagy was measured with the expression of the ATG5, MAP1L3, LC3-I, and LC3-II proteins. The percentage of mononuclear cells in early and late apoptosis was evaluated with flow cytometry, using the annexin V and propidium iodide (PI) binding assay.

Results: The percentage of apoptotic blast cells before treatment was not associated with the response. However, in the remission group, the overall percentage of apoptotic cells measured 12-24 h after the start of treatment was higher than in non-remission patients, which was statistically significant. In neither group we found any difference in the level of autophagy before and 12-24 h after the start of treatment. Nevertheless, we observed an increasing tendency of the MAP1LC3 protein expression (not statistically significant) in the remission group 12-24 h after the start of treatment. Patients with a higher percentage of blast cells in apoptosis and with a higher expression of MAP1LC3 protein measured 12-24 h after the start of the therapy had longer overall survival (OS).

Conclusions: A higher percentage of apoptotic as well as autophagic blast cells measured 12-24 h after the start of the chemotherapy is an independent factor associated with better outcomes.
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http://dx.doi.org/10.17219/acem/93849DOI Listing
July 2019

G-CSF administration favours SDF-1 release and activation of neutrophils and monocytes in recipients of autologous peripheral blood progenitor cells.

Cytokine 2019 04 24;116:38-47. Epub 2019 Jan 24.

Laboratory of Clinical Immunogenetics and Pharmacogenetics, Hirszfeld Institute of Immunology and Experimental Therapy, Polish Academy of Sciences, Weigla 12, 53-114 Wroclaw, Poland; Department of Internal Diseases, Occupational Medicine, Hypertension and Clinical Oncology, Wroclaw Medical University, Borowska 213, 50-556 Wroclaw, Poland.

G-CSF is a growth factor widely used to mobilise CD34+ progenitor cells for clinical applications. The present study aimed to assess expression of G-CSF receptor (CSF3R) on neutrophils and monocytes, as well as SDF-1 and G-CSF serum levels in relation to efficacy of G-CSF-induced mobilisation for autologous transplantation. For this purpose, 105 patients with haematological disorders and 46 healthy controls were investigated. Before mobilisation patients were characterised with significantly higher percentage of CSF3R expressing neutrophils (p < 0.001) and monocytes (p = 0.002), than controls. G-CSF administration resulted in a decrease of CSF3R+ neutrophils (p < 0.001) and monocytes (p < 0.001), while presence of G-CSF receptor on neutrophils tended to negatively affect mobilisation yield (p = 0.075). G-CSF concentration increased during mobilisation (p < 0.001). On the 5th day of mobilisation a positive correlation was observed between G-CSF and SDF-1 serum levels (p < 0.001) and the number of CD34+ cells released from bone marrow seemed to be related to both G-CSF (p = 0.036) and SDF-1 levels (p = 0.084). As compared to Hodgkin's lymphoma patients, those with multiple myeloma had lower basal percentage of CSF3R+ neutrophils (p = 0.014) while Non-Hodgkin's lymphoma cases exhibited higher G-CSF (p = 0.026) and SDF-1 (p = 0.006) concentration on mobilisation day 5. Hodgkin's lymphoma patients were also characterised with worse mobilisation efficacy than multiple myeloma (p = 0.022) and Non-Hodgkin's lymphoma (p = 0.013) patients. These results suggest that both SDF-1 and G-CSF play a role in HSC release into peripheral blood and show that G-CSF administration affects expression of CSF3R on monocytes and neutrophils, implying potential role of these cell subpopulations in mobilisation process.
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http://dx.doi.org/10.1016/j.cyto.2018.12.011DOI Listing
April 2019

Influence of temperature rise by 2.5°C on the increase of apoptosis of HL-60 cells treated with busulfan.

Adv Clin Exp Med 2019 May;28(5):581-585

Department and Clinic of Hematology, Blood Neoplasms and Bone Marrow Transplantations, Wroclaw Medical University, Poland.

Background: Hyperthermia is one of the new and still poorly known methods used in cancer treatment. It consists of raising the patient's body temperature for therapeutic purposes. The article presents the results of in vitro studies describing the effect of an elevated temperature of 39.5°C, the busulfan cytostatic and their combination on the level of apoptosis of human leukemia HL-60 cells.

Objectives: During the experiments, the influence of a 2.5°C temperature increase on the behavior of the population of 2 groups of HL-60 cells, with busulfan cytostatic and without the cytostatic, was investigated. The control group consisted of 2 groups of HL-60 cells incubated at 37.0°C with the cytostatic and without the cytostatic. Two questions were asked: 1. Is low-temperature hyperthermia likely to have an effect on the effectiveness of busulfan cytostatic? 2. Does the increase in temperature by 2.5°C have an effect on the level of apoptosis in the unsaturated HL-60 cell line?

Material And Methods: Human promyelocytic leukemia cell line HL-60 was used in the experiments to examine the influence of temperature on apoptosis HL-60 in 2 separated incubators set to 37.0°C and 39.5°C for 3 h. Apoptosis was assessed with flow cytometry using Annexin V.

Results: An increase in mortality of HL-60 cells was found in the case of simultaneous exposure to elevated temperature and busulfan in comparison to the group of cells treated with the cytostatic alone. There was no observed effect of an elevated temperature of 39.5°C alone on the level of HL-60 cell apoptosis.

Conclusions: Analysis of the study results indicates that low-temperature hyperthermia may be used to increase the effectiveness of busulfan treatment. No effect of an elevated temperature of 39.5°C on the level of apoptosis in HL-60 cells that were not treated with busulfan was observed. There is a need to test the efficacy of other cytostatic agents at elevated temperatures.
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http://dx.doi.org/10.17219/acem/91821DOI Listing
May 2019

Efficient method for isolation of reticulocyte RNA from healthy individuals and hemolytic anaemia patients.

J Cell Mol Med 2019 01 18;23(1):487-496. Epub 2018 Nov 18.

Department of Biochemistry and Bioinformatics, Faculty of Biological Sciences, University of Zielona Góra, Zielona Góra, Poland.

Despite enormous progress and development of high-throughput methods in genome-wide mRNA analyses, data on the erythroid transcriptome are still limited, even though they could be useful in medical diagnostics and personalized therapy as well as in research on normal and pathological erythroid maturation. Although obtaining normal and pathological reticulocyte transcriptome profiles should contribute greatly to our understanding of the molecular bases of terminal erythroid differentiation as well as the mechanisms of the hematological diseases, a basic limitation of these studies is the difficulty of efficient reticulocyte RNA isolation from human peripheral blood. The restricted number of possible parallel experiments primarily concern healthy individuals with the lowest number of reticulocytes in the peripheral blood and a low RNA content. In the present study, an efficient method for reticulocyte RNA isolation from healthy individuals and hemolytic anaemia patients is presented. The procedure includes leukofiltration, Ficoll-Paque gradient centrifugation, Percoll gradient centrifugation, and negative (CD45 and CD61) immunomagnetic separation. This relatively fast and simple four-stage method was successfully applied to obtain a reticulocyte-rich population from healthy subjects, which was used to efficiently isolate the high-quality RNA essential for successful NGS-based transcriptome analysis.
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http://dx.doi.org/10.1111/jcmm.13951DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6307756PMC
January 2019

Evaluation of the impact of treatment with hematopoietic stem cells transplantation (HSCT) on biochemical markers of heart function and novel electrocardiographic markers of repolarization in patients with hematological malignancies.

Med Oncol 2018 Oct 31;35(12):162. Epub 2018 Oct 31.

Department of Internal Medicine, Occupational Diseases and Hypertension, Wroclaw Medical University, Borowska 213, 50-556, Wroclaw, Poland.

High-dose chemotherapy (HDC) followed by stem cell transplantation (HSCT) is a well-established method in patients with hematological malignancies, and for last few years, many efforts have been made to estimate short- and long-term efficacy of this method, as well as early and late complications. The present study concentrates on cardiotoxic effects, mainly early changes using biochemical markers such as N-terminal natriuretic peptide type B (NT-proBNP) and cardiac troponins (cTn). Simultaneously, the analysis of 12-lead ECG was done before and after the procedure in which the novel repolarization markers: T and T/QT ratio were measured, together with standard markers: QT, QTc. It was found that NT-pro BNP was significantly increased after HSCT in comparison to results before it, and no significant changes were present in Troponin levels. Simultaneously, T interval and T/QT ratio were significantly higher after HSCT. The use of cyclophosphamide, advanced age, and higher level of blood cholesterol concentration were risk factors for the increase in NT-proBNP and treatment with cyclophosphamide as well as fludarabine and higher creatinine levels were risk factors for the increase in T/QT ratio. In conclusion, in the early term evaluation after HSCT in patients with no previously diagnosed heart disease, the mild changes in markers of heart overload and repolarization were noted. The observations suggest that in all patients undergoing HSCT, even the ones without pre-existing cardiovascular disease, the evaluation, and monitoring of heart function should be considered.
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http://dx.doi.org/10.1007/s12032-018-1221-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6208856PMC
October 2018

Constitutional mutations of the CHEK2 gene are a risk factor for MDS, but not for de novo AML.

Leuk Res 2018 07 3;70:74-78. Epub 2018 Jun 3.

Department of Clinical Genetics, Faculty of Medicine, Collegium Medicum, Bydgoszcz, Nicolaus Copernicus University, Toruń, Poland; Department of Hematology, Blood Neoplasms and Bone Marrow Transplantation, Medical University, Wrocław, Poland.

CHEK2 plays a key role in cellular response to DNA damage, and also in regulation of mitosis and maintenance of chromosomal stability. In patients newly diagnosed with myelodysplastic syndrome (MDS, n = 107) or acute myeloid leukemia (AML, n = 117) congenital CHEK2 mutations (c.444 + 1G > A, c.1100delC, del5395, p.I157 T) were tested by PCR and sequencing analysis. The karyotype of bone marrow cells of each patient was assessed at disease diagnosis using classical cytogenetic methods and fluorescence in situ hybridization. The CHEK2 mutations were strongly associated with the risk of MDS (p < 0.0001) but not with the risk of de novo AML (p = 0.798). In CHEK2-positive MDS patients, two times higher frequency of aberrant karyotypes than in CHEK2-negative patients was found (71% vs. 37%, p = 0.015). In CHEK2-positive patients with cytogenetic abnormalities, subtypes of MDS: refractory anemia with excess blasts-1 or 2, associated with unfavorable disease prognosis, were diagnosed two times more often than in CHEK2-negative cases with aberrations (78% vs. 44%). In conclusion, the congenital CHEK2 inactivation is strongly associated with the risk of MDS and with a poorer prognosis of the disease. However, the chromosomal instability in AML is not correlated with the hereditary dysfunction of CHEK2.
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http://dx.doi.org/10.1016/j.leukres.2018.05.013DOI Listing
July 2018

HLA-inferred extended haplotype disparity level is more relevant than the level of HLA mismatch alone for the patients survival and GvHD in T cell-replate hematopoietic stem cell transplantation from unrelated donor.

Hum Immunol 2018 Jun 29;79(6):403-412. Epub 2018 Mar 29.

Department of Hematology and Bone Marrow Transplantation, Silesian Medical University, Katowice, Poland.

Serious risks in unrelated hematopoietic stem cell transplantation (HSCT) including graft versus host disease (GvHD) and mortality are associated with HLA disparity between donor and recipient. The increased risks might be dependent on disparity in not-routinely-tested multiple polymorphisms in genetically dense MHC region, being organized in combinations of two extended MHC haplotypes (Ehp). We assessed the clinical role of donor-recipient Ehp disparity levels in N = 889 patients by the population-based detection of HLA allele phase mismatch. We found increased GvHD incidences and mortality rates with increasing Ehp mismatch level even with the same HLA mismatch level. In multivariate analysis HLA mismatch levels were excluded from models and Ehp disparity level remained independent prognostic factor for high grade acute GvHD (p = 0.000037, HR = 10.68, 95%CI 5.50-32.5) and extended chronic GvHD (p < 0.000001, HR = 15.51, CI95% 5.36-44.8). In group with single HLA mismatch, patients with double Ehp disparity had worse 5-year overall survival (45% vs. 56%, p = 0.00065, HR = 4.05, CI95% 1.69-9.71) and non-relapse mortality (40% vs. 31%, p = 0.00037, HR = 5.63, CI95% 2.04-15.5) than patients with single Ehp disparity. We conclude that Ehp-linked factors contribute to the high morbidity and mortality in recipients given HLA-mismatched unrelated transplant and Ehp matching should be considered in clinical HSCT.
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http://dx.doi.org/10.1016/j.humimm.2018.03.011DOI Listing
June 2018

The role of hypoxia-inducible factors in leukemias.

Adv Clin Exp Med 2018 Feb;27(2):271-275

Department of Hematology, Wroclaw Medical University, Poland.

Hypoxia, understood as low partial oxygen pressure, has become one of the most explored fields in recent years. Cellular response to hypoxia is mediated by hypoxia-inducible factors (HIFs) - potent transcription regulators, and their downstream pathways. In general, HIFs modify energy metabolism, inflammation and immune response, enhance cancer invasion, metastasis, resistance to treatment, and relapse. The influence of HIFs on the progression of leukemia is still under investigation in various studies, but in mice and some human models HIFs have been recognized as leukemia immortalizers by promoting leukemic stem cell quiescence and inhibiting their cell cycle. This makes leukemic stem cells resistant to most known treatment approaches. The role of HIFs in solid tumors and leukemia makes them almost ideal targets for an anticancer treatment. Although the first attempts with new molecules are encouraging, there is a need to investigate the ambiguous role of HIFs to develop a modern antileukemic treatment.
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http://dx.doi.org/10.17219/acem/69261DOI Listing
February 2018

Genetic variation of the gene coding for microRNA-204 (miR-204) is a risk factor in acute myeloid leukaemia.

BMC Cancer 2018 01 30;18(1):107. Epub 2018 Jan 30.

Department of Internal and Occupational Diseases, Hypertension and Clinical Oncology, Wroclaw Medical University, Wrocław, Poland.

Background: MicroRNAs (miRNAs or miRs) are small molecules known to be involved in post-transcriptional gene expression. Many of them have been shown to influence risk for various diseases. Recent studies suggest that lower expression of miR-204, a gene coding for miRNA-204, is correlated with shorter survival in patients with acute myeloid leukaemia (AML). This observation prompted us to analyse the effect of two polymorphisms of the miR-204 gene, one in the upstream flanking region (rs718447 A > G) and the other inside the gene itself (rs112062096 A > G), both also in intron 3 of the TRPM3 gene.

Methods: The study was conducted on DNA samples isolated from AML patients (n = 95) and healthy individuals (n = 148), who were genotyped using the Light SNiP assays.

Results: The miR-204 rs718447 GG homozygosity was found to constitute a risk factor associated with susceptibility to AML (73/95 vs 92/148, AML patients vs healthy controls, OR = 2.020, p = 0.017). Additionally, this genotype was more frequent in patients with subtypes M0-M1 in the French-American-British (FAB) classification as compared to patients with subtypes M2-M7 (23/25 vs 39/57, p = 0.026). We also found that presence of allele A was linked to longer survival of AML patients.

Conclusions: Our results show that polymorphism in miR-204 flanking region may constitute a risk and prognostic factor in AML.
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http://dx.doi.org/10.1186/s12885-018-4045-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5791219PMC
January 2018

The analysis of the parameters of 24-hr ECG Holter monitoring in patients with blood neoplasms undergoing high-dose chemotherapy and stem cell transplantation.

Ann Noninvasive Electrocardiol 2018 07 24;23(4):e12534. Epub 2018 Jan 24.

Department of Internal Medicine, Occupational Diseases and Hypertension, Wroclaw Medical University, Wroclaw, Poland.

Background: Hematopoietic stem cell transplantation (HSCT) is a widely used procedure in the treatment of malignant diseases, including blood neoplasms and has increased survival in hematological diseases. The aim of the study was to analyze parameters of 24-hr ECG monitoring in patients with selected blood neoplasms in whom the procedure of hematopoietic stem cell transplantation was performed.

Methods: The study group consisted of 64 adults diagnosed with hematologic cancer qualified for HSCT with the previous high dose chemotherapy (HDC). In all patients 24-hr Holter monitoring was carried out twice. First examination took place prior to the HSCT procedure, and the second after finishing the procedure of HSCT.

Results: The minimal and mean heart rate (HR min and HR max) from 24-hr ECG recording was statistically significantly higher after the transplantation in comparison with the first test. The number of premature ventricular complexes (PVCs) was higher in the test after HSCT. In the second examination there was significantly higher percentage of premature ventricular complexes, incidents of tachycardia, and Mobitz type 1 second degree atrioventricular block. In regression analysis, in a group of patients with blood neoplasms after HSCT and HDC, administration of cyclophosphamide, fludarabine and total body irradiation were independent risk factors for electrocardiographic abnormalities in 24-hr Holter monitoring, that is, the increase in HR min, HR mean and PVCs.

Conclusion: In patients with blood neoplasms undergoing HSCT more electrocardiographic abnormalities may be found after this procedure in comparison with the 24-hr Holter monitoring before transplantation.
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http://dx.doi.org/10.1111/anec.12534DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6931497PMC
July 2018

Bone marrow adipocytes in haematological malignancies.

Acta Histochem 2018 Jan 14;120(1):22-27. Epub 2017 Nov 14.

Department of Hematology, Blood Neoplasms and Bone Marrow Transplantation, Medical University, Wrocław, Poland.

Bone marrow adipocytes (BMAs) derived from mesenchymal stem cells (MSC) are an active and significant element of the bone marrow microenvironment. They are involved in metabolic functions, complex interactions with other stromal cells, and in the development and progression of tumours. Currently, there is little data regarding the role of BMAs in haematological malignancies. Due to this, we have attempted to characterise the BMAs in these malignancies in terms of quantity and morphology. Our study included 30 patients aged 22-76 with myelo- (n=17) and lymphoproliferative malignancies (n=13), both with and without bone marrow infiltration. Trepanobioptate was the evaluated material. The number and diameter of BMAs were measured, and the percentage of adipocytes (adipocyte fraction - AF), hematopoietic cells (hematopoietic fraction - HF) and trabecular bone (trabecular bone fraction - BF) was calculated. The obtained results were considered against the clinical parameters of age, sex, body weight, body surface area (BSA) and body mass index (BMI). We observed that as age increases, the number of BMA/mm, the diameter of adipocytes and AF increase while BF and HF decrease. However, this relationship was not statistically significant. A significant correlation of BMA parameters was also not found in relation to weight, BMI and BSA, and the number and diameter of BMAs were comparable in both sexes. The trepanobioptate of infiltrated bone marrow showed a decreased number of BMA/mm compared to the trepanobioptate from bone marrow without infiltration (97.44±69.16 vs. 164.14±54.16; p=0.010) with a marked difference in men (69.75±65.26 vs. 180.33±60.40; p=0.007). These trepanobioptate also showed an increase in the number of BMA/mm with age (r=0.472; p=0.041), and with an increase of BMI, an increase in diameter of BMAs (r=0.625; p=0.007) and AF (r=0.546; p=0.023). The number and size of BMAs, as well as AF, BF and HF in patients with myeloproliferative malignancies did not differ significantly compared to patients with lymphoproliferative malignancies.
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http://dx.doi.org/10.1016/j.acthis.2017.10.010DOI Listing
January 2018

MRP1 protein expression in leukemic stem cells as a negative prognostic marker in acute myeloid leukemia patients.

Eur J Haematol 2017 Nov 29;99(5):415-422. Epub 2017 Sep 29.

Department and Clinic of Hematology, Blood Neoplasms and Bone Marrow Transplantation, Wroclaw Medical University, Wroclaw, Poland.

Background: It is well established that expression of multi-drug resistance (MDR) proteins (MDR1, BCRP, MDR3, MRP1, and LRP) in leukemic blasts correlates with acute myeloid leukemia (AML) patients' clinical response. Assuming that leukemic stem cells (LSC) are resistant to chemotherapy and responsible for relapse, it might be clinically relevant to evaluate the expression level of MDR proteins in LSC and relate it to the clinical outcome.

Methods: Bone marrow samples from 26 patients with de novo AML were labeled with antibodies to distinguish CD34+CD38-CD123+ LSC population and with antibodies against MDR1, BCRP, MDR3, MRP1, or LRP proteins. Multicolor flow cytometry was applied to evaluate the expression of MDR proteins in blasts and LSC.

Results: Nine of 26 patients with AML attained CR (30%). High negative correlation was found between MDR1 and LRP expression in blasts and the patient's remission. MDR proteins were expressed more frequently in LSC than in leukemic blasts. High negative correlation was also observed between remission achievement and MRP1 expression in LSC.

Conclusions: Our data present for the very first time the high negative correlation between MRP1 protein expression in LSC and AML patients' remission. It does strongly suggest that MRP1 expression in LSC is an adverse prognostic marker in patients with de novo AML.
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http://dx.doi.org/10.1111/ejh.12938DOI Listing
November 2017

Predictive factors of thrombosis for patients with essential thrombocythaemia: A single center study.

Adv Clin Exp Med 2017 Jan-Feb;26(1):115-121

Department and Clinic of Hematology, Blood Neoplasms, and Bone Marrow Transplantation, Wroclaw Medical University, Poland.

Background: Thrombotembolic complications are the leading cause of mortality in essential thrombocythemia (ET), but the definition of thrombotic risk remains far from clear.

Objectives: The aim of this study was to evaluate the prognostic markers for thrombosis to identify ET patients at risk.

Material And Methods: Forty-five consecutive patients with ET were studied. This group was divided into two subgroups ET patients with (A) and without (B) history of thrombosis. Each patient has been tested for complete blood count, fibrinogen, factor VIII, D-dimer, protein C, APCR, TAT and F1+2. JAK2 mutation was assessed by RT-PCR. Factor V Leiden and prothrombin genes mutations were screened by DNA sequencing.

Results: The median age of ET patients was 62.0 years. JAK2 mutation was found in 24 patients, 21 of them had a history of thrombotic events, and 17/21 were JAK2 positive. Compared to controls, ET patients had a significantly higher WBC and PLT counts, and higher mean platelet volume (MPV), but not Hgb level or RBC count. In ET subgroup A, apart from changes seen in the whole ET, the Hgb level, RBC count, and Hct were also significantly elevated. Interestingly, the MPV was significantly larger in subgroup A, but not in B. Fibrinogen and D-dimers levels were significantly higher in ET group than in controls, but not F1+F2 or TAT. The results of hemostatic tests did not markedly differ between subgroups A and B. APCR was found in 5/45 patients with ET, and 2 out of 5 had a factor V Leiden heterozygous mutation. No prothrombin gene mutation was observed.

Conclusions: Our results suggest that MPV can serve as a simple test for assessing the hypercoagulable state in ET patients. It has been confirmed that JAK2 mutation and leukocytosis are independent predictors for thrombotic events in ET patients.
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http://dx.doi.org/10.17219/acem/68578DOI Listing
June 2017

Addition of cladribine to the standard induction treatment improves outcomes in a subset of elderly acute myeloid leukemia patients. Results of a randomized Polish Adult Leukemia Group (PALG) phase II trial.

Am J Hematol 2017 Apr 13;92(4):359-366. Epub 2017 Feb 13.

Department of Hematology, Medical University of Lodz, Lodz, Poland.

Intensive induction chemotherapy using anthracycline and cytarabine backbone is considered the most effective upfront therapy in physically fit older patients with acute myeloid leukemia (AML). However, outcomes of the standard induction in elderly AML are inferior to those observed in younger patients, and they are still unsatisfactory. As addition of cladribine to the standard induction therapy is known to improve outcome in younger AML patients. The present randomized phase II study compares efficacy and toxicity of the DAC (daunorubicin plus cytarabine plus cladribine) regimen with the standard DA (daunorubicin plus cytarabine) regimen in the newly diagnosed AML patients over 60 years of age. A total of 171 patients were enrolled in the study (DA, 86; DAC, 85). A trend toward higher complete remission (CR) was observed in the DAC arm compared to the DA arm (44% vs. 34%; P = .19), which did not lead to improved median overall survival, which in the case of the DAC group was 8.6 months compared to in 9.1 months in the DA group (P = .64). However, DAC appeared to be superior in the group of patients aged 60-65 (CR rate: DAC 51% vs. DA 29%; P = .02). What is more, a subgroup of patients, with good and intermediate karyotypes, benefited from addition of cladribine also in terms of overall survival (P = .02). No differences in hematological and nonhematological toxicity between the DA and DAC regimens were observed.
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http://dx.doi.org/10.1002/ajh.24654DOI Listing
April 2017

The Expression of Toll-Like Receptors in Patients with B-Cell Chronic Lymphocytic Leukemia.

Arch Immunol Ther Exp (Warsz) 2016 Dec 12;64(Suppl 1):147-150. Epub 2017 Jan 12.

Department of Hematology, Blood Neoplasms and Bone Marrow Transplantation, Wroclaw Medical University, Pasteura 4, 50-367, Wroclaw, Poland.

B-cell chronic lymphocytic leukemia (B-CLL) presents with progressive accumulation of monoclonal B cells in the peripheral blood, bone marrow and lymphoid organs. B-CLL is characterized by heterogeneous clinical outcome. The expression of Toll-like receptors (TLRs) and their association with other prognostic factors in B-CLL patients remain unclear. The aim of our study was to evaluate the expression of TLR2, TLR4 and TLR9 genes and their significance as biological markers in patients with B-CLL. Sixty patients with newly diagnosed B-CLL were evaluated. The healthy control group included 20 age-matched individuals. Using quantitative reverse transcriptase PCR, the mRNA expression of genes TLR2, TLR4 and TLR9 was measured. TLR4 gene expression was lower in B-CLL patients as compared to the control group and TLR2 gene expression was higher in B-CLL patients than in healthy individuals. TLR9 gene expression was higher in the control group than in patients with B-CLL. TLR4 mRNA expression was lower in patients with advanced-stage CLL (Rai stages III and IV) than in patients with early stage disease (Rai stages 0-II). TLR2 gene expression was higher in patients with advanced-stage CLL (Rai stages III and IV) than in patients with early stage disease (Rai stages 0-II; p < 0.05). Our results suggest that TLRs could become potential biological markers for the clinical outcome in patients with B-CLL.
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http://dx.doi.org/10.1007/s00005-016-0433-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5334378PMC
December 2016

Ofatumumab Versus Rituximab Salvage Chemoimmunotherapy in Relapsed or Refractory Diffuse Large B-Cell Lymphoma: The ORCHARRD Study.

J Clin Oncol 2017 Feb 28;35(5):544-551. Epub 2016 Dec 28.

Gustaaf W. van Imhoff, University Medical Center, University of Groningen; Bronno van der Holt, University Medical Center, Rotterdam; Anton Hagenbeek, Academic Medical Center, University of Amsterdam, Amsterdam, the Netherlands; Andrew McMillan, Nottingham University Hospital, Nottingham; John Radford and Kirit M. Ardeshna, Christie Hospital NHS Trust, Manchester; Andrew Davies, University of Southampton, Southampton, United Kingdom; Matthew J. Matasar, Memorial Sloan Kettering Cancer Center, New York, NY; Kazimierz Kuliczkowski, Wroclaw Medical University, Wroclaw, Poland; WonSeog Kim, Sungkyunkwan University School of Medicine, Seoul, Korea; Xiaonan Hong, Fudan University, Shanghai, China; Jette Soenderskov Goerloev, Rigshospitalet; Steen Lisby, Genmab A/S, Copenhagen, Denmark; María Dolores Caballero Barrigón, Hospital Universitario de Salamanca, Salamanca, Spain; Michinori Ogura, Nagoya Daini Red Cross Hospital, Nagoya; Michinori Ogura, Tokai Central Hospital, Kakamigahara, Japan; Sirpa Leppä, Helsinki University Central Hospital Cancer Center, Helsinki, Finland; and Michael Fennessy and Qiming Liao, Novartis AG, Basel, Switzerland.

Purpose We compared the efficacy of ofatumumab (O) versus rituximab (R) in combination with cisplatin, cytarabine, and dexamethasone (DHAP) salvage treatment, followed by autologous stem-cell transplantation (ASCT) in patients with relapsed or refractory diffuse large B-cell lymphoma (DLBCL). Patients and Methods Patients with CD20 DLBCL age ≥ 18 years who had experienced their first relapse or who were refractory to first-line R-CHOP (cyclophosphamide, doxorubicin, vincristine, prednisone)-like treatment were randomly assigned between three cycles of R-DHAP or O-DHAP. Either O 1,000 mg or R 375 mg/m was administered for a total of four infusions (days 1 and 8 of cycle 1; day 1 of cycles 2 and 3 of DHAP). Patients who experienced a response after two cycles of treatment received the third cycle, followed by high-dose therapy and ASCT. Primary end point was progression-free survival (PFS), with failure to achieve a response after cycle 2 included as an event. Results Between March 2010 and December 2013, 447 patients were randomly assigned. Median age was 57 years (range, 18 to 83 years); 17% were age ≥ 65 years; 63% had stage III and IV disease; 71% did not achieve complete response (CR) or experience response for < 1 year on first-line R-CHOP. Response rate for O-DHAP was 38% (CR, 15%) versus 42% (CR, 22%) for R-DHAP. ASCT on protocol was completed by 74 patients (33%) in the O arm and 83 patients (37%) in the R arm. PFS, event-free survival, and overall survival were not significantly different between O-DHAP versus R-DHAP: PFS at 2 years was 24% versus 26% (hazard ratio [HR], 1.12; 95% CI, 0.89 to 1.42; P = .33); event-free survival at 2 years was 16% versus 18% (HR, 1.10; P = .35); and overall survival at 2 years was 41% versus 38% (HR, 0.90; P = .38). Positron emission tomography negativity before ASCT was highly predictive for superior outcome. Conclusion No difference in efficacy was found between O-DHAP and R-DHAP as salvage treatment of relapsed or refractory DLBCL.
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http://dx.doi.org/10.1200/JCO.2016.69.0198DOI Listing
February 2017

Significance of OCT1 Expression in Acute Myeloid Leukemia.

Pathol Oncol Res 2017 Jul 26;23(3):665-671. Epub 2016 Dec 26.

Department of Hematology, Blood Neoplasms and Bone Marrow Transplantation, Wrocław Medical University, Wrocław, Poland.

Organic cation transporter 1 (OCT1) is one of the membrane proteins in the large solute carrier (SLC) family. It participates in the transport of organic cations, i.e. nutrients, neurotransmitters, metabolites or drugs in an electrogenic manner and translocate various cationic cytostatics. Knowledge concerning the expression of drug transporters in tumor cells may help to develop cytotoxic agents that are targeted to specific tumors. OCT1 expression and its relationship to the proliferation of cancer cells, development of metastases and resistance to chemotherapy has been observed in solid tumors. There is no data concerning the significance of OCT1 expression in the clinical course and treatment results in acute myeloid leukemia (AML). The objective of the study was firstly to evaluate OCT1 mRNA expression in patients with newly diagnosed de novo AML, and secondly to compare the obtained results to the healthy control group as well as analyze them according to leukemia subtypes, CD34 expression, cytogenetic and molecular factors and treatment results. 101 patients with AML, excluding the subtype classified as M3 by French-American-British (FAB) criteria, were analyzed. The control group consisted of 26 healthy individuals. The evaluated material was bone marrow (BM). Real-time quantitative polymerase chain reaction (RQ-PCR) was used in the study as a method of evaluating OCT1 mRNA expression. The study showed a statistically significant lower expression of OCT1 mRNA in patients with AML in comparison to the control group. The level of OCT1 mRNA expression was lowest for CD34+ leukemia. No significant correlation between OCT1 mRNA expression and cytogenetic and molecular factors was observed. A significant influence of OCT1 mRNA expression on the clinical outcome of the disease was observed: patients with lower expression had higher chances of achieving complete remission (CR) and longer overall survival (OS).
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http://dx.doi.org/10.1007/s12253-016-0161-7DOI Listing
July 2017

Phase 2 study of tabalumab, a human anti-B-cell activating factor antibody, with bortezomib and dexamethasone in patients with previously treated multiple myeloma.

Br J Haematol 2017 Mar 22;176(5):783-795. Epub 2016 Dec 22.

Myeloma Unit, Division of Haematology, University of Torino, Azienda Ospedaliero-Universitaria Città della Salute e della Scienza di Torino, Torino, Italy.

In this double-blind, Phase 2 study, 220 patients with relapsed/refractory multiple myeloma were randomly assigned 1:1:1 to receive placebo (N = 72), tabalumab 100 mg (N = 74), or tabalumab 300 mg (N = 74), each in combination with dexamethasone 20 mg and subcutaneous bortezomib 1·3 mg/m on a 21-day cycle. No significant intergroup differences were observed among primary (median progression-free survival [mPFS]) or secondary efficacy outcomes. The mPFS was 6·6, 7·5 and 7·6 months for the tabalumab 100, 300 mg and placebo groups, respectively (tabalumab 100 mg vs. placebo Hazard ratio (HR) [95% confidence interval (CI)] = 1·13 [0·80-1·59], P = 0·480; tabalumab 300 mg vs. placebo HR [95% CI] = 1·03 [0·72-1·45], P = 0·884). The most commonly-reported treatment-emergent adverse events were thrombocytopenia (37%), fatigue (37%), diarrhoea (35%) and constipation (32%). Across treatments, patients with low baseline BAFF (also termed TNFSF13B) expression (n = 162) had significantly longer mPFS than those with high BAFF expression (n = 55), using the 75th percentile cut-off point (mPFS [95% CI] = 8·3 [7·0-9·3] months vs. 5·8 [3·7-6·6] months; HR [95% CI] = 1·59 [1·11-2·29], P = 0·015). Although generally well tolerated, PFS was not improved during treatment with tabalumab compared to placebo. A higher dose of 300 mg tabalumab did not improve efficacy compared to the 100 mg dose. Nonetheless, BAFF appears to have some prognostic value in patients with multiple myeloma.
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http://dx.doi.org/10.1111/bjh.14483DOI Listing
March 2017

Health-related quality of life and patient-reported outcomes of ofatumumab plus fludarabine and cyclophosphamide versus fludarabine and cyclophosphamide in the COMPLEMENT 2 trial of patients with relapsed CLL.

Leuk Lymphoma 2017 07 10;58(7):1598-1606. Epub 2016 Nov 10.

r Department of Cancer Prevention, Faculty of Public Health , Medical University of Silesia , Katowice , Poland.

Chronic lymphocytic leukemia (CLL) is an incurable disease. Quality of life during treatment and periods of subsequent remission is therefore vital. Health-related quality of life (HRQoL) was compared in relapsed CLL during and after treatment with ofatumumab combined with fludarabine and cyclophosphamide versus fludarabine and cyclophosphamide alone. The European Organisation for Research and Treatment of Cancer (EORTC) QLQ-C30 v3 and QLQ-CLL16 were used to assess HRQoL in this open-label, phase 3 study. Improvements in prespecified domains of patient-reported outcomes (Global Health Status [GHS]/HRQoL and B symptom scores) were recorded in both treatment arms after three cycles and were sustained after 18 months of follow-up. The two treatment arms were not significantly different at the nominal 0.05 level for GHS/HRQoL (p = .7278) or B symptoms (p = .5968). Small improvements in quality of life were maintained after therapy. The addition of ofatumumab was without any adverse impact on HRQoL (NCT00824265).
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http://dx.doi.org/10.1080/10428194.2016.1253837DOI Listing
July 2017

The Hasford Score May Predict Molecular Response in Chronic Myeloid Leukemia Patients: A Single Institution Experience.

Dis Markers 2016 12;2016:7531472. Epub 2016 Oct 12.

Department of Hematology and Bone Marrow Transplantation, Wroclaw Medical University, Wroclaw, Poland; Department of Clinical Genetics, Collegium Medicum of Nicolaus Copernicus University, Bydgoszcz, Poland.

The Sokal, Hasford, and EUTOS scores were established in different treatment eras of chronic myeloid leukemia (CML). None of them was reported to predict molecular response. In this single center study we tried to reevaluate the usefulness of three main scores in TKI era. The study group included 88 CML patients in first chronic phase treated initially with standard imatinib dose. All of them achieved major molecular response (MMR) in time points defined by European LeukemiaNet (ELN). 42 patients lost MMR in a median time of 47 months and we found a significant difference in MMR maintenance between intermediate-risk (IR) and low-risk (LR) patients assessed by Hasford score. All 42 patients were switched to second-generation TKI (2G-TKI) treatment. At 18 months of 2G-TKI therapy we have still found a significant difference in BCR-ABL transcript levels and MMR rate between IR and LR groups. We did not find any of the described differences discriminating patients by Sokal or EUTOS score. In this retrospective single center analysis we found Hasford score to be useful in predicting molecular response in first chronic phase of CML patients.
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http://dx.doi.org/10.1155/2016/7531472DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5080519PMC
February 2017

Ofatumumab plus fludarabine and cyclophosphamide in relapsed chronic lymphocytic leukemia: results from the COMPLEMENT 2 trial.

Leuk Lymphoma 2017 05 12;58(5):1084-1093. Epub 2016 Oct 12.

r Department of Cancer Prevention, Faculty of Public Heath , Medical University of Silesia , Katowice , Poland.

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).
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http://dx.doi.org/10.1080/10428194.2016.1233536DOI Listing
May 2017

A new frameshift mutation of the β-spectrin gene associated with hereditary spherocytosis.

Ann Hematol 2017 Jan 6;96(1):163-165. Epub 2016 Oct 6.

Department of Cytobiochemistry, Biotechnology Faculty, University of Wrocław, F. Joliot-Curie 14a, 50-383, Wrocław, Poland.

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http://dx.doi.org/10.1007/s00277-016-2838-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5203818PMC
January 2017

Expression of microRNA-181 determines response to treatment with azacitidine and predicts survival in elderly patients with acute myeloid leukaemia.

Oncol Lett 2016 Oct 8;12(4):2296-2300. Epub 2016 Aug 8.

Department of Haematology, Blood Neoplasms and Bone Marrow Transplantation, Wroclaw Medical University, Wroclaw 50-367, Poland.

MicroRNAs (miRs) are small non-coding RNAs that play important roles in cell differentiation and survival. Abnormal expression of miRs has been demonstrated in numerous types of cancer, including acute myeloid leukaemia (AML). The aim of the present study was to evaluate miR-181 expression at diagnosis and following the completion of chemotherapy in AML patients, with regard to clinical response and outcome, particularly in patients treated with azacitidine. miR-181 expression was analysed using reverse transcription-quantitative polymerase chain reaction in 95 bone marrow specimens from newly diagnosed AML patients and in 20 healthy subjects for comparison. The results revealed upregulated miR-181 expression in the total cohort of AML patients, which was correlated with longer survival. However, in a subset of older AML patients treated with azacitidine, low miR-181 expression at diagnosis was a predictor for complete remission and prolonged survival. The findings indicated that miR-181 has an important role in AML and determines response to azacitidine treatment in older AML patients.
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http://dx.doi.org/10.3892/ol.2016.4970DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5038519PMC
October 2016

Ascites in the Course of Plasma Cell Myeloma Complicated by AL Amyloidosis.

Turk J Haematol 2018 Mar 16;35(1):71-72. Epub 2016 Aug 16.

Uniwersytet Medyczny im Piastow Slaskich we Wroclawiu, Department of Hematology, Blood Neoplasms and Bone Marrow Transplantation, Wroclaw, Poland.

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http://dx.doi.org/10.4274/tjh.2016.0262DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5843778PMC
March 2018

Efficacy and safety of rVIII-SingleChain: results of a phase 1/3 multicenter clinical trial in severe hemophilia A.

Blood 2016 08 21;128(5):630-7. Epub 2016 Jun 21.

Clinical Division of Haematology and Haemostaseology, Medical Clinic I, Medical University Vienna, Vienna, Austria.

Recombinant VIII (rVIII)-SingleChain is a novel B-domain-truncated recombinant factor VIII (rFVIII), comprised of covalently bonded factor VIII (FVIII) heavy and light chains. It was designed to have a higher binding affinity for von Willebrand factor (VWF). This phase 1/3 study investigated the efficacy and safety of rVIII-SingleChain in the treatment of bleeding episodes, routine prophylaxis, and surgical prophylaxis. Participants were ≥12 years of age, with severe hemophilia A (endogenous FVIII <1%). The participants were allocated by the investigator to receive rVIII-SingleChain in either an on-demand or prophylaxis regimen. Of the 175 patients meeting study eligibility criteria, 173 were treated with rVIII-SingleChain, prophylactically (N = 146) or on-demand (N = 27). The total cumulative exposure was 14 306 exposure days (EDs), with 120 participants reaching ≥50 EDs and 52 participants having ≥100 EDs. Hemostatic efficacy was rated by the investigator as excellent or good in 93.8% of the 835 bleeds treated and assessed. Across all prophylaxis regimens, the median annualized spontaneous bleeding rate was 0.00 (Q1, Q3: 0.0, 2.4) and the median overall annualized bleeding rate (ABR) was 1.14 (Q1, Q3: 0.0, 4.2). Surgical hemostasis was rated as excellent/good in 100% of major surgeries by the investigator. No participant developed FVIII inhibitors. In conclusion, rVIII-SingleChain is a novel rFVIII molecule showing excellent hemostatic efficacy in surgery and in the control of bleeding events, low ABR in patients on prophylaxis, and a favorable safety profile in this large clinical study. This trial was registered at www.clinicaltrials.gov as #NCT01486927.
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http://dx.doi.org/10.1182/blood-2016-01-687434DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4974198PMC
August 2016

A phase 2, multicenter study investigating ofatumumab and bendamustine combination in patients with untreated or relapsed CLL.

Am J Hematol 2016 09 3;91(9):900-6. Epub 2016 Jul 3.

Department of Internal Medicine, Universitair Ziekenhuis Gent, Gent, Belgium.

The purpose of this study is to assess the safety and efficacy of the combination of ofatumumab and bendamustine in patients with previously untreated or relapsed chronic lymphocytic leukemia. Patients received IV ofatumumab (cycle 1: 300 mg day 1 and 1,000 mg day 8; cycles 2-6: 1,000 mg on day 1 every 28 days) and IV bendamustine 90 mg m(-2) (previously untreated) or 70 mg m(-2) (relapsed) on days 1 and 2 of each 28-day cycle, for up to 6 cycles. Forty-four previously untreated and 53 relapsed patients were enrolled. Median age was 62.5 years (previously untreated) and 68 years (relapsed); relapsed patients had received a median of 1 (range 1-11) prior therapy. The investigator-assessed overall response rate was 95% (43% complete response [CR]) for the previously untreated, and 74% (11% CR) for the relapsed patients. The regimen was well tolerated with 89% (previously untreated) and 85% (relapsed patients) receiving all 6 cycles. No unexpected toxicities were reported. Grade 3/4 events occurred in 57% of previously untreated, and 72% of relapsed patients. At ∼29 months' follow-up, the median progression-free survival (PFS) was not reached for the previously untreated population, and the 28-month PFS estimate was 72.3%. The median PFS for the relapsed population was 22.5 months (95% CI: 14.0-27.3 months). The combination of ofatumumab and bendamustine was well tolerated and effective in these previously untreated or relapsed populations. Am. J. Hematol. 91:900-906, 2016. © 2016 Wiley Periodicals, Inc.
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http://dx.doi.org/10.1002/ajh.24430DOI Listing
September 2016

Pharmacokinetics, efficacy, and safety of a plasma-derived VWF/FVIII concentrate (VONCENTO) for on-demand and prophylactic treatment in patients with von Willebrand disease (SWIFT-VWD study).

Blood Coagul Fibrinolysis 2017 Mar;28(2):152-162

aSpecialized Hospital for Active Treatment (SHAT), Sofia, Bulgaria bGOUVPO Altaysky State Medical University of Roszdrav, Barnaul, Russian Federation cIndependent Public Clinical Hospital No. 1, Wroclaw, Poland dInstitute of Pathology and Transfusion Medicine AMN, Lviv, Ukraine eInstitute of Hematology, Rio de Janeiro, Brazil fDepartment of Pediatrics, Hematology and Oncology of Warsaw Medical University, Warsaw, Poland gClinical Research and Development, CSL Behring, Marburg, Germany.

VONCENTO (CSL Behring Gmbh, Marburg, Germany) is a plasma-derived, high concentration, lower volume [relative to HAEMATE P (CSL Behring)], high-purity von Willebrand factor (VWF)/factor VIII (FVIII) concentrate with a VWF/FVIII ratio similar to HAEMATE P. This open-label, multicentre study investigated the pharmacokinetic, haemostatic efficacy, and safety profiles of VONCENTO in study participants at least 12 years of age with von Willebrand disease (VWD) who required treatment of nonsurgical bleeding (NSB) events or underwent surgery or prophylaxis. The first 12-month on-demand treatment period comprised a pharmacokinetic investigation and an efficacy analysis. After 12 months, qualifying study participants were switched to prophylactic therapy and included in a further 12-month efficacy analysis. In total, 21 study participants (including three adolescents, and 13 study participants with VWD type 3) received VONCENTO as on-demand treatment for 12 months. 'Excellent'/'good' haemostatic efficacy was achieved in 98.3% of the 407 NSB events assessed by investigators. Following the switch to prophylactic treatment, the total number of NSBs in eight patients markedly decreased from 304 to 10 (with haemostatic efficacy judged to be 'excellent' for all). The annualised bleeding rate also significantly decreased from a median of 26.5 events to one event. Safety assessments showed no inhibitory antibodies to either FVIII or VWF, no transmission of infectious agents, no thromboembolic events and no treatment-related serious adverse events. VONCENTO was shown to be well tolerated and provided excellent haemostatic efficacy in the treatment of bleeds or during prophylaxis in study participants with VWD, including also those with type 3, the severest form of VWD.
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http://dx.doi.org/10.1097/MBC.0000000000000568DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5312726PMC
March 2017