Search

Background: Early antibiotic discontinuation in haematology patients with fever of unknown origin during chemotherapy-induced neutropenia has been advocated to reduce unnecessary antibiotic treatment, but the safety of this strategy is unknown. We aimed to assess if short treatment with carbapenems is non-inferior to extended treatment. Methods: In this randomised, multicentre, non-inferiority trial we assigned 292 haematology patients with fever of unknown origin during high-risk neutropenia (≥7 days) to short treatment, with carbapenem discontinuation after 72 hours (± 12 hours), or extended treatment, with carbapenem continuation for ≥ 9 days until being afebrile for 5 days or neutrophil recovery. The composite primary endpoint was treatment failure, defined as recurrent fever or a carbapenem-sensitive infection between day 4 and day 9 and septic shock/respiratory failure or death from day 4 until neutrophil recovery. Findings: Treatment failure in the intention-to-treat analysis (281 patients) was 19·4% (28/144) in the short treatment versus 15·3% (21/137) in the extended treatment arm (adjusted risk difference 4·0%, 90% confidence interval [CI] -1·7% to 9·7%, excluding the 10% non-inferiority threshold). Mortality until 30 days after neutrophil recovery occurred in five patients (3·5%) in the short treatment group and in one (0·7%) in the extended treatment group (adjusted risk difference 2·6%, 95% CI % 1·2 to 5·4%), of which none were related to infections with carbapenem-sensitive microorganisms. Interpretation: Early discontinuation of carbapenem treatment in neutropenic patients with fever was non-inferior to extended treatment with regard to treatment failure, but all-cause mortality before 30 days after neutrophil recovery was significantly higher in patients with persistent fever at day 3. Early discontinuation of carbapenem treatment is therefore possible in afebrile patients, but caregivers should be vigilant of other non-carbapenem susceptible infections in patients with persistent fever.: Clinical Trial Registration Details: This trial is registered with ClinicalTrials.gov (number NCT02149329). Funding Information: Dutch Research Council (ZonMw) and Fonds NutsOhra. Declaration of Interests: The authors 408 declare no competing interests. Ethics Approval Statement: The protocol was approved by the research ethics review committee of VU university medical centre (current name: Amsterdam University medical centres, location VUmc) and ethical bodies of each participating centre. An independent data and safety monitoring board oversaw study procedures and data quality during conduct of the study and performed a planned interim safety analysis. All participants provided written informed consent.

Background In hematology patients with high risk neutropenia due to intensive chemotherapy the optimal antibiotic treatment duration for fever of unknown origin (FUO) is unknown. Early antibiotic discontinuation has been advocated to reduce unnecessary exposure to broad-spectrum antibiotics, but there is limited evidence for the safety of this strategy. We aimed to assess if short treatment with carbapenems is non-inferior to extended treatment for neutropenic patients with FUO. Methods Multicenter, open-label, randomized clinical trial in 6 centers in the Netherlands. Hematology patients with FUO during high risk neutropenia (≥7 days) were eligible for participation. Eligible patients who gave informed consent were randomly assigned (1:1) to either the short treatment arm, where the carbapenem was discontinued after 72 hours, irrespective of presence of fever, or the extended treatment arm, where the carbapenem was continued for ≥ 9 days until afebrile for 5 days or end of neutropenia (EON), whichever came first. The primary endpoint was treatment failure defined as a composite of recurrent fever or a carbapenem-sensitive infection between day 4 and day 8 and septic shock or death from day 4 until EON. Secondary endpoints included all-cause and infection-related mortality until 30 days post-EON. We used 10% as noninferiority margin. Trial Intervention Flowchart Results Between December 2014 and August 2019 292 patients were included. Risk of treatment failure in the modified intention-to-treat analysis (mITT) was 23.5% (32/136) in the short treatment versus 18.3% (24/131) in the extended treatment arm (adjusted risk difference (ARD) 3.7% (90% CI -2.6% to 9.9%)) and in the per-protocol analysis 27.9% (29/104) versus 18.2% (22/121) (ARD 8.9% (90% CI 0.6% to 17.2%). Short treatment was non-inferior to extended treatment in the mITT population, but not in the per protocol population. All-cause mortality until 30 days post-EON was significantly higher in the short treatment group: 3.7% (5/136) versus 0.8% (1/131) (ARD 2.8%, 95% CI 1.3 to 4.4%), but infection-related mortality until 30 days post-EON was not statistically different between the treatment arms. Primary and Secondary Endpoint Results Subgroup Analyses Results Bloodstream infections after day 3 Conclusion Short treatment with a carbapenem in neutropenic patients with fever was noninferior to extended treatment with regard to treatment failure. Conclusion Summary Disclosures All Authors: No reported disclosures

The combination of melphalan, prednisone, and thalidomide (MPT) is considered standard therapy for newly diagnosed patients with multiple myeloma who are ineligible for stem cell transplantation. Long-term treatment with thalidomide is hampered by neurotoxicity. Melphalan, prednisone, and lenalidomide, followed by lenalidomide maintenance therapy, showed promising results without severe neuropathy emerging. We randomly assigned 668 patients between nine 4-week cycles of MPT followed by thalidomide maintenance until disease progression or unacceptable toxicity (MPT-T) and the same MP regimen with thalidomide being replaced by lenalidomide (MPR-R). This multicenter, open-label, randomized phase 3 trial was undertaken by Dutch-Belgium Cooperative Trial Group for Hematology Oncology and the Nordic Myeloma Study Group (the HOVON87/NMSG18 trial). The primary end point was progression-free survival (PFS). A total of 318 patients were randomly assigned to receive MPT-T, and 319 received MPR-R. After a median follow-up of 36 months, PFS with MPT-T was 20 months (95% confidence interval [CI], 18-23 months) vs 23 months (95% CI, 19-27 months) with MPR-R (hazard ratio, 0.87; 95% CI, 0.72-1.04; P = .12). Response rates were similar, with at least a very good partial response of 47% and 45%, respectively. Hematologic toxicity was more pronounced with MPR-R, especially grades 3 and 4 neutropenia: 64% vs 27%. Neuropathy of at least grade 3 was significantly higher in the MPT-T arm: 16% vs 2% in MPR-R, resulting in a significant shorter duration of maintenance therapy (5 vs 17 months in MPR-R), irrespective of age. MPR-R has no advantage over MPT-T concerning efficacy. The toxicity profile differed with clinically significant neuropathy during thalidomide maintenance vs myelosuppression with MPR.