Chemotherapy for elderly patients with acute myeloid leukemia (AML) results in a median overall survival (OS) of ≤1 year. Elderly patients often present with cardiac comorbidity. Gemtuzumab ...ozogamicin (GO) is active in elderly (≥60 years) patients with relapsed AML with low cardiac toxicity.
This randomized phase II study compared a standard combination of ara-C and daunorubicin (DNR; 7+3) versus ara-C plus gemtuzumab ozogamicin (7+GO) as the first course of induction therapy. Primary objectives were comparison of blast clearance on day 16, event-free survival (EFS), and remission duration. OS, complete remission (CR), and tolerability were secondary objectives.
One hundred and nineteen patients with de novo AML, treatment-related AML, AML with a history of myelodysplastic syndrome (MDS), or high-risk MDS entered the study. Median age of 115 patients (intent-to-treat population) was 69 years. Protocol outlined a second course 7+3 for patients without blast clearance and two courses of high-dose ara-C consolidation upon CR. Both treatments were equally effective in blast clearance, CR, EFS, remission duration, or OS (median: 7+3, 9 months; 7+GO, 10 months). Induction death rate was higher in the GO group due to veno-occlusive disease.
The study did not show significant superiority of 7+GO over standard 7+3.
Aspergillus niger strain LCP521 harbours a highly processive epoxide hydrolase (EH) that is of particular interest for the enantioselective bio-organic synthesis of fine chemicals. In the present ...work, we report the isolation of the gene and cDNA for this EH by use of inverse PCR. The gene is composed of nine exons, the first of which is apparently non-coding. The deduced protein of the A. niger EH shares significant sequence similarity with the mammalian microsomal EHs (mEH). In contrast to these, however, the protein from A. niger lacks the common N-terminal membrane anchor, in line with the fact that this enzyme is, indeed, soluble in its native environment. Recombinant expression of the isolated cDNA in Escherichia coli yielded a fully active EH with similar characteristics to the fungal enzyme. Sequence comparison with mammalian EHs suggested that Asp(192), Asp(348) and His(374) constituted the catalytic triad of the fungal EH. This was subsequently substantiated by the analysis of respective mutants constructed by site-directed mutagenesis. The presence of an aspartic acid residue in the charge-relay system of the A. niger enzyme, in contrast to a glutamic acid residue in the respective position of all mEHs analysed to date, may be one important contributor to the exceptionally high turnover number of the fungal enzyme when compared with its mammalian relatives. Recombinant expression of the enzyme in E. coli offers a versatile tool for the bio-organic chemist for the chiral synthesis of a variety of fine chemicals.
To evaluate whether cisplatin-based chemotherapy (gemcitabine, vinorelbine, and cisplatin GVP) prolongs overall survival in comparison to cisplatin-free chemotherapy (gemcitabine and vinorelbine GV) ...as first-line treatment in patients with advanced non-small-cell lung cancer (NSCLC).
Between September 1999 and June 2001, 300 patients with NSCLC stage IIIB with malignant pleural effusion or stage IV disease were randomly assigned to receive GV (gemcitabine 1000 mg/m(2) + vinorelbine 25 mg/m(2) on days 1 and 8 every 3 weeks) or GVP (gemcitabine 1000 mg/m(2) + vinorelbine 25 mg/m(2) on days 1 and 8 + cisplatin 75 mg/m(2) on day 2 every 3 weeks). Primary end point of the study was overall survival.
Two hundred eighty-seven patients (GV, 143 patients; GVP, 144 patients) were eligible for analysis. At the time of analysis, April 15, 2002, 209 patients (GV, 103 patients; GVP, 106 patients) of 287 patients had died (73%). No statistically significant difference was observed for overall survival (P =.73; median survival, 35.9 versus 32.4 weeks; 1-year survival rate, 33.6% versus 27.5%) as well as for event-free survival (P =.35; median time-to-event, 19.3 versus 22.3 weeks) between GV and GVP. Two hundred fourteen patients were assessable for best response. The overall response rates were 13.0% for GV versus 28.3% for GVP (P =.004; complete responders, 0% versus 3.8%; partial responders, 13.0% versus 24.5%). Hematologic and nonhematologic toxicity was significantly lower in the GV treatment arm compared with GVP. No statistically significant difference in quality of life was observed.
In this phase III study, the cisplatin-based GVP regimen showed no survival benefit as first-line chemotherapy in advanced NSCLC when compared with the cisplatin-free GV regimen, which was substantially better tolerated.
This phase 3 trial compared tandem autologous stem cell transplantation (autoSCT) versus autoSCT followed by reduced-intensity conditioning allogeneic stem cell transplantation (auto/alloSCT) in ...patients with newly diagnosed multiple myeloma (MM) with deletion of (del) chromosome 13q (del13q). The availability/absence of a human leukocyte antigen-matched-related or matched-unrelated donor (MUD) determined the nature of the second SCT. The primary endpoint was progression-free survival (PFS) in the intention-to-treat population (n = 199). Auto/alloSCT was performed in 126 patients; 74 received MUD allografts. After 91 months median follow-up, median PFS with auto/allo versus tandem autoSCT was 34.5 versus 21.8 months (P = 0.003; adjusted hazard ratio 0.55, 95% confidence interval 0.36-0.84). Median overall survival (OS) was 70.2 versus 71.8 months (P = 0.856). Two-year non-relapse mortality with auto/allo versus tandem autoSCT was 14.3% versus 4.1% (P = 0.008). In patients harboring both del13q and del17p, median PFS and OS were 37.5 and 61.5 months with auto/allo (n = 19) versus 6.1 and 23.4 months with tandem autoSCT (n = 6) (P = 0.0002 and 0.032). Our findings suggest that auto/alloSCT significantly extends PFS versus tandem autoSCT in del13q MM, and indicate some survival benefit for first-line alloSCT in high-risk MM.
The purpose of this phase II study was to investigate the efficacy and safety of gemcitabine plus vinorelbine as first-line chemotherapy in patients with advanced non-small cell lung cancer (NSCLC). ...Eligibility criteria included cytologically or histologically confirmed NSCLC (stage IIIB or IV), no previous chemotherapy, and bidimensionally measurable disease. Patients received 1000 mg/m2 gemcitabine and 30 mg/m2 vinorelbine on days 1, 8 and 15 every 4 weeks up to eight courses. From December 1997 to November 1998, 70 patients (59 stage IV and 11 stage IIIB disease), with a median age of 59 years (range 38–74 years) were enrolled. The intent-to-treat response rate was 41% (95% confidence interval (CI) 30–54%) with 1 complete responder (CR) and 28 partial responders (PRs), 15 patients had stable disease (SD) and 26 progressed (PD). Median survival was 8.3 months (95% CI 6.0–9.9 months), median progression-free survival (PFS) was 4.8 months (95% CI 3.9–5.5 months), and 1-year survival rate was 33.5% (95% CI 24.0–46.8%). Patients received a total of 229 cycles. Haematological and non-haematological toxicities were moderate. Transient World Health Organization (WHO)-grade IV leucopenia and thrombocytopenia occurred in 13 (6%) and two (1%) cycles, respectively. The predominant non-haematological toxicity was local reactions of the veins in 19 (27%) patients (WHO-grade II and III). Neurotoxicity was infrequent, non-cumulative, and reversible. The combination of gemcitabine and vinorelbine has demonstrated activity in metastatic NSCLC, with response and survival rates similar to those of cisplatin-based regimens and a more favourable toxicity profile that is well tolerated in an outpatient setting.
The purpose of this phase II trial was to investigate the efficacy and safety of a combination chemotherapy with gemcitabine, vinorelbine and cisplatin in the first-line treatment of advanced ...non-small cell lung cancer (NSCLC). Patients with NSCLC stage IIIB or IV disease received 1000 mg/m2 gemcitabine and 25 mg/m2 vinorelbine on days 1 and 8 and 75 mg/m2 cisplatin on day 2, every 3 weeks. From December 1998 to May 1999, 31 patients (21 stage IV and 10 stage IIIB disease), with a median age of 59 years (range 40–72 years) were enrolled. The overall intent-to-treat response rate was 45% (95% confidence interval (CI): 27–64%) with 2 complete responders (CR) and 12 partial responders (PR), 7 patients had stable disease and 10 progressed. Median survival was 12.8 months (95% CI: 6.5–12.8+ months), median time to progression was 5.1 months (95% CI: 3.5–7.7 months), and the 1-year survival rate was 52.9% (95% CI: 36.7–76.2%). Patients with stage IIIB disease had a significantly longer overall survival than patients with stage IV disease (P=0.05). Transient World Health Organization (WHO) grade IV leucopenia, anaemia and thrombocytopenia occurred in 3 (10%), 2 (6%) and 3 (10%) patients, respectively. The predominant non-haematological toxicities were alopecia and nausea/vomiting. 15 patients (48%) had WHO grade II and III alopecia and 14 patients (45%) nausea/vomiting. The combination of gemcitabine, vinorelbine and cisplatin has demonstrated major antitumour efficacy in advanced NSCLC with a manageable toxicity profile.
The aim of this multicenter-study was to evaluate the progression-free survival, response rate and toxicity of the combination of bendamustine and rituximab (BR) in patients with mantle cell or ...low-grade lymphomas in first to third relapse or refractory to previous treatment.
A total of 245 courses (median, four courses per patient) were administered to 63 patients. Bendamustine was given at a dose of 90 mg/m2 as a 30-minute infusion on days 1 and 2, combined with 375 mg/m2 rituximab on day 1, for a maximum of four cycles every 4 weeks. Histologies were 24 follicular, 16 mantle cell, 17 lymphoplasmacytoid, and six marginal zone lymphoma.
Fifty-seven of 63 patients responded to BR, corresponding to an overall response rate of 90% (95% CI, 80% to 96%) with a complete remission rate (CR) of 60% (95% CI, 47% to 72%). The median time of progression-free survival was 24 months (range, 5 to 44+ months), and the median duration of overall survival has not yet been reached. In mantle cell lymphomas, BR showed a considerable activity, achieving a response rate of 75% (95% CI, 48% to 93%) with a CR rate of 50%. Myelosuppression was the major toxicity, with 16% grade 3 and 4 leukocytopenia. Thrombocytopenia was rare, with only 3% grade 3 and 4.
These results demonstrate that the BR combination is a highly active regimen in the treatment of low-grade lymphomas and mantle cell lymphomas.
Very few patients with Behçet's disease (BD) have been treated with interferon alpha (IFN alpha) or interferon gamma (IFN gamma) to date. We report the successful longterm treatment of a female ...German patient with erosive arthritis and posterior uveitis with IFN alpha and IFN gamma sequentially and in combination.
Treatment standards are changing as a result of new findings in the therapy of multiple myeloma. So far, prednisone, dexamethasone and interferon-a have mainly been used as maintenance therapy after ...achieving remission or stable disease. At present, thalidomide is being considered as a new therapeutic option in several studies investigating maintenance therapy. As a result of the dose dependence of adverse effects such as neuropathy, constipation, sedation/vertigo and bradycardia, individual adjustment of the thalidomide dose is recommended. Only isolated cases of thrombosis occurred in the maintenance phase of therapy, and discontinuation of therapy is generally not necessary. While important study results on the efficacy of thalidomide following conventional chemotherapy are still awaited, it is the best documented drug so far for maintenance therapy following autologous stem cell transplantation. An upgrade of the response was seen in 22-73% of patients, as well as a significant prolongation of progression-free survival. For the first time, maintenance therapy with thalidomide showed a significant improvement in overall survival in a phase III study published recently. The tolerability of thalidomide could be further improved by including the option of intermittent administration of the drug.
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