GLORIA

GEOMAR Library Ocean Research Information Access

Your email was sent successfully. Check your inbox.

An error occurred while sending the email. Please try again.

Proceed reservation?

Export
Filter
  • American Society of Hematology  (110)
  • 1
    In: Blood, American Society of Hematology, Vol. 140, No. Supplement 1 ( 2022-11-15), p. 4882-4883
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
    RVK:
    RVK:
    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2022
    detail.hit.zdb_id: 1468538-3
    detail.hit.zdb_id: 80069-7
    Location Call Number Limitation Availability
    BibTip Others were also interested in ...
  • 2
    In: Blood, American Society of Hematology, Vol. 138, No. Supplement 1 ( 2021-11-05), p. 4127-4127
    Abstract: Introduction: As outcomes of patients with acute myeloid leukemia (AML) have improved over the past decades, the fraction of patients surviving long-term is increasing. Information on long-term somatic and psycho-social health consequences of AML and its treatment is sparse. Previous studies suggested a higher prevalence of cardiovascular diseases in AML survivors, especially those treated with allogeneic stem cell transplantation (alloHSCT). The aim of our study was to perform a multi-dimensional analysis of health outcomes in AML long-term survivors (AML-LTS). This report focuses on somatic, especially cardiovascular, morbidity in AML-LTS. Overall and health-related quality of life are reported separately (Telzerow et al.). Methods: We conducted a cross-sectional study including AML survivors who had been enrolled in clinical trials or the patient registry of the AML-CG study group and were alive ≥5 years after initial diagnosis. Data concerning somatic health status were collected through patient questionnaires, assessment by the patients' physicians, and medical and laboratory reports. An age- and sex-matched control cohort was derived from German population-based health surveys (Robert Koch Institute, DEGS1 survey; n=6013; persons diagnosed with leukemia [n=11] were excluded). Results: 427 AML-LTS, aged 28 to 93 years, participated in this study. Data on somatic health status is available for 355 survivors, 5 to 19 years after their AML diagnosis. Thirty-eight percent of survivors were treated with chemotherapy with or without an autologous transplant (autoHSCT), whereas 62% had undergone alloHSCT. Focusing on cardiovascular diseases and risk factors, we found that that 49% of AML-LTS had hypertension, 33% had hypercholesterolemia, 15% had type 1/2 diabetes, 10% had congestive heart failure (CHF), and 9% had coronary artery disease (Figure A). The mean body-mass index (BMI) of AML-LTS was 26.7, similar to the DEGS1 cohort (mean BMI, 26.8). Next, we compared the prevalence of cardiovascular diseases and risk factors between AML-LTS and the general German population (represented by the DEGS1 sample), using multivariate models adjusting for age and sex (Table B). Compared to persons not diagnosed with leukemia, AML survivors had similar risks of hypertension, coronary heart disease and myocardial infarction. Prevalence of diagnosed hypercholesterolemia was higher in AML-LTS compared to non-AML controls. In addition, AML-LTS had a 2-fold higher risk of having type 1/2 diabetes, and a 3.5-fold increased risk of CHF compared to the general population. To identify factors associated with the increased risks of diabetes and CHF among AML-LTS, we constructed multivariate models incorporating patient- and treatment related covariables (age, sex, BMI, smoking, prior AML relapse, treatment [chemotherapy + autoHSCT vs. alloHSCT] , and type of leukemia [de novo versus secondary / therapy-related]). We found an increased risk of CHF for AML-LTS who had had a relapse (OR, 3.16; 95% CI: 1.46 - 6.83; P=0.004) and, in trend, for patients with sAML or tAML (OR 2.19; 95%CI: 0.92 - 5.22, P=0.076). In addition, we found an increased risk of type 1/2 diabetes for AML-LTS who are smokers (OR: 3.43; 95% CI: 1.43 - 8.21; p: 0.006). Disease- or treatment-related factors did not significantly associate with any of the other comorbidities we studied. Conclusion: To the best of our knowledge, this is the largest analysis of somatic health outcomes in AML-LTS. Strengths of our study include the relatively large cohort representing a wide age range, the long follow-up period of 5 to nearly 20 years, and the heterogeneity regarding therapy regimens (chemotherapy + autoHSCT vs. alloHSCT). We found that, compared to the general population, AML-LTS have increased risks for CHF and diabetes, but not for hypertension or coronary artery disease. We identified AML relapse as a risk factor for the development of CHF, suggesting that cumulative chemotherapy exposure might be causally involved. On the other hand, we found no treatment- and disease-related risk factors that might explain the higher prevalence of diabetes in AML-LTS. Notably, AML-LTS who had undergone alloHSCT did not have increased risks of CHF, cardiovascular disease, hypertension or diabetes, compared to survivors treated with chemotherapy only. Our results may guide future recommendations for follow-up and inform personalized treatment decisions. Figure 1 Figure 1. Disclosures Berdel: Philogen S.p.A.: Consultancy, Current equity holder in publicly-traded company, Honoraria, Membership on an entity's Board of Directors or advisory committees. Hiddemann: Janssen: Research Funding; F. Hoffmann-La Roche: Membership on an entity's Board of Directors or advisory committees, Research Funding. Metzeler: Jazz Pharmaceuticals: Consultancy; Novartis: Consultancy; AbbVie: Honoraria; Celgene/BMS: Consultancy, Honoraria, Research Funding; Daiichi Sankyo: Honoraria; Pfizer: Consultancy; Astellas: Honoraria.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
    RVK:
    RVK:
    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2021
    detail.hit.zdb_id: 1468538-3
    detail.hit.zdb_id: 80069-7
    Location Call Number Limitation Availability
    BibTip Others were also interested in ...
  • 3
    In: Blood, American Society of Hematology, Vol. 140, No. Supplement 1 ( 2022-11-15), p. 10601-10602
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
    RVK:
    RVK:
    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2022
    detail.hit.zdb_id: 1468538-3
    detail.hit.zdb_id: 80069-7
    Location Call Number Limitation Availability
    BibTip Others were also interested in ...
  • 4
    In: Blood, American Society of Hematology, Vol. 140, No. Supplement 1 ( 2022-11-15), p. 11430-11431
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
    RVK:
    RVK:
    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2022
    detail.hit.zdb_id: 1468538-3
    detail.hit.zdb_id: 80069-7
    Location Call Number Limitation Availability
    BibTip Others were also interested in ...
  • 5
    In: Blood, American Society of Hematology, Vol. 138, No. 18 ( 2021-11-04), p. 1727-1732
    Abstract: Clonal hematopoiesis (CH) is an age-related condition predisposing to blood cancer and cardiovascular disease (CVD). Murine models demonstrate CH-mediated altered immune function and proinflammation. Low-grade inflammation has been implicated in the pathogenesis of osteoarthritis (OA), the main indication for total hip arthroplasty (THA). THA-derived hip bones serve as a major source of healthy hematopoietic cells in experimental hematology. We prospectively investigated frequency and clinical associations of CH in 200 patients without known hematologic disease who were undergoing THA. Prevalence of CH was 50%, including 77 patients with CH of indeterminate potential (CHIP, defined as somatic variant allele frequencies [VAFs] ≥2%), and 23 patients harboring CH with lower mutation burden (VAF, 1% to 2%). Most commonly mutated genes were DNMT3A (29.5%), TET2 (15.0%), and ASXL1 (3.5%). CHIP is significantly associated with lower hemoglobin, higher mean corpuscular volume, previous or present malignant disease, and CVD. Strikingly, we observed a previously unreported association of CHIP with autoimmune diseases (AIDs; multivariable adjusted odds ratio, 6.6; 95% confidence interval, 1.7-30; P = .0081). These findings underscore the association between CH and inflammatory diseases. Our results have considerable relevance for managing patients with OA and AIDs or mild anemia and question the use of hip bone–derived cells as healthy experimental controls.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
    RVK:
    RVK:
    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2021
    detail.hit.zdb_id: 1468538-3
    detail.hit.zdb_id: 80069-7
    Location Call Number Limitation Availability
    BibTip Others were also interested in ...
  • 6
    In: Blood, American Society of Hematology, Vol. 141, No. 8 ( 2023-02-23), p. 955-960
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
    RVK:
    RVK:
    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2023
    detail.hit.zdb_id: 1468538-3
    detail.hit.zdb_id: 80069-7
    Location Call Number Limitation Availability
    BibTip Others were also interested in ...
  • 7
    In: Blood, American Society of Hematology, Vol. 140, No. Supplement 1 ( 2022-11-15), p. 942-943
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
    RVK:
    RVK:
    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2022
    detail.hit.zdb_id: 1468538-3
    detail.hit.zdb_id: 80069-7
    Location Call Number Limitation Availability
    BibTip Others were also interested in ...
  • 8
    In: Blood, American Society of Hematology, Vol. 128, No. 22 ( 2016-12-02), p. 1209-1209
    Abstract: About 20-25% of patients with Acute Myeloid Leukemia (AML) have primary drug resistant disease and fail to achieve complete remission after induction therapy. These patients have an extremely poor prognosis and cannot reliably be identified prior to therapy with current methods. The aim of this work was to develop a predictive tool that can identify therapy resistant patients with high accuracy at the time of diagnosis. We used two independent Affymetrix gene expression (GE) data sets and standard molecular and clinical variables to develop a predictive score for response to cytarabine/anthracycline-based induction chemotherapy. The "training set 1" consisted of 407 adult AML patients enrolled in the AMLCG-1999 trial (GSE37642). Training set 2 included 449 adults treated in various HOVON trials (GSE6891). GE-based classifiers for primary treatment resistance were developed in training set 1 using a penalized logistic regression approach (Lasso). A cut off with a specificity of 90% was predefined in training set 1. Training set 2 was used to select the best classifier. The predictive score and cut off were then validated in a third, fully independent data set, comprising 260 patients enrolled in AMLCG-1999 and 2008 trials studied by RNA sequencing. Additionally, targeted amplicon sequencing data for 68 recurrently mutated genes in AML was available for training set 1 and the validation set. The final classifier (Predictive score 29 MRC - PS29MRC) consisted of 29 gene expression values and the cytogenetic risk group (defined according to the United Kingdom Medical Research Council (MRC) classification) and was calculated as a weighted sum of Lasso coefficients and predictor values. PS29MRC was a highly significant predictor of resistant disease in the validation set with an odds ratio of 2.32 (p=1.53x10-8, AUC: 0.75). We tested the signature in a multivariable model including all variables with univariate p-value & lt;0.05. TP53 mutations, age and PS29MRC (OR: 1.70; p=0.0020) were left significant in the validation set. In comparison to published predictive classifiers like the model by Walter et al. (integrating information on age, performance status, white blood cell count, platelet count, bone marrow blasts, gender, type of AML, cytogenetics and NPM1 and FLT3-ITD status; OR: 1.27; p=0.00083; AUC: 0.70) or the modified molecular version of this score (OR: 1.37; p=0.0027; AUC: 0.63) PS29MRC reached superior predictive accuracy. (Walter et al.; Leukemia 2015) Since we aimed to develop a clinically useful score, we categorized PS29MRC to distinguish between patients who have a high probability of refractory disease and those who are likely to benefit from induction therapy (complete remission or complete remission with incomplete hematologic recovery). By applying the predefined cut off, we were able to reach a specificity of 90% and sensitivity of 46% in the validation set (OR: 7.83; p=6.06x10-9). The accuracy of PS29MRC was 77%. In the multivariable model the categorized classifier was highly significant (OR: 4.45; p=0.00040) and only age and TP53 mutations were left as significant variables again. Within the cytogenetic subgroups favorable (n=14; refractory: n=0; responders: n=13), intermediate (n=189; refractory: n=43; responders: n=136) and adverse (n=49; refractory: n=29; responders: n=15) the classifier showed an accuracy of 100%, 78% and 66%, respectively. Furthermore, the classifier predicted survival and was able to unravel the intermediate MRC subgroup (Figure). Additionally, genes included in our predictive signature seem to be involved in AML pathogenesis and potentially actively contribute to mechanisms responsible for primary therapeutic resistance. For example MIR-155HG, an already known parameter of inferior outcome in AML, contributed significantly to PS29MRC. There are currently ongoing trials with the novel inhibitor Pevonedistat that aim to modulate this target in AML. In summary we were able to develop a predictive risk classifier summarizing 29 gene expression values and the MRC classification that outperformed all currently used methods to predict refractory disease in intensively treated adult AML patients. PS29MRC demonstrates that it is possible to identify patients at risk of treatment failure in AML at diagnosis with high specificity. Figure 1. Kaplan-Meier estimates showing overall survival of AML patients in the validation set according to PS29MRC Figure 1. Kaplan-Meier estimates showing overall survival of AML patients in the validation set according to PS29MRC Figure 2. Figure 2. Disclosures No relevant conflicts of interest to declare.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
    RVK:
    RVK:
    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2016
    detail.hit.zdb_id: 1468538-3
    detail.hit.zdb_id: 80069-7
    Location Call Number Limitation Availability
    BibTip Others were also interested in ...
  • 9
    In: Blood, American Society of Hematology, Vol. 132, No. Supplement 1 ( 2018-11-29), p. 3935-3935
    Abstract: Acute myeloid leukemia (AML) is an aggressive hematologic cancer resulting from the malignant transformation of myeloid progenitors. Despite intensive chemotherapy, relapse caused by intrinsic or acquired drug resistance remains a major hurdle in the treatment of AML. Recently, we found KDM6A as a novel relapse-associated gene in a cohorte of 50 cytogenetically normal AML patients. KDM6A (or UTX) is a histone 3 lysine 27 (H3K27)-specific demethylase and a member of the COMPASS (complex of proteins associated with Set1)-like complex, which is important for chromatin enhancer activation. KDM6A is targeted by inactivating mutations in a variety of cancer types with frequency of occurrence ranging from 0.7 to 4% in AML. In this study, we used matched diagnosis and relapse samples from AML patients, patient-derived xenografts (PDX), and myeloid leukemia cell lines to investigate the status of KDM6A during disease progression and the implications of KDM6A loss regarding chemotherapy resistance. We found three AML patients with enrichment of KDM6A mutations at relapse and mutation-independent, relapse-specific loss of KDM6A expression in three additional AML patients. KDM6A mutations comprise deletions and point mutations and appear to be mainly loss-of-function mutations. In addition, we examined the mutation profile and KDM6A expression in patient-derived xenograft (PDX) samples from 8 relapsed AML patients. In 4/8 samples, KDM6A protein levels were low or completely lost. Due to the fact that all patients had received induction therapy including single or combination treatment with agents such as cytarabine (AraC), daunorubicin (DNR), and 6-thioguanine (6-TG), we hypothesized that loss of KDM6A confers resistance to chemotherapy. To exclude gender-specific effects (KDM6A escapes X inactivation leading to higher levels in females), we compared male KDM6A knockout (KO) with WT leukemia cell lines and found increased AraC resistance in the KDM6A KO cells (unpaired, two-tailed Student's t-test; P=0.0441). In addition, we treated two relapsed PDX AML cells of the same gender, AML 491 (KDM6A WT and strong expression) and AML 393 (KDM6A mutation and weak expression) with AraC for 72h in vitro and found significantly increased AraC resistance in the KDM6A-mutant PDX AML 393 cells (P=0.016). To further investigate whether reduced expression or loss of KDM6A leads to increased resistance towards multiple drugs, we silenced KDM6A expression by shRNA or CRISPR/Cas9 in K562 and MM-1 cells. Compared to control, KDM6A knockdown (KD) and KO K562 cells showed a strong proliferative advantage after AraC and DNR but not 6-TG treatment. A similar drug resistance phenotype was observed in KDM6A KO MM-1 cells. To unravel the mechanism of drug resistance, we performed RNA-Seq analysis in K562 cells treated with siRNA or shRNA against KDM6A under native conditions and after AraC (150nM) treatment for 72h. We compared these differentially expressed genes with known key candidate genes in AraC, DNR, and 6-TG metabolic pathway and found that ENT1 was consistently downregulated in KDM6A KD cells in both siRNA- and shRNA-mediated RNA-Seq screenings. Decreased ENT1 levels were also detected in KDM6A KO K562 single cell clones. ENT1 (also known as SLC29A1) is a membrane transporter relevant for the cellular uptake of nucleosides and its analogues. Competitive inhibition of ENT1 by the small molecule antagonist NBMPR lead to decreased sensitivity towards AraC but not DNR and 6-TG suggesting that increased AraC resistance in KDM6A KO cells is caused, at least partially, by downregulation of ENT1. To elucidate the mechanism of ENT1 regulation by KDM6A, we performed ChIP-seq analysis for H3K27me3 and H3K27ac in the sister cell lines MM-1 (KDM6A WT) and MM-6 (KDM6A KO). ChIP-seq for H3K27me3 showed no enrichment on the ENT1 locus, but we detected differential H3K27ac peaks in the promoter and a putative enhancer region of ENT1 in MM-1 compared to MM-6. These data suggest that increased ENT1 expression may function through direct or indirect effects of KDM6A on enhancer regions, independent of its H3K27 demethylase activity. In conclusion, our results show that mutations in KDM6A are associated with the outgrowth of drug-resistant clones and highlight KDM6A as a novel biomarker of drug resistance in AML. Disclosures Hiddemann: Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; F. Hoffman-La Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Bayer: Consultancy, Research Funding. Metzeler:Novartis: Consultancy; Celgene: Consultancy, Research Funding.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
    RVK:
    RVK:
    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2018
    detail.hit.zdb_id: 1468538-3
    detail.hit.zdb_id: 80069-7
    Location Call Number Limitation Availability
    BibTip Others were also interested in ...
  • 10
    In: Blood, American Society of Hematology, Vol. 124, No. 21 ( 2014-12-06), p. 697-697
    Abstract: Background: Recurrent mutations in 〉 100 different genes have been described in AML, but the clinical relevance of most of these alterations has not been defined. Moreover, high-throughput sequencing techniques revealed that AML patients (pts) may harbor multiple, genetically related disease subclones. It is unclear whether clonal heterogeneity at diagnosis also associates with clinical characteristics or outcomes. To address these questions, we set out to characterize a relatively large, uniformly treated patient cohort for mutations in known and putative AML driver genes. Patients and Methods: We studied pretreatment blood or bone marrow specimens from adult AML pts who received high-dose cytarabine-based induction chemotherapy within the German multicenter AMLCG-2008 trial. Sequence variants (single nucleotide variants and insertions/deletions up to approx. 150bp) in 70 genes known to be mutated in AML or other hematologic neoplasms were analyzed by multiplexed amplicon resequencing (Agilent Haloplex; target region, 321 kilobases). Sequencing was performed on an Illumina MiSeq instrument using 2x250bp paired-end reads. A variant allele frequency (VAF) threshold of 2% was set for mutation detection, corresponding to heterozygous mutations present in 4% of cells in a specimen. Variants were classified as known/putative driver mutations, variants of unknown significance, or known germline polymorphisms based on published data (including dbSNP, the Catalogue Of Somatic Mutations In Cancer [COSMIC] and The Cancer Genome Atlas [TCGA]). In patients with more than one single nucleotide variant, the chi square test was used assess if the observed VAFs, adjusted for ploidy, were compatible with the presence of a single clone. Results: Material for genetic analyses was available for 280 of the 396 participants (71%) enrolled on the AMLC-2008 trial. To date, analyses have been completed for 248 pts (130 male, 118 female; median age, 54y; range 19-81y). Updated results for the entire cohort will be presented at the meeting. Mean coverage of target regions was 〉 600-fold, and on average, 98.2% of target bases were covered 〉 30-fold. We detected a total of 914 mutations in 46 genes, including 37 genes mutated in 〉 1 patient (Fig. A). Nine genes (NPM1, FLT3, DNMT3A, NRAS, WT1, IDH2, RUNX1, TET2 and ASXL1) were mutated in 〉 10% of patients (red dashed line in Fig. A). We found a median of 4 mutations per patient (range: 0-10). Of note, only 1 patient had no detectable mutation and no abnormality on cytogenetic analysis. Patients with Intermediate-risk cytogenetics according to the MRC classification harbored a higher number of driver gene mutations (median, 4) compared to patients with MRC Favorable (median, 2 mutations) or Unfavorable (median, 3 mutations) cytogenetics (P 〈 .001). When analyzing patterns of co-occurring and mutually exclusive mutations, we confirmed well-known associations (e.g., between CEBPA and GATA2 mutations) and identified novel pairs of mutations that frequently occur in combination and, to our knowledge, have not yet been reported in AML (e.g., ASXL1/STAG2, SRSF2/STAG2). These findings may guide functional studies on the molecular mechanisms of leukemogenesis. We found evidence for clonal heterogeneity in 129 (52%) of 248 pts, based on the presence of mutations with significantly (P 〈 .001) different VAFs within the same sample. Our analyses reveal differences in allele frequencies between different AML driver genes. Mutations can be grouped into "early" events that often are present in the founding clone, and "late" events which frequently appear to be restricted to subclones (Fig. B). Conclusion: Targeted sequencing allowed detection of mutations affecting a panel of known and putative AML driver genes in clinical specimens with high sensitivity. Our data from the AMLCG-2008 patient cohort reveal novel patterns of cooperating gene mutations, and show that the presence of subclonal driver mutations is a frequent event in AML pts. Differentiating between "founding clone" mutations, and subclonal mutations that typically occur later in the disease has implications for choosing targeted therapies aimed at disease eradication. Figure 1 Figure 1. Figure 2 Figure 2. Disclosures No relevant conflicts of interest to declare.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
    RVK:
    RVK:
    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2014
    detail.hit.zdb_id: 1468538-3
    detail.hit.zdb_id: 80069-7
    Location Call Number Limitation Availability
    BibTip Others were also interested in ...
Close ⊗
This website uses cookies and the analysis tool Matomo. More information can be found here...