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  • American Society of Hematology  (5)
  • 2005-2009  (5)
  • 2006  (5)
  • 1
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    Online Resource
    Multicenter Phase II Trial of Patients with Refractory or Recurrent Multiple Myeloma with Oral Treatment of Thalidomide Combined with Oral Cyclophosphamide, Idarubicin and Dexamethasone.
    American Society of Hematology ; 2006
    In:  Blood Vol. 108, No. 11 ( 2006-11-16), p. 3559-3559
    Details
    In: Blood, American Society of Hematology, Vol. 108, No. 11 ( 2006-11-16), p. 3559-3559
    Abstract: Introduction and rationale: The aim of our study is to evaluate the role of thalidomide in combination with oral CID therapy in order to replace the central venous line necessary for continuous infusion of chemotherapy and to avoid hospitalization. Patients and methods: Patients with refractory or recurrent myeloma were included into this trial. Concerning inclusion criteria, 9 patients had progressive disease after standard chemotherapy, 12 no change after standard chemotherapy, 6 recurrent disease after standard therapy and 21 recurrence after high dose chemotherapy. At start of the treatment patients were in stages IIA (15 patients), IIB (1) and IIIA (34). Idarubicin was given in capsules at 8–10 mg/m2/day for days 1–4, 40 mg dexamethasone were given on days 1–4 and 15–18, cyclophosphamide at 200 mg/m2/d d1–4 and thalidomide 100mg daily with scheduled increase to 400mg. Treatment cycles were repeated every 28 days. 3–8 cycles were applied. Supportive therapy consisted of PEG-filgrastim, cotrimoxazol, dalteparin and ibandronate. In addition, patients were randomized between thalidomide and thalidomide / idarubicin maintenance treatment. Results: At this interim analysis, 64 patients have been entered into the ongoing trial; 8 patients had to be excluded. Of the 56 included patients, 50 patients have been documented so far and are evaluable for toxicity. In total, 182 cycles have been applied. Median cycle number was 3 (1–8). There was one death during treatment due to progressive myeloma at cycle 1. The median age was 62 years (interquartile range 57–67). The following toxicities were observed: FUO (2 patients), pneumonia (4), pulmonary embolism (1), exsiccosis after diarrhea (1), constipation (1), sepsis (1), severe nausea (2), syncope (1), collaps after bleeding (1) and mucositis grade 4 (1). Hematologic toxicity was reported in 34% of the patients, mainly in cycles 1 and 2. Concerning response to treatment 39 patients are evaluable so far. Of these 30 (77%) achieved a PR or MR according to EBMT criteria, 4 patients a stable disease and 2 patients a PD. Three patients were not evaluable and scorded as failures. Conclusions: T-CID is feasible and seems to be highly effective in relapsed or refractory myeloma patients. Toxicity seems to be acceptable and mainly hematologic and infectiologic. The remission rate of 77% is encouraging. The trial is still ongoing. At the meeting a follow-up of the trial will be presented. Further information can be obtained at www.myelom.net.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
    URL: Article
    DOI: 10.1182/blood.V108.11.3559.3559
    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
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  • 2
    Online Resource
    Online Resource
    Bcr-Abl reduces endoplasmic reticulum releasable calcium levels by a Bcl-2–independent mechanism and inhibits calcium-dependent apoptotic signaling
    American Society of Hematology ; 2006
    In:  Blood Vol. 107, No. 10 ( 2006-05-15), p. 4003-4010
    Details
    In: Blood, American Society of Hematology, Vol. 107, No. 10 ( 2006-05-15), p. 4003-4010
    Abstract: The Bcr-Abl oncoprotein plays a major role in the development and progression of chronic myeloid leukemia (CML). Several studies have suggested that the expression levels of Bcr-Abl are elevated at disease progression to blast crisis and that this plays a significant role in the achievement of drug resistance. We have established cell lines expressing low and high levels of Bcr-Abl to study the molecular mechanisms involved in disease progression and drug resistance. It is now known that the endoplasmic reticulum (ER) can play a major role in the regulation of apoptosis. We therefore investigated whether Bcr-Abl expression modulates ER homeostasis and interferes with ER-mediated apoptotic pathways to promote survival. Bcr-Abl–expressing cells exhibit a decreased amount of free releasable calcium in the ER as well as a weaker capacitative calcium entry response, relative to parental cells. This effect is independent of Bcl-2, which is a known modulator of ER calcium homeostasis. The reduction in ER releasable calcium results in inhibition of the ER/mitochondria-coupling process and mitochondrial calcium uptake. This study demonstrates a novel downstream consequence of Bcr-Abl signaling. The ability to negate calcium-dependent apoptotic signaling is likely to be a major prosurvival mechanism in Bcr-Abl–expressing cells.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
    URL: Article
    DOI: 10.1182/blood-2005-04-1523
    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
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  • 3
    Online Resource
    Online Resource
    Changes in the Hierarchy of Risk Factors with Older Age in De-Novo Acute Myeloid Leukemia (AML).
    American Society of Hematology ; 2006
    In:  Blood Vol. 108, No. 11 ( 2006-11-16), p. 1977-1977
    Details
    In: Blood, American Society of Hematology, Vol. 108, No. 11 ( 2006-11-16), p. 1977-1977
    Abstract: After recent reports addressed prognostic factors and outcome in older age AML (Burnett et al. Blood106:162a,2005; Wheatley et al. Blood106:199a,2005; Appelbaum et al. Blood107:3481–5,2006; Farag et al. Blood108:63–73,2006) we evaluated 764 patients of 60–85 (median 66) years reduced to those with de-novo AML, known karyotype, and identical consolidation-maintenance chemotherapy, who were part of the 1992 and 1999 multicenter randomized trials by the German AMLCG (Buchner et al. J Clin Oncol21:4496–504,2003;24:2480–9,2006). 521 patients were 60 - 〈 70 (median 64) and 243 patients were 70–85 (median 73) years of age. 64% and 50% patients respectively went into complete remission, 24% and 29% remained with persistent AML, 12% and 21% succumbed to early and hypoplastic death (p 〈 .001). The overall survival in the younger (60- 〈 70y) and older (70+) patients was at a median of 13 vs 6 months and 18% vs 8% survived at 5 years (p 〈 .001). Once in complete remission, the remission duration was 14 vs 12 months (median) and equally 18% at 5 years; the relapse-free survival is 13 vs 11 months (median) and 14% vs 13% at 5 years. While all patients were randomized up-front for 2 versions of induction either by TAD-HAM (HAM, high-dose araC 1g/m2x6 and mitox 10mg/m2x3) or by HAM-HAM, response and survival did not differ between the two arms in neither age group. In contrast to response and survival between the younger (60- 〈 70y) and older (70+y) age group corresponding differences in the risk profiles were missing. Thus, favorable/intermediate/unfavorable karyotypes accounted for 8% vs 4% / 67% vs 73% / and 25% vs 24% of patients (p=.073); WBC 〉 20.000/ccm was found in 40% vs 39% (p=.52); LDH 〉 700U/L was remarkably 26% vs 18% (p=.014), and the day 16 b.m. blasts ≥ 10% accounted for 41% and 41% of patients. Conclusion: Approximately 50% of patients 70 years of age or older benefit from standard or intensive chemotherapy by complete remission which continues after 1 year in about 50% of responders. The inferior overall survival in the patients of 70+ versus those of 60- 〈 70 years is mainly explained by more frequent early and hypoplastic death (21% vs 12%) (p=.0016) and death with persistent AML (26% vs 18%) (p=.0145); while death in remission (7% vs 6%), relapse rate (50% vs 53%) and death after relapse (21% vs 26%) did not show this trend. In contrast to the important differences in outcome, established risk factors such as cytogenetic groups, WBC, and early blast clearance show concordance between the two age groups. The even lower LDH may support assumptions of older age AML as a less proliferative disease (Appelbaum et al. Blood 107:3481–5,2006). Thus, the hierarchical risk profiles cannot predict the age related outcome beyond 60 years in patients with de-novo AML.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
    URL: Article
    DOI: 10.1182/blood.V108.11.1977.1977
    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
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  • 4
    Online Resource
    Online Resource
    Intensification of Induction by High-Dose AraC and Outcome in Older Patients with De-Novo Acute Myeloid Leukemia (AML) and Subsets.
    American Society of Hematology ; 2006
    In:  Blood Vol. 108, No. 11 ( 2006-11-16), p. 1978-1978
    Details
    In: Blood, American Society of Hematology, Vol. 108, No. 11 ( 2006-11-16), p. 1978-1978
    Abstract: As recently reported modifications, dose or duration of treatment had no impact on outcome of AML in older patients (Burnett et al. Blood 106: 162a, 2005). We therefore evaluated 764 patients 60 years of age or older and their various prognostic subgroups in the 1992 and 1999 mulitcenter randomized trials by the German AMLCG where patients received uniform postremission consolidation by one course of TAD (standard dose thioguanine, araC, daunorubicin) and maintenance by monthly 5 day courses of reduced TAD. For maximum homogeneity this analysis was restricted to de-novo AML and to patients with known karyotype. Before treatment started, patients were assigned to induction treatment by either TAD followed by HAM (HAM, high-dose araC 1g/m2x6 / mitoxantrone 10mg/m2x3), or to induction by two courses of HAM. The second induction course (HAM) was given to only patients with 5% or more residual bone marrow blasts. Therapy administered to the two randomized groups differed by a factor 2 in their araC dose. Despite this difference in treatment intensity patients in the two arms show similar response rate, overall survival (OS), ongoing CR, and relapse-free survival (see table). The same similarity in outcome as for de-novo AML overall is true for established prognostic subgroups as listed below. Conclusion: Intensification of induction therapy by high-dose araC has no effect on outcome in older age de-novo AML. Since potential influences other than the randomized treatment were minimized, present results do not support a risk adapted intensification strategy. TAD-HAM HAM-HAM P TAD-HAM HAM-HAM P OS 4y % OS 4y % CR 4y % CR 4y % Total 18 13 .28 22 22 .53 Favorable Karyotype 17 16 .48 41 33 .82 Intermediate Karyotype 24 18 .31 24 26 .38 Unfavorable Karyotype 4 - .81 - - .37 LDH ≤ 700U/L 21 13 .86 23 24 .47 LDH 〉 700U/L 12 10 .07 - 16 .27 WBC ≤ 20x103/ccm 21 11 .91 22 21 .81 WBC 〉 20x103/ccm 15 16 .08 22 26 .19 Day 16 Blasts 〈 10% 26 16 .87 23 22 .81 Day 16 Blasts ≥ 10% 14 8 .28 18 19 .26
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
    URL: Article
    DOI: 10.1182/blood.V108.11.1978.1978
    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
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  • 5
    Online Resource
    Online Resource
    NPM-1, but Not FLT3-ITD Mutations Predict Early Blast Cell Clearance and CR Rate in Patients with Normal Karyotype AML or High-Risk Myelodysplastic Syndrome (MDS).
    American Society of Hematology ; 2006
    In:  Blood Vol. 108, No. 11 ( 2006-11-16), p. 805-805
    Details
    In: Blood, American Society of Hematology, Vol. 108, No. 11 ( 2006-11-16), p. 805-805
    Abstract: Background: Mutations in the NPM1 gene represent the most frequent alterations in patients with AML and are associated with a favourable clinical outcome. Patients and Methods: We analyzed 803 patients that were treated in the AMLCG2000 study. Patients with de novo or secondary AML or high-risk myelodysplastic syndrome (MDS) were randomly assigned upfront for induction therapy containing one course with standard dose and one course with high-dose cytarabine, or two courses with high-dose cytarabine, and in the same step received postremission prolonged maintenance or busulfan/cyclophosphamide chemotherapy with autologous stem-cell transplantation. At diagnosis mutations in the NPM1 and FLT3 gene were analyzed by routine molecular techniques. Results: The median age of all patients was 60 years and the median observation time 23 months. Results of the mutations status of FLT3 (FLT3-ITD) and NPM1 were available in 761/803 (94,8 %) and 690/803 (85,9 %) patients, respectively. NPM1 and FLT3-ITD mutation were found in 352 (51,1%) and 199 (28,9%), respectively. On the basis of these two molecular markers, patients were grouped in 4 subgroups: 1. NPM1+/FLT3−, N=214 (31%), 2. NPM1+/FLT3+, N=138 (20%); 3. NPM1−/FLT3−, N=276 (40%); NPM1−/FLT3+ (9%). The CR-rates were significantly higher in NPM1+ (74,4%) than in NPM1− (55,9%) patients, but were unaffected by the FLT3-ITD status. Overall survival (OS), event-free survival (EFS) and relapse free survival (RFS) was significantly higher in NPM1 positive and FLT3-ITD negative patients. In a multivariate analysis age, WBC, the presence of the NPM1 mutation and de novo AML were independent prognostic factors for the CR-rate. The NPM1− and FLT3 mutation status, age and LDH were identified as independent prognostic factors for RFS. To further characterize the biological effects of NPM1 and FLT3 mutations, we analyzed the in vivo blast cell clearance measured by the residual bone marrow blast cells one week after the end of the first induction cycle (d+16 blasts). The percentage of patients with adequate blast cell reduction (residual bone marrow blast & lt;10%) was significantly higher in NPM1+ patients (87,3%) compared to NPM1− (65,7%) patients. The presence of a FLT3-ITD mutation had no effect on early blast cell clearance. Conclusions: The presence of a NPM1 mutation represents an independent positive prognostic factor for the CR-rate and RFS/OS. In contrast, FLT3-ITD mutations do not affect the CR-rate, but have a negative prognostic impact on RFS and OS. The higher sensitivity of NPM1-positive blasts towards the induction therapy point to a central role of NPM1 in the regulation of apoptotic cell death in AML.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
    URL: Article
    DOI: 10.1182/blood.V108.11.805.805
    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
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