Refine
Year of publication
Document Type
- Article (19)
Language
- English (19)
Has Fulltext
- yes (19)
Is part of the Bibliography
- no (19)
Keywords
- HSCT (2)
- acute myeloid leukaemia (2)
- chemotherapy (2)
- 32D progenitor cells (1)
- AML (1)
- ASCT (1)
- Acute myeloid leukaemia (1)
- Acute myeloid leukemia (1)
- Apheresis (1)
- Azacitidine (1)
- BEZ235 (1)
- Bloodstream infections (1)
- CD34+ cell enumeration (1)
- CHIP (1)
- Cell processing (1)
- Chromosomal deletion (1)
- Engraftment (1)
- Fusion Proteins, BCR-ABL (1)
- G3BP (1)
- Graft (1)
- Graft quality (1)
- Gram negative bacteria (1)
- H1N1 (1)
- HDAC (1)
- HDACi (1)
- Hemagglutination inhibition assay (1)
- Hematopoietic stem cell (1)
- Hematopoietic stem cell transplant (1)
- Hematopoietic stem cell transplantation (1)
- Intensive care units (1)
- Leukemia, Myelogenous, Chronic, BCR-ABL Positive (1)
- Long-term follow-up (1)
- MYC (1)
- Molecularly targeted therapy (1)
- Multivariate analysis (1)
- Myelodysplastic syndrome (1)
- Neutropenia (1)
- PCR (1)
- PI3K/mTor inhibition (1)
- Phase I clinical trial (1)
- Phase I trials (1)
- Philadelphia Chromosome (1)
- Post-thaw recovery (1)
- Protein Kinase Inhibitors (1)
- Quality control (1)
- RBC (1)
- RBC-depletion (1)
- Refractory ALL (1)
- Refractory AML (1)
- Rho GTPases (1)
- SARS-CoV-2 (1)
- SARS-CoV-2-specific T cells (1)
- STAT5 (1)
- Sequelae (1)
- Stem cell dose (1)
- Stem cell enumeration (1)
- Stem-cell therapies (1)
- Stenotrophomonas maltophilia (1)
- TBI (1)
- Toxicity (1)
- Transplant logistics (1)
- WT1 (1)
- acute lymphoblastic leukemia (1)
- adhesion (1)
- antifungal management (1)
- antifungal prophylaxis (1)
- arsenic trioxide (1)
- autologous stem cell transplantation (1)
- cell therapy (1)
- chimeric antigen receptor (CAR) (1)
- clonal dominance (1)
- clonal hematopoiesis (1)
- costs (1)
- deletion 5q (1)
- flow cytometry (1)
- graft-versus host (1)
- hematopoietic stem cells (1)
- hematopoietic stress (1)
- homing (1)
- hospital exemption (1)
- immune monitoring (1)
- immunotherapy (1)
- indomethacin (1)
- induction chemotherapy (1)
- lethal toxin (1)
- leukemia (1)
- leukemia initiating cell (1)
- mesenchymal stromal cell (1)
- migration (1)
- molecular marker (1)
- myelodysplastic syndrome (1)
- posaconazole (1)
- refractory aGvHD (1)
- short tandem repeats (1)
- somatic mutations (1)
- steroid-resistant aGvHD (1)
- t(6;9) (1)
- toxin B (1)
- transfusion (1)
- transplantation (1)
- vaccination (1)
- β-catenin (1)
Institute
- Medizin (19)
- Pharmazie (1)
- Sonderforschungsbereiche / Forschungskollegs (1)
Objectives: To describe changes in costs of managing hospitalised patients with acute myeloid leukaemia (AML) after chemotherapy in Germany over 3 yr, with a special focus on prophylaxis and treatment patterns as well as resource use related to invasive fungal infections (IFI).
Methods: The study was conducted as a retrospective, single-centre chart review in patients with AML hospitalised for chemotherapy, neutropenia and infections after myelosuppressive chemotherapy from January 2004 to December 2006 in Germany. The following resource utilisation data were collected: inpatient stay, mechanical ventilation, parenteral feeding, diagnostics, systemic antifungal medication and cost-intensive concomitant medication. Direct medical costs were calculated from hospital provider perspective.
Results: A total of 471 episodes in 212 patients were included in the analysis. Occurrence of IFI decreased from 5.9% in 2004 to 1.9% in 2006. Mean (± standard deviation) hospital stay decreased from 28.7 ± 17.9 d in 2004 to 22.4 ± 11.8 d in 2006. From 2004 to 2006, the use of a single antifungal drug increased from 30.4% to 46.9%, whereas the use of multiple antifungal drugs decreased from 24.4% to 13.1%. The use of liposomal amphotericin B declined between 2004 and 2006 (21.4% vs. 3.8%) and caspofungin between 2005 and 2006 (19.3% vs. 8.1%). Total costs per episode declined from €19051 ± 19024 in 2004 to €13531 ± 9260 in 2006; major reductions were observed in the use of antimycotics and blood products as well as length of hospital stay.
Conclusion: Analysis of real-life data from one single centre in Germany demonstrated a change in antifungal management of patients with AML between 2004/2005 and 2006, accompanied by a decline in total costs.
Background: Red blood cell (RBC) depletion is a standard graft manipulation technique for ABO-incompatible bone marrow (BM) transplants. The BM processing module for Spectra Optia, “BMC”, was previously introduced. We here report the largest series to date of routine quality data after performing 50 clinical-scale RBC-depletions.
Methods: Fifty successive RBC-depletions from autologous (n = 5) and allogeneic (n = 45) BM transplants were performed with the Spectra Optia BMC apheresis suite. Product quality was assessed before and after processing for volume, RBC and leukocyte content; RBC-depletion and stem cell (CD34+ cells) recovery was calculated there from. Clinical engraftment data were collected from 26/45 allogeneic recipients.
Results: Median RBC removal was 98.2% (range 90.8–99.1%), median CD34+ cell recovery was 93.6%, minimum recovery being 72%, total product volume was reduced to 7.5% (range 4.7–23.0%). Products engrafted with expected probability and kinetics. Performance indicators were stable over time.
Discussion: Spectra Optia BMC is a robust and efficient technology for RBC-depletion and volume reduction of BM, providing near-complete RBC removal and excellent CD34+ cell recovery.
Background: CML presenting with a variant Philadelphia translocation, atypical BCR-ABL transcript, additional chromosomal aberrations, and evolving MDS is uncommon and therapeutically challenging. The prognostic significance of these genetic findings is uncertain, even as singular aberrations, with nearly no data on management and outcome when they coexist. MDS evolving during the course of CML may be either treatment-associated or an independently coexisting disease, and is generally considered to have an inferior prognosis. Tyrosine kinase inhibitors (TKI) directed against BCR-ABL are the mainstay of treatment for CML, whereas treatment modalities that may be utilized for MDS and CML include allogeneic stem cell transplant and – at least conceptually – hypomethylating agents.
Case report: Here, we describe the clinical course of such a patient, demonstrating that long-term combined treatment with dasatinib and azacitidine for coexisting CML and MDS is feasible and well tolerated, and may be capable of slowing disease progression. This combination therapy had no deleterious effect on subsequent potentially curative haploidentical bone marrow transplantation.
Conclusions: The different prognostic implications of this unusual case and new therapeutic options in CML are discussed, together with a review of the current literature on CML presenting with different types of genomic aberrations and the coincident development of MDS. Additionally, this case gives an example of long-term combined treatment of tyrosine kinase inhibitors and hypomethylating agents, which could be pioneering in CML treatment.
Acute myeloid leukemia (AML) is characterized by an aberrant self-renewal of hematopoietic stem cells (HSC) and a block in differentiation. The major therapeutic challenge is the characterization of the leukemic stem cell as a target for the eradication of the disease. Until now the biology of AML-associated fusion proteins (AAFPs), such as the t(15;17)-PML/RARα, t(8;21)-RUNX1/RUNX1T1 and t(6;9)-DEK/NUP214, all able to induce AML in mice, was investigated in different models and genetic backgrounds, not directly comparable to each other. To avoid the bias of different techniques and models we expressed these three AML-inducing oncogenes in an identical genetic background and compared their influence on the HSC compartment in vitro and in vivo.
These AAFPs exerted differential effects on HSCs and PML/RARα, similar to DEK/NUP214, induced a leukemic phenotype from a small subpopulation of HSCs with a surface marker pattern of long-term HSC and characterized by activated STAT3 and 5. In contrast the established AML occurred from mature populations in the bone marrow. The activation of STAT5 by PML/RARα and DEK/NUP214 was confirmed in t(15;17)(PML/RARα) and t(6;9)(DEK/NUP214)-positive patients as compared to normal CD34+ cells. The activation of STAT5 was reduced upon the exposure to Arsenic which was accompanied by apoptosis in both PML/RARα- and DEK/NUP214-positive leukemic cells. These findings indicate that in AML the activation of STATs plays a decisive role in the biology of the leukemic stem cell. Furthermore we establish exposure to arsenic as a novel concept for the treatment of this high risk t(6;9)-positive AML.
Clonal hematopoiesis of indeterminate potential (CHIP) is caused by recurrent somatic mutations leading to clonal blood cell expansion. However, direct evidence of the fitness of CHIP-mutated human hematopoietic stem cells (HSCs) in blood reconstitution is lacking. Because myeloablative treatment and transplantation enforce stress on HSCs, we followed 81 patients with solid tumors or lymphoid diseases undergoing autologous stem cell transplantation (ASCT) for the development of CHIP. We found a high incidence of CHIP (22%) after ASCT with a high mean variant allele frequency (VAF) of 10.7%. Most mutations were already present in the graft, albeit at lower VAFs, demonstrating a selective reconstitution advantage of mutated HSCs after ASCT. However, patients with CHIP mutations in DNA-damage response genes showed delayed neutrophil reconstitution. Thus, CHIP-mutated stem and progenitor cells largely gain on clone size upon ASCT-related blood reconstitution, leading to an increased future risk of CHIP-associated complications.
Maintenance therapy after allogeneic hematopoietic stem cell transplantation (HSCT) for acute myeloid leukemia (AML) or myelodysplastic syndrome (MDS) is conceptually attractive to prevent relapse, but has been hampered by the limited number of suitable anti-leukemic agents. The deacetylase inhibitor (DACi) panobinostat demonstrated moderate anti-leukemic activity in a small subset of patients with advanced AML and high-risk MDS in phase I/II trials.1, 2 It also displays immunomodulatory activity3 that may enhance leukemia-specific cytotoxicity4 and mitigate graft versus host disease (GvHD), but conversely could impair T- and NK cell function.5, 6 We conducted this open-label, multi-center phase I/II trial (NCT01451268) to assess the feasibility and preliminary efficacy of prolonged prophylactic administration of panobinostat after HSCT for AML or MDS. The study protocol was approved by an independent ethics committee and conducted in compliance with the Declaration of Helsinki. All patients provided written informed consent. ...
Allogeneic hematopoietic stem cell transplantation (allo-HSCT) offers potential cure to acute myeloid leukemia (AML) patients. However, infections with commensal bacteria are an important cause for non-relapse mortality (NRM). We have previously described the impact of multidrug-resistant organism (MDRO) colonization on the survival of allo-HSCT patients. In the aforementioned publication, according to consensus, we there did not consider the opportunistic gram-negative bacterium Stenotrophomonas maltophilia (S. maltophilia) to be an MDRO. Since rate of S. maltophilia colonization is increasing, and it is not known whether this poses a risk for allo-HSCT patients, we here analyzed here its effect on the previously described and now extended patient cohort. We report on 291 AML patients undergoing allo-HSCT. Twenty of 291 patients (6.9%) were colonized with S. maltophilia. Colonized patients did not differ from non-colonized patients with respect to their age, remission status before allo-HSCT, donor type and HSCT-comorbidity index. S. maltophilia colonized patients had a worse overall survival (OS) from 6 months up to 60 months (85% vs. 88.1% and 24.7% vs. 59.7%; p = 0.007) due to a higher NRM after allo-HSCT (6 months: 15% vs. 4.8% and 60 months: 40.1% vs. 16.2% p = 0.003). The main cause of mortality in colonized patients was infection (46.2% of all deaths) and in non-colonized patients relapse (58.8% of all deaths). 5/20 colonized patients developed an invasive infection with S. maltophilia. The worse OS after allo-HSCT due to higher infection related mortality might implicate the screening of allo-HSCT patients for S. maltophilia and a closer observation of colonized patients as outpatients.
(1) Background: Refractory acute graft-versus-host disease (R-aGvHD) remains a leading cause of death after allogeneic stem cell transplantation. Survival rates of 15% after four years are currently achieved; deaths are only in part due to aGvHD itself, but mostly due to adverse effects of R-aGvHD treatment with immunosuppressive agents as these predispose patients to opportunistic infections and loss of graft-versus-leukemia surveillance resulting in relapse. Mesenchymal stromal cells (MSC) from different tissues and those generated by various protocols have been proposed as a remedy for R-aGvHD but the enthusiasm raised by initial reports has not been ubiquitously reproduced.
(2) Methods: We previously reported on a unique MSC product, which was generated from pooled bone marrow mononuclear cells of multiple third-party donors. The products showed dose-to-dose equipotency and greater immunosuppressive capacity than individually expanded MSCs from the same donors. This product, MSC-FFM, has entered clinical routine in Germany where it is licensed with a national hospital exemption authorization. We previously reported satisfying initial clinical outcomes, which we are now updating. The data were collected in our post-approval pharmacovigilance program, i.e., this is not a clinical study and the data is high-level and non-monitored.
(3) Results: Follow-up for 92 recipients of MSC-FFM was reported, 88 with GvHD ≥°III, one-third only steroid-refractory and two-thirds therapy resistant (refractory to steroids plus ≥2 additional lines of treatment). A median of three doses of MSC-FFM was administered without apparent toxicity. Overall response rates were 82% and 81% at the first and last evaluation, respectively. At six months, the estimated overall survival was 64%, while the cumulative incidence of death from underlying disease was 3%.
(4) Conclusions: MSC-FFM promises to be a safe and efficient treatment for severe R-aGvHD.
Rho GTPases are involved in homing and mobilization of hematopoietic stem and progenitor cells due to their impact on cytoskeleton remodeling. We have previously shown that inhibition of Rho, Rac and Cdc42 clearly impairs adhesion of normal and leukemic hematopoietic progenitor cells (HPC) to fibronectin and migration in a three-dimensional stromal cell model. Here, we identified the Ras GTPase-Activating Protein SH3 Domain-Binding Protein (G3BP) as a target gene of Rho GTPases and analysed its role in regulating HPC motility. Overexpression of G3BP significantly enhanced adhesion of murine 32D HPC to fibronectin and human umbilical vein endothelial cells, increased the proportion of adherent cells in a flow chamber assay and promoted cell migration in a transwell assay and a three-dimensional stromal cell model suggesting a strong impact on the cytoskeleton. Immunofluorescent staining of G3BP-overexpressing fibroblasts revealed a Rho-like phenotype characterized by formation of actin stress fibers in contrast to the Rac-like phenotype of control fibroblasts. This is the first report implicating a role for G3BP in Rho GTPase-mediated signalling towards adhesion and migration of HPC. Our results may be of clinical importance, since G3BP was found overexpressed in human cancers.