Evaluation of the level of selected iron-related proteins/receptors in the liver of rats during separate/combined vanadium and magnesium administration.

BACKGROUND: The current knowledge about the effects of vanadium (V) on iron (Fe)-related proteins and Fe homeostasis (which is regulated at the systemic, organelle, and cellular levels) is still insufficient. OBJECTIVE: This fact and our earlier results prompted us to conduct studies with the aim to explain the mechanism of anemia accompanied by a rise in hepatic and splenic Fe deposition in rats receiving sodium metavanadate (SMV) separately and in combination with magnesium sulfate (MS). RESULTS: We demonstrated for the first time that SMV (0.125 mg V/mL) administered to rats individually and in conjunction with MS (0.06 mg Mg/mL) for 12 weeks did not cause significant differences in the hepatic hepcidin (Hepc) and hemojuvelin (HJV) concentrations, compared to the control. In comparison with the control, there were no significant changes in the concentration of transferrin receptor 1 (TfR1) in the liver of rats treated with SMV and MS alone (in both cases only a downward trend of 14% and 15% was observed). However, a significant reduction in the hepatic TfR1 level was found in rats receiving SMV and MS simultaneously. In turn, the concentration of transferrin receptor 2 (TfR2) showed an increasing trend in the liver of rats treated with SMV and/or MS. CONCLUSIONS: The experimental data suggest that the pathomechanism of the SMV-induced anemia is not associated with the effect of V on the concentration of Hepc in the liver, as confirmed by the unaltered hepatic HJV and TfR1 levels. Therefore, further studies are needed in order to check whether anemia that developed in the rats at the SMV administration (a) results from the inhibitory effect of V on erythropoietin (EPO) production, (b) is related to the effect of V on the induction of matriptase-2 (TMPRSS6) expression, or (c) is associated with the influence of this metal on haem synthesis.

High efficacy and safety of VTD as an induction protocol in patients with newly diagnosed multiple myeloma eligible for high dose therapy and autologous stem cell transplantation: A report of the Polish Myeloma Study Group.

The present retrospective analysis evaluated the efficacy and safety of the VTD (bortezomib, thalidomide, dexamethasone) regimen in 205 newly-diagnosed patients with multiple myeloma (MM) eligible for high dose therapy and autologous stem cell transplantation (HDT/ASCT) in routine clinical practice. With a median of 6 cycles (range, 1-8), at least partial response was achieved in 94.6% and at least very good partial response (VGPR) was achieved in 67.8% of patients. Peripheral neuropathy (PN) grade 2-4 was observed in 28.7% of patients. In 72% of patients undergoing stem cell mobilization one apheresis allowed the number of stem cells sufficient for transplantation to be obtained. Following HDT/ASCT the sCR rate increased from 4.9 to 14.4% and CR from 27.8 to 35.6%. The results demonstrated that VTD as an induction regimen was highly efficient in transplant eligible patients with MM with increased at least VGPR rate following prolonged treatment (≥6 cycles). Therapy exhibited no negative impact on stem cell collection, neutrophils and platelets engraftment following ASCT. Therapy was generally well tolerated and PN was the most common reason of dose reduction or treatment discontinuation.

Changes in T-cell subpopulations and cytokine network during early period of ibrutinib therapy in chronic lymphocytic leukemia patients: the significant decrease in T regulatory cells number.

B cell receptor (BCR) stimulation signal plays an important role in the pathogenesis of chronic lymphocytic leukemia (CLL), and kinase inhibitors directed toward the BCR pathway are now the promising anti-leukemic drugs. Ibrutinib, a Bruton tyrosine kinase inhibitor, demonstrates promising clinical activity in CLL. It is reported that ibrutinib, additionally to directly targeting leukemic cells, also inhibits the interactions of these cells with T cells, macrophages and accessory cells. Assessment of these mechanisms is important because of their non -direct anti-leukemic effects and to identify possible side effects connected with long-term drug administration.The aim of this study was to assess the in vivo effects of ibrutinib on T-cell subpopulations and cytokine network in CLL. The analysis was performed on a group of 19 patients during first month of ibrutinib therapy. The standard multicolor flow cytometry and cytometric bead array methods were used for assessment of T-cell subsets and cytokines/chemokines, respectively.The data obtained indicates that Ibrutinib treatment results in changes in T-cell subpopulations and cytokine network in CLL patients. Particularly, a significant reduction of T regulatory cells in peripheral blood was observed. By targeting these populations of T cells Ibrutinib can stimulate rejection of tumor cells by the immune system.

A clinical comparison of the efficacy and safety of biosimilar G-CSF and originator G-CSF in haematopoietic stem cell mobilization.

BACKGROUND: Recombinant granulocyte colony-stimulating factor (G-CSF) is widely used to mobilize haematopoietic stem cells. We compared the efficacy and safety of a biosimilar G-CSF (Zarzio(®), Sandoz Biopharmaceuticals) with the originator G-CSF (Neupogen(®), Amgen) in patients with haematological malignancies. METHODS: A total of 108 patients were included in this study, 59 of whom were female (49 male), with an overall median age of 51 years (range 19-69). Patients had multiple myeloma (n=46), non-Hodgkin's lymphoma (n=28), Hodgkin's lymphoma (n=26), or other diagnosis (n=8). After administration of mobilizing regimens (primarily high-dose etoposide, high-dose cyclophosphamide, intermediate-dose Ara-C or ESHAP), patients were randomized to a standard daily 10 µg/kg dose of biosimilar G-CSF (n=54) or originator G-CSF (n=54). RESULTS: Median duration of G-CSF administration was 8 days with both biosimilar G-CSF (range 4-17) and originator G-CSF (range 4-14). Both groups had a median of one apheresis with a median time until first apheresis of 11 days. There were no statistically significant differences between groups in the mean ± SD number of mobilized CD34+ cells/µL in peripheral blood or the number of CD34+ cells/kg body weight. Five patients (9%) in the originator G-CSF group and six patients in the biosimilar G-CSF group (11%) did not mobilize sufficient CD34+ cells. The adverse event profile was similar between groups. CONCLUSIONS: A biosimilar G-CSF (Zarzio(®)) demonstrated similar efficacy and safety as the reference originator G-CSF (Neupogen(®)) in hematopoietic stem cell mobilization in patients with haematological malignancies.

Bendamustine as monotherapy and in combination regimens for the treatment of chronic lymphocytic leukemia and non-hodgkin lymphoma: a retrospective analysis.

BACKGROUND/AIM: In this study, we carried out a retrospective analysis of the efficacy and toxicity of bendamustine in patients with B-cell lymphoproliferative diseases. METHODS: Bendamustine was administered both as monotherapy and in combined protocols to 92 patients, including 76 patients with chronic lymphocytic leukemia (CLL) and 16 patients with indolent lymphomas. Bendamustine plus rituximab was used to treat 65.2% of the patients, and 34.8% of the patients received bendamustine as monotherapy. RESULTS: The overall response rate was 64.2%, including the complete response rate (18.5%) and the partial response rate (45.7%). The median overall survival (OS) was 11.5 months. Among the pretreatment parameters, ß2-microglobulin (RR = 1.413; p = 0.001) and hemoglobin levels (RR = 0.85; p = 0.03) significantly influenced survival. The OS was significantly longer in patients who received ≤2 lines of previous therapy compared to >3 lines (p = 0.043; log-rank test) and those who received ≥4 courses of therapy with bendamustine (p = 0.0007; log-rank test). Toxicity was predominantly hematological, including grade III/IV neutropenia in 33.7%, thrombocytopenia in 13%, and anemia in 13% of patients. CONCLUSION: Bendamustine, both in monotherapy and in combination regimens, is an effective therapy with a favorable toxicity profile in patients with indolent B-cell malignancies.

Treatment of multiple myeloma patients with autologous stem cell transplantation - a fresh analysis.

Patients with multiple myeloma (MM) treated with conventional chemotherapy have an average survival of approximately three years. High dose chemotherapy followed by autologous stem cell transplantation (ASCT), first introduced in the mid-1980s, is now considered the standard therapy for almost all patients with multiple myeloma, because it prolongs overall survival and disease free survival. Between November 1997 and October 2006, 122 patients with MM (58 females, 64 males, median age 51.0 years [± 7.98] range: 30-66 years) were transplanted in the Department of Hematooncology and Bone Marrow Transplantation at the Medical University of Lublin: 47 patients were in complete remission or in unconfirmed complete remission, 66 patients were in partial remission, and nine had stable disease. Of these, there were 95 patients with IgG myeloma, 16 with IgA myeloma, one with IgG/IgA, one with IgM myeloma, five with non secretory type, two with solitary tumor and two with LCD myeloma. According to Durie-Salmon, 62 patients had stage III of the disease, 46 had stage II and four had stage I. Most patients (69/122) were transplanted after two or more cycles of chemotherapy, 48 patients were transplanted after one cycle of chemotherapy, one patient after surgery and rtg- -therapy and four patients had not been treated. In mobilisation procedure, the patients received a single infusion of cyclophosphamide (4-6 g/m(2)) or etoposide 1.6 g/m(2) followed by daily administration of G-CSF until the peripheral stem cells harvest. The number of median harvest sessions was 2.0 (± 0.89) (range: 1-5). An average of 7.09 (± 33.28) × 106 CD34(+) cells/kg were collected from each patient (range: 1.8-111.0 × 106/kg). Conditioning regimen consisted of high dose melphalan 60-210 mg/m(2) without TBI. An average of 3.04 (± 11.59) × 106 CD34+ cells/kg were transplanted to each patient. Fatal complications occured in four patients (treatment- -related mortality = 3.2%). In all patients there was regeneration of hematopoiesis. The median number of days for recovery to ANC > 0.5 × 109/l was 13 (± 4.69) (range: 10-38) and platelets recovery to > 50 × 109/l was 25 days (± 11.65) (range: 12-45). Median time of hospitalization was 22 days (± 7.14) (range: 14-50). Patients were evaluated on day 100 after transplantation: 74.9% achieved CR and nCR, 14.3% were in PR, 5.4% had SD and 5.4% had progressed. Median of OS was 45 months (± 30.67). OS at 3-years was 84% and at 7-years 59%. Median PFS was 25 months (± 26.13). PFS at 3-years was 68%, and at 7-years was 43%. At present (November 2009) 52 patients (42%) are still alive. High-dose chemotherapy followed by autologous stem cell transplantation is a valuable, well tolerated method of treatment for patients with MM that allows the achievement of long- -lasting survival.

Thalidomide, dexamethasone and lovastatin with autologous stem cell transplantation as a salvage immunomodulatory therapy in patients with relapsed and refractory multiple myeloma.

The treatment of patients with multiple myeloma usually includes many drugs including thalidomide, lenalidomide and bortezomib. Lovastatin and other inhibitors of HMG-CoA reductase demonstrated to exhibit antineoplasmatic and proapoptotic properties in numerous in vitro studies involving myeloma cell lines. We treated 91 patients with relapsed or refractory multiple myeloma with thalidomide, dexamethasone and lovastatin (TDL group, 49 patients) or thalidomide and dexamethasone (TD group, 42 patients). A clinical response defined of at least 50% reduction of monoclonal band has been observed in 32% of TD patients and 44% of TDL patients. Prolongation of overall survival and progression-free survival in the TDL group as compared with the TD group has been documented. The TDL regimen was safe and well tolerated. The incidence of side effects was comparable in both groups. Plasma cells have been cultured in vitro with thalidomide and lovastatin to assess the impact of both drugs on the apoptosis rate of plasma cells. In vitro experiments revealed that the combination of thalidomide and lovastatin induced higher apoptosis rate than apoptosis induced by each drug alone. Our results suggest that the addition of lovastatin to the TD regimen may improve the response rate in patients with relapsed or refractory myeloma.