X

Your email was sent successfully. Check your inbox.

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

Proceed reservation?

Export
  • 1
    Online Resource
    Online Resource
    Long-term results of all-trans retinoic acid and arsenic trioxide in non-high-risk acute promyelocytic leukemia: update of the APL0406 Italian-German randomized trial
    Springer Science and Business Media LLC ; 2020
    In:  Leukemia Vol. 34, No. 3 ( 2020-03), p. 914-918
    Details
    In: Leukemia, Springer Science and Business Media LLC, Vol. 34, No. 3 ( 2020-03), p. 914-918
    Type of Medium: Online Resource
    ISSN: 0887-6924 , 1476-5551
    URL: Article
    DOI: 10.1038/s41375-019-0589-3
    RVK:
    WA 15000
    Language: English
    Publisher: Springer Science and Business Media LLC
    Publication Date: 2020
    detail.hit.zdb_id: 2008023-2
    Library Location Call Number Volume/Issue/Year Availability
    BibTip Others were also interested in ...
    Online Resource
    Open Access Request
    Availability (electronic / print)
  • 2
    Online Resource
    Online Resource
    Continued Low-Dose Decitabine (DAC) Is an Active First-Line Treatment of Older AML Patients: First Results of a Multicenter Phase II Study.
    American Society of Hematology ; 2005
    In:  Blood Vol. 106, No. 11 ( 2005-11-16), p. 1852-1852
    Details
    In: Blood, American Society of Hematology, Vol. 106, No. 11 ( 2005-11-16), p. 1852-1852
    Abstract: Background: Few therapeutic options exist for older AML patients (pts) in whom induction chemotherapy is not feasible. Encouraged by the marked activity and low toxicity of the demethylating agent DAC in high-risk MDS, we initiated a phase II trial in untreated AML patients 〉 60 years not eligible for induction. Methods: low-dose DAC was given as for MDS (i.e. 135 mg/m2 i.v. over 72 hrs), repeated q 6 weeks for up to 4 courses, with all-trans retinoic acid (ATRA, 45mg/m2/day for 28 days) given during course 2 in DAC-sensitive pts. Maintenance with 20 mg/m2 DAC i.v. over 1 hour on 3 days (total dose 60mg/m2, outpatient administration) q 8 weeks was offered to pts completing all 4 courses. Pts with a WBC of 〉 20 000/ul received a short course of hydroxyurea (HU) prior to DAC. The primary endpoint was best response: complete (CR) or partial remission (PR) or an antileukemic effect (AE, 〉 25% bone marrow blast reduction). Pts requiring HU beyond day 28 of course 1 and/or showing blast increase had progressive disease (PD). Secondary endpoints were: overall (OS) and progression-free survival, toxicity and hospitalization duration. Accompanying studies included quality-of-life and geriatric assessment, p15/INK4b methylation analyses, and sequential measurement of HbF (a potential marker of DNA demethylating activity). Results: 51 pts have been recruited, with a median age of 72 years (range 63–85). 33% of pts were 〉 75 years. Complex karyotype and/or preceding MDS were present in 65 and 51 %, respectively. Median WBC before treatment was 5300/μl (range, 600–241,000, 33% of pts 〉 20 000/μl WBC). Median bone marrow blasts were 70%. The median number of DAC courses given was 2, and 6 pts received a total of 30 maintenance courses (median 4.5). In the 29 fully evaluable pts, the best response was CR in 4 pts (14%), and PR in 5 pts (17%), with a median of 13 weeks to best response. An AE occurred in 9 pts (31%), resulting in a 62% overall response rate. Stable disease (SD) was seen in 3 pts (10%), 7 had PD (24%), 1 pt (3%) died early (day 9 from start DAC). Two pts (1 SD, 1 AE) were taken off study after 2 courses because of prolonged neutropenia. Toxicities of inpatient DAC were very similar to those described for MDS (neutropenia, fever/infection, pancytopenia). No unexpected toxicities or ATRA syndrome were observed with the combination of DAC+ATRA. No hospitalizations occured during maintenance DAC. Median OS from start of treatment was 7.5 months (range, 0.3–21+), the 1-year survival 24%. In CR+PR pts, median OS was not reached, in pts with AE was 7.8 months, in nonresponders 1 month. Geriatric assessment revealed a high maintenance level of capabilities during the study period. Conclusion: low-dose DAC is very well tolerated by older AML pts ineligible for more aggressive treatment, with myelosuppression being the major toxicity. Objective responses occur in 31 % of pts. A frequent and often prolonged antileukemic effect, limited hospitalization times, the occurrence of late responses, and the good feasibility of outpatient maintenance also support continued DAC treatment.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
    URL: Article
    DOI: 10.1182/blood.V106.11.1852.1852
    RVK:
    XA 33000
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2005
    detail.hit.zdb_id: 1468538-3
    detail.hit.zdb_id: 80069-7
    Library Location Call Number Volume/Issue/Year Availability
    BibTip Others were also interested in ...
    Online Resource
    Open Access Request
    Availability (electronic / print)
  • 3
    Online Resource
    Online Resource
    High-Resolution Genomic Profiling of Adult and Pediatric Core Binding Factor Acute Myeloid Leukemia Reveals New Recurrent Genomic Aberrations
    American Society of Hematology ; 2010
    In:  Blood Vol. 116, No. 21 ( 2010-11-19), p. 849-849
    Details
    In: Blood, American Society of Hematology, Vol. 116, No. 21 ( 2010-11-19), p. 849-849
    Abstract: Abstract 849 Core-binding-factor (CBF) acute myeloid leukemia (AML) defined by the presence of t(8;21)(q22;q22) or inv(16)(p13.1q22)/t(16;16)(p13.1;q22) is associated with favorable outcome. However, about 30–40% of patients are not cured by current treatment approaches. Secondary genetic changes are believed to cause clinical heterogeneity. To identify new secondary genetic lesions, we performed high-resolution, genome-wide analysis of copy number aberrations (CNA) and copy neutral loss of heterozygosity (CN-LOH) using Affymetrix 6.0 single nucleotide polymorphism (SNP) microarrays in 300 adult and pediatric CBF AMLs; t(8;21), n=157 (adult, n=114; pediatric, n=43); and inv(16), n=143 (adult, n=104; pediatric, n=39). Germline control DNA from remission bone marrow or peripheral blood was available for paired analysis in 175 patients. In addition, for 42 patients matched relapse samples were analyzed. Data were processed using reference alignment, dChipSNP and circular binary segmentation. Paired analysis revealed a median of 1.28 somatic CNAs per case [t(8;21): 1.14, range: 0–5; inv(16): 1.45, range: 0–9], with deletions more common than gains [t(8;21): 0.94 losses/case vs. 0.2 gains/case; inv(16): 0.95 vs. 0.5] . Recurrent deletions were detected at chromosomal bands 7q36.1 (n=23), 9q21.13 (n=15), 11p13 (n=7), 17q11.2 (n=6), 10q24.32 (n=2), and at the chromosomal breakpoints of t(8;21) and inv(16) on 8q21.3 (n=9), 21q22 (n=16), 16p13.11 (n=28), and 16q22.11 (n=21). Deletions at 7q, 11p and 17q were validated using FISH analysis. Minimally deleted regions (MDR) less than 1.5 Mb were identified at 7q36.1 (647 Kb, 4 genes), 9q21.13 (1125 Kb, 9 genes), 11p13 (130 Kb, 1 gene), and 17q11.2 (902 Kb, 11 genes), with each region containing a putative tumor suppressor (e.g., MLL3 on 7q, FRMD3 on 9q, WT1 on 11p, and NF1 on 17q). Sequence analysis of MLL3 in 23 cases with del(7q), 1 case with 7q CN-LOH, and 23 randomly selected cases identified a MLL3 truncating mutation leading to a premature stop codon in a case that lacked a 7q alteration. The del(11p13) contained only WT1 and primarily affected inv(16)-cases (5 of 7). Sequence analysis of WT1 in four cases with del(11p) revealed an additional frame shift mutation in the remaining allele in one case. Sequence analysis of WT1 in an additional 103 inv(16)-containing cases revealed mutations in 10 (9%) of the cases. The MDR at 17q11.2 was exclusively identified in inv(16)-containing cases (n=6) and included the tumor supressor NF1. Sequence analysis of all coding exons in NF1 in 4 additional inv(16)-containing AMLs revealed no additional mutation. Recurrent gains were identified at 22q11.21-q13.33 (n=20; 32 Mb), 8q24.21 (n=14; 138 Kb), 13q21.1-q34 (n=6; 14 Mb), and 11q25 (n=5; 368 Kb). The smallest gains were identified at 8q24.21 and 11q25, both containing only a single non-coding RNA gene (CCDC26 and LOC283177, respectively). Somatic CN-LOH were uncommon and only found at 1p36.33-p12 (n=2), 4q (n=2), and 19p (n=2). In a comparative analysis of paired diagnostic and relapse samples, novel CNAs at the time of relapse were identified at 3q13.31 (n=5), 5q (n=2), 17p (n=2), and 17q (n=2). The MDR at 3q was only 46 kb in size and contains a single transcript that has been connected to LSAMP, a putative tumor suppressor located 404 Kb upstream of the deletion. In summary, our data provide a comprehensive profiling of copy number alterations in pediatric and adult CBF AML. These data demonstrate a very low number of CNAs, with no significant differences noted between pediatric and adult cases. Interestingly, a number of novel recurrent secondary genetic alterations are identified. Exploring the biological role of these lesions in leukemogenesis and drug resistance should provide important insights into the CBF leukemias. Disclosures: No relevant conflicts of interest to declare.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
    URL: Article
    DOI: 10.1182/blood.V116.21.849.849
    RVK:
    XA 33000
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2010
    detail.hit.zdb_id: 1468538-3
    detail.hit.zdb_id: 80069-7
    Library Location Call Number Volume/Issue/Year Availability
    BibTip Others were also interested in ...
    Online Resource
    Open Access Request
    Availability (electronic / print)
  • 4
    Online Resource
    Online Resource
    Assessment of Clonal Evolution in 42 AML with NPM1 Mutations by Molecular Characterization of Paired Diagnosis and Relapse Samples
    American Society of Hematology ; 2011
    In:  Blood Vol. 118, No. 21 ( 2011-11-18), p. 237-237
    Details
    In: Blood, American Society of Hematology, Vol. 118, No. 21 ( 2011-11-18), p. 237-237
    Abstract: Abstract 237 Mutations in the nucleophosmin 1 (NPM1) gene represent one of the most frequent gene mutations in acute myeloid leukemia (AML), in particular in cytogenetically normal (CN)-AML. NPM1 mutations (NPM1mut) are considered as an early genetic event in the pathogenesis of AML. To address the role of clonal evolution from diagnosis to relapse in NPM1mut AML, we applied high-resolution genome-wide single nucleotide polymorphism (SNP) array analysis using the Affymetrix 6.0 platform to detect copy number alterations (CNAs) and uniparental disomies (UPDs) in paired samples from 42 patients. In addition, we determined NPM1 and FLT3 [internal tandem duplication (ITD) and tyrosine kinase domain (TKD)] mutation status in all samples. Blood or bone marrow samples obtained at complete morphologic remission were available for all patients to exclude germline copy number variations. At diagnosis, 29 cases (69%) had a normal karyotype by cytogenetics and no CNAs and UPDs by SNP analysis. In the 13 remaining cases, we found a total of 10 CNAs in 7 cases (19%), and 6 UPDs in 6 cases (14%): deletions of 9q21 (size range 0.9 to 17 Mb) were detected in 5 cases and were the only recurrent CNA; the only recurrent UPD affected the long arm of chromosome 13 in 4 cases, all resulting in homozygous FLT3-ITD mutations with FLT3-ITD/wildtype ratios 〉 1; heterozygous FLT3-ITD and –TKD mutations were detected in 9 and 7 patients, respectively. At the time of relapse, the number of CNAs increased (34 CNAs in 16 cases, 38%) while the frequency of UPDs remained unchanged (6 UPDs in 6 cases, 14%). Of note, in 6 patients (14%) the NPM1 mutation was no longer detectable at the time of relapse; SNP analysis showed completely distinct CNAs/UPDs in 4 of these patients; 3 of these 4 cases had a small gain at 11q23 corresponding to MLL partial tandem duplications as confirmed by PCR. These findings suggest that these 4 cases were therapy-related AMLs (t-AML) rather than relapsed AML. The median interval from diagnosis to relapse/tAML in these 4 cases was 65 months compared with 9 months for the relapsed cases still having the NPM1 mutation. In the two remaining cases, genetic alterations were neither present at diagnosis nor at relapse. Analysis of other gene mutations (eg, IDH1 and 2, DNMT3A, ASXL1, p53) is currently under way to further elucidate the clonal origin of these cases. Of the 36 NPM1mut positive relapse samples, 15 maintained a “normal karyotype”, and 2 showed the CNAs already present at diagnosis; 19 relapse samples (53%) displayed clonal evolution with acquiring new (n=15) and/or loosing single aberrations (n=4): Acquired recurrent alterations comprised deletions of tumor suppressor genes [ETV6 (n=2), TP53 (n=2), NF1 (n=2), WT1 (n=2)], most of which are uncommon in de novo NPM1mut AML. All 6 UPDs detected in relapse samples affected 13q, of which 3 were already present at diagnosis. One patient with initial heterozygous FLT3-ITD mutation developed a homozygous state by acquiring UPD13q at relapse. Two cases with wild-type FLT3 at diagnosis acquired UPD13q at relapse. Of note, one UPD13q was not present in the corresponding relapse sample anymore. In conclusion, almost half (45%) of NPM1mut AML showed evolution to a more aberrant karyotype at relapse, including acquisition of high-risk genetic changes that may account for the adverse prognosis of relapsed patients. Conversely, other alterations such as UPD13q or del(9q) detected at diagnosis were not always present in relapse samples, implying that relapse had evolved from a more ancestral clone. In addition, our data suggest that in a proportion of cases t-AML rather than relapse had developed. Further analysis, such as gene mutation studies of paired diagnosis/ relapse samples, will provide more detailed information on clonal evolution events in the pathogenesis of NPM1mut AML. Disclosures: No relevant conflicts of interest to declare.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
    URL: Article
    DOI: 10.1182/blood.V118.21.237.237
    RVK:
    XA 33000
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2011
    detail.hit.zdb_id: 1468538-3
    detail.hit.zdb_id: 80069-7
    Library Location Call Number Volume/Issue/Year Availability
    BibTip Others were also interested in ...
    Online Resource
    Open Access Request
    Availability (electronic / print)
  • 5
    Online Resource
    Online Resource
    The Genotype NPM1mut/FLT3-ITDneg Is a Highly Significant Predictive Factor for Response to Therapy with All-Trans Retinoic Acid in Acute Myeloid Leukemia - Results from AMLSG Trial AML HD98B.
    American Society of Hematology ; 2007
    In:  Blood Vol. 110, No. 11 ( 2007-11-16), p. 297-297
    Details
    In: Blood, American Society of Hematology, Vol. 110, No. 11 ( 2007-11-16), p. 297-297
    Abstract: Background: In a previous randomized trial (AML HD98B) of the AMLSG in elderly ( 〉 60 yrs) patients with AML (excluding APL), we could demonstrate that all-trans retinoic acid (ATRA) given as adjunct to intensive chemotherapy significantly improved complete remission (CR) rate and overall survival (OS). Our hypothesis for this study was that this beneficial effect of ATRA may be confined to a specific genotypic subset of AML. Aims: To evaluate the impact of ATRA on clinical outcome in cytogenetic and molecular genetic subsets of AML. Methods: Between 1998 and 2004, a total of 372 patients were enrolled. 242 patients were randomized for ATRA as adjunct to intensive induction (idarubicin, cytarabine, etoposide) and first consolidation therapy (intermediate-dose cytarabine) (Schlenk et al., Leukemia 2004), followed by a second randomization between further intensive consolidation versus a one-year oral maintenance therapy (Schlenk et al., Leukemia 2006). After an interim analysis in 2003, first randomization was stopped; the following 130 patients received chemotherapy without ATRA. Data from conventional cytogenetics and from fluorescence in-situ hybridization were previously reported (Fröhling et al., Blood 2006). All available leukemia specimens were analyzed for mutations in the genes encoding NPM1, CEBPA, and FLT3. Results: Median age of the 372 patients was 67 years (range: 61 to 83 yrs); median follow-up time was 68 months. 67% of the patients had de novo AML, 33% had secondary AML. Incidences of mutations were as follows (no. of specimens analyzed): NPM1 mutation, 25% (n=242); FLT3 internal tandem duplication (ITD), 18% (n=263); FLT3 tyrosine kinase domain mutation, 5% (n=244); CEBPA mutation, 8% (CEBPA analyzed only in normal karyotype samples; n=109). Logistic regression analysis performed on all patients identified three significant variables for achievement of CR: the genotype NPM1mut (OR 2.6; 95%-CI, 1.2–5.5), non-adverse karyotype subsuming core-binding factor and cytogenetically normal AML (OR 2.7; 95%-CI, 1.4–4.9); and age (diff. of 10 years, OR 0.58; 95%-CI, 0.3–1.0). Cox proportional hazard model for OS was performed on patients who were up-front randomized for ATRA. This model revealed a significant interaction between ATRA and the NPM1mut/FLT3-ITDneg genotype, confining the beneficial effect of ATRA to patients in that subgroup (HR, 0.29; 95%-CI, 0.10–0.87). Additional variables were log(LDH) (HR, 2.6; 95%-CI, 1.4 – 4.6), age (HR, 1.6; 95%-CI, 1.2– 2.2) and non-adverse karyotype (HR, 0.7; 95%-CI, 0.5–1.0). Univariable analysis revealed a survival after 5 years in patients with the genotype NPM1mut/FLT3-ITDneg of 57% (95%-CI, 28%–78%) in the ATRA-arm (n=16) compared to only 6% (95%-CI, 0%–25%) in the standard-arm (n=14) (p=0.002). In contrast, there was no difference in survival in all other patients with a survival of 2% (95%-CI, 0%–7%) in both arms (p=0.23). Conclusions: The genotype NPM1mut/FLT3-ITDneg emerges as highly significant predictive factor for response to ATRA in elderly patients with AML. This finding is validated prospectively in the ongoing AMLSG 07–04 study randomizing for ATRA in younger adults (ClinicalTrials.gov Identifier: NCT00151242).
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
    URL: Article
    DOI: 10.1182/blood.V110.11.297.297
    RVK:
    XA 33000
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2007
    detail.hit.zdb_id: 1468538-3
    detail.hit.zdb_id: 80069-7
    Library Location Call Number Volume/Issue/Year Availability
    BibTip Others were also interested in ...
    Online Resource
    Open Access Request
    Availability (electronic / print)
  • 6
    Online Resource
    Online Resource
    All-Trans Retinoic Acid Improves Outcome in Younger Adult Patients with Nucleophosmin-1 Mutated Acute Myeloid Leukemia – Results of the AMLSG 07-04 Randomized Treatment Trial
    American Society of Hematology ; 2011
    In:  Blood Vol. 118, No. 21 ( 2011-11-18), p. 80-80
    Details
    In: Blood, American Society of Hematology, Vol. 118, No. 21 ( 2011-11-18), p. 80-80
    Abstract: Abstract 80 Background: Mutations in the nucleophosmin-1 gene (NPM1) are the most common genetic abnormalities in acute myeloid leukemia (AML) and define a provisional AML entity in the current WHO classification. In a retrospective biomarker study within a randomized trial of older patients with AML, we demonstrated that patients with mutated NPM1 and absence of a FLT3 internal tandem duplication (ITD) benefit from all-trans retinoic acid (ATRA) as adjunct to conventional chemotherapy (Schlenk et al. Haematologica 2009;94:54–69). Aims: To evaluate the impact of ATRA in combination with conventional chemotherapy on outcome, and to assess the NPM1 mutational status as predictive marker for response to this therapy in younger adult patients with AML entered in the prospective randomized controlled treatment trial AMLSG 07-04 (ClinicalTrials.gov Identifier: NCT00151242). Methods: Patients (18 to 60 years of age) were accrued between August 2004 and August 2009. They were randomized up-front for open-label treatment with ATRA. Induction therapy consisted of two cycles of ICE (idarubicin 12mg/m2, day 1,3,5 [in induction II reduced to d 1, 3]; cytarabine 100mg/m2 continuous i.v., day 1 to 7; etoposide 100mg/m2, day 1–3). For consolidation therapy, patients with high-risk AML, defined either by high-risk cytogenetics or induction failure, were assigned to receive allogeneic hematopoietic stem cell transplantation (HSCT) from a matched related (MRD) or unrelated donor (MUD). Starting from November 2006, AML with FLT3-ITD was also categorized as high-risk. All other patients were assigned to 3 cycles of high-dose cytarabine (HiDAC; 18g/m2 per cycle). In all but patients with core-binding-factor AML an allogeneic HSCT was intended when a MRD was available. During induction cycles, ATRA was given in a dosage of 45mg/m2 from day 6 to 8, and 15mg/m2 from day 9 to 21; and during HiDAC cycles in a dosage of 15mg/m2 from day 6 to 28. The primary end points of the study were event-free survival (EFS) and rate of complete remission (CR) after induction therapy; secondary end points were, relapse-free (RFS) and overall survival (OS). For survival analyses, patients receiving an allogeneic HSCT in first CR were censored at the date of transplantation. Forty patients were treated either with or without ATRA despite being randomized in the opposite treatment arm; predictive marker analyses were performed on a per protocol basis excluding those patients. Results: A total of 1112 patients were randomized, 562 (per protocol 542) in the standard arm, and 550 (per protocol 530) in the investigational arm with ATRA. Median follow-up was 3.3 years. NPM1 mutational status was assessed in 1018 patients (92%) and a mutation was identified in 289 (28%) patients. Pretreatment patient characteristics at diagnosis were well balanced between the standard and the ATRA-arm of the study, except for higher white blood counts (WBC) in the standard arm (median, 16.1/nl vs. 8.9/nl, p=0.001). The CR-rate was significantly increased in NPM1-mutated AML by ATRA (OR, 2.20; p=0.05), independent of the FLT3-ITD status (OR, 0.66; p=0.33); there was no effect of ATRA in NPM1-wild-type AML (OR, 1.00; p=0.99). Multivariable analyses on EFS revealed a significant risk reduction in NPM1-mutated AML by ATRA (hazard ratio [HR], 0.65; p=0.02), whereas there was no effect of ATRA in NPM1-wild-type AML (HR, 0.99; p=0.95). Other significant factors in NPM1-mutated AML were IDH1R132 mutation (HR, 1.72; p=0.04), IDH2R140 mutation (HR,1.73; p=0.03), FLT3-ITD (HR, 1.55; p=0.04), log-transformed WBC (HR, 1.47; p=0.03), and in NPM1-wild-type AML IDH2R172 mutation (HR,1.82; p=0.03), FLT3-ITD (HR, 1.56; p=0.002), logarithm of WBC (HR, 1.20; p=0.02), male gender (HR, 1.34; p=0.003), cytogenetic risk (p 〈 0.001; HR (high-risk vs intermediate risk), 2.18; HR (low-risk vs intermediate risk) 0.31). ATRA had no influence on the cumulative incidence of relapse. OS of patients treated with ATRA (n=549) was significantly better (p=0.02) compared with that of patients not treated with ATRA (n=562). Rates and severity of toxicities were similar in both treatment arms. Conclusions: ATRA in addition to conventional chemotherapy significantly improved response to induction therapy and EFS in NPM1 mutated-AML, as well as OS in the whole cohort of younger adult patients with AML. NPM1 mutation was confirmed as a predictive factor for response to this combination therapy. Disclosures: Schlenk: Roche GmbH: Research Funding; Amgen GmbH: Research Funding; Pfizer GmbH: Research Funding. Krauter:Novartis: Consultancy, Honoraria. Kuendgen:Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees. Fiedler:Pfizer: Research Funding.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
    URL: Article
    DOI: 10.1182/blood.V118.21.80.80
    RVK:
    XA 33000
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2011
    detail.hit.zdb_id: 1468538-3
    detail.hit.zdb_id: 80069-7
    Library Location Call Number Volume/Issue/Year Availability
    BibTip Others were also interested in ...
    Online Resource
    Open Access Request
    Availability (electronic / print)
  • 7
    Online Resource
    Online Resource
    A Phase I/II Study Combining Sunitinib with Standard Ara-C/Daunorubicin Chemotherapy In Patients 60 Years or Older with FLT3 Mutated AML
    American Society of Hematology ; 2010
    In:  Blood Vol. 116, No. 21 ( 2010-11-19), p. 3285-3285
    Details
    In: Blood, American Society of Hematology, Vol. 116, No. 21 ( 2010-11-19), p. 3285-3285
    Abstract: Abstract 3285 Acute myeloid leukemia (AML) with mutated FLT3 in patients over the age of 60 years is associated with a dismal prognosis despite intensive chemotherapeutic approaches. Analysis of the AMLSG database revealed that for this patient group the CR rate was below 50% and the 5-year event-free (EFS) and overall survival (OS) was less than 5%. Sunitinib is a potent FLT3 inhibitor with a cellular IC50 value of 0.05μM for mutated FLT3 vs. 0.25μM for wild-type (wt) FLT3 and has already shown activity as single agent treatment in refractory AML patients. In the current phase–I study two schedules of sunitinib were evaluated in conjunction with standard chemotherapy: Either 25 mg daily continuously during the chemotherapy treatment phase (dose level 1) or 25 mg sunitinib days 1–7 during each chemotherapy cycle followed by a break until recovery of blood counts (dose level -1). After consolidation therapy all patients received sunitinib 25mg daily continuously in both groups. Induction chemotherapy consisted of Ara-C 100 mg/m2 by CI days 1–7 and daunorubicin 60 mg/m2 days 1–3 and consolidation therapy of Ara-C 1g/m2 day 1,3,5 for 3 cycles. Dose limiting toxicity (DLT) was defined as time to recovery of blood counts of not later than 35 days after start of treatment and any grade 3 toxicity probably related to sunitinib. Occurrence of a DLT should be observed in no more than 1 of 6 evaluable patients in each dose group according to the modified Fibonacci design. Twelve patients have been included up to now (2 male and 10 female). Median age was 71 years (range 60–78). Determination of FLT3 status was performed by a central lab within 48 hours. Eight patients had FLT3-ITD and 4 patients FLT3-TKD mutation. Four patients had an additional NPM1 mutation. Eight patients exhibited a normal karyotype and 4 patients additional unfavourable chromosomal aberrations. In the continuous dosing group 6 patients were entered. Two DLTs in three evaluable patients were noted, 1 patient had prolonged aplasia ( 〉 day 35) and the second a hand-leg syndrome. This schedule was therefore abandoned. In the intermittent dosing cohort one DLT (prolonged aplasia) was seen in 4 evaluable patients. Main toxicities of all 12 patients included grade 4 neutropenia (100%) and thrombocytopenia (100%), grade 3 for anemia (33%), febrile neutropenia (58%), infections (42%), diarrhea/colitis (50%), bleeding (25%), hypertension (16%), tachyarrhythmia absoluta (16%), syncope (16%) and mucositis (8%). Three patients died during induction or consolidation therapy due to infectious complications, 2 in the continuous and one in the intermittent dosing group. Ten patients are evaluable for response. Seven patients achieved a CR/CRi, one patient had a PR and two patients had refractory disease. Three patients with FLT3-TKD mutation obtained a CR and the forth a PR. In conclusion, addition of sunitinib 25mg (days 1–7) in parallel to induction and consolidation therapy is feasible. Side effects consist mainly of hematotoxicity and infectious complications and are expected in an elderly patient group receiving intensive chemotherapy. No cases of cardiac insufficiency due to sunitinib in conjunction with the administration of anthracyclines were recorded. The response rate of 70% CR/CRi is encouraging. Additional patients will be entered at this schedule to further define tolerability and efficacy. Disclosures: Fiedler: Pfizer: Consultancy, Research Funding. Salih:Pfizer: Research Funding. Bokemeyer:Pfizer: Research Funding, Speakers Bureau. Döhner:Pfizer: Research Funding. Schlenk:Pfizer: Research Funding.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
    URL: Article
    DOI: 10.1182/blood.V116.21.3285.3285
    RVK:
    XA 33000
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2010
    detail.hit.zdb_id: 1468538-3
    detail.hit.zdb_id: 80069-7
    Library Location Call Number Volume/Issue/Year Availability
    BibTip Others were also interested in ...
    Online Resource
    Open Access Request
    Availability (electronic / print)
  • 8
    Online Resource
    Online Resource
    Array-CGH and Gene Expression Profiling Based Molecular Characterization of Myeloid Leukemia Cell Lines.
    American Society of Hematology ; 2005
    In:  Blood Vol. 106, No. 11 ( 2005-11-16), p. 4397-4397
    Details
    In: Blood, American Society of Hematology, Vol. 106, No. 11 ( 2005-11-16), p. 4397-4397
    Abstract: Myeloid leukemias are characterized by cytogenetic and molecular-genetic aberrations resulting in altered gene expression. Nevertheless, so far still little is known regarding the underlying mechanisms of leukemogenesis. To model and investigate the different aspects of leukemia pathogenesis a widely accepted approach is to use immortalized leukemia cell lines. While these provide powerful tools for the investigation of gene function, the dissection of signal transduction pathways and the analysis of drug effects, to our knowledge only few studies have addressed the question whether hematopoietic cell lines represent reliable model systems. In order to improve the molecular characterization of these model systems we therefore analyzed 18 myeloid leukemia cell lines using DNA microarray technology. To determine the secondary aberrations acquired in addition to their characteristic primary cytogenetic aberrations during numerous passages in vitro, we first analyzed all cell lines by array-CGH (comparative genomic hybridization). Using a BAC/PAC platform with an average resolution of ~ 1.5 Mb across the entire genome we identified recurrent losses and gains, as well as high level amplifications like e.g. an amplification in 4q12 (Kasumi1) and in 8q24 (HL60). The parallel analysis of gene expression using a whole genome cDNA microarray platform helped to further delineate potential candidate genes in the affected regions (e.g. overexpression of KIT in the 4q12 and MYC in the 8q24 amplicon). Furthermore, unsupervised hierarchical cluster analysis revealed distinct gene signatures pointing towards dysregulated transcriptional networks. Comparison of our findings with acute myeloid leukemia patient data (Bullinger et al. 2004) showed the signatures underlying characteristic cytogenetic aberrations like e.g. t(15;17) were conserved in cell lines. Interestingly, these signatures were also quite robust as they displayed a highly significant correlation with published cell line data profiled on a different DNA microarray platform in a different laboratory. Thus, our analyses demonstrate that cell lines exhibit conserved signatures correlating with the primary balanced cytogenetic aberrations, and that most cell lines even when grown and analyzed under different conditions provide highly robust signatures. Therefore, our refined molecular characterization of myeloid cell lines supports the utility of cell lines as powerful model systems and provides additional insights into the molecular mechanisms of leukemogenesis.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
    URL: Article
    DOI: 10.1182/blood.V106.11.4397.4397
    RVK:
    XA 33000
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2005
    detail.hit.zdb_id: 1468538-3
    detail.hit.zdb_id: 80069-7
    Library Location Call Number Volume/Issue/Year Availability
    BibTip Others were also interested in ...
    Online Resource
    Open Access Request
    Availability (electronic / print)
  • 9
    Online Resource
    Online Resource
    Expression of tumor-associated antigens in acute myeloid leukemia: implications for specific immunotherapeutic approaches
    American Society of Hematology ; 2006
    In:  Blood Vol. 108, No. 13 ( 2006-12-15), p. 4109-4117
    Details
    In: Blood, American Society of Hematology, Vol. 108, No. 13 ( 2006-12-15), p. 4109-4117
    Abstract: The expression of tumor-associated antigens (TAAs) might play a critical role in the control of minimal residual disease (MRD) in acute myeloid leukemia (AML), and therefore might be associated with clinical outcome in AML. In a DNA microarray analysis of 116 AML samples, we found a significant correlation between high mRNA levels of G250/CA9 and longer overall survival (P = .022), a similar trend with high mRNA levels of PRAME (P = .103), and a hint for RHAMM/HMMR. In contrast, for other TAAs like WT1, TERT, PRTN3, BCL2, and LAMR1, we found no correlation with clinical outcome. High expression of at least 1 of the 3 TAAs, RHAMM/HMMR, PRAME, or G250/CA9, provided the strongest favorable prognostic effect (P = .005). Specific T-cell responses were detected in 8 (47%) of 17 patients with AML in complete remission for RHAMM/HMMR-R3 peptide, in 7 (70%) of 10 for PRAME-P3 peptide, and in 6 (60%) of 10 for newly characterized G250/CA9-G2 peptide, a significant increased immune response compared with patients with AML patients who had refractory disease (P 〈 .001). Furthermore, we could demonstrate specific lysis of T2 cells presenting these epitope peptides. In conclusion, expression of the TAAs RHAMM/HMMR, PRAME, and G250/CA9 can induce strong antileukemic immune responses, possibly enabling MRD control. Thus, these TAAs represent interesting targets for polyvalent immunotherapeutic approaches in AML.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
    URL: Article
    DOI: 10.1182/blood-2006-01-023127
    RVK:
    XA 33000
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2006
    detail.hit.zdb_id: 1468538-3
    detail.hit.zdb_id: 80069-7
    Library Location Call Number Volume/Issue/Year Availability
    BibTip Others were also interested in ...
    Online Resource
    Open Access Request
    Availability (electronic / print)
  • 10
    Online Resource
    Online Resource
    Prognosis of Adult Patients ≤60 Years with AML and Aberrations of Chromosome 11q23: Pooled Data Analysis of the German AML-Intergroup.
    American Society of Hematology ; 2006
    In:  Blood Vol. 108, No. 11 ( 2006-11-16), p. 16-16
    Details
    In: Blood, American Society of Hematology, Vol. 108, No. 11 ( 2006-11-16), p. 16-16
    Abstract: Aberrations of the MLL gene on chromosome 11q23 occur in about 5–10% of adult patients with acute myeloid leukemia (AML). Most frequently, the MLL gene is fused to the genes AF9 on chromosome 9 or AF6 on chromosome 6 resulting in the translocation t(9;11) and t(6;11), respectively. The remaining patients with aberrations of chromosome 11q23 constitute a heterogeneous group with numerous fusion partners. This heterogeneity hampers risk stratification of the patients. Accordingly, AML patients with 11q23 aberrations have varyingly been stratified as intermediate or high risk patients by different study groups. To analyze the prognostic impact of different 11q23 aberrations in AML patients up to 60 years, a pooled data analysis of 6 consecutive studies for the treatment of adult AML patients was performed. All patients received double induction treatment with araC and an anthracycline followed by an intensive consolidation with either a high dose araC based chemotherapy regimen or an autologous or allogeneic stem cell transplantation. In total, 150 patients with 11q23 aberrations were identified by cytogenetics and/or molecular techniques. 53 patients (35%) had a t(9;11), 27 patients (18%) a t(6;11), 10 patients (7%) a t(11;19), 8 patients (5%) a t(11;17) and 6 patients (4%) a t(10;11). 46 patients (31%) had other fusion partners or deletions of 11q23. Median age of all patients was 39 years (range 16–60). Overall complete remission rate was 73% with no significant difference between the groups (79% for t(9;11), 74% for t(6;11) and 66% for others). Altogether, 9% of the patients had treatment failure and 7% died during induction. Relapse-free survival (RFS) and overall survival (OS) at 5 years for the entire group was 24% and 26%, respectively. RFS and OS of the t(6;11) group was 6% and 13% and thus was significantly inferior to patients with t(9;11) (RFS: 48%, OS: 31%) and patients with other 11q23 translocations (RFS: 20%, OS: 18%) or 11q23 deletions (RFS: 38%, OS: 33%). Within the t(9;11) group there was no difference in RFS or OS between patients who had a t(9;11) as a sole aberration (n=36) and patients with additional aberrations (n=17) and between patients with de novo or secondary AML. Moreover, in t(9;11) no difference in RFS was observed between treatment with high dose araC, autologous or allogeneic stem cell transplantation as late consolidation. Regarding other translocations of 11q23, there was no difference in RFS and OS between patients with t(11;17), t(11;19), t(10;11) and patients with various other fusion partners. In conclusion, these data demonstrate that the prognosis of patients with 11q23 is heterogeneous. Patients with t(9;11) who enter CR have a relatively good outcome independent of the consolidation therapy used. In contrast, the prognosis of patients with t(6;11) is extremely poor. Therefore, patients with t(6;11) should be regarded as high risk and alternative treatment strategies for this subgroup are required.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
    URL: Article
    DOI: 10.1182/blood.V108.11.16.16
    RVK:
    XA 33000
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2006
    detail.hit.zdb_id: 1468538-3
    detail.hit.zdb_id: 80069-7
    Library Location Call Number Volume/Issue/Year Availability
    BibTip Others were also interested in ...
    Online Resource
    Open Access Request
    Availability (electronic / print)
Nothing or not found what you are looking for? Please check your search query or use the Interlibrary Loan Search.
Close ⊗
This website uses cookies and the analysis tool Matomo. Further information can be found on the KOBV privacy pages