Safety and Efficacy of Antibiotic De-escalation and Discontinuation in High-Risk Hematological Patients With Febrile Neutropenia: A Single-Center Experience.

BACKGROUND: There is currently no consensus on optimal duration of antibiotic treatment in febrile neutropenia. We report on the clinical impact of implementation of antibiotic de-escalation and discontinuation strategies based on the Fourth European Conference on Infections in Leukaemia (ECIL-4) recommendations in high-risk hematological patients. METHODS: We studied 446 admissions after introduction of an ECIL-4-based protocol (hereafter "ECIL-4 group") in comparison to a historic cohort of 512 admissions. Primary clinical endpoints were the incidence of infectious complications including septic shock, infection-related intensive care unit (ICU) admission, and overall mortality. Secondary endpoints included the incidence of recurrent fever, bacteremia, and antibiotic consumption. RESULTS: Bacteremia occurred more frequently in the ECIL-4 group (46.9% [209/446] vs 30.5% [156/512]; P < .001), without an associated increase in septic shock (4.7% [21/446] vs 4.5% [23/512]; P = .878) or infection-related ICU admission (4.9% [22/446] vs 4.1% [21/512]; P = .424). Overall mortality was significantly lower in the ECIL-4 group (0.7% [3/446] vs 2.7% [14/512]; P = .016), resulting mainly from a decrease in infection-related mortality (0.4% [2/446] vs 1.8% [9/512]; P = .058). Antibiotic consumption was significantly reduced by a median of 2 days on antibiotic therapy (12 vs 14; P = .001) and 7 daily antibiotic doses (17 vs 24; P < .001) per admission period. CONCLUSIONS: Our results support implementation of ECIL-4 recommendations to be both safe and effective based on real-world data in a large high-risk patient population. We found no increase in infectious complications and total antibiotic exposure was significantly reduced.

Comparison of the Power of Procalcitonin and C-Reactive Protein to Discriminate between Different Aetiologies of Fever in Prolonged Profound Neutropenia: A Single-Centre Prospective Observational Study.

Management of fever in prolonged, profound neutropenia remains challenging with many possible infectious and non-infectious causes. We investigated whether procalcitonin (PCT) is superior to C-reactive protein (CRP) in discriminating between different aetiologies of fever in this setting. CRP and PCT were tested daily during 93 neutropenic episodes in 66 patients. During this study period, 121 febrile episodes occurred and were classified into four categories based on clinical and microbiological findings: microbiologically documented infection (MDI); clinically documented infection (CDI); proven or probable invasive fungal disease (IFD); fever of unknown origin (FUO). Values of PCT and CRP at fever onset as well as two days later were considered for analysis of their performance in distinguishing aetiologies of fever. At fever onset, no significant difference in PCT values was observed between different aetiologies of fever, whereas median CRP values were significantly higher in case of IFD (median 98.8 mg/L vs 28.8 mg/L, p=0.027). Both PCT and CRP reached their peak at a median of 2 days after fever onset. Median PCT values on day 2 showed no significant difference between the aetiologies of fever. Median CRP values on day 2 were significantly higher in IFD (median 172 mg/L versus 78.4 mg/L, p=0.002). In MDI median CRP values rose > 100 mg/L, whereas they did not in CDI or FUO. PCT has no added value over CRP for clinical management of fever in prolonged, profound neutropenia. When performing reassessment 2 days after fever onset, CRP has better discriminatory power between aetiologies of fever.

Dendritic cell vaccination as postremission treatment to prevent or delay relapse in acute myeloid leukemia.

Relapse is a major problem in acute myeloid leukemia (AML) and adversely affects survival. In this phase 2 study, we investigated the effect of vaccination with dendritic cells (DCs) electroporated with Wilms' tumor 1 (WT1) messenger RNA (mRNA) as postremission treatment in 30 patients with AML at very high risk of relapse. There was a demonstrable antileukemic response in 13 patients. Nine patients achieved molecular remission as demonstrated by normalization of WT1 transcript levels, 5 of which were sustained after a median follow-up of 109.4 months. Disease stabilization was achieved in 4 other patients. Five-year overall survival (OS) was higher in responders than in nonresponders (53.8% vs 25.0%; P = .01). In patients receiving DCs in first complete remission (CR1), there was a vaccine-induced relapse reduction rate of 25%, and 5-year relapse-free survival was higher in responders than in nonresponders (50% vs 7.7%; P < .0001). In patients age ≤65 and >65 years who received DCs in CR1, 5-year OS was 69.2% and 30.8% respectively, as compared with 51.7% and 18% in the Swedish Acute Leukemia Registry. Long-term clinical response was correlated with increased circulating frequencies of polyepitope WT1-specific CD8+ T cells. Long-term OS was correlated with interferon-γ+ and tumor necrosis factor-α+ WT1-specific responses in delayed-type hypersensitivity-infiltrating CD8+ T lymphocytes. In conclusion, vaccination of patients with AML with WT1 mRNA-electroporated DCs can be an effective strategy to prevent or delay relapse after standard chemotherapy, translating into improved OS rates, which are correlated with the induction of WT1-specific CD8+ T-cell response. This trial was registered at www.clinicaltrials.gov as #NCT00965224.

Adult acute precursor B-cell lymphoblastic leukemia presenting as hypercalcemia and osteolytic bone lesions.

BACKGROUND: Osteolytic bone lesions and hypercalcemia without peripheral blasts B-cell acute lymphoblastic leukemia (B-ALL) is reported in children but rarely seen in adults. CASE PRESENTATION: We describe the case of a 34-year old man presenting with hypercalcemia and symptomatic osteolytic bone lesions of vertebrae and ribs who was initially suspected as having a solid malignancy. Diagnostic work-up including peripheral blood examination, radiographic and nuclear studies could, however, not detect a primary tumor. Because of a mild thrombocytopenia and the lack of a primary focus, a bone marrow biopsy was performed leading to the diagnosis of Philadelphia chromosome positive precursor B-ALL. After correction of the hypercalcemia with intravenous fluid administration, corticoids and bisphosphonates, the patient was treated according to the HOVON 100 protocol achieving complete molecular remission after the first cycle of induction chemotherapy. CONCLUSION: Hypercalcemia and osteolytic bone lesions are rare complications of adult B-ALL and can occur in the absence of peripheral blastosis. With this case report we would like to emphasize the importance of clinical awareness. Immediate treatment of hypercalcemia and initiation of antileukemic treatment is mandatory as a delay of diagnosis might pose a real and possible life-threatening risk in these patients.

Clinical and microbiological impact of discontinuation of fluoroquinolone prophylaxis in patients with prolonged profound neutropenia.

BACKGROUND: Infections remain a leading cause of morbidity and mortality in patients with reduced immunity caused by haematological disease and chemotherapy-induced neutropenia. We evaluated the clinical and microbiological impact of discontinuing fluoroquinolone prophylaxis in these patients. METHODS: We analysed 154 admissions in three sequential periods of 8 months: long-standing use, discontinuation of prophylaxis and reintroduction of prophylaxis. Clinical endpoints were occurrence of febrile neutropenia, bacteraemia, severe sepsis, septic shock, response to antibiotic therapy, total antibiotic consumption and duration of hospital stay. Microbiological analysis included bacterial isolates from stool and blood cultures and their resistance pattern. RESULTS: No significant increase in serious infectious complications was seen with the discontinuation of prophylaxis. The overall incidence of bacteraemia did not change, but a higher proportion of bacterial isolates were Gram-negative (22.2% vs. 5.9% & 8.6%; P = 0.030), more often multisusceptible (50% vs. 0%) and less fluoroquinolone resistant (10% vs. 100%). Screening of stools showed a higher prevalence of organisms in the discontinuation period (86.7% vs. 37.3% & 55.2%; P ≤ 0.001), but they were more frequently multisusceptible (53.8% vs. 10.5% & 6.3%; P ≤ 0.001). After discontinuation of prophylaxis, fluoroquinolone resistance decreased rapidly from 73.7 to 7.7%, in association with a significant decrease in extended spectrum beta-lactamase (ESBL)-producing isolates from 42.1 to 10.3%. Resistance figures immediately returned to prediscontinuation values after reinstitution of prophylaxis. CONCLUSIONS: No clinically relevant short-term drawbacks were observed with the discontinuation of fluoroquinolone prophylaxis in patients with chemotherapy-induced prolonged profound neutropenia, which led to a significant decrease in fluoroquinolone resistance as well as occurrence of ESBL-producing isolates.

Self-monitoring of oral anticoagulation: systematic review and meta-analysis of individual patient data.

BACKGROUND: Uptake of self-testing and self-management of oral anticoagulation [corrected] has remained inconsistent, despite good evidence of their effectiveness. To clarify the value of self-monitoring of oral anticoagulation, we did a meta-analysis of individual patient data addressing several important gaps in the evidence, including an estimate of the effect on time to death, first major haemorrhage, and thromboembolism. METHODS: We searched Ovid versions of Embase (1980-2009) and Medline (1966-2009), limiting searches to randomised trials with a maximally sensitive strategy. We approached all authors of included trials and requested individual patient data: primary outcomes were time to death, first major haemorrhage, and first thromboembolic event. We did prespecified subgroup analyses according to age, type of control-group care (anticoagulation-clinic care vs primary care), self-testing alone versus self-management, and sex. We analysed patients with mechanical heart valves or atrial fibrillation separately. We used a random-effect model method to calculate pooled hazard ratios and did tests for interaction and heterogeneity, and calculated a time-specific number needed to treat. FINDINGS: Of 1357 abstracts, we included 11 trials with data for 6417 participants and 12,800 person-years of follow-up. We reported a significant reduction in thromboembolic events in the self-monitoring group (hazard ratio 0·51; 95% CI 0·31-0·85) but not for major haemorrhagic events (0·88, 0·74-1·06) or death (0·82, 0·62-1·09). Participants younger than 55 years showed a striking reduction in thrombotic events (hazard ratio 0·33, 95% CI 0·17-0·66), as did participants with mechanical heart valve (0·52, 0·35-0·77). Analysis of major outcomes in the very elderly (age ≥85 years, n=99) showed no significant adverse effects of the intervention for all outcomes. INTERPRETATION: Our analysis showed that self-monitoring and self-management of oral coagulation is a safe option for suitable patients of all ages. Patients should also be offered the option to self-manage their disease with suitable health-care support as back-up. FUNDING: UK National Institute for Health Research (NIHR) Technology Assessment Programme, UK NIHR National School for Primary Care Research.

Induction of complete and molecular remissions in acute myeloid leukemia by Wilms' tumor 1 antigen-targeted dendritic cell vaccination.

Active immunization using tumor antigen-loaded dendritic cells holds promise for the adjuvant treatment of cancer to eradicate or control residual disease, but so far, most dendritic cell trials have been performed in end-stage cancer patients with high tumor loads. Here, in a phase I/II trial, we investigated the effect of autologous dendritic cell vaccination in 10 patients with acute myeloid leukemia (AML). The Wilms' tumor 1 protein (WT1), a nearly universal tumor antigen, was chosen as an immunotherapeutic target because of its established role in leukemogenesis and superior immunogenic characteristics. Two patients in partial remission after chemotherapy were brought into complete remission after intradermal administration of full-length WT1 mRNA-electroporated dendritic cells. In these two patients and three other patients who were in complete remission, the AML-associated tumor marker returned to normal after dendritic cell vaccination, compatible with the induction of molecular remission. Clinical responses were correlated with vaccine-associated increases in WT1-specific CD8+ T cell frequencies, as detected by peptide/HLA-A*0201 tetramer staining, and elevated levels of activated natural killer cells postvaccination. Furthermore, vaccinated patients showed increased levels of WT1-specific IFN-gamma-producing CD8+ T cells and features of general immune activation. These data support the further development of vaccination with WT1 mRNA-loaded dendritic cells as a postremission treatment to prevent full relapse in AML patients.

Therapeutic quality control of oral anticoagulant therapy comparing the short-acting acenocoumarol and the long-acting phenprocoumon.

To investigate whether the different pharmacokinetics of acenocoumarol (t(1/2) = 11 h) and phenprocoumon (t(1/2) = 140 h) result in a different quality of anticoagulation, we studied patients from the Leiden anticoagulation clinic treated between 1998 and 1999 for more than 16 weeks. Two hundred and twenty-eight pairs were closely matched for indication for oral anticoagulant therapy (OAT), age, sex and date of start of treatment. Four hundred and fifty six patients with 7245 International Normalized Ratio (INR) checks yielded 230 patient-years. Quality of OAT calculated over the whole treatment period was higher with phenprocoumon as expressed by the number of INR checks in the therapeutic range (phenprocoumon: 42.7%, acenocoumarol: 36.5%, difference: 6.1%, CI(95) of the difference: 3.0-9.3%) and by time in range (phenprocoumon: 46.6%, acenocoumarol: 41.6%, difference: 5.0%, CI(95) of the difference: 1.3-8.6%). After the initial 6 weeks of OAT, the differences became more pronounced (difference: 6.1%, CI(95): 1.8-10.4%). The incidence of severe bleeding complications was similar (phenprocoumon: 0.04/patient/year vs acenocoumarol: 0.03/patient/year) with a slight excess of minor bleeds with phenprocoumon (0.19/patient/year vs 0.06/patient/year). We conclude that phenprocoumon leads to a better quality of OAT than acenocoumarol. As there is no difference in major bleeding complications and only a small difference in minor bleeding complications, phenprocoumon is preferable to acenocoumarol for prolonged OAT.