In a prospective, randomized trial, netilmicin given once daily (OD) was compared in terms of efficacy and safety with the conventional 8-hourly dosing regimen (TD), both in combination with a broad spectrum beta-lactam, as initial empirical therapy for febrile neutropenic patients; the total daily dosage of netilmicin in each group was 6 mg/kg body weight. Twenty-nine of the 116 (25%) evaluable patients had microbiologically documented septicaemia, most of which were caused by Gram-positive bacteria, 41 (35%) had microbiologically documented infection without bacteraemia and 46 (40%) had possible infection. Highest peak serum concentrations of netilmicin in the OD group were significantly higher and trough serum concentrations significantly lower than in the TD group. A multivariate analysis revealed that neither the dosage regimen nor the peak serum concentration of netilmicin were determinants of a favourable outcome. The response rates of both groups to the initial treatment regimens were comparable and increased similarly following modification of the initial therapy. Response rates were particularly poor in patients with lower respiratory tract infection and in those who remained neutropenic throughout the course of treatment. The incidence of nephrotoxicity was low and did not differ significantly between groups. Once-daily dosing of netilmicin appears to be as effective and as safe as thrice-daily dosing, but is unlikely to further improve the response of febrile neutropenic patients to empirical therapy.
We randomized 3375 adults with newly diagnosed acute myeloid leukemia (AML) or high-risk myelodysplastic syndrome to test whether increasingly intensive chemotherapies assigned at study-entry and analyzed on an intent-to-treat basis improved outcomes. In total, 1529 subjects <60 years were randomized to receive: (1) a first course of induction therapy with high-dose cytarabine and mitoxantrone (HAM) or with standard-dose cytarabine, daunorubicin and 6-thioguanine (TAD) followed by a second course of HAM; (2) granulocyte-colony stimulating factor (G-CSF) or no G-CSF before induction and consolidation courses; and (3) high-dose therapy and an autotransplant or maintenance chemotherapy. In total, 1846 subjects ⩾60 years were randomized to receive: (1) a first induction course of HAM or TAD and second induction course of HAM (if they had bone marrow blasts ⩾5% after the first course); and (2) G-CSF or no G-CSF as above. Median follow-up was 7.4 years (range, 1 day to 14.7 years). Five-year event-free survivals (EFSs) for subjects receiving a first induction course of HAM vs TAD were 17% (95% confidence interval, 15, 18%) vs 16% (95% confidence interval 14, 18%; P=0.719). Five-year EFSs for subjects randomized to receive or not receive G-CSF were 19% (95% confidence interval 16, 21%) vs 16% (95% confidence interval 14, 19%; P=0.266). Five-year relapse-free survivals (RFSs) for subjects <60 years receiving an autotransplant vs maintenance therapy were 43% (95% confidence interval 40, 47%) vs 40 (95% confidence interval 35, 44%; P=0.535). Many subjects never achieved pre-specified landmarks and consequently did not receive their assigned therapies. These data indicate the limited impact of more intensive therapies on outcomes of adults with AML. Moreover, none of the more intensive therapies we tested improved 5-year EFS, RFS or any other outcomes.
Invasive fungal infections (IFI) are major causes of death in high-risk haematological patients receiving induction therapy for acute leukaemia or intensified immunosuppression due to acute or chronic graft-vs.-host disease (GvHD) following allogeneic stem cell transplantation (SCT). Recently, two randomised studies showed the efficacy of a posaconazole prophylaxis (PP) in these patients to prevent IFI. This prompted the strong recommendation for the use of PP in national and international guidelines. As we started PP in our leukaemia and transplantation unit in summer 2007, we retrospectively analysed the impact of PP on the incidence of possible, probable or proven IFI in this group of patients. Incidence of IFI according to the revised EORTC criteria, published in 2008, was reviewed retrospectively in a group of high-risk patients treated in our unit 1 year before the start of PP compared with the same group in the following year with PP. First analysis was performed on an intention-to-treat basis comparing patients during 1 year of PP with the same group of patients in the year before the start of PP. In a second, deeper analysis, patients were grouped for fluconazole or posaconazole irrespective of the time period the prophylaxis was given. In a first intent-to-treat analysis, 56 patients were analysed in the period without PP (noPP) compared with 34 patients in the period with PP. Overall IFI rates (possible, probable and proven IFI) were reduced from 47% (noPP group) to 35% (PP group). In a second analysis, only patients receiving either fluconazole or PP were analysed, resulting in 29 patients in the noPP group and 36 patients in the PP group. There was a reduction in overall IFI in the PP group especially in the acute myeloid leukaemia (AML) induction patients, but this does not reach statistical significance because of low patient numbers. However, initiation of antifungal therapy was significantly less frequent in AML induction patients in the PP group compared with the noPP group. Unfortunately, this does not result in reduced mortality rates, as mortality in the PP group is higher (15% vs. 7%) than in noPP patients because of double the number of patients with severe GvHD in the PP group. Both breakthrough infections were documented in this subgroup of patients. Our data, collected in every day clinical practice, add further evidence to the advantage of a PP strategy in this group of high-risk patients. However, more data are urgently needed to assess the impact of PP on the incidence and pattern of fungal infections and the strategies to be used in patients with persisting fever and pulmonary infiltrates receiving PP, especially in the setting of SCT and GvHD.
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