Doorduijn, J.K.

Acute painful lumbosacral paresthesia after intrathecal rituximab (Article)

2011-08-10T00:00:00Z

EBV related cerebral lymphoma in a leukemia patient treated with alemtuzumab (Article)

2010-12-10T00:00:00Z

Severe akathisia as a side effect of metoclopramide (Article)

2010-12-01T00:00:00Z

Case description A case of severe metoclopramide-induced akathisia in a breast cancer patient being treated with chemotherapy is presented, eventually culminating in hospital admission. In retrospect, this adverse effect was not recognized for several weeks because the prescription had not been properly recorded in the chart, the patient initially denied using the drug, and extensive psychological adjustment difficulties were also present. Conclusion Movement disorders as an adverse effect of metoclopramide have been described on a regular basis over the past decades. Case reports such as this confirm there is under-recognition of adverse effects and emphasize the need to take a comprehensive medication history and recognize well known side effects of medications such as metoclopramide.

Primary central nervous system lymphoma in the elderly: A multicentre retrospective analysis (Article)

2010-10-01T00:00:00Z

Elderly patients with primary central nervous ystem lymphoma (PCNSL) do not tolerate treatment with combined radio-chemotherapy well because of leuco-encephalopathy; they are usually treated initially with chemotherapy or radiotherapy alone. Little is known about the efficacy and toxicity of these treatments outside clinical studies. This study was a retrospective analysis of all patients aged 60 years or over who were admitted with PCNSL to one of five Dutch centers between 1998 and 2007. A total of 74 patients were identified. Twenty-nine were treated with radiotherapy only (Group A), in 36 the intended treatment was chemotherapy alone (Group B), and nine were planned to receive chemotherapy followed by radiotherapy (Group C). Median overall survival was 20 months; 4 months in patients with a Karnofsky performance status (KPS) <70, 25 months in patients with a KPS ≥ 70 (P < 0·001). Treatment modality was not an independent prognostic factor. Forty patients were treated with methotrexate 3 g/m2: there were two toxic deaths. Ten patients discontinued chemotherapy because of toxicity. Delayed encephalopathy was reported in 10 patients. In conclusion, community hospitals still frequently utilize whole brain radiotherapy in elderly PCNSL patients, though a majority tolerates chemotherapy well. Performance status was the most important variable determining prognosis. Short and long term toxicities must be weighed against possible clinical benefits of each treatment, making treatment decisions a highly individualized process.

Differences in clearance of mycophenolic acid among renal transplant recipients, hematopoietic stem cell transplant recipients, and patients with autoimmune disease (Article)

2010-10-01T00:00:00Z

For more than a decade, mycophenolate mofetil (MMF) has been used as an immunosuppressive drug in solid organ transplant recipients to prevent graft rejection. After oral administration, the prodrug MMF is rapidly hydrolyzed to the active metabolite mycophenolic acid (MPA). MMF is being used increasingly in hematopoietic stem cell transplantation (HSCTx) and autoimmune diseases (AID). The pharmacokinetics of MPA are markedly different in these patients. In comparison with renal transplant recipients (RTx), MPA clearance is increased in HSCTx patients and decreased in AIDS. The aim of this study was to characterize MPA clearance in RTx, HSCTx, and AID patients and to test whether the differences in clearance can be described by clinical chemical parameters. MPA concentration-time profiles from 19 RTx patients coprescribed cyclosporine, 17 RTx patients coprescribed tacrolimus, 38 HSCTx patients coprescribed cyclosporine, and 36 patients with AID were analyzed retrospectively with nonlinear mixed effects modeling (first-order conditional estimate). The following covariates were tested: indication for MMF treatment, sex, age, weight, plasma albumin, cyclosporine cotreatment, dose and predose blood concentration, creatinine clearance, and hemoglobin. Pharmacokinetics of MPA were described by a two-compartment model with time-lagged first-order absorption. MPA clearance was correlated in univariate analysis with plasma albumin, cyclosporine dose and predose blood concentration, creatinine clearance, hemoglobin, and indication for MMF treatment (RTx, HSCTx, or AID) (P < 0.001). All significant covariates were combined in an intermediate multivariate model followed by backward elimination. The indication for MMF treatment could be removed from the intermediate model without compromising the fit. The correlation between clearance and cyclosporine predose concentrations and plasma albumin remained significant in the final model and could describe the difference in clearance between the different indications for MMF treatment. Median clearance was 30.2, 45.6, and 10.7 L/h in RTx, HSCTx, and AID patients, respectively. In conclusion, plasma albumin concentrations and cyclosporine predose concentrations are able to describe the difference in MPA clearance among RTx, HSCTx, and AID patients. Copyright

Prevention of catheter-related bacteremia with a daily ethanol lock in patients with tunnelled catheters: A randomized, placebo-controlled trial (Article)

2010-09-17T00:00:00Z

Background: Catheter-related bloodstream infection (CRBSI) results in significant attributable morbidity and mortality. In this randomized, double-blind, placebo-controlled trial, we studied the efficacy and safety of a daily ethanol lock for the prevention of CRBSI in patients with a tunnelled central venous catheter (CVC). Methodology: From 2005 through 2008, each lumen of the CVC of adult hematology patients was locked for 15 minutes per day with either 70%-ethanol or placebo, where after the lock solution was flushed through. As a primary endpoint, the incidence rates of endoluminal CRBSI were compared. Principal Findings: The intent-to-treat analysis was based on 376 patients, accounting for 448 CVCs and 27,745 catheter days. For ethanol locks, the incidence of endoluminal CRBSI per 1000 CVC-days was 0.70 (95%-CI, 0.4-1.3), compared to 1.19 (95% confidence interval, 0.7-1.9) for placebo (incidence rate-ratio, 0.59; 95% confidence interval, 0.27-1.30; P = .19). For endoluminal CRBSI according to the strictest definition (positive hub culture and identical bacterial strain in blood), a 3.6-fold, non-significant, reduction was observed for patients receiving ethanol (2 of 226 versus 7 of 222; P = .103). No lifethreatening adverse events were observed. More patients receiving ethanol discontinued lock-therapy (11 of 226 versus 1 of 222; P = .006) or continued with decreased lock-frequency (10 of 226 versus 0 of 222; P = .002), due to non-severe adverse events. Conclusions: In this study, the reduction in the incidence of endoluminal CRBSI using preventive ethanol locks was nonsignificant, although the low incidence of endoluminal CRBSI precludes definite conclusions. Therefore, the lack of statistical significance may partially reflect a lack of power. Significantly more patients treated with ethanol locks discontinued their prophylactic treatment due to adverse effects, which were non-severe but reasonably ethanol related. Additional studies should be performed in populations with higher incidence of (endoluminal) CRBSI. Alternative sources of bacteremia, like exoluminal CRBSI or microbial translocation during chemotherapy-induced mucositis may have been more important in our patients. Trial Registration: ClinicalTrials.gov NCT00122642.

Outcome and medical costs of patients with invasive aspergillosis and acute myelogenous leukemia-myelodysplastic syndrome treated with intensive chemotherapy: An observational study (Article)

2008-12-15T00:00:00Z

Background. Invasive aspergillosis (IA) is a leading cause of mortality in patients with acute leukemia. Management of IA is expensive, which makes prevention desirable. Because hospital resources are limited, prevention costs have to be compared with treatment costs and outcome. Methods. In 269 patients treated for acute myelogenous leukemia-myelodysplastic syndrome (AML-MDS) during 2002-2007, evidence of IA was collected using high-resolution computed tomography and galactomannan measurement in bronchoalveolar lavage fluid specimens. IA was classified on the basis of updated European Organization for Research and Treatment of Cancer/Mycoses Study Group definitions. Outcome of infection was registered. Diagnostic and therapeutic IA-related costs, corrected for neutropenia duration, were comprehensively analyzed from a hospital perspective. Voriconazole treatment was given orally from day 1 if possible. Results. A total of 80 patients developed IA; 48 (18%) had probable or proven infection, and 32 (12%) had possible IA. Seventy-three patients were treated with voriconazole; 55 (75%) took oral voriconazole from day 1. In patients with IA, the mortality rate 12 weeks after starting antifungal therapy was 22% (16 of 73 patients). The overall mortality rate, registered 12 weeks after neutrophil recovery from the last dose of antileukemic treatment, was 26% in patients with IA versus 16% in patients without IA (P = .08), reflecting an IA-attributable mortality rate of 10%. In a Cox regression analysis, IA was associated with an increased mortality risk (hazard ratio, 2.4; 95% confidence interval, 1.3-4.4). Total IA-related costs increased to €8360 and €15,280 for patients with possible and probable or proven IA, respectively, compared with patients without IA (P < .001). Conclusions. Early diagnosis and treatment of IA with oral voriconazole result in acceptable mortality rates. Nevertheless, IA continues to have substantial attributable mortality combined with a major impact on hospital resource use, so effective prevention in high-incidence populations has the potential to save lives and costs.

Aerosolized liposomal amphotericin B for the prevention of invasive pulmonary aspergillosis during prolonged neutropenia: A randomized, placebo-controlled trial (Article)

2008-05-01T00:00:00Z

Background. Invasive pulmonary aspergillosis (IPA) is a significant problem in patients with chemotherapyinduced prolonged neutropenia. Because pulmonary deposition of conidia is the first step in developing IPA, we hypothesized that inhalation of liposomal amphotericin B would prevent IPA. Methods. We performed a randomized, placebo-controlled trial of patients with hematologic disease with expected neutropenia for ≥10 days. Patients were randomized to receive liposomal amphotericin B or placebo inhalation twice a week, using an adaptive aerosol delivery system, until neutrophil counts increased to >300 cells/mm3. In subsequent neutropenic episodes, the assigned treatment was restarted. The primary end point was the occurrence of IPA according to European Organization for Research and the Treatment of Cancer-Mycoses Study Group definitions. Kaplan-Meier curves were compared with log-rank tests for intent-to-treat and on-treatment populations. Results. A total of 271 patients were studied during 407 neutropenic episodes. According to the intent-totreat analysis, 18 of 132 patients in the placebo group developed IPA versus 6 of 139 patients in the liposomal amphotericin B group (odds ratio, 0.26; 95% confidence interval, 0.09-0.72; P = .005). According to the on-treatment analysis, 13 of 97 patients receiving placebo versus 2 of 91 receiving liposomal amphotericin B developed IPA (odds ratio, 0.14; 95% confidence interval, 0.02-0.66; P = .007). Some adverse effects, but none serious, in the liposomal amphotericin B group were reported, most frequently coughing (16 patients vs. 1 patient; P = .002). Conclusion. In high-risk patients, prophylactic inhalation of liposomal amphotericin B significantly reduced the incidence of IPA.

Pharmacokinetics of mycophenolate mofetil in hematopoietic stem cell transplant recipients (Article)

2007-06-01T00:00:00Z

Mycophenolate mofetil (MMF), a prodrug of mycophenolic acid (MPA), is increasingly used in the prophylaxis of graft-versus-host disease (GVHD) after hematopoietic stem cell transplantation (HCT). Few pharmacokinetic data are available about the use of MMF for this indication. This case series aimed at analyzing the pharmacokinetics of MMF in a population of HCT recipients representative for everyday practice. From 15 HCT recipients, serial plasma samples were taken after twice-daily oral intake of MMF. Plasma concentrations of total MPA and its glucuronide metabolites, as well as free MPA, were quantified. Median apparent oral MPA clearance (CL/F), apparent half-life, and total MPA area under the curve for hours 0 to 12 (AUC0-12, normalized to 1000 mg MMF) were, respectively, 56 L/h (range: 29-98 L/h), 2.3 hours (range: 0.8-5.7 hours), and 18.0 mg*h/L (range: 10-35 mg*h/L). Total MPA concentrations were below 2 mg/L 8 hours after MMF administration, indicating reduced enterohepatic recirculation. Median free MPA AUC0-12 (normalized to 1000 mg MMF) was 224 μg*h/L (range: 56-411 μg*h/L). Because of high CL/F, total MPA exposure in HCT recipients is low and apparent half-life is short in comparison with reference values from renal transplantation. Exposure may be improved in HCT recipients by higher or more frequent MMF dosing.

Intensified 12-week CHOP (I-CHOP) plus G-CSF compared with standard 24-week CHOP (CHOP-21) for patients with intermediate-risk aggressive non-Hodgkin lymphoma: A phase 3 trial of the Dutch-Belgian Hemato-Oncology Cooperative Group (HOVON) (Article)

2007-04-01T00:00:00Z

Optimal dose and timing of CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisone) chemotherapy for aggressive non-Hodgkin lymphoma (NHL) is still an unresolved issue. We assessed whether dose intensifications with cyclophosphamide and doxorubicin might improve outcome in younger patients with intermediate-risk aggressive NHL. Previously untreated patients were assigned to receive either 8 courses of standard CHOP (n = 239) or 6 courses of intensified (I)-CHOP (n = 238). Although there was a tendency in favor of I-CHOP for overall survival (OS), disease-free survival (DFS), and event-free survival (EFS), the differences were not significant. However, although these analyses were not planned, when the intermediate-risk group was divided into low-intermediate- and high-intermediate-risk patients according to the International Prognostic Index (IPI), low-intermediate-risk patients had improved 6-year OS (67% vs 52%; P = .05), DFS (58% vs 45%; P = .06), and EFS (41% vs 30%; P = .21) when they were treated with I-CHOP compared with standard CHOP. On the other hand, high-intermediate-risk patients seem to have no benefit from I-CHOP. Although clinically relevant side effects occurred more often in the I-CHOP arm, treatmen-trelated mortality was similar. These data suggest that I-CHOP might be preferable to standard CHOP in younger patients with low-intermediate-risk aggressive NHL.

Candida krusei transmission among hematology patients resolved by adapted antifungal prophylaxis and infection control measures. (Article)

2006-03-01T00:00:00Z

A sudden increase in neutropenic hematology patients with Candida krusei colonization and bacteremia prompted a longitudinal epidemiological investigation. We identified 39 patients; 13 developed candidemia, and three died; 25 patients carried the same genotype. We intervened by changing antifungal prophylaxis and implementing strict infection control measures. The incidence dropped immediately.

The Treatment of Elderly Patients with Aggressive Non-Hodgkin’s Lymphoma (Doctoral Thesis)

2005-10-05T00:00:00Z

The treatment of elderly patients with an aggressive non-Hodgkin’s lymphoma has gradually changed over the last decades. The first publications concerning elderly patients with lymphoma emphasized the increased toxicity and poor outcome of this patient group.(1-3) The aim of many subsequent studies has been to decrease toxicity.(4-6) Most of these studies however reported decreased response rates and deterioration of survival if age adapted therapy was used. It also became evident that doxorubicin proved to be a toxic, but essential drug in any regimen prescribed with a curative intention.(7-9) The development of recombinant granulocyte colony-stimulating factor (G-CSF) raised expectations that this growth factor could improve the results of therapy because it would become possible to maintain the dose-intensity of the chemotherapy regimen by inducing rapid hematopoietic recovery.(10) Moreover, a shorter duration of the neutropenic phase could probably reduce the incidence of neutropenic fever, bacterial infections and the number of hospital admissions.(11, 12) In the current thesis the results of a large prospective multicenter clinical trial are reported. This trial was designed to investigate if prophylactic G-CSF administration could improve the poor results of treatment in elderly patients with an aggressive non-Hodgkin’s lymphoma. The primary question was whether a higher relative dose-intensity would lead to improved treatment outcome. Secondary endpoints were the quality of life and the cost-effectiveness associated with such treatment. This trial was supported by the Dutch government.