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Amotosalen/UVA pathogen inactivation technology reduces platelet activatability, induces apoptosis and accelerates clearance.
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Amotosalen/UVA pathogen inactivation technology reduces platelet activatability, induces apoptosis and accelerates clearance.

Haematologica. 2017 Jul 20;:

Authors: Stivala S, Gobbato S, Infanti L, Reiner MF, Bonetti N, Meyer SC, Camici GG, Lüscher TF, Buser A, Beer JH

Abstract
Amotosalen and ultraviolet A photochemical-based pathogen reduction using the InterceptTM Blood System is an effective and established technology for platelet and plasma components, which is adopted in more than 40 countries worldwide. Several reports point towards a reduced platelet function after Amotosalen/UVA exposure. The current study was undertaken to identify the mechanisms responsible for the early impairment of platelet function by the InterceptTM Blood System. Twenty-five platelet apheresis units were collected from healthy volunteers following standard procedures and split into 2 components, one untreated and the other treated with Amotosalen/UVA. Platelet impedance aggregation in response to collagen and thrombin was reduced by 80% and 60%, respectively, in InterceptTM Blood System-treated units already at day 1 of storage. GpIb levels were significantly lower in Intercept™ Blood System samples and soluble glycocalicin correspondingly augmented; furthermore, GpIb alpha was significantly more desialylated as shown by Erythrina Cristagalli Lecting binding. The pro-apoptotic Bak protein was significantly increased, as well as the MAPK p38 phosphorylation and caspase-3 cleavage. Stored Intercept™ Blood System -treated platelets injected into immune-deficient NOD/SCID mice showed a faster clearance. We conclude that the Intercept™ Blood System induces platelet p38 activation and GpIb shedding, and platelet apoptosis through a caspase-dependent mechanism, thus reducing platelet function and survival. These mechanisms are of relevance in transfusion medicine, where the Intercept™ Blood System increases patient safety at the expense of platelet function and survival.

PMID: 28729303 [PubMed - as supplied by publisher]




Vosaroxin in combination with decitabine in newly diagnosed older patients with acute myeloid leukemia or high-risk MDS.
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Vosaroxin in combination with decitabine in newly diagnosed older patients with acute myeloid leukemia or high-risk MDS.

Haematologica. 2017 Jul 20;:

Authors: Daver N, Kantarjian H, Garcia-Manero G, Jabbour E, Borthakur G, Brandt M, Pierce S, Vaughan K, Ning J, Nogueras González GM, Patel K, Jorgensen J, Pemmaraju N, Kadia T, Konopleva M, Andreeff M, DiNardo C, Cortes J, Ward R, Craig A, Ravandi F

Abstract
Vosaroxin is an anti-cancer quinolone derived DNA topoisomerase II inhibitor. We investigated vosaroxin with decitabine in patients ≥ 60 years of age with newly diagnosed acute myeloid leukemia (AML) (n=58) or myelodysplastic syndrome (MDS) (≥ 10% blasts) (n=7) in a phase 2 non-randomized trial. The initial 22 patients received vosaroxin 90 mg/m2 on Days 1 and 4 with decitabine 20 mg/m2 Days 1-5 every 4-6 weeks for up to 7 cycles. Due to high incidence of mucositis the subsequent 43 patients received vosaroxin 70 mg/m2 Days 1 and 4. Sixty-five patients with median age 69 years (range 60-78), secondary AML/MDS (22%), adverse karyotype (35%), TP53 mutation (20%) are evaluable. The overall response rate (ORR) was 74% including complete remission (CR) in 31 (48%), complete remission with incomplete platelet recovery (CRp) in 11 (17%), and complete remission with incomplete count recovery (CRi) in 6 (9%). The median number of cycles to response was 1 (1-4). The median duration of response was 9.9 months (0.5-32.0). The ORR among adverse karyotype (n=23) and TP53 mutated (n=13) patients was 65% and 77%, respectively. Grade 3/4 mucositis was noted in 17% of all patients. We compared outcomes between the 70 mg/m2 and the 90 mg/m2 induction doses of vosaroxin. The 70 mg/m2 induction dose of vosaroxin was associated with similar ORR (74% versus 73%) and CR rate (51% versus 41%, P=0.44), reduced incidence of mucositis (30% versus 59%, P=0.02), reduced 8-week mortality (9% versus 23%; P=0.14), and improved median overall survival (OS) (14.6 months versus 5.5 months, P=0.007). MRD-negative status by multiparametric flow-cytometry at response (+/- 3 months) was achieved in 21 of 39 (54%) evaluable responders and was associated with improved median OS (34.0 months versus 8.3 months, P=0.023). The combination of vosaroxin with decitabine is effective and well tolerated at 70 mg/m2 and warrants randomized prospective evaluation. ClinicalTrials.gov: NCT01893320.

PMID: 28729302 [PubMed - as supplied by publisher]




Changes in the incidence and mortality of candidemia in patients with hematological malignancies in the last ten years. SEIFEM 2015-B report.
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Changes in the incidence and mortality of candidemia in patients with hematological malignancies in the last ten years. SEIFEM 2015-B report.

Haematologica. 2017 Jul 20;:

Authors: Pagano L, Dragonetti G, Cattaneo C, Marchesi F, Veggia B, Busca A, Candoni A, Prezioso L, Criscuolo M, Cesaro S, Delia M, Fanci R, Stanzani M, Ferrari A, Martino B, Melillo L, Nadali G, Simonetti E, Ballanti S, Picardi M, Castagnola C, Decembrino N, Gazzola M, Fracchiolla NS, Mancini V, Nosari A, Del Principe MI, Aversa F, Tumbarello M

PMID: 28729301 [PubMed - as supplied by publisher]




Rapamycin is highly effective in murine models of immune-mediated bone marrow failure.
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Rapamycin is highly effective in murine models of immune-mediated bone marrow failure.

Haematologica. 2017 Jul 20;:

Authors: Feng X, Lin Z, Sun W, Hollinger MK, Desierto MJ, Keyvanfar K, Malide D, Muranski P, Chen J, Young NS

Abstract
Acquired aplastic anemia, the prototypical bone marrow failure disease, is characterized by pancytopenia and marrow hypoplasia. Most aplastic anemia patients respond to immunosuppressive therapy, usually as anti-thymocyte globulin and cyclosporine, but some relapse on cyclosporine withdrawal or require long-term administration of cyclosporine to maintain blood counts. In the current study, we tested efficacy of rapamycin as a new or alternative treatment in mouse models of immune-mediated bone marrow failure. Rapamycin ameliorated pancytopenia, improved bone marrow cellularity, and extended animal survival in a manner comparable to the standard dose of cyclosporine. Rapamycin effectively reduced Th1 inflammatory cytokines interferon-γ and tumor necrosis factor-α increased the Th2 cytokine interleukin-10; stimulated expansion of functional regulatory T cells; eliminated effector CD8+ T cells, notably T cells specific to target cells bearing minor histocompatibility antigen H60; and preserved hematopoietic stem and progenitor cells. Rapamycin, but not cyclosporine, reduced the proportion of memory and effector T cells and maintained a pool of naive T cells. Cyclosporine increased cytoplasmic nuclear factor of activated T-cells-1 following T cell receptor stimulation, whereas rapamycin suppressed phosphorylation of two key signaling molecules in the mammalian target of rapamycin pathway, S6 kinase and protein kinase B. In summary, rapamycin was an effective therapy in mouse models of immune-mediated bone marrow failure, acting by mechanisms different from cyclosporine; its specific expansion of regulatory T cells and elimination of clonogenic CD8+ effectors support potential clinical utility in aplastic anemia treatment.

PMID: 28729300 [PubMed - as supplied by publisher]




Notch2 blockade enhances hematopoietic stem cell mobilization and homing.
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Notch2 blockade enhances hematopoietic stem cell mobilization and homing.

Haematologica. 2017 Jul 20;:

Authors: Wang W, Yu S, Myers J, Wang Y, Xin WW, Alkabri M, Xin AW, Li M, Huang AY, Xin W, Siebel CW, Lazarus HM, Zhou L

Abstract
Despite use of newer approaches, some patients being considered for autologous hematopoietic cell transplantation may mobilize limited numbers of hematopoietic progenitor cells into blood, precluding use of the procedure, or being placed at increased risk for complications due to slow hematopoietic reconstitution. Developing more efficacious hematopoietic progenitor cell mobilization regimens and strategies may enhance the mobilization process and improve patient outcome. Although Notch signaling is dispensable for homeostasis of adult hematopoietic stem cells, Notch-ligand adhesive interaction maintains hematopoietic stem cell quiescence and niche retention. Using Notch receptor blocking antibodies, we report that Notch2 blockade but not Notch1 blockade sensitizes hematopoietic stem cell and progenitors to mobilization stimuli and leads to enhanced egress from marrow to the periphery. Notch2 blockade leads to transient myeloid progenitor expansion without affecting hematopoietic stem cell homeostasis and self-renewal. We show that transient Notch2 blockade or Notch2-loss in mice lacking Notch2 receptor leads to decreased CXCR4 expression by hematopoietic stem cell but increased cell cycling with CXCR4 transcription being directly regulated by the Notch transcriptional protein RBPJ. In addition, we found that Notch2-blocked or Notch2-deficient marrow hematopoietic stem cells and progenitors show an increased homing to the marrow, while mobilized Notch2-blocked but not Notch2-deficient stem cells and progenitors displayed a competitive repopulating advantage and enhanced hematopoietic reconstitution. These findings suggest that blocking Notch2 combined with the current clinical regimen may further enhance hematopoietic progenitor cell mobilization and improve engraftment during hematopoietic cell transplantation.

PMID: 28729299 [PubMed - as supplied by publisher]