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Berlin Brandenburg

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  • 1
    Language: English
    In: Haematologica, November 2012, Vol.97(11), pp.1674-7
    Description: Steroid-refractory graft-versus-host disease causes significant morbidity and mortality after allogeneic stem cell transplantation. The pathomechanism of steroid resistance is currently not understood, but it has been suggested that endothelial cell dysfunction plays a role. Endothelial thrombomodulin was quantified along with histological markers of epithelial damage and cytotoxic T cells in colon biopsies from 51 allografted patients, and retrospectively correlated with response to steroids and survival. Loss of endothelial thrombomodulin was the strongest predictor of response to steroids (P=0.02) and nonrelapse mortality (P=0.01) in multivariate analyses adjusting for T-cell infiltrates, histological grading, vessel density, disease status, donor type, and conditioning therapy. Our data provide evidence that at disease onset, loss of endothelial thrombomodulin expression rather than excessive T-cell infiltration associates with steroid-refractory graft-versus-host disease and mortality. Prospective histological investigations are now warranted to improve diagnosis and prognostication of this core complication of stem cell transplantation.
    Keywords: Graft Vs Host Disease ; Intestinal Diseases ; Endothelium, Vascular -- Metabolism ; Steroids -- Administration & Dosage ; Thrombomodulin -- Biosynthesis
    ISSN: 03906078
    E-ISSN: 1592-8721
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  • 2
    Language: English
    In: Haematologica, April 2019, Vol.104(4), pp.827-834
    Description: Increasing evidence suggests that endothelial cell distress is associated with mortality after allogeneic stem cell transplantation and acute graft--host disease. Asymmetric dimethylarginine is an endogenous nitric oxide synthase inhibitor that induces endothelial cell dysfunction. We analyzed the impact of pre-transplant serum levels of asymmetric dimethylarginine on outcome after allogeneic stem cell transplantation. Since acute graft--host disease and its treatment are major contributors to post-transplant mortality, the effect of asymmetric dimethylarginine on outcome measures was also assessed after onset of acute graft--host disease. A total of 938 patients allografted at two centers between 2002 and 2013 were included in the retrospective study. In multivariable models, higher pre-transplant asymmetric dimethylarginine levels were significantly associated with an increased risk of non-relapse mortality (hazard ratio 1.43 per 1-log increase, =0.005) but not with relapse (hazard ratio 1.21, =0.109) within the first year after transplantation. This translated into worse overall survival (hazard ratio 1.45, 〈0.0001) and shorter progression-free survival (hazard ratio 1.30, =0.002) in the first year after transplantation. Higher pre-transplant asymmetric dimethylarginine levels were also associated with shorter overall survival (hazard ratio 1.46, =0.001) and progression-free survival (hazard ratio 1.32, =0.010) and higher non-relapse mortality (hazard ratio 1.36, =0.042) within 1 year after the onset of acute graft--host disease. Taken together, our data indicate an association between pre-transplant asymmetric dimethylarginine status and early non-relapse mortality in allografted patients, both overall and after the onset of acute graft--host disease. These findings underline the relevance of endothelial dysfunction for transplant complications.
    Keywords: Article;
    ISSN: 03906078
    E-ISSN: 1592-8721
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  • 3
    Language: English
    In: Haematologica, March 2014, Vol.99(3), pp.541-7
    Description: Steroid-refractory graft-versus-host disease is a life-threatening complication after allogeneic stem cell transplantation. Evidence is accumulating that steroid-refractory graft-versus-host disease is associated with endothelial distress. Endothelial cell homeostasis is regulated by nitric oxide, and serum nitrates are derived from nitric oxide synthase activity or dietary sources. In this retrospective study based on 417 patients allografted at our institution we investigated whether quantification of serum nitrates could predict steroid-refractory graft-versus-host disease. Elevated pre-transplant levels of serum nitrates (〉26.5 μM) predicted steroid-refractory graft-versus-host disease (P=0.026) and non-relapse mortality (P=0.028), particularly in combination with high pre-transplant angiopoietin-2 levels (P=0.0007 and P=0.021, respectively). Multivariate analyses confirmed serum nitrates as independent predictors of steroid-refractory graft-versus-host disease and non-relapse mortality. Differences in serum nitrate levels did not correlate with serum levels of tumor necrosis factor or C-reactive protein or expression of inducible nitric oxide synthase in blood cells. Patients with high pre-transplant nitrate levels had significantly reduced rates of refractory graft-versus-host disease (P=0.031) when pravastatin was taken. In summary, patients at high risk of developing steroid-refractory graft-versus-host disease could be identified prior to transplantation by serum markers linked to endothelial cell function. Retrospectively, statin medication was associated with a reduced incidence of refractory graft-versus-host disease in this endothelial high-risk cohort.
    Keywords: Graft Vs Host Disease -- Diagnosis ; Hematopoietic Stem Cell Transplantation -- Adverse Effects ; Nitrates -- Blood
    ISSN: 03906078
    E-ISSN: 1592-8721
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  • 4
    Language: English
    In: Haematologica, July 2012, Vol.97(7), pp.1085-91
    Description: Mantle cell lymphoma accounts for 6% of all B-cell lymphomas and is generally incurable. It is characterized by the translocation t(11;14) leading to cyclin D1 over-expression. Cyclin D1 is downstream of the mammalian target of rapamycin threonine kinase and can be effectively blocked by mammalian target of rapamycin inhibitors. We set out to examine the single agent activity of the orally available mammalian target of rapamycin inhibitor everolimus in a prospective, multicenter trial in patients with relapsed or refractory mantle cell lymphoma (NCT00516412). Eligible patients who had received a maximum of three prior lines of chemotherapy were given everolimus 10 mg for 28 days (one cycle) for a total of six cycles or until disease progression. The primary endpoint was the best objective response. Adverse reactions, progression-free survival and molecular response were secondary endpoints. Thirty-six patients (35 evaluable) were enrolled and treatment was generally well tolerated with Common Terminology Criteria grade ≥ 3 adverse events (〉5%) including anemia (11%), thrombocytopenia (11%) and neutropenia (8%). The overall response rate was 20% (95% CI: 8-37%) with two complete remissions and five partial responses; 49% of the patients had stable disease. At a median follow-up of 6 months, the median progression-free survival was 5.5 months (95% CI: 2.8-8.2) overall and 17.0 (6.4-23.3) months for 18 patients who received six or more cycles of treatment. Three patients achieved a lasting complete molecular response, as assessed by polymerase chain reaction analysis of peripheral blood. Everolimus as a single agent is well tolerated and has anti-lymphoma activity in relapsed or refractory mantle cell lymphoma. Further studies of everolimus in combination with chemotherapy or as a single agent for maintenance treatment are warranted.
    Keywords: Lymphoma, Mantle-Cell -- Drug Therapy ; Protein Kinase Inhibitors -- Administration & Dosage ; Sirolimus -- Analogs & Derivatives
    ISSN: 03906078
    E-ISSN: 1592-8721
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  • 5
    Language: English
    In: Haematologica, October 2014, Vol.99(10), pp.1582-90
    Description: Acquired chromosomal abnormalities are important prognostic factors in patients with myelodysplastic syndromes treated with supportive care and with disease-modifying therapeutic interventions, including allogeneic hematopoietic stem cell transplantation. To assess the prognostic impact of cytogenetic characteristics after hematopoietic stem cell transplantation accurately, we investigated a homogeneous group of 523 patients with primary myelodysplastic syndromes who have received stem cells from human leukocyte antigen-identical siblings. Overall survival at five years from transplantation in good, intermediate, and poor cytogenetic risk groups according to the International Prognostic Scoring System was 48%, 45% and 30%, respectively (P〈0.01). Both the disease status (complete remission vs. not in complete remission) and the morphological classification at transplant in the untreated patients were significantly associated with probability of overall survival and relapse-free survival (P〈0.01). The cytogenetic risk groups have no prognostic impact in untreated patients with refractory anemia ± ringed sideroblasts (P=0.90). However, combining the good and intermediate cytogenetic risk groups and comparing them to the poor-risk group showed within the other three disease-status-at-transplant groups a hazard ratio of 1.86 (95%CI: 1.41-2.45). In conclusion, this study shows that, in a large series of patients with primary myelodysplastic syndromes, poor-risk cytogenetics as defined by the standard International Prognostic Scoring System is associated with a relatively poor survival after allogeneic stem cell transplantation from human leukocyte antigen-identical siblings except in patients who are transplanted in refractory anemia/refractory anemia with ringed sideroblasts stage before progression to higher myelodysplastic syndrome stages.
    Keywords: Hematopoietic Stem Cell Transplantation ; Siblings ; HLA Antigens -- Immunology ; Myelodysplastic Syndromes -- Immunology
    ISSN: 03906078
    E-ISSN: 1592-8721
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  • 6
    Language: English
    In: Haematologica, June 2006, Vol.91(6), pp.788-94
    Description: After allogeneic stem cell transplantation treatment failures are mostly caused by graft rejection or graft-versus-host disease (GVHD). T-cell depletion is an appropriate tool to prevent GvHD. However, it might be associated with an increased risk of graft rejection, which can be recognized by serial and quantitative characterization of chimerism. Thus, pre-emptive immunotherapy might be helpful to avoid graft rejection. We present the outcome of 56 transplants performed in 53 children with non-malignant diseases. T-cell depletion was conducted in 27/56 grafts. When increasing mixed chimerism over 30% autologous cells occurred low dose donor lymphocyte transfusions (DLT) were performed. During the course of the follow-up 29 out of 53 patients achieved complete chimerism or low mixed chimerism (0-1%) and 28/29 remained in continuous complete remission. Donor engraftment failed in 2/53 patients who died of serious infection. Increasing mixed chimerism was found in 19 out of 56 transplantations. Fifteen of these 19 patients received additional immunotherapy with DLT. Eleven out of the 15 remained in complete remission. One of the 15 patients developed GvHD grade III that turned out to extensive chronic GvHD. The 3-year overall survival was 100% for patients transplanted from matched related or unrelated donors and 75% for patients transplanted from mismatched donors. We demonstrated that children transplanted for non-malignant diseases have an excellent overall survival. T-cell depletion is associated with an increased risk of graft rejection. Pre-emptive immunotherapy with DLT, administered on the basis of increasing mixed chimerism, is feasible and might prevent graft rejection.
    Keywords: Hematopoietic Stem Cell Transplantation ; Transplantation, Homologous -- Immunology
    E-ISSN: 1592-8721
    Source: MEDLINE/PubMed (U.S. National Library of Medicine)
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  • 7
    Language: English
    In: Haematologica, January 2009, Vol.94(1), pp.141-4
    Description: Recently, mutations of MPL , the gene coding for the thrombopoetin receptor, were demonstrated in ~5% of cases of primary myelofibrosis (PMF) and in ~1% of all cases of essential thrombocytosis (ET).[1][1],[2][2] They represent gain-of-function mutations that confer constitutive activation of the
    Keywords: Primary Myelofibrosis -- Genetics ; Receptors, Thrombopoietin -- Metabolism ; Thrombocythemia, Essential -- Genetics
    ISSN: 03906078
    E-ISSN: 1592-8721
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  • 8
    Language: English
    In: Haematologica, 11 July 2019
    Description: Testosterone is an important determinant of endothelial function and vascular health in men. As both factors play a role for mortality after allogeneic stem cell transplantation, we retrospectively evaluated the impact of pre-transplant testosterone levels on outcome in male patients undergoing allogeneic stem cell transplantation. In the discovery cohort (n=346), an impact on outcome was observed only in the subgroup of patients allografted for acute myeloid leukemia (n=176, hereafter termed training cohort). In the training cohort, lower pre-transplant testosterone levels were significantly associated with shorter overall survival (hazard ratio for a decrease of 100 ng/dL, 1.11, P=0.045). This was based on a higher hazard of non-relapse mortality (cause-specific hazard ratio 1.25, P=0.013), but not relapse (cause-specific hazard ratio 1.06, P=0.277) in the multivariable models. These findings were replicated in a confirmation cohort of 168 male patients allografted for acute myeloid leukemia in a different center (overall survival, hazard ratio 1.15, P=0.012 and non-relapse mortality, cause-specific hazard ratio 1.23, P=0.008). Next, an optimized cut-off point for pre-transplant testosterone was derived in the training set and evaluated in the confirmation cohort. In multivariable models, low pre-transplant testosterone status (〈250 ng/dL) was associated with worse overall survival (hazard ratio 1.95, P=0.021) and increased non-relapse mortality (cause-specific hazard ratio 2.68, P=0.011) but not with relapse (cause-specific hazard ratio 1.28, P=0.551). Our findings may provide a rationale for prospective studies on testosterone/androgen assessment and supplementation in male patients undergoing allogeneic stem cell transplantation for acute myeloid leukemia.
    Keywords: Graft-Versus-Host-Disease ; Stem Cell Transplantation ; Vascular Wall Biology and Platelet Adhesion ; Endothelial Cell Dysfunction ; Testosterone
    E-ISSN: 1592-8721
    Source: MEDLINE/PubMed (U.S. National Library of Medicine)
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  • 9
  • 10
    Language: English
    In: Haematologica, May 2019, Vol.104(5), pp.955-962
    Description: Standard first-line therapy of chronic myeloid leukemia is treatment with imatinib. In the randomized German Chronic Myeloid Leukemia-Study IV, more potent BCR-ABL inhibition with 800 mg ('high-dose') imatinib accelerated achievement of a deep molecular remission. However, whether and when a de-escalation of the dose intensity under high-dose imatinib can be safely performed without increasing the risk of losing deep molecular response is unknown. To gain insights into this clinically relevant question, we analyzed the outcome of imatinib dose reductions from 800 mg to 400 mg daily in the Chronic Myeloid Leukemia-Study IV. Of the 422 patients that were randomized to the 800 mg arm, 68 reduced imatinib to 400 mg after they had achieved at least a stable major molecular response. Of these 68 patients, 61 (90%) maintained major molecular remission on imatinib at 400 mg. Five of the seven patients who lost major molecular remission on the imatinib standard dose regained major molecular remission while still on 400 mg imatinib. Only two of 68 patients had to switch to more potent kinase inhibition to regain major molecular remission. Importantly, the lengths of the intervals between imatinib high-dose treatment before and after achieving major molecular remission were associated with the probabilities of maintaining major molecular remission with the standard dose of imatinib. Taken together, the data support the view that a deep molecular remission achieved with high-dose imatinib can be safely maintained with standard dose in most patients. Study protocol registered at .
    Keywords: Article;
    ISSN: 03906078
    E-ISSN: 1592-8721
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