Ronan Desmond

Variability in trough total and unbound teicoplanin concentrations and achievement of therapeutic drug monitoring targets in adult patients with hematological malignancy

ABSTRACT The objective of this study was to explore the following aspects of teicoplanin use in patients with hematological malignancy: early attainment of target trough concentrations with current high-dose teicoplanin regimens, variability in unbound teicoplanin fractions, factors associated with observed total and unbound trough concentrations, efficacy and toxicity, and renal function estimation. This was a single-center, prospective study. Samples for determination of trough concentrations were taken on days 3, 4, 7, and 10. Total and unbound teicoplanin concentrations were determined using validated high-performance liquid chromatography methods. Regression analyses were used to identify the factors associated with the trough concentration. Thirty teicoplanin-treated adults with hematological malignancy were recruited. Despite the use of dosages higher than the conventional dosages, the proportions of patients with a trough concentration of ≥20 mg/liter at 48 h and at 72 h were 16.7% and 37.9%, respectively. Renal function was significantly negatively associated with total trough concentrations at 48 h and 72 h (P < 0.05). For an average hematological malignancy patient (creatinine clearance = 70 ml/min), sequential loading doses of at least 12 mg/kg of body weight may be needed to achieve early adequate exposure. In the absence of measured creatinine clearance, estimates obtained using the Cockcroft-Gault (total body weight) equation could prove to be an acceptable surrogate. The unbound fractions of teicoplanin were highly variable (3.4 to 18.8%). Higher unbound fractions were observed in patients with low serum albumin concentrations. Teicoplanin was well tolerated. Teicoplanin loading doses higher than those in current use appear to be necessary. Increased dosing is needed in patients with increased renal function. The high variability in protein binding supports the contention for therapeutic drug monitoring of unbound teicoplanin concentrations. (This study has been registered with EudraCT under registration no. 2013-004535-72.)

Population pharmacokinetics of total and unbound teicoplanin concentrations and dosing simulations in patients with haematological malignancy

Objectives To develop a pharmacokinetic model describing total and unbound teicoplanin concentrations in patients with haematological malignancy and to perform Monte Carlo simulations to evaluate target attainment of unbound trough concentrations with various dose regimens. Methods This was a hospital-based clinical trial (EudraCT 2013-004535-72). The dosing regimen was 600/800 mg q12h for three doses then 600/800 mg daily. Serial total and unbound teicoplanin concentrations were collected. Maximum protein binding was estimated from serum albumin concentration. Population pharmacokinetic analyses and Monte Carlo simulations were conducted using Pmetrics®. Target total and unbound trough concentrations were ≥20 and ≥1.5 mg/L, respectively. Results Thirty adult patients were recruited with a mean (SD) bodyweight of 69.1 (15.8) kg, a mean (SD) CLCR of 72 (41) mL/min and a median (IQR) serum albumin concentration of 29 (4) g/L. A three-compartment complex binding pharmacokinetic model best described the concentration-time data. Total and unbound teicoplanin concentrations were related by serum albumin concentration and a dissociation constant. CLCR and bodyweight were supported as covariates for CL and volume of the central compartment, respectively. Dosing simulations showed that high CLCR was associated with reduced probability of achieving target total and unbound trough concentrations. Low serum albumin concentration was associated with a reduced probability of attaining target total but not unbound trough concentrations. A method to estimate the unbound teicoplanin concentration from the measured total concentration at different serum albumin concentration was demonstrated. Conclusions Standard teicoplanin dosing regimens should be used with caution in patients with haematological malignancy. Bodyweight, CLCR and serum albumin concentration are important considerations for appropriate dosing.

A review of therapy-related myelodysplastic syndromes and acute myeloid leukaemia (t-MDS/AML) in Irish patients: a single centre experience

ABSTRACT Objectives: To demonstrate the incidence, characteristics, treatment and outcomes of patients with therapy-related myelodysplastic syndromes and therapy-related acute myeloid leukaemia (t-MDS/AML) in a tertiary referral centre. Methods: Patients meeting the diagnostic criteria for t-MDS/AML from 2003 to 2014 were reviewed to analyse their diagnostic features, details of antecedent disorder and treatment, approach to management and survival. Results: 39 patients who developed t-MDS/AML were identified with incidence of 8.7%. Median age and gender distribution were similar to de novo MDS but t-MDS/AML patients had greater degree of cytopenia and adverse karyotypes. Time to development of t-MDS/AML was shortest for patients with antecedent haematological malignancy compared to solid tumours and autoimmune disorders (46, 85 and 109 months). Patients with prior acute leukaemia had the shortest latency and poor overall survival. Treatment options included best supportive care (56%), Azacitidine (31%) or intensive chemotherapy/allogeneic transplant (13%). Median OS of all patients was 14 months. Survival declined markedly after two years and 5-year OS was 13.8%. Longer survival was associated with blast count <5% at diagnosis, previous haematological disorder, lower risk IPSS-R and a normal karyotype. Four out of five patients who received intensive therapy/transplant remain alive with median OS of 14 months. Median OS of Azacitidine-treated group was 11 months. Discussion: t-MDS/AML patients showed unique characteristics which influenced their treatment and outcomes. IPSS-R may be useful in risk-adapted treatment approaches and can predict outcomes. Survival remains poor but improved outcomes were seen with allogeneic transplantation. Azacitidine may be effective in patients unfit for intensive therapies.

A coincidence or a rare occurrence? A case of plasmablastic lymphoma of the small intestines following infliximab treatment for Crohn’s disease

Dear Editor, Plasmablastic lymphoma (PBL) is an extremely rare lymphoma usually associated with an immunocompromised state, particularly HIV. It is an aggressive lymphoma and, despite initial response to treatment, most patients relapse and die within 12–14 months of diagnosis [1, 2]. We report a 50-year-old gentleman with a 12-year history of ileo-caecal Crohn’s disease who was admitted with vomiting, abdominal pain, and diarrhoea due to small-bowel obstruction. He underwent laparotomy with resection of a small-bowel mass. This patient had multiple prior therapies for Crohn’s disease including 6-Mercaptopurine, Sulphasalazine, steroids and most recently infliximab commenced 9 months previously (four doses in total). The resected small bowel showed a fungating mass measuring 7×7 cm with invasion through the muscularis propria involving the serosa. Microscopically, a diffuse infiltrate of large neoplastic lymphoid cells was seen, some with recognisable plasmablastic morphology. Some areas showed a ‘Starry-sky’ appearance and multiple reactive histiocytes were present. The neoplastic cells expressed CD138 and MUM-1 and lacked panB cell markers, most notably CD20 (Fig. 1). There was no evidence of lymphomatous involvement elsewhere. HIV 1 and 2 antibody tests by ELISA were negative and the serology showed previous exposure to EBV. EBER of the tumour tissue by in situ hybridisation was negative (positive in 46 % of HIV-negative PBL cases). The patient received chemotherapy with dose-adjusted EPOCH (etoposide, vincristine, daunorubicin, cyclophosphamide) and prophylactic intrathecal chemotherapy for 6 cycles given the aggressive nature of PBL. He tolerated chemotherapy well and remains in remission for over 3 years following completion of treatment. Infliximab therapy was discontinued after the diagnosis of lymphoma. PBL was first described in 1997 as a distinct subtype of diffuse large B-cell lymphoma occurring in immunocompromised patients, particularly HIV infection. Oral cavity and gastrointestinal tracts are the most commonly involved sites and 60 % of patients present with advanced clinical stage [2]. Over the last decade, an association between immunosuppressive therapy with antiTNF-α agents and an increased risk of malignancy including lymphoma has been described. In 2004, the FDA expressed concerns regarding a greater frequency of lymphoma in all clinical trials involving antiTNF-α agents. A meta-analysis of all randomised controlled trials in patients with rheumatoid arthritis treated with antiTNF-α therapy over a 10-year period by Wong in 2011 showed an increased incidence of lymphoma in the antiTNF group compared to controls (1.65 versus 0.36 per 1000 person-years) [3]. However, other studies by Seigel and Biancone described the risk as being low or even absent for patients with Crohn’s disease treated with anti-TNF agents. Other risk factors may be present such as age, fistulising pattern of disease and reactivation of EBV by other immunosuppressive agents [4, 5]. To our knowledge, PBL following infliximab therapy has only been described as case reports [6, 7]. The excellent outcome in our patient was favoured by early presentation, localised disease allowing complete resection of the tumour and aggressive * Su Wai Maung Suwmaung@physicians.ie