Aaron Cumpston

A post-marketing evaluation of posaconazole plasma concentrations in neutropenic patients with haematological malignancy receiving posaconazole prophylaxis

This is one of the first studies to report on therapeutic drug monitoring (TDM) of posaconazole (PCZ) for antifungal prophylaxis in patients with acute myelogenous leukaemia or myelodysplastic syndrome outside of the rigours of clinical licencing trials. A number of factors have been identified or proposed as causing poor oral absorption of PCZ. Putative PCZ concentrations have been recommended for TDM (0.5 μg/mL or 0.7 μg/mL). In this study, 19 (90.5%) of 21 patients failed to reach the higher putative target of 0.7 μg/mL, and 16 patients (76.2%) failed to reach the lower target of 0.5 μg/mL. Increasing the dose did not help four of six patients reach target concentrations. Three of the patients developed proven or possible fungal infections, all with PCZ concentrations <0.5 μg/mL. Use of acid-suppressing agents appears to explain some of the poor absorption. TDM of PCZ is warranted in patients receiving this orally administered agent.

Impact of alcohol-impregnated port protectors and needleless neutral pressure connectors on central line–associated bloodstream infections and contamination of blood cultures in an inpatient oncology unit

BACKGROUNDnA major risk factor for the development of bloodstream infection is the presence of a central venous catheter (CVC), especially in immunocompromised patients. CVC hub contamination is a risk factor for central line-associated bloodstream infection (CLABSI).nnnMETHODSnThis observational before-after trial in a tertiary care hospitals oncology unit included adult patients with a CVC. During the intervention period, the practice of central line hub care was changed from cleaning with alcohol wipes to using alcohol-impregnated port protectors. To accommodate the protectors, the needless hubs were changed to a neutral pressure connector. The intervention period (January-July 2010) was compared with a historical control (January-December 2009).nnnRESULTSnA total of 3,005 central line-days and 1 CLABSI (a rate of 0.3 infections/1,000 central line-days) were documented during the intervention period, compared with 6,851 central line-days and 16 CLABSIs (2.3 infections/1,000 central line-days) during the control period (relative risk, 0.14; 95% confidence interval [CI], 0.02-1.07; Pxa0= .03). The rate of contaminated blood cultures (CBCs) from central lines was 2.5% (17 of 692) during the control period, but only 0.2% (1 of 470) during the intervention period (relative risk, 0.09; 95% CI, 0.01-0.65; Pxa0= .002).nnnCONCLUSIONSnThe implementation of alcohol-impregnated port protectors and needleless neutral pressure connectors significantly reduced the rates of CLABSIs and CBCs in our oncology patient population.

Bendamustine-Associated Hemolytic Anemia

Objective: To report a case of probable bendamustine-related hemolytic anemia. Case Summary: A 64-year-old white female had recently received treatment with bendamustine for stage III follicular lymphoma. After her fourth cycle, she was admitted to an outside facility with severe right upper quadrant pain across her back and findings consistent with obstructive jaundice. She was found to have pancytopenia and elevations in total bilirubin, alkaline phosphatase, and transaminase levels. A bone marrow biopsy showed no evidence of lymphoma and presence of megakaryocytes on 2 occasions. Upon transfer to West Virginia University Hospitals, her haptoglobin was found to be undetectable, total bilirubin 10.3 mg/dL (unconjugated bilirubin 4.9 mg/dL), reticulocyte count 21.4% (reticulocyte index ≥2%), alkaline phosphatase 1125 U/L, and lactate dehydrogenase 421 U/L. The peripheral smear showed evidence of spherocytes and very rare schistocytes. Based on these findings, the woman was diagnosed with hemolytic anemia secondary to bendamustine exposure. She was started on prednisone 1 mg/kg (60 mg) daily and, soon after, her platelets and hemoglobin stabilized. Discussion: Drug-induced hemolytic anemia is an acquired or extrinsic process that results in antibody-mediated red blood cell destruction. The patient was not taking any medications commonly associated with hemolytic anemia; however, her laboratory test results were consistent with hemolytic anemia. Based on bendamustines structural similarity to fludarabine and fludarabine s association with causing hemolytic anemia, we considered exposure to bendamustine to be the most likely contributory factor for her diagnosis. According to the Naranjo probability scale, a probable likelihood was reflected in bendamustine causing the hemolytic anemia. Conclusions: Continued monitoring of postmarketing data is necessary to correlate this occurrence of hemolytic anemia with bendamustine therapy.

Incidence and Pattern of Graft-Versus-Host Disease in Patients Undergoing Allogeneic Hematopoietic Cell Transplantation After Non-Myeloablative Conditioning with Total Lymphoid Irradiation and Antithymocyte Globulin

Nonmyeloablative (NMA) conditioning with total lymphoid irradiation and antithymocyte globulin (TLI/ATG) has been shown to protect against acute graft-versus-host disease (GVHD). We report here our institutional experience with allogeneic transplantation following NMA conditioning with TLI/ATG (n = 21). GVHD prophylaxis consisted of a combination of a calcineurin inhibitor and mycophenolate mofetil. Median patient age was 59 years. The median followup of surviving patients is 545 days. One patient experienced primary graft rejection. The median time to neutrophil engraftment was 18 days and platelet engraftment was 9.5 days. The cumulative incidence (CI) of grade II–IV acute GVHD at day +100 was 28.6% and 38.1% at day +180. The CI for grade III-IV acute GVHD was 28.6% at day +180. CI of chronic GVHD was 45.2% at 1 year. The CI of disease relapse was 9.5% at 1 year. The rate of nonrelapse mortality (NRM) was 0% at day +100 and only 9.5% at 1 year. The overall and progression free survival at 1 year was 81% and 80.4%, respectively. Our limited, retrospective data show encouraging relapse and NRM rates with TLI/ATG-based NMA conditioning, but with higher than previously reported rates of acute and chronic GVHD, underscoring the need for novel strategies designed to effectively prevent GVHD.

Long-term outcomes after thiotepa-based high-dose therapy (HDT) and autologous hematopoietic cell transplantation (auto-HCT) in non-Hodgkin lymphoma (NHL)

Autologous hematopoietic cell transplantation (auto-HCT) is considered the standard approach for relapsed or refractory non-Hodgkin lymphoma (NHL).1 The therapeutic rationale for auto-HCT is the delivery of myeloablative doses of chemotherapy and/or radiation without overlapping toxicities, thus increasing the response of the resistant lymphoma cells. Relapse/progression of lymphoma and to a lesser extent non-relapse mortality (NRM) remain limitations to treatment success. Although several conditioning regimens are available, including the commonly utilized BEAM (carmustine, etoposide, cytarabine, melphalan)2 and CBV (cyclophosphamide, carmustine, etoposide),3 there is no general consensus regarding a standard conditioning approach in lymphoproliferative disorders.

Prospective, Controlled Study of Acyclovir Pharmacokinetics in Obese Patients

ABSTRACT The current recommendations for intravenous (i.v.) acyclovir dosing in obese patients suggest using ideal body weight (IBW) rather than total body weight (TBW). To our knowledge, no pharmacokinetic analysis has validated this recommendation. This single-dose pharmacokinetic study was conducted in an inpatient oncology population. Enrollment was conducted by 1:1 matching of obese patients (>190% of IBW) to normal-weight patients (80 to 120% of IBW). All patients received a single dose of i.v. acyclovir, 5 mg/kg, infused over 60 min. Consistent with current recommendations, IBW was used for obese patients and TBW for normal-weight patients. Serial plasma concentrations were obtained and compared. Seven obese and seven normal-weight patients were enrolled, with mean body mass indexes of 45.0 and 22.5 kg/m2, respectively. Systemic clearance was substantially higher in the obese than normal-weight patients (mean, 19.4 ± 5.3 versus 14.3 ± 5.4 liters/h; P = 0.047). Area under the concentration-time curve was lower in the obese patients (15.2 ± 2.9 versus 24.0 ± 9.4 mg · h/liter; P = 0.011), as was maximum concentration (5.8 ± 0.9 versus 8.2 ± 1.3 mg/liter; P = 0.031). Utilization of IBW for dose calculation of i.v. acyclovir in obese patients leads to lower systemic exposure than dosing by TBW in normal-weight patients. While not directly evaluated in this study, utilization of an adjusted body weight for dose determination appears to more closely approximate the exposure seen in normal-weight patients. (This study has been registered at ClinicalTrials.gov under registration no. NCT01714180.)