Epidemiology of invasive aspergillosis and triazole-resistant Aspergillus fumigatus in patients with haematological malignancies: a single-centre retrospective cohort study.

Objectives: To investigate the epidemiology and clinical relevance of triazole resistance among patients undergoing treatment for haematological malignancies who are at risk of invasive aspergillosis (IA). Methods: This was a retrospective cohort study for which the records of consecutive patients given chemotherapy for AML or myelodysplastic syndrome (MDS) or who had received an allogeneic HSCT from 2006 to 2012 were reviewed for IA. Triazole resistance was detected by the VIPcheck™ screening method and confirmed by determining the MIC by EUCAST methodology. Results: A total of 432 patients were included, comprising 182 (42.1%) patients who had undergone chemotherapy for AML or MDS, and 250 (57.9%) patients who had undergone an allogeneic HSCT. Probable or proven IA was diagnosed in 36 cases (8.3%, 95% CI 6.0%-11.4%). Of these, 12 (33.3%) were based on recovery of Aspergillus fumigatus from sputum, bronchoalveolar lavage or biopsy, and triazole resistance was found in 2 instances. A. fumigatus was also recovered from one or more specimens from 13 patients without probable or proven IA. Triazole resistance was documented for three patients. The survival rate of patients with IA caused by voriconazole-resistant isolates could not be assessed. Conclusions: The overall frequency of voriconazole-resistant IA among patients at high risk was low. However, the rate of triazole resistance may have been underestimated by the low detection rate based on recovery of A. fumigatus. Alternative diagnostic tests, such as PCR-based assays, may prove better at detecting IA due to triazole-resistant A. fumigatus.

Pharmacokinetics of extended dose intervals of micafungin in haematology patients: optimizing antifungal prophylaxis.

Background: Extended dosing intervals for micafungin could overcome the need for hospitalization for antifungal prophylaxis. Objectives: This multicentre, open-label, randomized trial compared the pharmacokinetics of 300 mg of micafungin given twice weekly with 100 mg once daily as antifungal prophylaxis in adult haematology patients at risk of developing invasive fungal disease. Secondary objectives were assessment of adequate exposure with an alternative dosing regimen of micafungin (700 mg once weekly) through Monte Carlo simulations and assessment of safety in this patient population. Patients and methods: Twenty adult patients were randomized to receive either 300 mg of micafungin twice weekly or 100 mg once daily for 8 days. Blood samples were drawn daily and pharmacokinetic curves were determined on days 4/5 and 8. Monte Carlo simulations were performed for both investigated regimens as well as a frequently proposed alternative regimen (700 mg once weekly). Results: The predicted median AUC0-168h (IQR) for a typical patient on the investigated regimens of 100 mg once daily and 300 mg twice weekly and the hypothetical regimen of 700 mg once weekly were 690 (583-829), 596 (485-717) and 704 (585-833) mg·h/L, respectively. Conclusions: We observed comparable exposure with 300 mg of micafungin twice weekly and 100 mg of micafungin once daily. We provide the pharmacokinetic proof for an extended dosing regimen, which now needs to be tested in a clinical trial with hard endpoints.

A rationale for reduced-frequency dosing of anidulafungin for antifungal prophylaxis in immunocompromised patients.

OBJECTIVES: Reduced-frequency dosing strategies of anidulafungin may offer a more convenient way of providing adequate antifungal prophylaxis to patients at high risk of invasive fungal diseases. We aimed to provide the pharmacological rationale for the applicability of reduced-frequency dosing regimens. METHODS: We defined two groups of 10 patients that were to receive anidulafungin at 200 mg every 48 h or 300 mg every 72 h. Blood samples were drawn daily and two pharmacokinetic curves were constructed after 1 and 2 weeks of treatment. A population pharmacokinetic model was developed using non-linear mixed-effects modelling. ClinicalTrials.gov identifier: NCT01249820. RESULTS: The AUC over a 6 day period (IQR) for a typical patient on 200 mg every 48 h or 300 mg every 72 h resulted in 348 mg ·â€Šh/L (310.6-386.7) and 359 mg ·â€Šh/L (319.1-400.9), respectively, comparable to the licensed regimen [397.0 mg ·â€Šh/L (352.4-440.5)]. In the final model, the volume of distribution proved to be dependent on the lean body mass and CL of cyclosporine A. All three regimens resulted in comparable dose-normalized exposure over time. CONCLUSIONS: We now have sufficient evidence to start using less frequent dosing regimens and demonstrate their value in clinical practice. These less frequently applied infusions enable more personalized care in an outpatient setting with reduced costs.

Mucositis not neutropenia determines bacteremia among hematopoietic stem cell transplant recipients.

BACKGROUND: In the 1960s, it was reported that infectious complications were the main cause of fever during neutropenia that followed hematopoietic stem cell transplant (HSCT). More recently, mucositis has become recognized as an important determinant of the inflammatory response and infectious complications. METHODS: The objective of this prospective study was to determine the impact of intestinal mucositis, as measured by plasma citrulline, and neutropenia on the systemic inflammatory response (C-reactive protein) and the occurrence of bacteremia among 2 cohorts of HSCT recipients: 1 composed of 18 patients who had been treated with a myeloablative (MA) regimen (high-dose melphalan) and the other involving 19 patients who had received the non-myeloablative (NMA) regimen (fludarabine and cyclophosphamide). Blood cultures were obtained for surveillance from admission onwards as well as at the onset of fever. RESULTS: The MA regimen induced severe intestinal mucositis manifest by citrullinemia <10 µmol/L, which was accompanied by an inflammatory response, and bacteremia affected 8 (44%) of 18 patients and coincided with the nadir of citrullinemia. By contrast, those who had been treated with the NMA regimen did not develop severe intestinal mucositis, had a moderate inflammatory response, and only 2 (11%) of the 19 patients developed bacteremia. However, both groups experienced profound neutropenia and its duration was significantly longer for those receiving the NMA regimen. CONCLUSION: This study suggests that severe intestinal mucositis, i.e., citrullinemia <10 µmol/L, defines the period of risk of bacteremia better than does neutropenia, and that measuring plasma citrulline may prove useful in deciding who needs empirical antimicrobial therapy and when.

Case report: A successful second autologous hematopoietic stem cell transplantation in refractory systemic sclerosis, with positive effect on skin involvement, pulmonary function and microcirculation.

Background: Systemic sclerosis (SSc) is a complex autoimmune disease characterized by inflammation, vasculopathy and fibrosis of the skin and internal organs. Treatment with autologous hematopoietic cell transplantation (HCT) for progressive SSc has improved overall and event-free survival rates significantly, but unfortunately disease progression after HCT is seen in a subset of patients. Data on the efficacy and safety of second HCT is scarce. Case: We present a patient with diffuse cutaneous SSc and associated interstitial lung disease (ILD) who successfully underwent a second HCT for progressive disease five years after a first HCT. We describe changes in skin involvement and pulmonary involvement as well as the changes observed in sequential nailfold microcapillaroscopy (NCM), performed from first presentation up to this moment. Conclusion: This case adds to the current limited literature on efficacy and safety of a second HCT in SSc refractory cases. Furthermore it outlines the potential of HCT on amelioration of microvasculopathy in SSc.

Grading bloodstream infection risk using citrulline as a biomarker of intestinal mucositis in patients receiving intensive therapy.

Earlier studies have suggested that severe intestinal mucositis (IM; citrulline < 10 µmol/L) is an independent risk factor for bloodstream infections (BSI) after cytotoxic therapy. Our aim was to grade IM in patients receiving commonly used chemotherapy and conditioning regimens, and characterize its relationship with BSI incidence. In a retrospective analysis of remission induction (RI) chemotherapy, or conditioning for autologous and allogeneic hematopoietic stem cell transplantation (HSCT; myeloablative conditioning [MAC] and non-myeloablative and reduced-intensity conditioning [NMA/RIC]), data were collected on central venous catheter (CVC) characteristics and BSI. The relationship between BSI occurrence and the degree of IM (determined by citrulline levels) and neutropenia was analyzed. In 626 CVC episodes, 268 (42.8%) laboratory-confirmed BSIs (LCBIs) occurred, classified as mucosal barrier injury (MBI)-LCBIs in 179 (28.6%) episodes, central line-associated BSIs in 113 (18.1%) episodes, and catheter-related BSIs in 55 (8.8%) episodes. In NMA/RIC, the mean duration of hypocitrullinemia was 0.77 days, with LCBI and MBI-LCBI occurring in 11.1% and 4.8% of episodes. In autologous HSCT, RI, and MAC allogeneic HSCT, LCBI and MBI-LCBI occurred frequently (40.0-63.8% and 22.8-53.2% of episodes, respectively) and the mean duration of hypocitrullinemia was significantly higher (9.2-13.8 days). There was a strong correlation between LCBI and the duration of hypocitrullinemia (Pearson's correlation coefficient R = 0.96), as opposed to the relationship between LCBI and the duration of neutropenia (R = 0.42). We conclude that citrulline can be used to grade BSI risk for commonly used intensive treatment regimens.

Supporting the gastrointestinal microenvironment during high-dose chemotherapy and stem cell transplantation by inhibiting IL-1 signaling with anakinra.

High-dose chemotherapy causes intestinal inflammation and subsequent breakdown of the mucosal barrier, permitting translocation of enteric pathogens, clinically manifesting as fever. Antibiotics are mainstay for controlling these complications, however, they are increasingly recognized for their detrimental effects, including antimicrobial resistance and dysbiosis. Here, we show that mucosal barrier injury induced by the mucotoxic chemotherapeutic agent, high-dose melphalan (HDM), is characterized by hyper-active IL-1b/CXCL1/neutrophil signaling. Inhibition of this pathway with IL-1RA, anakinra, minimized the duration and intensity of mucosal barrier injury and accompanying clinical symptoms, including diarrhea, weight loss and fever in rats. 16S analysis of fecal microbiome demonstrated a more stable composition in rats receiving anakinra, with reduced pathogen expansion. In parallel, we report through Phase IIA investigation that anakinra is safe in stem cell transplant patients with multiple myeloma after HDM. Ramping-up anakinra (100-300 mg administered intravenously for 15 days) did not cause any adverse events or dose limiting toxicities, nor did it change time to neutrophil recovery. Our results reinforce that strengthening the mucosal barrier may be an effective supportive care strategy to mitigate local and systemic clinical consequences of HDM. We are now conducting a Phase IIB multicenter, placebo-controlled, double-blinded trial to assess clinical efficacy of anakinra (AFFECT-2).Trial registration: ClinicalTrials.gov identifier: NCT03233776.

Surveillance of catheter-related bloodstream infections in haemato-oncology patients: comparison of two definitions.

In the Netherlands, the PREZIES surveillance is used for registration and surveillance of central venous catheter (CVC) -related bloodstream infections (CRBSI). We investigated how this Dutch definition correlated with internationally used definitions for CRBSI, central line-associated bloodstream infections (CLABSI) and mucosal barrier injury laboratory-confirmed bloodstream infections (MBI-LCBI). We determined that the Dutch PREZIES definition of CRBSI is appropriate for surveillance control of CVC care bundle use in haemato-oncology patients managed with multi-lumen CVCs.

Correction: Lenalidomide added to standard intensive treatment for older patients with AML and high-risk MDS.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

Lenalidomide added to standard intensive treatment for older patients with AML and high-risk MDS.

More effective treatment modalities are urgently needed in patients with acute myeloid leukemia (AML) of older age. We hypothesized that adding lenalidomide to intensive standard chemotherapy might improve their outcome. After establishing a safe lenalidomide, dose elderly patients with AML were randomly assigned in this randomized Phase 2 study (n = 222) to receive standard chemotherapy ("3 + 7") with or without lenalidomide at a dose of 20 mg/day 1-21. In the second cycle, patients received cytarabine 1000 mg/m2 twice daily on days 1-6 with or without lenalidomide (20 mg/day 1-21). The CR/CRi rates in the two arms were not different (69 vs. 66%). Event-free survival (EFS) at 36 months was 19% for the standard arm versus 21% for the lenalidomide arm and overall survival (OS) 35% vs. 30%, respectively. The frequencies and grade of adverse events were not significantly different between the treatment arms. Cardiovascular toxicities were rare and equally distributed between the arms. The results of the present study show that the addition of lenalidomide to standard remission induction chemotherapy does not improve the therapeutic outcome of older AML patients. This trial is registered as number NTR2294 in The NederlandsTrial Register (www.trialregister.nl).

Palifermin-induced flexural hyperpigmentation: a clinical and histological study of five cases.

Palifermin is a human keratinocyte growth factor that is efficacious in reducing duration and severity of oral mucositis during autologous haematopoietic stem-cell transplantation for haematological cancer as well as chemotherapy for colorectal cancers. We report the clinical and histological characteristics of a series of five patients who developed flexural hyperpigmentation after treatment with palifermin. All patients showed ill-defined symmetrical hyperpigmented papillomatous plaques with slight erythema in the skin folds, especially affecting axillary and inguinal areas. The most striking histological finding was the thickened granular layer in all patients. We demonstrate that filaggrin, an essential component in the terminal differentiation of the epidermis, was upregulated in these cases. Palifermin-induced flexural hyperpigmentation is a newly defined clinical and histological entity. The possible aetiology is discussed.

The potential role of lactoferrin and derivatives in the management of infectious and inflammatory complications of hematology patients receiving a hematopoietic stem cell transplantation.

Human lactoferrin is a natural defense protein belonging to the innate immune system present in several body fluids and secretions, as well as in the secondary granules of polymorphonuclear neutrophils. Lactoferrin and its derivatives have pleiotropic functions including broad-spectrum anti-microbial activity, anti-tumor activity, regulation of cell growth and differentiation, and modulation of inflammatory as well as humoral and cellular immune responses. This is the reason why much research has addressed the potential therapeutic activity of these molecules in different clinical settings, especially regarding infectious diseases and uncontrolled inflammatory conditions. In patients with hematological malignancies treated with a hematopoietic stem cell transplantation (HSCT), morbidity and mortality due to infections and uncontrolled inflammation remains high, despite many advances in supportive care. These life-threatening complications are a result of the damage caused by the conditioning regimens to the mucosal barrier, and the innate and adaptive, humoral, and cellular immune defenses. These complications necessitate the continued exploration of new treatment modalities. Systemic and probably local levels of lactoferrin are decreased following HSCT. Therefore, the use of lactoferrin, or short peptide derivatives that retain the cationic N-terminal moiety that is essential for the anti-microbial and anti-inflammatory activity, may prove to be a promising versatile class of agents for managing the complications that arise from HSCT.

[Invasive zygomycosis in patients treated for haematological malignancies]. / Invasieve zygomycose bij patiënten die worden behandeld voor een hematologische maligniteit.

A 52-year-old man underwent haematopoietic stem-cell transplant for myelodysplastic syndrome; after treatment with voriconazole for invasive aspergillosis, he was diagnosed with invasive zygomycosis caused by Rhizopus microsporus. He died despite treatment with intravenous liposomal amphotericin B and posaconazole. A 5-year-old boy with acute lymphatic leukaemia was diagnosed with invasive zygomycosis at autopsy. In a third case, a 16-year-old boy with acute myeloid leukaemia received repeated courses of empiric antifungal therapy, although the presence of an invasive fungal infection was not demonstrated. The patient died, and disseminated invasive zygomycosis caused by Rhizomucor pusillus was found at autopsy. Invasive infections by Zygomycetes are difficult to diagnose and are associated with a high mortality rate. The incidence of invasive zygomycosis appears to be increasing. Therefore, awareness of this type of invasive fungal infection is warranted. Lipid formulations ofamphotericin B remain the first choice for therapy.

Impact of palifermin on intestinal mucositis of HSCT recipients after BEAM.

The matched-control study failed to show a clinical relevant impact of palifermin on intestinal mucositis, although there was a reduced inflammatory response and less febrile neutropenia among patients who had no bacteraemia.

Incidence of and risk factors for persistent gram-positive bacteraemia and catheter-related thrombosis in haematopoietic stem cell transplantation.

A cohort of 439 haematopoietic SCT recipients was analysed to determine the incidence of Gram-positive coccal bacteraemia and thromboembolic events associated with the use of central venous catheters (CVCs) and to determine risk factors for these complications. The incidences of persistent coagulase-negative staphylococcal (CoNS) bacteraemia, symptomatic thrombosis and thrombophlebitis were 25%, 9.6% and 6.6%, respectively. Duration of neutropenia (in days, odds ratio (OR) 1.02; P=0.04) and left-sided placement of the CVCs (OR 1.73; P=0.03) were independent risk factors for the occurrence of persistent CoNS bacteraemia, whereas the use of less mucotoxic conditioning regimens was associated with a lower risk (high-dose melphalan (HDM)/BEAM vs other regimens, OR 0.24; P<0.001). Use of TBI, persistent CoNS bacteraemia and tip colonisation were all significantly associated with an increased risk of symptomatic thrombosis (OR 6.03, 3.36 and 2.80, respectively; P0.02). The risk factors found in this cohort of SCT recipients differed from those found in the general cancer population, showing an important role for persisting bacteraemia in the pathogenesis of CVC-associated thrombosis. Therefore, we constructed a new algorithm in order to improve catheter management and prevent these CVC-related complications.

Trends in the outcomes of Dutch haematological patients receiving intensive care support.

BACKGROUND: Because of the assumed dismal prognosis there is still reluctance to admit haematological patients to the intensive care unit (ICU). This study was conducted to determine trends in outcome of allogeneic haematopoietic stem cell transplant (HSCT) recipients transferred to the intensive care unit in a Dutch tertiary care hospital. METHODS: All patients who received allogeneic HSCT between 2004-2010 were included in the analyses. Baseline and outcome characteristics were compared and risk factors for ICU admission and survival were identified. Changes in outcome over time of three cohorts of HSCT recipients were investigated. RESULTS: Of 319 consecutive HSCT recipients, 49 (15%) were transferred to the ICU for a median (IQR) of 10 (6-45) days following their transplantation, of whom 43% were severely neutropenic and 90% had received systemic immunosuppressive therapy for graft-versus-host disease prophylaxis. Univariate logistic regression showed that transplantation from an unrelated donor and myeloablative conditioning were significant risk factors for ICU admission. Prolonged use of vasopressors, invasive mechanical ventilation and male gender were significant predictors for ICU mortality, while neutropenia and graft-versus-host disease were not. Over the years, APACHE-II severity of illness scores remained unchanged (21.0±7.1, 20.1±5.6, 21.2±6.6), while 100-day post-transplant mortality of patients who had been transferred to the ICU decreased significantly from 78% (2004÷2005) to 57% (2006÷2007), and 35% (2008÷2009). CONCLUSIONS: While for allogeneic HSCT patients the severity of illness on admission to the ICU did not change, the 100-day post-transplant survival improved. These data indicate that reluctance to submit haematological patients to the ICU is not warranted.