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  • 1
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    TG-0054, a Novel and Potent Stem Cell Mobilizer, Displays Excellent PK/PD and Safety Profile in Phase I Trial.
    American Society of Hematology ; 2009
    In:  Blood Vol. 114, No. 22 ( 2009-11-20), p. 866-866
    Details
    In: Blood, American Society of Hematology, Vol. 114, No. 22 ( 2009-11-20), p. 866-866
    Abstract: Abstract 866 Background: Stem cells are retained in the bone marrow via the trophic effects of the binding of chemokine stromal cell-derived factor-1α (SDF-1α) to its receptor, CXC chemokine receptor 4 (CXCR4). TG-0054 inhibits SDF-1α/CXCR4 binding and therefore mobilizes stem cells into peripheral blood. Animal studies in mice showed rapid and effective mobilization of CD34+ hematopoietic stem cells (HSCs) and CD133+ endothelial progenitor cells (EPCs) into peripheral blood after TG-0054 administration. A Phase I study was conducted in healthy volunteers to assess safety, tolerability, pharmacokinetics (PK) and stem cell mobilization of TG-0054. Materials and Methods: This is a phase I, randomized, double-blind, placebo-controlled, single ascending dose study. In each cohort, 2 volunteers received placebo and 6 received 0.10, 0.14, 0.28, 0.56, 1.12, 2.24, 3.14, or 4.40 mg/kg of TG-0054 (dose was calculated based on TG-0054 free base) via 15 minutes single IV infusion. All subjects underwent PK sampling at pre-dose, 5 and 15 minutes during infusion, and at 1, 2.5, 5, 10, 30 minutes and 1, 2, 4, 6, 9, 12, 24, 36 hours after infusion. The pharmacodynamics (PD) sampling time points were at pre-dose, 1, 2, 4, 6, 9, 24, and 36 hours after infusion. General tolerability, adverse events (AEs), electrocardiogram (ECG), vital signs and laboratory tests were recorded. Results: In this study, the maximum tolerated dose (MTD) was not reached in TG-0054 doses up to 4.40 mg/kg in healthy volunteers. Dose escalation was stopped due to plateau of mobilized CD34+ and CD133+ cell numbers. TG-0054 was well tolerated up to 4.40 mg/kg. The majority of AEs were mild in severity (53 out of 55 events), and all AEs resolved by the end of the study without medical treatment. The number of subjects reporting the most common AEs included: abdominal pain (7/64, 11%), diarrhea/loose stools (5/64, 8%), dizziness (3/64, 5%), nausea (3/64, 5%), and diaphoresis (3/64, 5%). No significant abnormalities were noted in vital signs, ECG, holter monitoring, telemetry, pulse oximetry, physical examination, or laboratory tests. The area under the plasma concentration vs. time curve (AUC0-t) and maximum plasma concentration (Cmax) showed dose proportionality over the dose range studied. The mean of terminal elimination half-life (t1/2) was approximately 2.5 to 5 hrs. Single-dose administration of 1.12 - 4.40 mg/kg of TG-0054 significantly increased CD34+ cell counts in peripheral blood. At peak time, TG-0054 caused a 3 - 14 fold increase in circulating CD34+ cells from baseline. The mean CD34+ cell counts at peak time were 27.1 ± 9.3 cells/μL (1.12 mg/kg TG-0054), 35.9 ± 27.3 cells/μL (2.24 mg/kg), 32.5 ± 27.7 cells/μL (3.14 mg/kg), and 29.2 ± 12.9 cells/μL (4.40 mg/kg). The increase in circulating CD34+ cell counts was evident within 2 hours of TG-0054 administration, peaked at 4 - 6 hours after TG-0054 administration, followed by a gradual decline to baseline at 24 hours post-dosing. Similarly, increases in WBC and CD133+ cell counts were observed in all subjects. No AEs were deemed to be associated with WBC increases. Conclusion: TG-0054 exhibited a favorable safety and PK profile in healthy subjects in this Phase I study. PD analysis also displayed potent mobilization of CD34+ HSCs and CD133+ EPCs from TG-0054 dose levels of 1.12 - 4.40 mg/kg. These results support subsequent clinical investigations. Disclosures: Chung: TaiGen Biotechnology, Inc.: Employment. Chang:TaiGen Biotechnology, Inc.: Employment. Huang:TaiGen Biotechnology, Inc.: Employment. Tsai:TaiGen Biotechnology, Inc.: Employment. Hsu:TaiGen Biotechnology, Inc.: Employment. King:TaiGen Biotechnology, Inc.: Employment. Yuan:TaiGen Biotechnology, Inc.: Employment. Yen:TaiGen Biotechnology, Inc.: Employment. Chen:TaiGen Biotechnology, Inc.: Employment. Lu:TaiGen Biotechnology, Inc.: Employment. Hsu:TaiGen Biotechnology, Inc.: Membership on an entity's Board of Directors or advisory committees.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
    URL: Article
    DOI: 10.1182/blood.V114.22.866.866
    RVK:
    XA 33000
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2009
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  • 2
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    The Clinical Association and Prognostic Impact of IL1RAP Expression in Patients with De Novo Acute Myeloid Leukemia
    American Society of Hematology ; 2019
    In:  Blood Vol. 134, No. Supplement_1 ( 2019-11-13), p. 2705-2705
    Details
    In: Blood, American Society of Hematology, Vol. 134, No. Supplement_1 ( 2019-11-13), p. 2705-2705
    Abstract: Introduction One of the contributing factors to the relapse of acute myeloid leukemia (AML) is the presence of leukemia stem cells (LSCs). Interleukin 1 receptor accessory protein (IL1RAP) was reported to be one of the LSC markers. Most studies regarding clinical implications of IL1RAP expression in AML focused on small and selected patient groups. Besides, its correlation with other molecular alterations has not been reported yet in literature. In this study, we aimed to elucidate the relationship between bone marrow IL1RAP expression level and clinical and biological features in patients with de novo non-M3 AML. Furthermore, we would like to explore its prognostic impact and potential underlying mechanism. Method We enrolled 275 newly diagnosed de novo non-M3 AML patients. Among them, 187 (68%) patients received standard induction chemotherapy and 2-4 courses of high-dose cytarabine based post-remission therapy. Analyses of 54 gene mutations were performed by next generation sequencing. The global gene expressions were profiled with the Affymetrix GeneChip Human Transcriptome Array 2.0. Result We used the median as the cut-off value to define the higher and lower IL1RAP expression groups. The patients with higher IL1RAP expression had significantly higher white blood cell counts at diagnosis, higher peripheral blast counts, and higher lactate dehydrogenase levels. Higher IL1RAP expression was closely associated with t(8;21), favorable-risk cytogenetics based on the refined MRC classification, but inversely with unfavorable-risk cytogenetics. Compared with low-expression patients, the high-expression patients had significantly more FLT3/ITD and KIT mutations, but less mutations in U2AF1, TP53, or CEBPA. Among the 187 patients receiving standard intensive chemotherapy, those with lower IL1RAP expression had significantly longer overall survival (OS) than those with higher expression (P=0.047) after a median follow-up time of 91.1 months, but disease-free survival (DFS) was not significantly different between the two groups (P=0.311). Among the 77 patients who relapsed after first complete remission (CR), the second CR rate was similar between the two groups (P=0.649), but the second DFS was significantly longer in the low-expression patients than the high-expression patients (P=0.028) which was also reflected in a significantly longer survival after first relapse in the former group than the latter group (P=0.014). The prognostic impact of IL1RAP expression on OS could be externally validated in the TCGA cohort (P=0.038). Its prognostic implication remained significant in the subgroup of our cohort with intermediate-risk cytogenetics (P=0.006) and those with normal karyotype (P=0.025). In multivariate analysis incorporating age, transplantation status, 2017 ELN risk-stratification and IL1RAP expression as covariates, the higher IL1RAP expression was an independent poor prognostic factor for OS (HR=1.555, P=0.025). The Gene Set Enrichment Analysis revealed significant up-regulation of LSC related genes in the higher IL1RAP expressed patients (Figure 1 and 2). We further profiled genome-wide RNA expression with 70,523 probes to survey the potential molecular mechanisms underlying the IL1RAP expression signature. Totally, 313 differentially expressed genes were identified ( 〉 1.5-fold change and Student t-test P 〈 0.0001, Figure 3). We used Ingenuity Pathway Analysis (Qiagen) to analyze the possible underlying mechanism and found that the top upstream regulators were transcription factors, such as GATA1/GATA2 (P=1.39*10-11 and 1.61*10-10, respectively), and ABCB6 (P=3.84*10-8), one of the ATP-Binding Cassette transporter superfamily. The hub genes in the regulation network included ELAVL1 and NFκB, in addition to GATA1 and GATA2. Conclusion Higher IL1RAP expression is associated with distinct clinical and genetic alterations. It is an independent prognostic factor for OS irrespective of the risk category based on the ELN classification. Transcription factors, such as GATA1 and GATA2, ABCB6, ELAVL1 and NFκB might be involved in the underlying mechanism. Further prospective large cohort is warrant to validate our findings. Disclosures Tien: Novartis: Other: Travel Grant. Hou:Celgene: Research Funding; Abbvie, Astellas, BMS, Celgene, Chugai, Daiichi Sankyo, IQVIA, Johnson & Johnson, Kirin, Merck Sharp & Dohme, Novartis, Pfizer, PharmaEssential, Roche, Takeda: Honoraria. Tien:Daiichi Sankyo: Honoraria; Roche: Honoraria; Abbvie: Honoraria; Alexion: Honoraria; Celgene: Honoraria; Johnson & Johnson: Honoraria; Novartis: Honoraria; Celgene: Research Funding; BMS: Honoraria; Pfizer: Honoraria; Roche: Research Funding.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
    URL: Article
    DOI: 10.1182/blood-2019-124657
    RVK:
    XA 33000
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2019
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  • 3
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    Minimal Residual Disease Monitoring By Next-Generation Sequencing in Patients with Acute Myeloid Leukemia: MRD Positivity after First Consolidation Chemotherapy Can Better Predict Clinical Outcomes Than That after Induction Chemotherapy
    American Society of Hematology ; 2019
    In:  Blood Vol. 134, No. Supplement_1 ( 2019-11-13), p. 2698-2698
    Details
    In: Blood, American Society of Hematology, Vol. 134, No. Supplement_1 ( 2019-11-13), p. 2698-2698
    Abstract: Introduction Presence of minimal residual disease (MRD) detected by multicolor flow cytometry (MCFC) or quantitative polymerase chain reaction has been recognized as an independent important prognosticator for patients with acute myeloid leukemia (AML). Next-generation sequencing (NGS) can simultaneously detect various mutations and be applied to the majority of patients with AML, but the clinical implication of its use in MRD monitoring remains to be clarified. Recently, it was shown that NGS MRD of mutants other than the common mutations occurring in clonal hematopoiesis of indeterminate potential, including the DTA (DNMT3A, TET2, and ASXL1) mutations, carry prognostic impacts on relapse rates and overall survival (OS) in AML patients. However, the proper time point for NGS MRD detection after treatment is still unclear. Our hypothesis is that the NGS MRD detected at different time points might have different clinical implications. In this regard, we aimed to explore the clinical implication of NGS MRD at different time points in AML patients after chemotherapy. Method We enrolled 306 de novo non-M3 and non-M6 AML patients who attained complete remission (CR) after standard induction chemotherapy and received 2-4 courses of post-remission chemotherapy with high-dose cytarabine with or without anthracycline. We analyzed bone marrow samples serially collected at diagnosis, first CR (1st time point for MRD analysis), and after the first consolidation chemotherapy (2nd time point). We used the TruSight myeloid panel (Illumina) to survey the 54 genes related to myeloid malignancies. Because of the sequencing sensitivity issue, we excluded CEBPA mutation and FLT3-ITD in the subsequent analyses. The median follow-up time was 92.0 months. Result At diagnosis, 91% of patients had at least one gene mutation with a median of 2.0 mutations (range 1-6) per patient; 49.4% had molecular gene mutations alone and 41.6% had both cytogenetic changes and molecular mutations. Mutations in NPM1, DNMT3A, NRAS and IDH2 were the most common mutations. According to the 2017 ELN recommendation, 49.3% of patients were in the favorable-risk group; 29.1%, the intermediate-risk group; and 21.6%, the unfavorable-risk group. Among the patients harboring at least one gene mutation at diagnosis, we randomly assigned them into the training (n=167) and validation cohort (n=111); the two cohorts had similar clinical features, and distribution of cytogenetic and molecular abnormalities. Based on the result from the analysis in the training cohort, we set 0.3% as the cut-off for MRD positivity because patients carried gene mutations lower than this limit had a similar outcome as those without detectable mutations. The allele frequencies of the mutants in MRD ranged from 0.3 to 50.5%. Excluding DTA mutations, 47.3% patients in the training cohort had MRD at 1st time point, and 26.9% at 2nd time point. The patients with positive NGS MRD had significantly higher relapse rate (P=0.042 for 1st MRD and P=0.035 for 2nd MRD), shorter disease-free survival (DFS, P=0.037 for 1st MRD and P=0.007 for 2nd MRD) and OS (P=0.015 for 1st MRD and P 〈 0.001 for 2nd MRD, Figure 1). In multivariate Cox proportional hazards regression model incorporating age, white blood cell counts at diagnosis, transplantation status, 2017 ELN risk-stratification, number of chemotherapy cycles to attain CR, and the MRD status into analyses (Table 1), the 2nd MRD was an independent poor prognostic factor (P=0.040 for DFS and P=0.005 for OS) but not 1st MRD (P=0.113 for DFS and P=0.072 for OS). In the validation cohort, 2nd MRD positivity also predicted poorer OS and DFS (P=0.023 and P 〈 0.001) but not 1st MRD (P=0.996 and P=0.461). A comparison of NGS with MCFC for the detection of MRD in 73 patients showed that MRD by NGS had significant additive prognostic value. Conclusion NGS-based MRD monitoring can be applied to more than 90% of AML patients who have detectable mutations at diagnosis. The presence of NGS MRD after treatment can predict outcome of AML patients, especially after the first consolidation chemotherapy (2nd MRD). Positivity of 2nd MRD is an independent unfavorable prognostic factor for DFS and OS. Further prospective trials are warranted to validate these findings and to clarify the role of pre-emptive treatment. Disclosures Tsai: Celgene: Research Funding; Astellas, BMS, Celgene, Chugai, Johnson & Johnson, Kirin, Novartis, Pfizer, Roche, Takeda: Honoraria. Tien:Novartis: Other: Travel Grant. Hou:Celgene: Research Funding; Abbvie, Astellas, BMS, Celgene, Chugai, Daiichi Sankyo, IQVIA, Johnson & Johnson, Kirin, Merck Sharp & Dohme, Novartis, Pfizer, PharmaEssential, Roche, Takeda: Honoraria. Tien:Celgene: Honoraria; Novartis: Honoraria; Alexion: Honoraria; BMS: Honoraria; Roche: Research Funding; Pfizer: Honoraria; Roche: Honoraria; Celgene: Research Funding; Abbvie: Honoraria; Johnson & Johnson: Honoraria; Daiichi Sankyo: Honoraria.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
    URL: Article
    DOI: 10.1182/blood-2019-126870
    RVK:
    XA 33000
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2019
    detail.hit.zdb_id: 1468538-3
    detail.hit.zdb_id: 80069-7
    Location Call Number Limitation Availability
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