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J Kienast

Publications and source records attributed to J Kienast.

At least 19 recordsLinked to original sources
PubMed2006

Treatment effects of high-dose antithrombin without concomitant heparin in patients with severe sepsis with or without disseminated intravascular coagulation.

BACKGROUND: Disseminated intravascular coagulation (DIC) is a serious complication of sepsis that is associated with a high mortality. OBJECTIVES: Using the adapted International Society on Thrombosis and Haemostasis (ISTH) diagnostic scoring algorithm for DIC, we evaluated the treatment effects of high-dose antithrombin (AT) in patients with severe sepsis with or without DIC. PATIENTS AND METHODS: From the phase III clinical trial in severe sepsis (KyberSept), 563 patients were identified (placebo, 277; AT, 286) who did not receive concomitant heparin and had sufficient data for DIC determination. RESULTS: At baseline, 40.7% of patients (229 of 563) had DIC. DIC in the placebo-treated patients was associated with an excess risk of mortality (28-day mortality: 40.0% vs. 22.2%, P < 0.01). AT-treated patients with DIC had an absolute reduction in 28-day mortality of 14.6% compared with placebo (P = 0.02) whereas in patients without DIC no effect on 28-day mortality was seen (0.1% reduction in mortality; P = 1.0). Bleeding complications in AT-treated patients with and without DIC were higher compared with placebo (major bleeding rates: 7.0% vs. 5.2% for patients with DIC, P = 0.6; 9.8% vs. 3.1% for patients without DIC, P = 0.02). CONCLUSIONS: High-dose AT without concomitant heparin in septic patients with DIC may result in a significant mortality reduction. The adapted ISTH DIC score may identify patients with severe sepsis who potentially benefit from high-dose AT treatment.

Aged↗
PubMed2004

Modern diagnostics in chronic myeloproliferative diseases (CMPDs).

According to the new WHO classification a group of chronic myeloproliferative diseases (CMPDs) were defined: chronic myeloid leukemia (CML), chronic neutrophilic leukemia (CNL), chronic eosinophilic leukemia and hypereosinophilic syndrome (CEL/HES), polycythemia vera (PV), chronic idiopathic myelofibrosis (with extramedullary hematopoiesis, CIMF), essential thrombocythemia (ET), and so called CMPD/unclassifiable. As clinical features and laboratory findings differ widely between these diseases several diagnostic approaches are mandatory at diagnosis for classification and are needed also for follow up studies, especially for the measurement of minimal residual disease (MRD). We here outline the laboratory set up at diagnosis and during follow up in CMPDs with specific focus on the respective therapeutical consequences. Only by using a comprehensive diagnostic panel including cytomorphology, cytogenetics, and molecular genetic methods establishing the correct diagnosis, optimizing treatment as well as evaluating treatment response is possible in CMPDs today.

Blood Cell Count↗
PubMed2003

Evidence of a graft-versus-leukemia effect in chronic lymphocytic leukemia after reduced-intensity conditioning and allogeneic stem-cell transplantation: the Cooperative German Transplant Study Group.

PURPOSE: To study whether hematopoietic stem-cell transplantation (HSCT) after reduced-intensity conditioning is effective and tolerable in patients with advanced chronic lymphocytic leukemia (CLL). PATIENTS AND METHODS: Thirty patients with advanced B-cell CLL were included into the study. After reduced-intensity conditioning with fludarabine, busulfan, and antithymocyte globulin, patients received a transplant from related (n = 15) or unrelated donors (n = 15). Minimal residual disease (MRD) was monitored with a clone-specific polymerase chain reaction. RESULTS: After a median follow-up of 2 years, 23 patients are alive (to date). Neutrophil and platelet engraftment occurred after a median of 17.5 and 15 days, respectively. Acute graft-versus-host disease (GVHD) grade 2 to 4 was observed in 17 patients (56%), and chronic GVHD was observed in 21 patients (75%). Twelve patients (40%) achieved a complete remission (CR), and 16 patients (53%) achieved a partial remission. Late CR occurred up to 2 years after transplantation. MRD was monitored in eight patients with CR. All patients achieved a molecular CR. At last follow-up, six patients were in ongoing molecular CR. Causes of death were treatment-related complications in four patients and progressive disease in three patients. The probability of overall survival, progression-free survival, and nonrelapse mortality at 2 years was 72% (95% confidence interval [CI], 54% to 90%), 67% (95% CI, 49% to 85%), and 15% (95% CI, 1% to 29%), respectively. CONCLUSION: Treatment-related mortality after reduced-intensity conditioning followed by allogeneic HSCT was low. The procedure induced molecular remissions in patients with advanced CLL. The observation of late remissions provided evidence of a graft-versus-leukemia effect.

Adult↗
PubMed2003

Reduced intensity conditioning for allogeneic hematopoietic stem cell transplantation in patients with acute myeloid leukemia: disease status by marrow blasts is the strongest prognostic factor.

We analyzed predictive factors for the outcome of 113 acute myeloid leukemia patients receiving reduced-intensity conditioning prior to allogeneic hematopoietic stem cell transplantation (HSCT). Patients were ineligible for conventional-intensity HSCT. Conditioning consisted of fludarabine and 50% of the conventional dose of busulfan (n=93) or total body irradiation (n=20). The source of stem cells was blood in 102 patients, marrow in 10, and both in one. In total, 50 (44.2%) donors were HLA-matched siblings, 50 (44.2%) unrelated fully matched and 13 (11.5%) partially mismatched family (n=1) or unrelated (n=12) donors. In all, 107 (94.6%) patients showed neutrophil and platelet engraftment after a median time of 13.5 and 13 days. The probabilities of event-free survival (EFS) (median follow-up: 12 months) were 49% for patients with less than 5% blasts in the marrow, 24% for patients with 5-20% blasts (P=0.002) and 14% with >20% blasts (P<or=0.001). Death occurred because of relapse in 29 patients (25.6%), infection in 12 patients (10.6%), acute graft-versus-host disease in eight patients (7.0%) and organ toxicity in nine patients (7.9%). In multivariate analysis, higher number of blasts in the marrow, alternative donors and low Karnofsky performance score were independent adverse prognostic factors for EFS.

Adolescent↗
PubMed2003

Thalidomide for the treatment of acute myeloid leukemia.

In analogy to solid neoplasms, accumulating data suggest the requirement of angiogenesis also for the development and progression of hematopoietic malignancies including acute myeloid leukemia (AML). Inhibition of increased microvessel density in bone marrow (BM) might be a promising target for pharmacological interventions aimed at reducing disease activity. Among the putative inhibitors of angiogenesis, thalidomide has demonstrated a considerable efficacy in myelodysplastic syndromes (MDS) and AML with overall response rates up to 56% and 25%, respectively. Responders experienced hematologic improvements with increased hemoglobin and platelet counts resulting in temporary transfusion independence. In AML, partial responses--defined as reduction of the leukemic blast cell infiltration of at least 50% in BM--occurred in four of 20 patients after one month of thalidomide administration in a previous phase I/II study. Additionally, we observed a long-term response in one AML patient of more than 20 months, meanwhile fulfilling the criteria of complete remission. The decrease in leukemic blast infiltration in BM of responders was accompanied by a significant reduction of the microvessel density. Overall adverse events caused by the drug consisted mainly of fatigue, constipation, skin rash and polyneuropathy with a tolerable dose of 200-400 mg p.o. per day. In conclusion, thalidomide as a single agent has significant anti-leukemic activity with some evidence for anti-angiogenic effects in BM, although the precise mechanism of action remains to be elucidated.

Acute Disease↗
PubMed2002

Overexpression of vascular endothelial growth factor (VEGF) and its cellular receptor KDR (VEGFR-2) in the bone marrow of patients with acute myeloid leukemia.

Vascular endothelial growth factor (VEGF) and its cellular receptor VEGFR-2 have been implicated as the main endothelial pathway required for tumor neovascularization. However, the importance of the VEGF/VEGFR-2 system for angiogenesis in hematologic malignancies such as AML remains to be elucidated. In 32 patients with newly diagnosed untreated AML, we observed by immunohistochemical analysis of bone marrow biopsies significantly higher levels of VEGF and VEGFR-2 expression than in 10 control patients (P <0.001). In contrast, VEGFR-1 staining levels in AML patients were in the same range as in the controls. Expression of VEGF and VEGFR-2 was significantly higher in patients with a high degree of microvessel density compared to those with a low degree (VEGF: P =0.024; VEGFR-2: P =0.040) and correlated well with bone marrow microvessel density (r(s)=0.566 and 0.609, respectively; P <0.001). Furthermore, in patients who achieved a complete remission following induction chemotherapy VEGFR-2 staining levels decreased into the normal range. In conclusion, our results provide evidence for increased expression of VEGF/VEGFR-2 of leukemic blasts and correlation with angiogenesis in the bone marrow of AML patients. Thus, VEGF/VEGFR-2 might constitute promising targets for antiangiogenic and antileukemic treatment strategies in AML.

Acute Disease↗
PubMed2002

Early tandem high-dose ifosfamide, carboplatin, etoposide therapy with stem cell rescue for small-cell lung cancer: brief report on the results of a phase-I/II trial.

OBJECTIVE: High-dose therapy (HDT) for small-cell lung cancer is experimental. Late intensification HDT for chemosensitive disease can increase the number and quality of remissions and prolong relapse-free survival, but has not yet shown impact on overall survival. This is possibly due to resistant residual disease. To overcome the development of resistance, we have tested early intensification tandem HDT. METHODS: We performed a phase-I/II trial using 1 conventional cycle of ifosfamide, carboplatin, etoposide (ICE) plus granulocyte colony-stimulating factor for stem cell recruitment followed by 2 cycles of high-dose ICE with rescue by CD34+ cell-enriched peripheral blood mononuclear cells. Dose escalation was performed for the 2 high-dose ICE cycles. Radiotherapy for limited disease was according to standard protocols. RESULTS: 17 patients were entered: 2 female patients; 15 male patients; median age 53 (range 36-65) years; 2 patients with limited disease, and 15 patients with extensive disease. We treated 4 patients at dose level 1, 11 patients at level 2, and 2 patients at level 3. The maximum tolerable dose was at level 2 with neuropathy being dose-limiting. Overall, toxicity was < or = grade 2 for all patients up to dose level 2 with hematotoxicity being grade 4 for all patients. There were 15 partial remissions (88%), 1 no change (6%), and 1 progressive disease (6%). Median time to progression was 7.9 months. Overall survival was 12.9 months (median). CONCLUSIONS: Early intensification with this protocol is feasible. Although a comparatively good response rate and median time to progression have been observed in this group dominated by patients with extensive disease, overall survival is short and no substantial long-term survival was found.

Adult↗
PubMed2002

Reduced non-relapse mortality after reduced intensity conditioning in advanced chronic lymphocytic leukemia.

We studied in 30 patients with progressive or relapsing chronic lymphocytic leukemia (CLL) if hematopoietic stem cell transplantation (HSCT) after conditioning with fludarabine, busulfan and ATG is effective and if treatment related mortality can be reduced compared to myeloablative conditioning regimens. Patients had 15 matched related and 15 matched unrelated donors. Graft-versus-host disease (GVHD) prophylaxis consisted of cyclosporine alone or a combination with "short course" methotrexate or mycophenolate mofetil. The median follow-up is 24 months. At last follow up 11 patients were in complete and 13 in partial remission. Six patients had stable or progressive disease. Late complete remissions occurred up to one year after transplantation and the number of patients with CR is still increasing. Four patients died due to treatment related complications resulting in a probability of treatment-related mortality of 15% (CI 95%, 1% to 29%) at 2 years. The probability of overall survival and progression free survival at two years was 79% and 61%, respectively. In conclusion, HSCT after reduced conditioning may lower the treatment-related toxicity and has the capacity to induce complete remissions.

Busulfan↗
PubMed2001

Kinetics of standardized large volume leukapheresis (LVL) in patients do not show a recruitment phenomenon of peripheral blood progenitor cells (PBPC).

Although several studies have demonstrated the efficacy of large volume leukapheresis (LVL) to yield high numbers of peripheral blood progenitor cells (PBPC), the mechanisms of stem cell release into circulation and the postulated phenomenon of PBPC recruitment during apheresis have not been investigated in detail. Therefore, we analyzed the kinetics of stem cell enrichment in a total of 34 standardized LVL for patients with hematologic malignancies (lymphoma, multiple myeloma) and solid tumors (breast cancer, rhabdomyosarcoma). LVL was started 2 h after administration of G-CSF processing six times the patient's blood volume. Cells were sequentially collected into six bags and the numbers of leukocytes, mononuclear cells (MNC), CD34+ cells and colony-forming cells (CFU-GM) in each collection bag were analyzed. The numbers of PBPC collected demonstrated a continuous decrease starting after an early maximum during the second processed blood volume (P = 0.001). Interestingly, these kinetics of decreasing stem cell yields during LVL were similar for both entities of patients with hematologic malignancies as well as for both groups of patients with solid tumors. In summary, a recruitment phenomenon, defined as a time-dependent and LVL-induced increase of PBPC, could not be demonstrated in any of the diseases investigated.

Adolescent↗
PubMed2001

[Angiogenesis in patients with hematologic malignancies].

Angiogenesis in Patients with Hematologic Malignancies The importance of angiogenesis for the progressive growth and viability of solid tumors is well established. Emerging data suggest an involvement of angiogenesis in the pathophysiology of hematologic malignancies as well. Recently, we and others have reported increased angiogenesis in the bone marrow of patients with acute myeloid leukemia (AML) and normalization of bone marrow microvessel density when patients achieved a complete remission (CR) after induction chemotherapy. Tumor angiogenesis depends on the expression of specific mediators that initiate a cascade of events leading to the formation of new microvessels. Among these, VEGF (vascular endothelial growth factor), FGF (fibroblast growth factor) and angiopoietins play a pivotal role in the induction of neovascularization in solid tumors. These cytokines stimulate migration and proliferation of endothelial cells and induce angiogenesis in vivo. Recent data suggest an important role for these mediators in hematologic malignancies as well. Isolated AML blasts overexpress VEGF and VEGF receptor 2. Thus, the VEGF/VEGFR-2 pathway can promote the growth of leukemic blasts in an autocrine and paracrine manner. Therefore, neovascularization and angiogenic mediators/receptors may be promising targets for anti-angiogenic and anti-leukemic treatment strategies. The immunomodulatory drug thalidomide inhibits angiogenesis in animal models. Moreover, it has significant activity in refractory multiple myeloma. In a current phase II study for patients with primary refractory or relapsed multiple myeloma using a combination of thalidomide with hyperfractionated cyclophosphamide and dexamethasone (Hyper-CDT), we observed a partial remission in 12 of 14 evaluable patients (86%). Thus, this combination seems to be very potent. Furthermore, we evaluated the safety and efficacy of thalidomide in patients with AML not qualifying for intensive cytotoxic chemotherapy. 20 patients aged 58-85 (median 69) years were recruited to this phase I/II study and were treated with a dose of 200-400 mg per os daily for a duration of 1-40 (median 6) weeks, dependent on the individual tolerability of the drug. In 4 patients we observed a partial response (PR - defined as more than 50% reduction in leukemic blast infiltration in the bone marrow). This was accompanied by an increase in platelet counts and hemoglobin values. One additional patient showed a significant improvement of peripheral blood counts without fulfilling the criteria of a PR. In parallel, we observed a significant decrease in microvessel density in these 5 patients during treatment with thalidomide. In conclusion, thalidomide seems to have anti-angiogenic as well as anti-leukemic activity in AML. The VEGF/VEGFR-2 pathway seems to play an important role in AML. Therefore, receptor tyrosine kinase inhibitors like SU5416 or SU6668 are currently evaluated in the context of phase II studies in AML. We could recently induce a stable remission in a patient with second relapse of her AML refractory towards chemotherapy by administration of SU5416 (compassionate use), a tyrosine kinase inhibitor of VEGFR-2 and ckit. Current and future studies will clarify the role of anti-angiogenic treatment strategies in AML and other hematologic malignancies.

Aged↗
PubMed2001

Simultaneous immunomagnetic CD34+ cell selection and B-cell depletion in peripheral blood progenitor cell samples of patients suffering from B-cell non-Hodgkin's lymphoma.

The reduction of residual tumor cells is one of the main targets of leukapheresis product (LP) processing. Immunomagnetic enrichment/selection of CD34+ progenitor cells (Baxter Isolex 300i) can achieve a reduction of contaminating B-cells of approximately 2-3 logs in B-cell non-Hodgkin's lymphoma patients. Specific release of the enriched CD34+ cells (stem cell releasing agent PR34+; Baxter) and the use of antibody-coated immunobeads targeted against B-cell markers (CD10, CD19, CD20, CD22, CD23, and CD37) during this procedure allows the GMP-like simultaneous capture of residual B cells within a closed system. This combination of two purging techniques enhances the B-cell depletion capacity up to 4.5 logs. By performing 10 clinical-scale purging procedures, we could show that the simultaneous immunomagnetic purging method is easy to perform and highly efficient. We evaluated B-cell log depletion by flow cytometry for cases with marker-positive cells detectable before and after the purging procedure. The mean reduction of B-cells in these cases was 3.5 logs; the mean CD34+ cell yield and purity were 47 and 92%. Using three LPs, we tested the procedure on a modified Baxter Isolex 300i device with software adaptations for this procedure (software version 2.0) in direct comparison with CD34+ cell selection only, using the former version (version 1.12). The CD34+ cell yield was 49% (40-54%) for the CD34+ cell selection and 51% (19-72%) for simultaneous double selection. The mean purity was 96% for CD34+ cell selection and 98% for simultaneous double selection. B-cell depletion was 1.9 logs for CD34+ cell selection, and after simultaneous double selection, the B-cell content was decreased by 3.7 log steps (P = 0.0495). Clinical application of double-purged cells has not prolonged the hematopoietic recovery times after high-dose therapy as compared with nonpurged peripheral blood progenitor cell autotransplants. In conclusion, we could show that the simultaneous double selection protocol developed leads to a highly increased B-cell purging efficacy when compared with CD34+ cell selection without any negative effects regarding CD34+ cell yield and engraftment times after high-dose therapy.

Antigens, CD34↗
PubMed2000

Flt3 mutations from patients with acute myeloid leukemia induce transformation of 32D cells mediated by the Ras and STAT5 pathways.

Somatic mutations of the receptor tyrosine kinase Flt3 consisting of internal tandem duplications (ITD) occur in 20% of patients with acute myeloid leukemia. They are associated with a poor prognosis of the disease. In this study, we characterized the oncogenic potential and signaling properties of Flt3 mutations. We constructed chimeric molecules that consisted of the murine Flt3 backbone and a 510-base pair human Flt3 fragment, which contained either 4 different ITD mutants or the wild-type coding sequence. Flt3 isoforms containing ITD mutations (Flt3-ITD) induced factor-independent growth and resistance to radiation-induced apoptosis in 32D cells. Cells containing Flt3-ITD, but not those containing wild-type Flt3 (Flt3-WT), formed colonies in methylcellulose. Injection of 32D/Flt3-ITD induced rapid development of a leukemia-type disease in syngeneic mice. Flt3-ITD mutations exhibited constitutive autophosphorylation of the immature form of the Flt3 receptor. Analysis of the involved signal transduction pathways revealed that Flt3-ITD only slightly activated the MAP kinases Erk1 and 2 and the protein kinase B (Akt) in the absence of ligand and retained ligand-induced activation of these enzymes. However, Flt3-ITD led to strong factor-independent activation of STAT5. The relative importance of the STAT5 and Ras pathways for ITD-induced colony formation was assessed by transfection of dominant negative (dn) forms of these proteins: transfection of dnSTAT5 inhibited colony formation by 50%. Despite its weak constitutive activation by Flt3-ITD, dnRas also strongly inhibited Flt3-ITD-mediated colony formation. Taken together, Flt3-ITD mutations induce factor-independent growth and leukemogenesis of 32D cells that are mediated by the Ras and STAT5 pathways. (Blood. 2000;96:3907-3914)

Acute Disease↗
PubMed2000

Vascular endothelial growth factor and interleukin-6 in paracrine tumor-stromal cell interactions in multiple myeloma.

Vascular endothelial growth factor (VEGF), a multifunctional cytokine, potently stimulates angiogenesis including tumor neovascularization. Although well established in solid tumors, the role of VEGF in bone marrow neoangiogenesis and paracrine tumor-stromal cell interactions in lymphohematopoietic malignancies has not been fully elucidated. In multiple myeloma (MM), marrow neovascularization parallels disease progression. This parallel prompted us to investigate the expression and secretion of VEGF by myeloma cells and its potential effects in myeloma-marrow stroma interactions. The biologically active splice variants VEGF165 and VEGF121 were expressed and secreted by myeloma cell lines and plasma cells isolated from the marrow of patients with MM. As shown by immunocytochemistry or RT-PCR, myeloma cells did not express or weakly expressed the VEGF receptors FLT-1 and FLK-1/KDR, indicating that autocrine stimulation is unlikely. In contrast, FLK-1/KDR was abundantly expressed by marrow stromal cells. Therefore, we studied the effects of VEGF on marrow stroma, focusing on the secretion of interleukin-6 (IL-6), a potent growth factor for myeloma cells and an inhibitor of plasma cell apoptosis. Exposure of stromal and microvascular endothelial cells to recombinant human (rh) VEGF165 or VEGF121 induced a time- and dose-dependent increase in IL-6 secretion (14- to 27-fold at 50 ng/mL after 24 hours, P <.001). Conversely, rhIL-6 stimulated VEGF expression and secretion in myeloma cell lines (40%-60%; P <.05) and to a variable degree (up to 5.3-fold; P <.005) in plasma cells purified from the marrow of patients with MM. This mutual stimulation suggests paracrine interactions between myeloma and marrow stromal cells triggered by VEGF and IL-6. (Blood. 2000;95:2630-2636)

Adult↗