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  • 1
    Online Resource
    Online Resource
    Azacitidine Prolongs Survival and Time to AML Transformation in High-Risk Myelodysplastic Syndrome (MDS) Patients ≥ 65 Years of Age.
    American Society of Hematology ; 2005
    In:  Blood Vol. 106, No. 11 ( 2005-11-16), p. 2524-2524
    Details
    In: Blood, American Society of Hematology, Vol. 106, No. 11 ( 2005-11-16), p. 2524-2524
    Abstract: The prognosis for patients with refractory anemia with excess blasts (RAEB) or RAEB in transformation (RAEB-T) ≥ 65 years of age has been poor. These high-risk patients are often not eligible for intensive induction/transplantation regimens or combination chemotherapies, leaving few treatment options besides supportive or palliative care. In the publication of the CALGB trial by Silverman et al (JCO2002;20:2429), no age- and/or risk- related subgroup analyses for azacitidine (Vidaza®) were presented. To assess the treatment effect of azacitidine versus supportive care on survival and time to AML transformation in a homogeneous sample of high-risk patients with MDS, we performed a subgroup analysis on the 191 patients included in the CALGB trial. All patients with a baseline diagnosis of RAEB or RAEB-T who were ≥ 65 years of age were included in the comparative analysis, using intent-to-treat (ITT) principles based on randomization to azacitidine or supportive care. Efficacy was analyzed using three survival endpoints: overall survival, time to death or AML transformation, and time to AML transformation. In all, 31 azacitidine patients and 37 supportive care patients met the criteria for this high-risk subgroup analysis. No significant differences in demographics or disease characteristics between the two groups were observed. For all three survival analyses, a statistically significant difference was observed for patients in the azacitidine group compared with those in the supportive care group. (Table) Median time to transformation to AML, in particular, was prolonged for 24 months in azacitidine patients compared with patients in the supportive care group. A sensitivity analysis of the overall survival results was conducted by performing 10 additional subgroup analyses based on ages ≥ 60 through ≥ 70 years in increments of one year with all overall survival results remaining significant (p & lt; 0.05, except for 2 subgroup analyses based on ages ≥ 60 and ≥ 66 where both p-values were 0.051). The sensitivity results demonstrated robust patient benefit in the subgroup ≥ 65 years of age. The most common adverse event observed with azacitidine was myelosuppression, which decreased in frequency as therapy continued. Azacitidine provided clear treatment effect and patient benefit to this difficult-to-treat, high-risk group of RAEB and RAEB-T patients ≥ 65 years of age by significantly prolonging overall survival and time to AML transformation. Time of Even Analysis
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
    URL: Article
    DOI: 10.1182/blood.V106.11.2524.2524
    RVK:
    XA 33000
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2005
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  • 2
    Online Resource
    Online Resource
    A New Validated Myelodysplastic Syndrome (MDS) Prognostic Model for Use When Cytogenetics Are Unavailable.
    American Society of Hematology ; 2005
    In:  Blood Vol. 106, No. 11 ( 2005-11-16), p. 2527-2527
    Details
    In: Blood, American Society of Hematology, Vol. 106, No. 11 ( 2005-11-16), p. 2527-2527
    Abstract: The International Prognostic Scoring System (IPSS) provides relatively homogeneous prognoses for untreated patients with MDS in terms of survival and transformation to AML. In many cases, cytogenetic results are not available and prevent use of the IPSS. Our objective was to create and validate a dynamic prognostic model that would allow identification of high-risk MDS patients when cytogenetics are unavailable. We followed the methodological approach used by Greenberg et al (Blood1997;89:2079) and used our new model to re-analyze the FAB-based CALGB data (JCO2002;20:2429). The variables used in the prognostic model were identified as statistically significant independent variables by Greenberg and included % marrow blasts, number of cytopenias, the multivariate risk factors (age and gender), the univariate risk factor (FAB classification), and time since diagnosis because CALGB data were collected at randomization and IPSS at diagnosis. Both blasts and FAB were included in our model since there is considerable outcome heterogeneity within FAB subtypes. Predicted survival for each of the 191 CALGB patients was determined from a stratified proportional hazards regression model fitted to patients’ survival times. The 191 patients were stratified using their randomized treatment assignment (azacitidine or supportive care). All patients with predicted survival ≤ 1.2 years (median survival of IPSS INT-2 risk group) comprised a high-risk subgroup; those with predicted survival & gt; 1.2 years formed the low-risk subgroup. To assess its predictive accuracy, our model was validated by demonstrating significant segregation of risk groups in an independent dataset of 2,318 untreated primary MDS patients from the MDS Registry, Düsseldorf. In all, 964 (42%) registry cases and 72 (38%) CALGB cases fit into the high-risk subgroup. Log-rank analyses of overall survival and time to AML transformation demonstrated clear separation of the low- and high-risk subgroups (both p-values & lt; 0.0001). Figure 1: Validation of Pregnostic Model with MDS Registry, Düsselderf, Overall Survival Figure 1:. Validation of Pregnostic Model with MDS Registry, Düsselderf, Overall Survival There was fair agreement between the low and high subgroups from our model with the low (low+INT-1) and high (INT-2+high) subgroups from the IPSS, Cohen’s Kappa = 0.30 (95% CI: 0.21 to 0.39) in 547 patients from the MDS Registry, Düsseldorf. A sensitivity analysis of the CALGB efficacy results was conducted by varying the ≤ 1.2 years survival criterion from our model. High-risk subgroups, defined by using predicted survival of 1.0 to 2.8 years in increments of 0.1 years, were investigated. In general, the sensitivity analyses revealed that clinically meaningful benefit was statistically demonstrated in the smaller subgroups but lost significance as the subgroups approached the full data set. The smaller subgroups were more homogeneous in predicted survival. In conclusion, our model is a valid prognostic model that bridges reasonably well to the IPSS high-risk group and identified a high-risk homogeneous subgroup of CALGB patients to further investigate the effects of azacitidine.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
    URL: Article
    DOI: 10.1182/blood.V106.11.2527.2527
    RVK:
    XA 33000
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2005
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  • 3
    Online Resource
    Online Resource
    Response Rates Using International Working Group (IWG) Criteria in Patients with Myelodysplastic Syndromes (MDS) Treated with Azacitidine.
    American Society of Hematology ; 2005
    In:  Blood Vol. 106, No. 11 ( 2005-11-16), p. 2526-2526
    Details
    In: Blood, American Society of Hematology, Vol. 106, No. 11 ( 2005-11-16), p. 2526-2526
    Abstract: The CALGB conducted a series of clinical trials with azacitidine (Vidaza®) administered subcutaneously or intravenously in patients with MDS using the FAB classification (JCO2002;20:2429). Since the publication of these CALGB studies (8421, 8921, 9221), new response criteria for evaluating new treatments for MDS have been published by the IWG (Blood2000;96:3671). Two general differences between the CALGB and IWG response criteria are the required duration of improvement (CALGB: ≥4 weeks; IWG: ≥8 weeks) and peripheral blood values (CALGB: different criteria for hemoglobin targets for males and females; IWG: same criteria for males and females). The results reported here are based on re-collected data from patients described in the published report. After applying the IWG response criteria, the overall response rate (CR+PR+HI) in the azacitidine groups were similar across studies 8421, 8921, and 9221: 44% (21/48), 40% (28/70), and 48% (47/99), respectively. Best Response using IWG Response Criteria for MDS in Studies 8421, 8921, and 9221 Median duration of any response (CR, PR or HI) in the 114 azacitidine-treated responders was 366 days (range: 56 to 4641+ days). The median duration of CR in the 32 azacitidine-treated responders was 379 days (range: 92 to 4412+ days). The median number of cycles from first treatment with azacitidine to any response (CR, PR or HI) was 3 cycles (range: 1 to 17 cycles). Although 75% of the responders achieved a response by cycle 4, the other 25% achieved a response as late as cycle 17. The majority (90%) of responders achieved a response by cycle 6. Best response was observed, on average, 2 cycles after the initial response. In summary, reanalysis of the response rates using IWG criteria demonstrate consistent results across three sequential studies and further validate the superiority of azacitidine over supportive care alone.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
    URL: Article
    DOI: 10.1182/blood.V106.11.2526.2526
    RVK:
    XA 33000
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2005
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    detail.hit.zdb_id: 80069-7
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  • 4
    Online Resource
    Online Resource
    Rates of Infection and Bleeding Are Not Increased in Patients with Myelodysplastic Syndromes (MDS) Treated with Azacitidine Compared with Supportive Care.
    American Society of Hematology ; 2005
    In:  Blood Vol. 106, No. 11 ( 2005-11-16), p. 2525-2525
    Details
    In: Blood, American Society of Hematology, Vol. 106, No. 11 ( 2005-11-16), p. 2525-2525
    Abstract: MDS are heterogeneous hematopoietic disorders characterized by dyspoiesis and cytopenias. Most patients with high-risk MDS die within 1 year from infection or hemorrhage usually attributable to bone marrow failure or progression to AML. In a phase 3, open-label, multicenter, randomized study comparing azacitidine (Vidaza®) plus supportive care (N=99) versus supportive care alone (N=91) in patients with MDS (JCO2002;20:2429), treatment with azacitidine was associated with worsening of pre-existing cytopenias in up to 78% (115/147) of patients with pre-existing cytopenias. The median time to first occurrence of any worsening cytopenia was 8 days (interquartile range: 6 to 15 days). All patients were treated with the same initial dose of azacitidine (75 mg/m2/day); no dose adjustments were made for pre-existing cytopenias despite the severity. We examined rates of infection and bleeding associated with azacitidine therapy in comparison with the rates seen with the underlying disease (supportive care). Our results are based on re-collected data from patients described in the published report; our analyses were conducted separately and independently. Total exposure for azacitidine was the cumulative time from the first dose to the end of study (30 days after last dose), and for supportive care was the cumulative time from randomization to withdrawal from study or day prior to crossover. The azacitidine group included all patients exposed to azacitidine (N=150), which included patients randomized to azacitidine (N=99) and patients after crossing over from supportive care (N=51). Similar to the rate of infections previously reported in patients with MDS (AJM1991; 90:338), infections occurred in patients in the supportive care group at nearly one per patient-year. However, infections occurred at an overall lower rate (patient-years) in the azacitidine group (0.64) compared with the supportive care group (0.95). (Table). Similarly, the overall rate (patient-years) of bleeding events was comparable between azacitidine (0.56) and supportive care (0.60). In particular, bleeding events in the gastrointestinal system occurred at a similar rate between the azacitidine group (0.26) and the supportive care group (0.25). This was also true for bleeding events in the central nervous system (azacitidine: 0.01, supportive care: 0.02). The rates of infection and bleeding were 3 to 4 times higher during cycles 1 and 2 in both treatment groups, reflecting the severity of the underlying disease at study entry. In summary, despite the potential to exacerbate pre-existing cytopenias early in therapy, treatment with azacitidine did not increase the rate of infection and bleeding above the rate due to the underlying disease. Infection Rates (Patient-Years of Exposure) in Protocol 9221
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
    URL: Article
    DOI: 10.1182/blood.V106.11.2525.2525
    RVK:
    XA 33000
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2005
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  • 5
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    Online Resource
    Response Rates in Patients with Acute Myeloid Leukemia (AML), Treated with Azacitidine, Using WHO and International Working Group (IWG) Criteria for Myelodysplastic Syndrome (MDS).
    American Society of Hematology ; 2005
    In:  Blood Vol. 106, No. 11 ( 2005-11-16), p. 1848-1848
    Details
    In: Blood, American Society of Hematology, Vol. 106, No. 11 ( 2005-11-16), p. 1848-1848
    Abstract: The CALGB conducted a series of clinical trials with azacitidine (Vidaza®) administered subcutaneously or intravenously in patients with MDS using the FAB classification (JCO2002;20:2429). Since completion of these CALGB studies (8421, 8921, 9221), a new classification system was developed by the WHO that distinguishes MDS from AML (blasts 〉 20%). Although studies with azacitidine in patients with AML had previously shown activity, the 75 mg/m2/day dose in the CALGB studies was lower than previously studied. Using the WHO system, the diagnosis for CALGB study patients was redefined and patients with AML were analyzed separately. Most of the 105 patients were previously considered refractory anemia with excess blasts in transformation (RAEB-T). Also, new treatment response criteria for MDS were published by the IWG (Blood2000; 96:3671). Using IWG response criteria, azacitidine patients with WHO AML in studies 8421, 8921, or 9221 had an overall response rate (CR+PR+HI) of 48% (12/25), 32% (9/28), and 37% (10/27), respectively. Best Response using IWG Response Criteria for WHO AML Patients in Studies 8421, 8921, and 9221 Median duration of any response (CR, PR or HI) in the 33 azacitidine-treated responders was 279 days (range: 61 to 724 days). The median duration of CR in the 8 azacitidine-treated responders was not achieved; however, the 25th percentile was 115 days (range: 92 to 274+ days). In Study 9221, the median duration of transfusion independence (defined as ≥56 days) in patients independent at baseline was significantly longer in the azacitidine group compared with supportive care for red blood cells (azacitidine [n=8]: 411 days vs. supportive care [n=9] : 133 days, p=0.02) and platelets (azacitidine [n=13]: 363 days vs. supportive care [n=18] : 125 days, p=0.004). In the azacitidine group, 22% (6/27) of patients had a hemoglobin improvement to 〉 11 g/dL that was maintained for ≥56 days compared with 8% (2/25) in the supportive care group (p=0.2). The proportions of patients with ANC 〉 1500/m3 and platelets 〉 100,000/mm3 lasting for ≥56 days were similar between the treatment arms. Azacitidine patients with WHO AML had a longer median survival (19.3 months) compared with the supportive care group (12.9 months) (p=0.2). Further studies investigating azacitidine in patients with AML with dysplasia are warranted.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
    URL: Article
    DOI: 10.1182/blood.V106.11.1848.1848
    RVK:
    XA 33000
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2005
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  • 6
    Online Resource
    Online Resource
    Analysis of Survival, AML Transformation, and Transfusion Independence in Patients with High-Risk Myelodysplastic Syndromes (MDS) Receiving Azacitidine Determined Using a Prognostic Model.
    American Society of Hematology ; 2005
    In:  Blood Vol. 106, No. 11 ( 2005-11-16), p. 2523-2523
    Details
    In: Blood, American Society of Hematology, Vol. 106, No. 11 ( 2005-11-16), p. 2523-2523
    Abstract: The International Prognostic Scoring System (IPSS) requires cytogenetic data to evaluate risk in MDS. Cytogenetic data were not available for all patients from the CALGB trial 9221 (Silverman et al, JCO2002; 20:2429). Therefore, we developed an alternative prognostic model that identified a homogeneous subgroup of high-risk MDS patients based on the following risk factors: percent marrow blasts, number of cytopenias, age, gender, FAB classification, and time since diagnosis (IPSS used data at time of diagnosis; CALGB 9221 used data at time of randomization). The model was validated using 2,318 patients from the MDS Registry, Düsseldorf. Using these baseline prognostic factors, we predicted survival for each of the 191 CALGB patients, identified a high-risk subgroup with a survival prognosis of ≤ 1.2 years (the IPSS INT-2 survival median), and compared azacitidine to supportive care. Patients were analyzed as randomized (azacitidine or supportive care) according to the intention-to-treat (ITT) principle. The two groups had similar demographic and disease characteristics. All 70 high-risk patients were followed until death. There was a statistically significant difference in overall survival curves between the azacitidine and supportive care groups (p=0.03). The one-year survival rate was 63% (95% CI: 47 to 78%) in the azacitidine group and 37% (95% CI: 19 to 54%) in the supportive care group (p=0.03; 26% difference with a 95% CI of 3 to 49%). The two-year survival rate was 35% (95% CI: 20 to 50%) in the azacitidine group and 13% (95% CI: 1 to 25%) in the supportive care group (p=0.03; 22% difference with a 95% CI of 3 to 41%). Similarly, statistically significant differences in time to AML transformation, and death or AML transformation, were observed. Transfusion independence was defined as free from transfusions for at least 2 months. Among patients who were RBC transfusion dependent at baseline, a significantly greater number of patients from the azacitidine group (11/25, 44%) compared with patients from the supportive care group (1/14, 7%) achieved transfusion independence (p=0.03; 37% difference with a 95% CI of 7 to 59%). Additionally, patients in the azacitidine group with baseline transfusion independence experienced significantly prolonged duration of RBC (p & lt;0.0001) and platelet (p=0.0002) transfusion independence compared with those in the supportive care group. Use of this prognostic model has identified a subgroup of high-risk MDS patients who significantly benefited from treatment with azacitidine. Time of Even Analysisa
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
    URL: Article
    DOI: 10.1182/blood.V106.11.2523.2523
    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
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  • 7
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    Quality of life among patients with Stage II and III breast carcinoma randomized to receive high-dose chemotherapy with autologous bone marrow support or intermediate-dose chemotherapy : Results from Cancer and Leukemia Group B 9066
    Wiley ; 2005
    In:  Cancer Vol. 104, No. 8 ( 2005-10-15), p. 1580-1589
    Details
    In: Cancer, Wiley, Vol. 104, No. 8 ( 2005-10-15), p. 1580-1589
    Type of Medium: Online Resource
    ISSN: 0008-543X , 1097-0142
    URL: Issue
    URL: Journal
    URL: Article
    DOI: 10.1002/cncr.v104:8
    DOI: 10.1002/(ISSN)1097-0142
    DOI: 10.1002/cncr.21363
    Language: English
    Publisher: Wiley
    Publication Date: 2005
    detail.hit.zdb_id: 1479932-7
    detail.hit.zdb_id: 2599218-1
    detail.hit.zdb_id: 2594979-2
    detail.hit.zdb_id: 1429-1
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  • 8
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    Online Resource
    Gefitinib in Patients with Malignant Mesothelioma: A Phase II Study by the Cancer and Leukemia Group B
    American Association for Cancer Research (AACR) ; 2005
    In:  Clinical Cancer Research Vol. 11, No. 6 ( 2005-03-15), p. 2300-2304
    Details
    In: Clinical Cancer Research, American Association for Cancer Research (AACR), Vol. 11, No. 6 ( 2005-03-15), p. 2300-2304
    Abstract: Purpose: The Cancer and Leukemia Group B conducted a phase II study of gefitinib, an inhibitor of the epidermal growth factor receptor (EGFR) tyrosine kinase, in patients with previously untreated malignant mesothelioma. Experimental Design: Eligible patients had unresectable pleural or peritoneal mesothelioma, measurable disease, no prior therapy, and performance status 0-1 by Cancer and Leukemia Group B criteria. Gefitinib (500 mg p.o.) was administered once a day for 21 days. Patients underwent restaging after every two cycles. Therapy was continued until disease progression or unacceptable toxicity. Results: The most common grade 3 toxicities were diarrhea (16%) and nausea (12%). Of 43 patients enrolled, 1 patient (2%) had a complete response, 1 patient (2%) had a partial response, 21 (49%) had stable disease lasting two to eight cycles, 15 (35%) had progressive disease, and 5 (12%) had early deaths. One-year survival was 32% [95% confidence interval (CI), 21-50%]. Median survival and failure-free survival were 6.8% (95% CI, 3.5-10.3) and 2.6 months (95% CI, 1.5-4.0), respectively. The 3-month failure-free survival was 40% (95% CI, 25-56%). EGFR expression score by immunohistochemistry done in 28 patients was categorized as low (EGFR 1+ or 2+) or high (EGFR 3+) expression: 97% had EGFR overexpression (2+ or 3+). The median and 3-month failure-free survival were 3.6 months and 40% for those patients with low EGFR expression compared with 8.1 and 40% for those with high EGFR expression. Conclusions: Although 97% of patients with mesothelioma had EGFR overexpression, gefitinib was not active in malignant mesothelioma. EGFR expression does not correlate with failure-free survival.
    Type of Medium: Online Resource
    ISSN: 1078-0432 , 1557-3265
    URL: Article
    DOI: 10.1158/1078-0432.CCR-04-1940
    RVK:
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    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2005
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