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
  • 1
    In: European Journal of Haematology, Wiley, Vol. 99, No. 6 ( 2017-12), p. 544-552
    Abstract: To evaluate the prognostic impact of gene expression levels ( EL s) of two tumor suppressor genes, sprouty 4 ( SPRY 4, located on 5q) and lysine methyltransferase 2C ( KMT 2C, located on 7q) in correlation with clinical characteristics and genetic abnormalities assessed at initial diagnosis in acute myeloid leukemia ( AML ). Method Gene expression levels were measured on cDNA by RT ‐ qPCR from diagnostic bone marrow samples of 275 intensively treated adult AML patients (median age, 48 years). Results KMT 2C EL s were significantly lower in abn7q/‐7 ( P  = .001), whereas SPRY 4 EL s were not associated with abn5q/‐5. Higher KMT 2C and SPRY 4 EL s were significantly associated with lower genetic risk groups as defined by the European LeukemiaNet classification. Additionally, KMT 2C EL s were lower in cytogenetically normal patients with DNMT 3A ( P  = .01) or FLT 3 ‐ ITD mutations ( P  = .05). KMT 2C EL s were not associated with prognosis, whereas higher SPRY 4 EL s showed a favorable impact on event‐free ( EFS , P  = .01), relapse‐free ( RFS , P  = .01) and in‐trend on overall survival ( P  = .06) for cytogenetically abnormal patients, which was confirmed in multivariable analysis for EFS ( HR , 0.84; 95%‐ CI , 0.73‐0.97; P  = .02) and RFS ( HR , 0.85; 95%‐ CI , 0.73‐0.98; P  = .02). Conclusion Our data indicate that KMT 2C EL s are associated with specific genetic features and that SPRY 4 EL s may add prognostic information.
    Type of Medium: Online Resource
    ISSN: 0902-4441 , 1600-0609
    URL: Issue
    Language: English
    Publisher: Wiley
    Publication Date: 2017
    detail.hit.zdb_id: 2027114-1
    Location Call Number Limitation Availability
    BibTip Others were also interested in ...
  • 2
    In: Blood, American Society of Hematology, Vol. 128, No. 22 ( 2016-12-02), p. 1663-1663
    Abstract: Background:Recent publications suggest important roles of lysine methyltransferase 2C (KMT2C, located on 7q) and sprouty 4 (SPRY4, located on 5q) as candidate genes in leukemogenesis of acute myeloid leukemia (AML). The prognostic impact of the gene expression levels (ELs) of both genes on outcome in AML patients (pts) is currently unclear. Aim:To evaluate the prognostic impact of KMT2C and SPRY4 expression in correlation to clinical characteristics and genetic abnormalities assessed at diagnosis in a cohort of intensively treated adult AML pts. Methods: We retrospectively studied 268 AML pts (median age, 48 years; range, 17-60 years) who had been enrolled on 2 AML SHG trials (0295 and 0199, n=148; only normal cytogenetics pts (CN)) and the SAL-AML2003 trial (n=120; only abnormal cytogenetics pts (CA)). Acute promyelocytic and core-binding factor leukemia pts were excluded. Type of AML was de novo in 235 (88%), secondary in 19 (7%) and therapy-related in 14 (5%) of the 268 pts. Regarding baseline characteristics, CN pts had significantly higher white blood counts (WBC; p=0.001) and blast cells in peripheral blood (p=0.02) as compared to CA pts; all other factors were comparable. Cytogenetic analyses could be performed in 263 (98%) of the 268 pts. Cytogenetic risk classification according to ELN guidelines was intermediate-II in 55 (47%) and adverse in 63 (53%) of the CA pts, respectively. Abnormalities (abn) of 5q were present in 21 (18%) and abn of 7q in 16 (14%) of the CA pts. NPM1 and FLT3-ITD were analyzed in 145 (98%) of the CN pts. Of those, 59 (41%) were only NPM1 positive (pos), 12 (8%) were only FLT3-ITD pos, 34 (23%) were double pos and 40 (28%) were double negative (neg). KMT2C and SPRY4 ELs, normalized to ABL1and log2-transformed for analysis, were measured in triplets on cDNA obtained at diagnosis by RT-qPCR. Based on cDNA availability, KMT2C ELs could be analyzed in 143 (97%) of the CN and in all of the 120 CA pts, respectively. SPRY4 ELs could be measured in 30 (21%) of the CN and 107 (89%) of the CA pts, respectively. Results: KMT2C ELs were significantly lower in CN pts with de novo as compared to secondary AML (p= 0.02), whereas there was no difference in CA pts. No significant association was found for SPRY4 and type of AML. KMT2C ELs were significantly lower in FLT3-ITD pos as compared to FLT3-ITD neg CN pts (p=0.046), whereas there was no difference for SPRY4 ELs between the two groups (p=0.57). In addition, there was a significantly lower KMT2C expression in CN pts with intermediate-I risk as compared to NPM1 pos / FLT3-ITD neg pts (p=0.01). Regarding CA pts, there was no difference of KMT2C or SPRY4 ELs in adverse as compared to intermediate-II risk pts (p=0.08; p=0.20, respectively). When focusing on specific subgroups, KMT2C ELs were significantly lower in abn7q CA pts as compared to those without abn7q (p=0.002), whereas there was no difference of SPRY4 ELs in CA pts with or without abn5q (p=0.27). In univariate analysis higher SPRY4 ELs showed a significant favorable impact on relapse-free (RFS, p=0.03) and a trend towards a beneficial impact on overall survival (OS, p=0.06) for CA patients. A similar effect for KMT2C was not observed (RFS, p=0.96; OS, p=0.92). In subgroup analyses of pts with adverse risk cytogenetics, there was no impact of KMT2C or SPRY4 ELs on RFS (p=0.73; p=0.39) or OS (p=0.49; p=0.46), respectively. The same was true for FLT3-ITD pos CN pts (RFS, p=0.73; p=0.37; OS, p=0.91; p=0.36, respectively). In multivariate analyses on RFS and OS in CA pts including age, gender, KMT2C and SPRY4 ELs, logarithm of WBC, blast cells in bone marrow and cytogenetic risk group as variables, only higher age (OS, Hazard ratio (HR),1.28 per 10 years; 95%-confidence interval (CI): 1.02-1.59; p=0.03) and complex karyotype as compared to intermediate-II risk cytogenetics (RFS, HR: 2.25; 95%-CI: 1.20-4.22; p=0.01; OS, HR: 2.97; 95%-CI: 1.65-5.35; p 〈 0.001) had an adverse impact. An effect of KMT2C or SPRY4 on RFS (p=0.84; p=0.16) or OS (p=0.85; p=0.45) was not found in the multivariate setting. In addition, in a multivariate model on CN pts (risk class according to NPM1 and FLT3-ITD mutational status instead of cytogenetic risk class) neither KMT2C nor SPRY4 had an impact on RFS (p=0.13; p=0.39, respectively) or OS (p=0.36; p=0.56, respectively). Conclusions:Lower KMT2C and SPRY4 ELs are associated with distinct genetic risk groups. An impact on prognosis was evident in univariable analyses for SPRY4 but not for KMT2C ELs in CA pts. Disclosures Kayser: Novartis: Consultancy. Platzbecker:Amgen: Honoraria, Research Funding; Novartis: Honoraria, Research Funding; TEVA Pharmaceutical Industries: Honoraria, Research Funding; Janssen-Cilag: Honoraria, Research Funding; Celgene Corporation: Honoraria, Research Funding. Heuser:Tetralogic: Research Funding; Novartis: Consultancy, Research Funding; Celgene: Honoraria; Bayer Pharma AG: Research Funding; Pfizer: Research Funding; Karyopharm Therapeutics Inc: Research Funding; BerGenBio: Research Funding. Thiede:AgenDix: Employment, Other: Ownership.
    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 ...
  • 3
    In: Journal of Clinical Oncology, American Society of Clinical Oncology (ASCO), Vol. 33, No. 5 ( 2015-02-10), p. 403-410
    Abstract: The presence of a mutated nucleophosmin-1 gene (NPM1 mut ) in acute myeloid leukemia (AML) is associated with a favorable prognosis. To assess the predictive value with regard to allogeneic stem-cell transplantation (SCT), we compared the clinical course of patients with NPM1 mut AML eligible for allogeneic SCT in a donor versus no-donor analysis. Patients and Methods Of 1,179 patients with AML (age 18 to 60 years) treated in the Study Alliance Leukemia AML 2003 trial, we identified all NPM1 mut patients with an intermediate-risk karyotype. According to the trial protocol, patients were intended to receive an allogeneic SCT if an HLA-identical sibling donor was available. Patients with no available donor received consolidation or autologous SCT. We compared relapse-free survival (RFS) and overall survival (OS) depending on the availability of a suitable donor. Results Of 304 eligible patients, 77 patients had a sibling donor and 227 had no available matched family donor. The 3-year RFS rates in the donor and no-donor groups were 71% and 47%, respectively (P = .005); OS rates were 70% and 60%, respectively (P = .114). In patients with normal karyotype and no FLT3 internal tandem duplication (n = 148), the 3-year RFS rates in the donor and no-donor groups were 83% and 53%, respectively (P = .004); and the 3-year OS rates were 81% and 75%, respectively (P = .300). Conclusion Allogeneic SCT led to a significantly prolonged RFS in patients with NPM1 mut AML. The absence of a statistically significant difference in OS is most likely a result of the fact that NPM1 mut patients who experienced relapse responded well to salvage treatment. Allogeneic SCT in first remission has potent antileukemic efficacy and is a valuable treatment option in patients with NPM1 mut AML with a sibling donor.
    Type of Medium: Online Resource
    ISSN: 0732-183X , 1527-7755
    RVK:
    RVK:
    Language: English
    Publisher: American Society of Clinical Oncology (ASCO)
    Publication Date: 2015
    detail.hit.zdb_id: 2005181-5
    Location Call Number Limitation Availability
    BibTip Others were also interested in ...
  • 4
    In: OncoImmunology, Informa UK Limited, Vol. 5, No. 5 ( 2016-05-03), p. e1139662-
    Type of Medium: Online Resource
    ISSN: 2162-402X
    Language: English
    Publisher: Informa UK Limited
    Publication Date: 2016
    detail.hit.zdb_id: 2645309-5
    Location Call Number Limitation Availability
    BibTip Others were also interested in ...
  • 5
    In: Blood, American Society of Hematology, Vol. 126, No. 23 ( 2015-12-03), p. 2008-2008
    Abstract: Background: Allogeneic hematopoietic stem cell transplantation (SCT) is considered to be the treatment strategy with the highest anti-leukemic efficacy for acute myeloid leukemia (AML) patients in morphological complete remission (CR). The prognostic impact of pretransplant minimal residual disease (MRD) levels measured by real-time quantitative polymerase chain reaction (RT-qPCR) on outcome is currently unclear. Aims: To evaluate the prognostic impact of pretransplant NPM1 MRD levels in correlation to clinical characteristics and genetic abnormalities assessed at initial diagnosis in a cohort of adult AML patients receiving SCT. Methods: We retrospectively studied 238 AML patients (median age at time of SCT, 53.5 years; range, 17-73 years) who received a SCT between 2005 and 2013 at the University of Heidelberg. Patients with acute promyelocytic leukemia were excluded from the analysis. Based on material availability, the mutational status of NPM1 and FLT3 -ITD were analyzed in 208 and 215 of the patients, respectively. Sixty-seven of the 208 patients (32%) were NPM1 -mutated; of those, 28 patients had a concurrent FLT3 -ITD (42%). Source of donor was matched-related in 20, matched-unrelated in 45 and haplo-identical in 2 of the 67 patients, respectively. The majority of patients (n=61) received reduced intensity conditioning. SCT was performed in first CR in 31, in second CR in 20 and in 16 refractory patients, respectively. Pretransplant MRD could be measured in 53 of the 67 patients with NPM1- mutated AML (79%), and in 39 of the 51 NPM1 -mutated patients who were in morphological CR at SCT (76%). MRD negativity prior to SCT was defined as less than 100 copies of mutated NPM1 / 104 ABL copies; the sensitivity level was 10-5-6. Results: Overall survival (OS) for NPM1 -mutated patients transplanted in morphological CR was significantly longer as compared to patients with active disease (5-year estimates of OS: 63% vs. 38%; p=0.004) irrespective of first or second CR (p=0.74). There was no difference in outcome in CR patients with or without MRD measurement (OS: p=0.84; relapse-free survival (RFS): p=0.29). However, when focusing on patients with MRD measurement, MRD-positive (MRDpos) patients (n=20) had a higher incidence of concurrent FLT3 -ITD mutations (p=0.008) as compared to MRD-negative (MRDneg) patients (n=19). There was a highly significant difference in RFS and OS between MRDpos and MRDneg patients: estimated 5-year RFS and OS were each 40% vs. 89% (p=0.001, each). In a multivariate Cox model for RFS, the hazard ratio (HR) for pretransplant MRD was 13.20 (95% confidence interval: 3.22-77.70; p 〈 0.001), whereas FLT3 -ITD measured at diagnosis was not significant (p=0.94). OS of patients receiving SCT in active disease was 38% at five years and was comparable to that observed in patients with MRDpos disease before transplant (40%; p=0.42). Conclusions: Pretransplant NPM1 MRD positivity was a significant predictor of poor outcome in patients with NPM1 -mutated AML, heralding a prognosis not better than that of patients transplanted with refractory disease. Disclosures Kayser: EUSA Pharma: Other: travel support . Thiede:Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; AgenDix GmBH: Equity Ownership. Bochtler:TEVA: Other: travel support. Hegenbart:Janssen: Honoraria, Other: travel support. Kraemer:TEVA: Other: travel support.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
    RVK:
    RVK:
    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2015
    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. 128, No. 22 ( 2016-12-02), p. 2869-2869
    Abstract: Introduction: Cytogenetic testing is routinely performed in newly diagnosed acute myeloid leukemia (AML) for risk stratification. Elaborate risk classifications based on karyotyping are provided by both the European Leukemia Net (ELN) and the Medical Research Council (MRC). Complex aberrant, monosomal and abnl(17p) karyotypes confer a poor prognosis. In cytogenetic studies, chromosome aberrations that cannot be identified due to gross rearrangement, thereby preventing the allocation to a specific chromosome, are designated as "Marker Chromosomes" (MC). The significance of MC as prognostic factor for AML has remained elusive so far. In this study we have assessed frequency, cytogenetic characteristics and prognostic impact of MC as well as their underlying biological origin. Given the gross structural chromosomal damage inherent to MC we speculated that they may arise from chromothripsis, a recently described phenomenon of chromosome fragmentation in a single catastrophic event. Patients and Methods: Patients recruited intwo large consecutive, prospective, randomized, multicenter clinical trials for newly diagnosed non-M3 AML patients from the German Study Alliance Leukemia (SAL) were analyzed (AML96, NCT00180115; AML2003, NCT00180102). All karyotypes were retrospectively screened for MC. For the detection of chromothripsis array-CGH was used. For each sample 50 ng of DNA were hybridized to an Affymetrix® CytoScan HD Oligo/SNP-array and scanned with the Affymetrix GeneChip® Scanner 3000 7G. Chromothripsis was defined according to the criteria of Rausch et al., which require at least 10 switches in segmental copy number involving two or three distinct copy number states on a single chromosome. Results: MC were detectable in 165/1026 (16.1%) of aberrant non-CBF karyotype cases. Adverse-risk karyotypes displayed a higher frequency of MC (40.3% in complex aberrant, 26.5% in adverse-risk as defined by MRC criteria and 41.2% in abnl(17p) karyotypes, p 〈 .001 each). MC were associated with a poorer prognosis compared to other non-CBF aberrant karyotypes as well as with lower remission rates (CR+CRi; 36.0% vs. 55.8% in AML96 ≤60 years, p=0.01; 14.3% vs. 44.1% in AML2003, p 〈 0.001), inferior event-free survival (2.24 vs. 6.54 months, p 〈 0.001; 3.45 vs. 8.03 months, p 〈 0.001) and overall survival (5.72 vs. 11.87 months, p 〈 0.001; 8.68 vs. 20.78, p=0.01). In multivariate analysis with co-variables age, prior MDS, therapy-related AML and adverse-risk cytogenetics according to MRC criteria, MC independently predicted poor prognosis in AML96 ≤60 years but not in AML2003 with its higher allogeneic transplantation rate. As detected by array-CGH, in about one third of MC karyotypes (18/49, 36.7%, including 3 cases with 8 or 9 copy number switches) MC had arisen from chromothripsis, whereas this phenomenon was virtually undetectable in a control group of complex aberrant karyotypes without MC (1/34) (p 〈 0.001). Chromothripsis in MC karyotypes typically involved one single chromosome (n=11), with two or three chromosomes affected in 5 and 2 patients, respectively. There was no predilection for a particular chromosome. MC karyotypes positive for chromothripsis were characterized by a particularly high degree of karyotype complexity as compared to those that were negative for chromothripsis (complex aberrant 100% vs. 64.5% p 〈 0.01; abnl(17p) 50.0% vs. 16.1%, p=0.01). In 12/18 (66.7%) cases, at least one of the chromothriptic chromosomes was reported as loss in the karyotype formula, suggesting that the grouping of a chromothriptic chromosome as a marker is paralleled by a putative loss of the affected chromosome. The chromothripsis positive MC karyotype subgroup had a particularly dismal prognosis with a combined CR+CRi rate of 2/16 vs. 10/31 (p=0.14). It also displayed inferior event-free and overall survival, though statistical significance was not reached for either endpoint, likely due to the already poor prognosis of the entire MC positive group. Conclusion: This is the first study showing that MC are a frequent finding predominantly in adverse-risk AML and associated with particularly poor prognosis. Our data provide evidence that a substantial portion of MC arise from chromothripsis. Disclosures Thiede: AgenDix: Employment, Other: Ownership.
    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 ...
  • 7
    In: Blood, American Society of Hematology, Vol. 129, No. 10 ( 2017-03-09), p. 1333-1342
    Abstract: Marker chromosomes are frequently found in AML, particularly among aneuploid adverse-risk karyotypes and confer a poor prognosis. About one-third of marker and ring chromosome karyotypes arise from chromothripsis.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
    RVK:
    RVK:
    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2017
    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: European Journal of Haematology, Wiley, Vol. 101, No. 3 ( 2018-09), p. 318-325
    Abstract: To improve monitoring of myeloid neoplasms by flow cytometry‐based minimal residual disease ( MRD ) analysis, we analyzed the significance of leukemia‐associated immunophenotype ( LAIP ) markers in 44 patients. Methods In a pilot study cohort, peripheral blood or bone marrow samples from 13 patients with myeloid neoplasms and one case of B lymphoblastic leukemia in complete hematologic remission after allogeneic bone marrow or stem cell transplantation were subjected to selection for leukemia‐specific phenotypes by fluorescence‐activated cell sorting using individual marker combinations, followed by PCR ‐based chimerism analysis. Results The feasibility of this method could be demonstrated, with selection being successful in 12 cases, including two cases where mixed chimerism was found exclusively in sorted cells. Interestingly, four specimens displayed full donor chimerism in cells expressing the presumably aberrant combination CD 34 + / CD 7 + . Further analyses, including assessment of an independent cohort of 25 patients not affected by neoplastic bone marrow infiltration, revealed that normal myeloid precursors usually include a population coexpressing CD 34, CD 13, CD 33, and CD 7. Conclusion We conclude that the combination CD 34 + / CD 7 + might not be suitable as an LAIP for MRD diagnostics and that a subset of normal myeloid precursors in the bone marrow expresses CD 7.
    Type of Medium: Online Resource
    ISSN: 0902-4441 , 1600-0609
    URL: Issue
    Language: English
    Publisher: Wiley
    Publication Date: 2018
    detail.hit.zdb_id: 2027114-1
    Location Call Number Limitation Availability
    BibTip Others were also interested in ...
  • 9
    In: British Journal of Haematology, Wiley, Vol. 171, No. 5 ( 2015-12), p. 710-719
    Type of Medium: Online Resource
    ISSN: 0007-1048
    RVK:
    Language: English
    Publisher: Wiley
    Publication Date: 2015
    detail.hit.zdb_id: 1475751-5
    Location Call Number Limitation Availability
    BibTip Others were also interested in ...
  • 10
    In: Molecular Case Studies, Cold Spring Harbor Laboratory, Vol. 2, No. 5 ( 2016-09), p. a001123-
    Abstract: Here, we report the case of an acute promyelocytic leukemia (APL) patient who—although negative for FLT3 mutations at diagnosis—developed isolated FLT3 tyrosine kinase II domain ( FLT3 -TKD)-positive meningeal relapse, which, in retrospect, could be traced back to a minute bone marrow subclone present at first diagnosis. Initially, the 48-yr-old female diagnosed with high-risk APL had achieved complete molecular remission after standard treatment with all- trans retinoic acid (ATRA) and chemotherapy according to the AIDA (ATRA plus idarubicin) protocol. Thirteen months after the start of ATRA maintenance, the patient suffered clinically overt meningeal relapse along with minute molecular traces of PML/RARA (promyelocytic leukemia/retinoic acid receptor alpha) in the bone marrow. Following treatment with arsenic trioxide and ATRA in combination with intrathecal cytarabine and methotrexate, the patient achieved a complete molecular remission in both cerebrospinal fluid (CSF) and bone marrow, which currently lasts for 2 yr after completion of therapy. Whole-exome sequencing and subsequent ultradeep targeted resequencing revealed a heterozygous FLT3- TKD mutation in CSF leukemic cells (p.D835Y, c.2503G 〉 T, 1000/1961 reads [51%]), which was undetectable in the concurrent bone marrow sample. Interestingly, the FLT3- TKD mutated meningeal clone originated from a small bone marrow subclone present in a variant allele frequency of 0.4% (6/1553 reads) at initial diagnosis. This case highlights the concept of clonal evolution with a subclone harboring an additional mutation being selected as the “fittest” and leading to meningeal relapse. It also further supports earlier suggestions that FLT3 mutations may play a role for migration and clonal expansion in the CSF sanctuary site.
    Type of Medium: Online Resource
    ISSN: 2373-2865 , 2373-2873
    Language: English
    Publisher: Cold Spring Harbor Laboratory
    Publication Date: 2016
    detail.hit.zdb_id: 2835759-0
    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...